Psiconeuroendocrinology PDF

PSYCHONEURO-
ENDOCRINOLOGY
The Scientific Basis of Clinical Practice
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PSYCHONEURO-
ENDOCRINOLOGY
The Scientific Basis of Clinical Practice
Edited by
Owen M. Wolkowitz, M.D.

Anthony J. Rothschild, M.D.
Washington, DC
London, England
Note: The authors have worked to ensure that all information in this
book is accurate at the time of publication and consistent with general
psychiatric and medical standards, and that information concerning drug
dosages, schedules, and routes of administration is accurate at the time of
publication and consistent with standards set by the U. S. Food and Drug
Administration and the general medical community. As medical research
and practice continue to advance, however, therapeutic standards may
change. Moreover, specific situations may require a specific therapeutic
response not included in this book. For these reasons and because human
and mechanical errors sometimes occur, we recommend that readers fol-
low the advice of physicians directly involved in their care or the care of
a member of their family.
Books published by American Psychiatric Publishing, Inc., represent the
views and opinions of the individual authors and do not necessarily rep-
resent the policies and opinions of APPI or the American Psychiatric As-
sociation.
Copyright © 2003 American Psychiatric Publishing, Inc.
ALL RIGHTS RESERVED
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Library of Congress Cataloging-in-Publication Data
Psychoneuroendocrinology : the scientific basis of clinical practice /
edited by Owen M. Wolkowitz, Anthony J. Rothschild.
p. cm.
Includes bibliographical references and index.
ISBN 0-88048-857-3 (alk. paper)
1. Psychoneuroendocrinology. 2. Mental illness—Endocrine aspects.
I. Wolkowitz, Owen M., 1952– II. Rothschild, Anthony J.
QP356.45 .P795 2003
616.89—dc21
2002028228
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
To Janet, Gavin, and Mikaela
and to the memory of my parents
O.M.W.
To Judy, Rachel, and Amanda;

to my mother and the memory of my father
A.J.R.
This book is also dedicated to our dear colleague and con-

tributor to this volume, Dr. Martin Szuba, who passed
away. Marty was a generous and gentle colleague, a
thoughtful and compassionate man, and a psychiatrist who
worked hard for his patients and taught his students well.
Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi
Part I
Introduction
Chapter 1
Introduction and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Owen M. Wolkowitz, M.D., and Anthony J. Rothschild, M.D.
Chapter 2
Historical Roots of Psychoneuroendocrinology . . . . . . . . . . . . . . . . . . 9
Steven E. Lindley, M.D., Ph.D., and Alan F. Schatzberg, M.D.
Part II
Peptide Hormones
Chapter 3
Neuropeptides and Hypothalamic
Releasing Factors in Psychiatric Illness . . . . . . . . . . . . . . . . . . . . . . . 29
Dominique L. Musselman, M.D., M.S., and
Charles B. Nemeroff, M.D., Ph.D.
Chapter 4
Chronobiology and Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Robert L. Sack, M.D., Alfred J. Lewy, M.D., Ph.D.,
Magda Rittenbaum, M.D., and Rod J. Hughes, Ph.D.
Chapter 5
Prolactin, Growth Hormone, Insulin, Glucagon, and Parathyroid
Hormone: Psychobiological and Clinical Implications . . . . . . . . . . . 107
Mady Hornig, M.D., and Jay D. Amsterdam, M.D.
Part III
Adrenocortical Hormones
Chapter 6
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness . . 139
Chapter 7
Psychiatric Manifestations of Hyperadrenocorticism and
Hypoadrenocorticism (Cushing’s and Addison’s Diseases). . . . . . . 165
Monica N. Starkman, M.D., M.S.
Chapter 8
Psychiatric Effects of Glucocorticoid Hormone Medications . . . . . . 189
Victor I. Reus, M.D., and Owen M. Wolkowitz, M.D.
Chapter 9
Dehydroepiandrosterone in Psychoneuroendocrinology . . . . . . . . . 205
Owen M. Wolkowitz, M.D., and Victor I. Reus, M.D.
Part IV
Gonadal Hormones
Chapter 10
Menstrual Cycle–Related and Perimenopause-
Related Affective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
David R. Rubinow, M.D., and Peter J. Schmidt, M.D.
Chapter 11
Endogenous Gonadal Hormones in
Postpartum Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Lisa S. Weinstock, M.D., and Lee S. Cohen, M.D.
Chapter 12
Clinical Psychotropic Effects of Gonadal
Hormone Medications in Women . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Uriel Halbreich, M.D., Steven J. Wamback, B.S., and
Linda S. Kahn, Ph.D.
Chapter 13
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids . . . 331
Harrison G. Pope Jr., M.D., and David L. Katz, M.D., J.D.
Part V
Thyroid Hormones
Chapter 14
Thyroid Function in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . 361
David O’Connor, M.D., Harry Gwirtsman, M.D., and
Peter T. Loosen, M.D., Ph.D.
Chapter 15
Psychiatric and Behavioral Manifestations of
Hyperthyroidism and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . 419
Michael Bauer, M.D., Ph.D., Martin P. Szuba, M.D., and
Peter C. Whybrow, M.D.
Chapter 16
Thyroid Hormone Treatment of Psychiatric Disorders . . . . . . . . . . 445
Stephen Sokolov, M.D., F.R.C.P.C., and Russell Joffe, M.D.
Part VI
Laboratory Testing
Chapter 17
Laboratory Evaluation of Neuroendocrine Systems . . . . . . . . . . . . . 469
David Michelson, M.D., and Philip W. Gold, M.D.
Chapter 18
Endocrine Imaging in Depression . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Kishore M. Gadde, M.D., and K. Ranga R. Krishnan, M.D.
Part VII
Stress
Chapter 19
Stress and Neuroendocrine Function: Individual
Differences and Mechanisms Leading to Disease. . . . . . . . . . . . . . . 513
Bruce S. McEwen, Ph.D.
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
Contributors
Jay D. Amsterdam, M.D.

Professor of Psychiatry, University of Pennsylvania School of Medicine,
and Director, Depression Research Unit, University of Pennsylvania Med-
ical Center, Philadelphia, Pennsylvania
Michael Bauer, M.D., Ph.D.

Head, Department of Psychiatry and Psychotherapy, Humboldt Univer-
sity at Berlin, Berlin, Germany; Visiting Professor of Psychiatry, Neuro-
psychiatric Institute and Hospital, Department of Psychiatry and Bio-
behavioral Sciences, University of California at Los Angeles, Los Angeles,
California
Lee S. Cohen, M.D.

Director, Perinatal and Reproductive Psychiatry Clinical Research Pro-
gram, Massachusetts General Hospital; Associate Professor of Psychiatry,
Harvard Medical School, Boston, Massachusetts
Kishore M. Gadde, M.D.

Assistant Clinical Professor, Department of Psychiatry, Duke University
Medical Center, Durham, North Carolina
Philip W. Gold, M.D.

Chief, Clinical Neuroendocrinology Branch, National Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland
xi
xii PSYCHONEUROENDOCRINOLOGY
Harry Gwirtsman, M.D.

Associate Professor, Department of Psychiatry, Vanderbilt University
Medical Center and Veterans Affairs Medical Center, Nashville, Tennes-
see
Uriel Halbreich, M.D.

Professor of Psychiatry and Research Professor of Gynecology/Obstetrics,
Director of BioBehavioral Research, State University of New York at Buf-
falo, BioBehavioral Program, Buffalo, New York
Mady Hornig, M.D.

Director of Translational Research, Center for Immunopathogenesis and
Infectious Diseases, and Associate Professor, Department of Epidemiol-
ogy, Mailman School of Public Health, Columbia University, New York,
New York
Rod J. Hughes, Ph.D.

Circadian, Neuroendocrine and Sleep Disorders Section, Endocrine Divi-
sion, Department of Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts
Russell Joffe, M.D.

Dean and Professor of Psychiatry, UMDNJ–New Jersey Medical School,
Newark, New Jersey

Research Assistant Professor, BioBehavioral Research Program, State
University of New York, Buffalo, New York
David L. Katz, M.D., J.D.

Senior Director of Medical Affairs, The Advisory Board Company, Wash-
ington, D.C.
K. Ranga R. Krishnan, M.D.

Professor and Chair, Department of Psychiatry, Duke University Medical
Center, Durham, North Carolina
Alfred J. Lewy, M.D., Ph.D.

Professor of Psychiatry and Associate Chairman, Department of Psy-
chiatry, and Director, Sleep and Mood Disorders Laboratory, Oregon
Health and Science University, Portland, Oregon
Contributors xiii
Steven E. Lindley, M.D., Ph.D.

Clinical Faculty, Department of Psychiatry and Behavioral Sciences, Stan-
ford University School of Medicine, Stanford, California; Associate Di-
rector for Research, National Center for PTSD, Palo Alto VA Health
Care System, Palo Alto, California

Professor, Departments of Psychiatry and Medicine, Vanderbilt Uni-
versity Medical Center and Veterans Affairs Medical Center, Nashville,
Tennessee

Professor and Head, Laboratory of Neuroendocrinology, Rockefeller Uni-
versity, New York, New York
David Michelson, M.D.

Medical Director, Lilly Research Laboratories, Indianapolis, Indiana; Asso-
ciate Professor of Psychiatry, Indiana University
Dominique L. Musselman, M.D., M.S.

Associate Professor, Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia

Reunette W. Harris Professor and Chairman, Department of Psychiatry
and Behavioral Sciences, Emory University School of Medicine, Atlanta,
Georgia
David O’Connor, M.D.

Department of Psychiatry, Vanderbilt University Medical Center and
Veterans Affairs Medical Center, Nashville, Tennessee
Harrison G. Pope Jr., M.D.

Professor of Psychiatry, Harvard Medical School; Chief, Biological Psy-
chiatry Laboratory, McLean Hospital, Belmont, Massachusetts
Victor I. Reus, M.D.

Professor of Psychiatry, University of California School of Medicine, San
Francisco, California
xiv PSYCHONEUROENDOCRINOLOGY
Magda Rittenbaum, M.D.

Resident in Neurology, Oregon Health and Science University, Portland,
Oregon

Irving S. and Betty Brudnick Professor of Psychiatry and Director of Clin-
ical Research, Department of Psychiatry, University of Massachusetts
Medical School, Worcester, Massachusetts
David R. Rubinow, M.D.

Clinical Director and Chief, Behavioral Endocrinology Branch, National
Institute of Mental Health, Bethesda, Maryland
Robert L. Sack, M.D.

Professor of Psychiatry and Medical Director, Sleep Disorders Medicine
Service, Oregon Health and Science University, Portland, Oregon
Alan F. Schatzberg, M.D.

Kenneth T. Norris Jr. Professor and Chairman, Department of Psychiatry
and Behavioral Sciences, Stanford University School of Medicine, Stan-
ford, California
Peter J. Schmidt, M.D.

Chief, Unit on Reproductive Endocrinology, Behavioral Endocrinology
Branch, National Institute of Mental Health, Bethesda, Maryland
Stephen Sokolov, M.D., F.R.C.P.C.

Assistant Professor, Department of Psychiatry, University of Toronto;
Staff Psychiatrist, Mood Disorders Clinic, Department of Psychiatry, Sun-
nybrook and Women’s College Health Sciences Centre, Toronto, On-
tario, Canada

Associate Professor, Department of Psychiatry, University of Michigan
Medical Center, Ann Arbor, Michigan
Martin P. Szuba, M.D.†

Assistant Professor of Psychiatry, Department of Psychiatry, University
of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
†
Deceased.
Contributors xv
Steven J. Wamback, B.S.

State University of New York, Buffalo, New York
Lisa S. Weinstock, M.D.

Massachusetts General Hospital, Harvard Medical School, Boston, Mas-
sachusetts

Professor and Executive Chairman, Department of Psychiatry and Bio-
behavioral Sciences; Director, Neuropsychiatric Institute and Hospital,
University of California at Los Angeles, Los Angeles, California

Professor of Psychiatry and Director, Psychopharmacology Assessment
Clinic, University of California School of Medicine, San Francisco, Cali-
fornia
Part I
Introduction
Chapter 1
Introduction and Overview

T he importance of endocrinology for psychiatric practice has

never been stronger than it is now. We are currently witnessing a para-
digm shift in understanding endocrinologic aspects of psychiatric illness.
Hormonal aberrations (and even so-called normal changes that occur with
aging and in response to physical or emotional stress) are increasingly viewed
less as epiphenomena, diagnostic tests, or “windows into the brain” and
more as vital pathophysiological changes and as potential targets for novel
hormonally based pharmacotherapies. The recent discovery of neuroster-
oids, which indicates that the brain itself is a steroidogenic organ, further
blurs the boundaries between endocrinology and neuropsychiatry.
An enormous amount of information has now been gathered regarding
hormone effects on the brain and behavior. Excellent textbooks of psycho-
neuroendocrinology, some encyclopedic in their coverage, have already
been published. The goal of this volume is to be no less authoritative but
to fill an important niche: to show how the principles and emerging find-
ings of psychoneuroendocrinology can inform modern clinical practice
and lead to new breakthroughs in future practice. With that goal in mind,
leading authorities, all of whom are internationally renowned researchers
and most of whom are active clinicians themselves, were invited to con-
tribute the individual chapters. They were asked to review not only the
latest empirical scientific findings in their areas of expertise but to high-
light the clinical significance of these findings and to provide, wherever
appropriate, clinical guidelines for the management of patients.
This book, then, was designed with the clinician, as well as the re-
searcher-scientist, in mind, and we hope that it will prove useful to psychi-
3
4 PSYCHONEUROENDOCRINOLOGY
atrists, neurologists, endocrinologists, obstetrician-gynecologists, internists,

family and general practitioners, psychologists, nurses, and advanced stu-
dents. More broadly, we hope that it will be of interest to anyone seeking
to learn more about the bidirectional interaction of the mind and the
body and of the psyche and the soma.
Psychoneuroendocrinologic investigation has generally followed three
paths, each of which is discussed in this volume: 1) alterations in endogen-
ous hormone levels observed in primary psychiatric illness; 2) psychiatric
concomitants or sequelae of hormonal dysregulation in primary endo-
crinologic illness; and 3) behavioral effects of exogenously administered
hormones or hormone antagonists (both the study of the side effects of
hormonal medications and the use of hormones and hormone antagonists
as psychotropic medications). In this volume, each of these paths is ex-
plored in turn for each hormonal system presented (e.g., the hypotha-
lamic-pituitary-adrenal axis hormones, gonadal hormones, and thyroid
hormones). In addition, special topics of interest are included, such as the
role of neuropeptides and hypothalamic releasing factors in psychiatric
illness, the use of laboratory tests and imaging procedures in evaluating
hormonal function in psychiatric patients, the place of newer alternative
hormonal medications such as melatonin and dehydroepiandrosterone
(DHEA) in therapeutics, and consideration of the particular role of stress
in precipitating illness.
Drs. Lindley and Schatzberg begin this volume with a lively history of
psychoneuroendocrinology, recounting the many false starts in this field,
pointing optimistically to more promising recent advances, and empha-
sizing where the field is now headed. This account of the development
of the field sets the stage for the chapters that follow. In particular, their
account of the earliest conceptualizations of the role of stress in mental
and physical illness nicely complements the final chapter of the volume
(by Dr. McEwen), which points to very newly developed conceptuali-
zations.
Drs. Musselman and Nemeroff then review the work of their own group
and that of others in elucidating the role of neuropeptides and hypotha-
lamic releasing factors in neuroendocrine regulation and in psychiatric ill-
ness. Moving from the historical contexts of the neuroendocrine window
and the pharmacologic bridge approaches, they consider whether neuro-
peptide changes are secondary to or are causal of aspects of psychiatric
illness, and they point the way to the development of novel psychophar-
macologic agents.
Drs. Sack, Lewy, Rittenbaum, and Hughes review the physiological
roles and therapeutic potential of melatonin, distinguishing fact from
current fad. They emphasize the potential of melatonin and melatonin
Introduction and Overview 5
analogs as chronobiotic drugs (i.e., they reset circadian rhythms) in con-

ditions such as jet lag, shiftwork maladaptation, and other sleep disor-
ders, as well as their (separate) hypnotic properties.
Drs. Hornig and Amsterdam review the psychiatric manifestations of
the most common endocrinopathy, diabetes mellitus, along with those
of the least common ones—such as those affecting secretion of prolactin,
parathyroid hormone, glucagon, and growth hormone and those associ-
ated with panhypopituitarism. In addition to reviewing the behavioral
correlates of disturbances in each of these systems, they concisely review
the use of several of these hormones as “windows into the brain” in phar-
macologic challenge studies.
Dr. Rothschild summarizes and synthesizes data pertaining to the
best-studied of psychoneuroendocrine topics: corticosteroids in psychiat-
ric illness. It has been estimated that well over 8,000 scientific articles
have appeared in the medical literature regarding the utility (or lack
thereof) of the dexamethasone suppression test in psychiatric patients.
Dr. Rothschild comments on the proper (and improper) use of tests of
the hypothalamic-pituitary-adrenal (HPA) axis and discusses the inci-
dence and significance of HPA axis aberrations in psychiatric illnesses. He
concludes with suggestions for novel therapies aimed at normalizing HPA
axis secretion.
Dr. Starkman reviews the particular endocrine disease that has both
historically and currently stimulated the greatest discussion about the de-
pendence of behavior, mood, and memory on hormonal activity. In her
review of Cushing’s syndrome and its counterpart, Addison’s disease, Dr.
Starkman considers the relative roles of corticotropin-releasing hormone
and adrenocorticotropic hormone versus cortisol (and other less well-
studied hormones) in determining behavioral outcome in these condi-
tions, as well as their relative utility in differential diagnosis and treat-
ment planning. She also reviews studies of behavioral response after
treatment of these disorders and summarizes data from her own group on
certain intriguing neuroanatomical changes seen in Cushing’s syndrome.
Drs. Reus and Wolkowitz examine exogenous corticosteroid effects
on mood and cognition in their chapter on steroid psychosis. Behavioral
effects of steroid medications have been recognized since the time of their
introduction into clinical practice, but few controlled trials have studied
their incidence, character, etiology, and response to treatment. Drs. Reus
and Wolkowitz review the latest developments in understanding these
side effects (which affect literally thousands of patients yearly), and they
review currently available prophylactic and treatment strategies.
Drs. Wolkowitz and Reus then review the rapidly expanding database
concerning the role of DHEA in memory, mood, and neuropsychiatric ill-
ness. DHEA and its metabolite, DHEA sulfate, are the most plentiful
adrenal corticosteroids in humans, yet their functions remain uncertain.
Moderating between claims of a youth-enhancing super-hormone and
therapeutic nihilism, the authors put the current DHEA hype into scien-
tific perspective and point to possible novel treatments involving this in-
teresting hormone.
Drs. Rubinow and Schmidt review the prevalent psychiatric disorders
associated with the menstrual cycle and the perimenopausal years in
women. In addition to reviewing the normal physiology of these occur-
rences and posing questions regarding hormonal causality of these be-
havioral disturbances, they highlight current approaches to diagnosis and
treatment.
Drs. Weinstock and Cohen review postpartum behavioral changes,
distinguishing between postpartum “blues,” depression, and psychosis. In
addition to reviewing what is known about the endocrine and nonendo-
crine causes of these disorders, they suggest prophylactic and therapeutic
approaches for patients who are experiencing or are at risk for contract-
ing these conditions.
Dr. Halbreich, Mr. Wamback, and Dr. Kahn review the mood and
cognitive effects of exogenously administered female gonadal hormones
(e.g., oral contraceptives and estrogen replacement therapy), paying par-
ticular attention to the specific behavioral effects of estrogen alone versus
estrogen-progestin combinations. The chapter includes abundant clinical
recommendations, often derived from the authors’ clinical experience, in
areas where controlled data are not yet available.
Drs. Pope and Katz extensively review the literature on use of ana-
bolic and androgenic steroids, including studies from their own labora-
tory. Although they acknowledge that much remains to be discovered
regarding vulnerability to anabolic steroid–induced behavioral changes,
the authors provide general conclusions, treatment recommendations,
and forensic guidelines.
Drs. O’Connor, Gwirtsman, and Loosen provide a thorough review of
thyroid function in psychiatric disorders. Included are delineations of dif-
ferent levels of thyroid dysfunction (e.g., peripheral thyroid hormone lev-
els, thyroid-stimulating hormone levels, and antithyroid antibodies) in
disorders as diverse as mood disorders, alcoholism, anxiety disorders, pre-
menstrual dysphoric disorder, eating disorders, and schizophrenia. Im-
portant, but often overlooked, effects of somatic treatments on thyroid
function are also reviewed.
Drs. Bauer, Szuba, and Whybrow delineate psychiatric syndromes
seen in patients with hyperthyroidism or hypothyroidism. Examination
of the psychiatric sequelae of such endocrinologic diseases illuminates
Introduction and Overview 7
the importance of hormonal homeostasis for proper central nervous sys-

tem functioning. In addition to describing the psychiatric comorbidities
of thyroid disease, the authors comment on laboratory evaluations of
such diseases and emphasize psychiatric responses to therapeutic endo-
crine correction.
The observed relationships between thyroid disease states and psychi-
atric symptomatology led to a sizable number of studies evaluating exog-
enously administered thyroid hormones as psychopharmacologic agents.
These trials are reviewed and synthesized by Drs. Sokolov and Joffe, whose
own research group has conducted much of this research. Of special in-
terest to clinicians is the authors’ comparison of the efficacy of different
thyroid hormones (e.g., T3 versus T4) as well as T3 versus lithium in aug-
menting antidepressant response.
Drs. Michelson and Gold provide a detailed overview of laboratory
testing in clinical psychoneuroendocrinology. With proper attention to
methodology and to the correct use and interpretation of these tests, ac-
curate diagnosis and treatment are greatly facilitated. Clinicians involved
in the evaluation and care of psychiatric, endocrine, and general medical
patients will find this chapter both practical and thorough.
Drs. Gadde and Krishnan describe another approach to diagnosing
and investigating neuroendocrine alterations in psychiatric illnesses: ra-
diographic imaging of endocrine tissues and other organs. Although com-
puted tomographic or magnetic resonance imaging of organs such as the
pituitary and the adrenal gland may not be routinely indicated in evalu-
ating psychiatric illness, abnormalities in volumetric measurements of
these and other structures speak directly to endocrine-associated physical
alterations that relate to major behavioral disturbances.
Dr. McEwen closes the volume with a provocative and compelling
chapter examining the relationship between stress and illness. An as-
sumption underlying much of this volume is that changes in the body’s
internal milieu can significantly alter behavioral and affective experience.
In a complementary way, changes in the individual’s external milieu often
provoke hormonal adaptations. Drawing on a wide body of experimental
data, Dr. McEwen distinguishes between the protective and destructive
effects of hormonal responses to stress and introduces the concept of al-
lostatic load to explain some of the health consequences of chronic stress.
In his 1956 book, The Stress of Life, Hans Selye (the father of stress
physiology) wrote
We are on our guard against external intoxicants, but hormones are parts
of our bodies; it takes more wisdom to recognize and overcome the foe
who fights from within....
What can we do about this? Hormones are probably not the only reg-
ulators of our emotional level. Besides, we do not yet know enough about
their workings to justify any attempt at regulating our emotional key by
taking hormones.
Now, more than 45 years after Selye wrote these words and with the
cumulative benefit of the observations reviewed in this volume, we are in
a much stronger position to “regulate our emotional key” by recognizing
and correcting hormonal imbalances that may result in behavioral distur-
bances.
Chapter 2
Historical Roots of
Psychoneuroendocrinology
Steven E. Lindley, M.D., Ph.D.

Alan F. Schatzberg, M.D.
C linical psychoneuroendocrinology is a relatively young area

of research, but its historical roots go back to antiquity. Psychoneuroendo-
crinology is grounded in advances in basic scientific knowledge, evolving
from developments in endocrinology, neurochemistry, and behavioral
pharmacology and from clinical observations. The subsequent chapters of
this book contain reviews of the exciting recent advances in the field of
psychoneuroendocrinology, emphasizing areas of possible direct clinical
utility. The purpose of this chapter is to take a step back and examine
some of the early scientific and social developments that shaped the devel-
opment of the field from the beginning of history to the 1960s (Table 2–1).
Specifically, we examine 1) how it was first appreciated that endocrine
abnormalities can affect behavior; 2) how the nature of endocrine com-
munication was discovered, which led to the discovery of chemical neu-
rotransmission; 3) what observations indicated that endocrine secretions
are regulated by the brain; and finally 4) the development of the modern
understanding of how psychological states can alter endocrine systems. In
reviewing these developments, we focus on the hypothalamic-pituitary-
adrenal (HPA) axis, in part because it is one of our interests, but also be-
cause the HPA axis has been the most intensely studied neuroendocrine
system in psychiatry. We emphasize past missteps and dead ends to pro-
Work for this chapter was supported by NIMH Grant MH50604, a NARSAD
Young Investigator Award, and a DANA Research Fellowship.
9
TABLE 2–1. Early conceptual advances in the

psychoneuroendocrinology of the hypothalamic-
pituitary-adrenal axis: antiquity to 1950s
469–399 B.C. Hippocrates on black bile and melancholia
A.D.130–200 Galen of Pergamum—anatomy of humors
1628 Harvey’s description of the circulation
1719 First chemical analysis of brain by Hensing
1811 Vauquelin’s chemical composition of the brain
1849 Berthold’s description of testicular replacement
1849 Pavlov’s neural reflexes
1855 Bernard’s observation of internal secretions from the liver
1855 Addison’s description of adrenal atrophy
1856 Brown-Séquard’s description of effects of adrenalectomy
1884 Thudichum’s work on brain chemical constitution
1889 Brown-Séquard’s advocacy of organotherapy
1891 Murray injects thyroid extracts into myxedema patient
1894 Oliver and Schäfer’s vasoconstrictor effects of adrenal extracts
1899 Abel and Crawford isolate epinephrine
1905 Bayliss and Starling discover secretin; coin the term hormone
1907 Langley hypothesizes receptors
1921 Loewi demonstrates release on chemical neurotransmitters
1926 Cannon’s concept of homeostasis
1932 Cushing’s syndrome described
1936 Selye’s concept of stress as general adaptation syndrome
1940s Harris’s work on hypothalamic neurohumoral pituitary control
1946 von Euler demonstrates norepinephrine neuronally released
1954 Vogt demonstrates norepinephrine unevenly distributed in
central nervous system
vide clues for avoiding future mistakes in this very exciting and expanding
field. This review is not meant to be exhaustive, and it relies mostly on the
insight and material provided by other authors (Bleuler 1982; Hughes
1977; McCann 1992a; Money 1983; Peart 1979; Sawyer 1988; Tattersall
1994; Tourney 1969; Tower 1981; Welbourn 1992; Wilson 1984), but its
goal is to try to set the historical stage for the chapters that follow.
Ancient Concepts
The beginnings of psychoneuroendocrinology can be traced to black bile

and phlegm. The concepts of the four humors and the brain as the source
of intelligence and mental illness were described in the writings of Alc-
Historical Roots of Psychoneuroendocrinology 11
maeon of Croton (a pupil of Pythagoras, around 500 B.C.), Hippocrates

of Cos (469–399 B.C.), and other ancient philosophers. These ideas were
developed, in part, based on data derived from animal experimentation.
It was believed at that time that the four bodily humors—yellow and
black bile, blood, and phlegm—could cause mental illness by influencing
the brain. For instance, phlegm, which was believed to cool the brain,
could accumulate in sites throughout the body, such as in joints and se-
men. Treatment for an excess of phlegm included removal from the body
by ejaculation (Peart 1979). A less enjoyable therapy involved black bile.
Black bile, a product of the spleen, was thought to be the cause of mel-
ancholia. The treatment for melancholia involved black hellebore, the
Christmas rose, a cathartic and diuretic herb (Mora 1975).
Roman physicians expanded on these theories. The writings of Galen
(A.D. 130–200) contributed significantly to the advancement of anatomy
and pathology, but they also solidified the belief in humoral causes of dis-
ease. Galen’s philosophy, which became known as Galenism, had a strong
influence on the practice of psychiatry until the middle of the nineteenth
century (Mora 1975). Galen described intraarterial “vital spirits” that were
converted by the brain into “animal spirits.” The waste products of this
reaction were funneled down the infundibular stalk to the pituitary gland,
through ducts in the sphenoid and ethmoid bones to the nasopharynx,
where they appeared as nasal mucus or “pituita” (from Harris, quoted in
Sawyer 1988, p. 23). Galen’s treatments included phlebotomy for mel-
ancholia, a practice that continued for the next one and a half millennia,
and sexual activity for hysterical symptoms, which he hypothesized to be
the result of a lack of sexual relations (Mora 1975).
Early Modern Endocrinology
During the Renaissance period, scientists described the anatomy of most of

the endocrine glands, but their function was unknown until the late eigh-
teenth century. In 1716, the Academia des Sciences de Bordeaux offered a
prize for an answer to the question “what is the role of the adrenals?” The
judge did not award the prize to any of the conflicting theories offered and
closed his criticism with the words “perhaps some day chance will reveal
what all of this work was unable to do” (Nelson 1988, p. 87).
To understand the role of endocrine glands in general, one needed to
appreciate their lack of a direct physical connection to the rest of the
body, an idea that did not develop until the eighteenth century (Bleuler
1982). In 1742, Théophile de Bordeu, a medical practitioner in Paris,
noted that glands, as well other tissues, influence each other by releasing
products into the bloodstream (Peart 1979, p. 274), and Albert von
Haller in 1766 hypothesized that glands without ducts, such as the thy-
roid, pour special substances into the circulation (Welbourn 1992,
p. 138). By 1844, a recognizable modern concept of endocrine glands
was described by the physiologist Johannes Mueller, who wrote, “Glands
without ducts exercise their plastic influences on the fluids within them
and those which circulate through them and return to the general circu-
latory system” (see Bleuler 1982, p. 2).
Clues to the chemical nature of endocrine products were first ob-
tained from the most externally accessible gland, the testes (Money
1983). The physiological and behavioral effects of the testes had been ob-
served with the first castrations of domesticated animals and in eunuchs.
Aristotle (384–322 B.C.) wrote about the effects of castration in both an-
imals and humans, and Galen concluded, “Is it then astonishing that a
certain power is communicated from the testicles to the whole body?...
This faculty is the cause in man of masculinity” (quoted in Peart 1979,
p. 272). However, these early investigators and philosophers attributed
the loss of testicular functioning to semen, not hormones. Evidence to the
contrary was provided by the experiments of John Hunter, an English
anatomist and surgeon, in the mid-eighteenth century. In experiments
with cockerels, he noted that testicular replacement produces secondary
sex characteristics in castrated animals. However, because he was mainly
interested in organ transplantation, he published only a few brief reports
on his observations (reviewed in Money 1983; Welbourn 1992).
Not until 1849 did Arnold Adolph Berthold describe evidence for
what are now known as hormones. Berthold observed that transplanta-
tion of testes reversed the effects of castration on sexual and aggressive
behaviors and physical characteristics in chickens, confirming Hunter’s
findings. But Berthold attributed this effect to internal secretions from
the gland. Furthermore, he commented that the effects of testicular se-
cretions must influence “the whole organism of which, it must be admit-
ted, the nervous system forms a very substantial part,” foreshowing our
understanding of the effect of androgens on the central nervous system
(CNS) (Sawyer 1988). Because his experiments involved problems with
immune rejection associated with organ transplantation, they were diffi-
cult to replicate and were largely ignored until the early twentieth cen-
tury (Peart 1979; Welbourn 1992).
In 1855 Claude Bernard, professor of physiology at the Collége de
France, Paris, coined the term internal secretion to describe the secretion
of newly synthesized glucose from the liver. In the same year, Thomas
Addison correctly ascribed a role to the adrenal glands in his descriptions
of a syndrome in patients with gross adrenal disease (Addison’s disease).

The next year, Charles-Edouard Brown-Séquard, more famous for his de-
scription of the syndrome associated with spinal cord hemisection, reported
that bilateral adrenalectomy was fatal in many animals, usually within 24
hours. He concluded that the syndrome was similar to that found in pa-
tients dying from Addison’s disease (Tattersall 1994).
The first endocrine therapy was developed as a treatment for thyroid
disease. Goiters were described throughout recorded history and were at-
tributed to iodine deficiency. Because of the similarities between patients
with cretinism and myxedema and patients who had undergone thy-
roidectomy, Felix Semon proposed in 1883 that both cretinism and
myxedema resulted from a degeneration of the thyroid gland. A “myx-
edema committee” that was set up at St. Thomas’ Hospital in London in-
vestigated his theory. Five years later, after obtaining further clinical and
animal data, this committee agreed with Semon that myxedema was in-
deed caused by loss of thyroid secretions. Three years later, George Mur-
ray, a medical resident, successfully treated a myxedematous patient with
glycerinated sheep thyroid extract with the help of the myxedema com-
mittee. This was the first successful endocrinologic replacement treat-
ment, and it understandably generated a great deal of enthusiasm (see
accounts in Peart 1979; Welbourn 1992).
The Era of Organotherapy
The enthusiasm generated by the advances described above was soon

dampened by a peculiar setback, which was set into motion by a scientist
who had made tremendous contributions to both neurology and endocri-
nology, Charles-Edouard Brown-Séquard (Beach 1981; Tattersall 1994;
Welbourn 1992; Wilson 1984). On June 1, 1889, at age 72, Dr. Brown-
Séquard announced to the Société de Biologie in Paris the results of an en-
docrine experiment. Serving as his own experimental subject, he had in-
jected himself subcutaneously with dog and guinea pig testicular extracts.
He stated that he had conducted these experiments because “it is well
known that seminal losses from any cause produce a mental and physical
disability which is in proportion to their frequency” (Tattersall 1994,
p. 729). He reported that this treatment had remarkable effects on his
physiology, including his being able to move 7 kg more weight, greater reg-
ularity of his bowel function, a decrease in mental fatigue, and a 25% in-
crease in the jet of his urine. He asked the elder members of the society to
make an effort to replicate his findings (Tattersall 1994; Welbourn 1992).
The initial reaction of the scientific community and the public in general
was skepticism and ridicule. For example, an editorial in Wiener Mediz-
inische Wochenschrift stated, “Professor Brown-Séquard’s audience ap-
pears to have received an impression of the intellectual capacity of the
aged scientist very different from the one which he, in his elevated frame
of mind, evidently expected to produce. This lecture must be regarded as
further proof of the necessity of retiring professors who have attained
their threescore years and ten” (Beach 1981, p. 332). Despite this initial
reaction, by the end of 1889, 12,000 physicians had tested his extract and
had reported remarkable cures for a wide variety of illnesses. Besides se-
nile disability, efficacy for this treatment was reported for glycosuria,
neurasthenia, tabes dorsalis (314 cures out of 415 trials), pulmonary tu-
berculosis, heart disease, leprosy, malaria, Addison’s disease, and cancer
(Tattersall 1994). Dr. Brown-Séquard reportedly believed that the ex-
tract increased the “nervous force” in the body, allowing one to better
fight disease. A number of pharmaceutical companies, including Bur-
roughs, Wellcome, began to manufacture various organ extracts, a craze
that continued into the 1920s (Tattersall 1994).
The bad reputation that these organ extract therapies—generally
called organotherapy—received in the general medical community re-
sulted in a loss of respectability for endocrinology. It was said that “any
young physician who dared embark on a career in the field of internal se-
cretions was looked [at] askance, [was] considered naive and gullible[,]
or [was] suspected of straying into the realm of quackery and heading for
the endocrine gold fields” (Tattersall 1994, p. 730). Even the reported ef-
ficacy of thyroid replacement for myxedema was viewed with skepticism
because of the similarities to organotherapy (Peart 1979). Furthermore,
because of the remarkable psychological effects reported, many endocri-
nologists doubted whether scientific methods could be applied to inves-
tigating the psychological effects of hormones (from Beach 1981).
Birth of Modern Endocrinology
Despite its negative impact, organotherapy did generate advances in en-

docrinology that eventually led to the development of neurochemistry
and modern biological psychiatry. In 1893, an English general practitioner
named George Oliver began experimenting with extracts of various tis-
sues. During these investigations, he is reported to have fed an adrenal
extract to his son and observed evidence of vasoconstriction—an experi-
ment that would not pass even the most lenient human subjects commit-
tee today. Dr. Oliver approached Edward A. Schäfer, a professor of phys-

iology at his former medical school, with his findings. Using an experi-
mental dog that he had already prepared for the measurement of arterial
blood pressure, a skeptical Dr. Schäfer was surprised at the large increase
in blood pressure produced by the extract (Peart 1979; Welbourn 1992;
Wilson 1984). Oliver and Schäfer concluded that they had found the se-
cretion that was missing in Addison’s disease patients. Investigations con-
ducted the following winter revealed that the substance was restricted to
the adrenal medulla and was missing at autopsy in two patients with Ad-
dison’s disease (Peart 1979; Welbourn 1992; Wilson 1984).
The general scientific community was excited by these findings, and
several researchers turned their attention to identifying this substance.
Within 5 years, John Jacob Abel and Albert Crawford, both of Johns
Hopkins University, had isolated the extract and named it epinephrine. A
Japanese chemist named Jokichi Takamine later purified the substance in
crystalline form and gave it the name adrenaline, producing the first pu-
rified hormone. This accomplishment set off a race to isolate other hor-
mones (Peart 1979; Welbourn 1992; Wilson 1984). Although it could
not be known then, the isolation of epinephrine also marked the begin-
ning of the modern era of neurochemistry by illustrating the interrela-
tionship between endocrine secretions and neural transmission.
During this period, chemical messengers were being investigated at
another level in a separate line of research. In 1902, William Bayliss and
Ernst Starling began an investigation of the regulation of pancreatic se-
cretions in dogs. They discovered that extracts of the intestinal mucosa
stimulated pancreatic secretions in the absence of neuronal input. They
named this hypothetical chemical messenger in the extract secretin and
proposed a new classification for this extract: a hormone, meaning “I
arouse to activate” (Peart 1979; Welbourn 1992; Wilson 1984). They de-
fined a hormone as “being produced in particular organs, carried in the
blood current, acting as chemical messengers, and influencing cell pro-
cesses in distant organs.… They provide chemical coordination of the or-
ganism, working side by side with that of the nervous system” (Welbourn
1992, p. 146).
Growth of an Appreciation for Psychiatric

Aspects of Endocrinologic Disorders
With the expansion of knowledge in hormones came a greater apprecia-

tion for the psychiatric aspects of endocrine disease. But, as noted by
Bleuler (1982, p. 6), “most early descriptive studies of the behavioral con-
sequences of endocrine disorders based their findings on single observa-
tions and therefore often over-generalized their findings, sometimes with
unfortunate results.” For example, Benjamin Rush is quoted as stating
that the larger size of the thyroid gland in women “was necessary to guard
against the female system from the influence of the more numerous
causes of irritation and vexation of the mind to which they are exposed
than the male sex” (Kathol 1992, p. 400). Sometimes these simplistic
generalizations led to invasive therapies. In 1872, Robert Battery, a Geor-
gia surgeon, advocated ovariectomy for dysmenorrhea. Over time the
clinical indications for ovariectomy were broadened to include psychiat-
ric conditions such as neurosis (Welbourn 1992). A theory that schizo-
phrenia resulted from a defect in adrenal hormone production led to
adrenalectomies in a number of schizophrenic patients (Bleuler 1982).
Despite these clinical misadventures, the availability of efficacious
treatments for endocrine disorders produced many real dramatic psychi-
atric cures, as illustrated in the following 1892 description by Drs. Shaw
and Stansfield of the treatment a female patient with myxedema (see
Kathol 1992, p. 403):
Following the birth of her second child she had an attack of lactational
melancholia and inflicted a wound on her throat....Symptoms of myxe-
dema were first noticed when she was pregnant with her third child. The
principal mental symptoms were mental confusion and inability to con-
centrate or employ herself. She had considerable insight into her mental
state and became languid and disinterested in her occupation and her
children....The mental condition became worse and she was certified and
sent to the Banstead Asylum in April 1891....To the ordinary symptoms
of myxedema were added occasional stupor, aphonia, rigidity, and eroto-
mania. She would periodically get into other patients’ beds and when be-
ing bathed, unless the nurses were careful, would seize and almost
strangle them in excess of her sexual desire. All sorts of remedies were
tried to no avail: hot baths, massage, injections of pilocarpine (until, in-
deed, profuse salivations resulted), tonics and electricity....Finally it was
decided to treat the patient with glycerine extract of the thyroid of the
sheep. The committee purchased the sheep, killed them, and dissected
out the thyroid. A 20% glycerine extract was made by pounding and mac-
erating the gland for forty-eight hours and then straining it through sev-
eral layers of very fine muslin. The patient was given an injection every
second day. The reaction was remarkable. In ten weeks’ time, Mrs. H was
out on trial and at the expiration of her trial she was discharged and re-
covered.
Such successes with hormonal therapy generated curiosity as to whether

hormones were involved in the pathophysiology of psychiatric disorders
in general. Emil Kraepelin theorized about endocrine etiologies for de-

mentia praecox, and Sigmund Freud wondered if the damaging effects of
hormones on the psyche could be the basis of the “actual neurosis” (Bleu-
ler 1982). Endocrinologists also shared this enthusiasm. In the first edi-
tion of the journal Endocrinology in January 1917, Charles E. De Medicis
Sajous, commenting on recent evidence suggesting adrenalin was located
in neurons, wrote
In the great field of neurology and psychiatry, to which work beyond com-
pution and praise has been devoted, discouragement has remained the dom-
inant note precisely where efforts on behalf of sufferers should have proved
more telling. Nowhere has therapeutics remained less efficient....And
yet, no single line of medical thought offers greater opportunity for de-
velopment through the intermediary of the ductless glands. (Sajous 1917,
p. 1)
Growth of Modern Neurochemistry

From Roots in Endocrinology
The link between psychology and endocrinology is exemplified by the

growth of neurochemistry out of endocrinology. An appreciation for the
chemical nature of neural transmission started with the discovery of epi-
nephrine at the turn of the century, although the first chemical investi-
gations of the brain began with the first recorded chemical analysis of the
brain in 1719 (Tower 1981). However, when it came to the mechanism of
how neurons communicated, most of the attention remained focused on
the electrical nature of neuronal transmission. There was evidence in the
late nineteenth century suggestive of chemical neurotransmission, from
investigations of neuroactive compounds such as nitrous oxide, ether,
bromide, and phenobarbital. Claude Bernard demonstrated that curare
blocked nerve transmission at the nerve-muscle junction (Tower 1981).
In 1877, the electrophysiologist Du Bois-Reymond suggested that nerves
might act chemically as well as electrically (Brooks 1988).
It was Oliver and Schäfer’s isolation of adrenal extract that sparked
the modern development of neurochemistry. Starting in 1905, Thomas
Renton Elliott began publishing papers noting the similarities between
the effects of adrenaline and those produced by stimulation of the sym-
pathetic nervous system. He suggested that adrenaline might be acting as
a chemical neural transmitter (Fleming 1984). In 1914, Sir Henry Dale
noted similarities with acetylcholine and parasympathetic stimulation and
described the “muscarinic” and “nicotinic” actions of acetylcholine. Then,
in a series of simple experiments in 1921, Otto Loewi demonstrated that

a chemical signal released on stimulation of the vagus nerve, which he
termed vagustoff, could mimic vagus stimulation when placed on a den-
ervated heart, an effect that was blocked by atropine. Dale and Loewi
won the Nobel Prize for their work on the chemical nature of neural
transmission (Fleming 1984; Peart 1979; Welbourn 1992; Wilson 1984).
Despite this conceptual breakthrough, technical limitations would
slow further advances on chemical neurotransmission until after World
War II. In 1946, the Swedish physiologist Ulf von Euler (and later in Ger-
many) demonstrated that mammalian sympathetic nerves release norepi-
nephrine as a transmitter. In 1954, Vogt observed that norepinephrine is
distributed unevenly in the CNS, a finding that strongly suggested its
function as central neurotransmitter rather than an artifact from sympa-
thetic nerve endings (Cooper et al. 1991). Since that time, the field has
expanded at a tremendous rate, with the discovery of increasing numbers
of transmitter substances and receptors, and has served as the cornerstone
of modern biological psychiatry.
Development of Neuroendocrinology
Another set of developments was taking place during the first half of the
twentieth century that would further link hormones with brain function:
the discoveries of endocrine secretions from the pituitary and of CNS
control of these secretions. These developments have been outlined in
detail by a number of investigators in the field (Brooks 1988; Hughes
1977; McCann 1975, 1992a, 1992b; Sawyer 1988). Although its anat-
omy had been investigated, the function of the pituitary remained a mys-
tery until the description of two cases of acromegaly by Pierre Marie in
1886. In 1927 Philip Smith demonstrated that the pituitary gland pro-
duced hormones that stimulated the adrenal cortex, thyroid, and gonads
and also stimulated growth. By the early 1930s, the remaining pituitary
hormones had been discovered (reviewed in McCann 1992b).
The role of the hypothalamus in control of the pituitary was also first
suggested from clinical observations of patients with endocrine disorders
as early as the beginning of the twentieth century. In 1901, Alfred Fröh-
lich in Vienna diagnosed the adiposogenital syndrome in a 14-year-old
obese boy with arrested sexual development that Fröhlich attributed to
damage in the hypothalamus (Sawyer 1988). In 1921, Percival Bailey and
Frédéric Bremer confirmed and extended early findings that lesions of
discrete areas of the hypothalamus in dogs induced the adiposogenital
syndrome, experimentally demonstrating hypothalamic control over the

pituitary. This and other work led to Harvey Cushing’s 1929 description
of the hypothalamus: “Here in this well-concealed spot, almost to be cov-
ered by a thumb nail, lies the very main-spring of primitive existence”
(see Brooks 1988, p. 657).
The way the hypothalamus directs the pituitary was postulated by
Hinsey and Markee in 1933, when they suggested that hypothalamic
neurohypophyseal hormones might control the secretions of the anterior
pituitary. In the late 1940s, in a series of experiments involving pituitary
stalk lesions, Geoffrey W. Harris provided experimental evidence that
factors released into the portal blood from the hypothalamus exerted
control over pituitary secretion (McCann 1992b). By the 1950s, the
search turned to the identification of these hypothalamic releasing and
inhibiting factors. Some of these factors proved more difficult to isolate
then others; the chemical identity of corticotropin-releasing hormone
was not discovered until 1981 (Vale et al. 1981). As the hypothalamic
neurohumoral factors were isolated and were also found to be present,
along with their receptors, in brain regions outside the medial basal hypo-
thalamus, the line separating endocrine and neuronal control became
blurred even further.
Homeostasis and Stress
The growth of knowledge about hormones and chemical neural trans-

mission led to the development of two important concepts for modern
psychoneuroendocrinology: homeostasis and stress. The Harvard Univer-
sity physiologist Walter Bradford Cannon began to develop the concept
of homeostasis from work that he began while a medical student in 1896.
At that time, he observed the impact of emotional states on physiology
while working on a research project on the digestive system. As reviewed
by Fleming (1984), he brought together contemporary knowledge of the
functioning of the adrenal gland with the work he began as a medical stu-
dent on the autonomic nervous system to formulate a theory of psycho-
endocrine relationships. In his book Bodily Changes in Pain, Hunger, Fear
and Rage (Cannon 1915), he postulated that strong emotions influenced
physiology through the “sympathico-adrenal medullary system” and de-
scribed the fight-or-flight response. Expanding on Claude Bernard’s con-
cept of a “milieu interior” that was held in balance, Cannon theorized
that the purpose of a fight-or-flight response was to maintain the body’s
physiological balance. He coined the term homeostasis to describe this
process, which he defined as the process by which the body’s regulatory

mechanisms allow it to maintain physiological stability despite environ-
mental changes. He thereby linked the impact of emotional states on the
endocrine systems with a normal physiological function (Fleming 1984).
Cannon referred to “stresses and strains” as the physical and psycho-
logical forces that could disturb homeostatic processes (Cannon 1935).
This concept of stress was greatly expanded a decade and a half later in
the work of the physician-physiologist Hans Selye from the Université de
Montréal. Selye developed his theories from work he began in the 1930s.
During failed attempts to isolate a new sex hormone, Selye observed that
the toxic, nonspecific effects of his extract often included adrenal cortical
hypertrophy, atrophy of the thymus, and gastrointestinal ulcers (Mason
1975). By examining the effects of a variety of stressors—including bacte-
ria inoculation, toxins, physical trauma, and exposure to heat and cold—
on the responses of the anterior pituitary and adrenal cortex, he devel-
oped his theory of the organism’s “general adaptation syndrome” to stress
(Selye 1950). The popularization of his work on the stress response con-
tinues to have a lasting effect on all areas of medical science (reviewed in
Mason 1975) .
HPA Axis Activity and Depression
The seminal studies of Cannon and Selye sparked a great deal of inter-
est in psychiatry, because since antiquity many psychiatric disorders—
depressive disorders in particular—had been linked to “stress” (Board and
Persky 1957). Early studies were limited methodologically and relied on
indirect measures of adrenal function, such as changes in lymphocyte and
eosinophil levels, alterations in levels of inorganic phosphates, and varia-
tions in urinary concentrations of potassium, sodium, and uric acid. In
retrospect, it is not surprising that many of these early studies generated
conflicting results. In the 1950s, as more direct measures of urinary and
plasma cortisol levels became available, a number of researchers demon-
strated that stressful life situations, states of arousal, and various states of
emotional distress in humans were linked with these indices of increased
adrenal activity (Bliss et al. 1955, 1956; Bryson and Mertin 1954; Cleghorn
and Graham 1950; Friedman et al. 1963; Price et al. 1957; Renold et al.
1951; Rubin and Mandell 1966).
In these early HPA axis studies, clinical depression was a focus of in-
quiry because it was viewed as a common, time-limited state of profound
emotional distress and therefore should have an influence on adrenal
activity (Board and Persky 1957; Bryson and Mertin 1954; Rizzo et al.
1954). In 1956, using a direct measure of adrenal activity, plasma concen-
tration of 17-hydroxycorticosteroid, a group of researchers from Michael
Reese Hospital demonstrated increased levels of this substance in pa-
tients with severe depression (Board and Persky 1957; Board et al. 1956).
This finding has been widely replicated since that time, using various di-
rect measures of adrenal activity (Carpenter and Bunney 1971; Gibbons
1964; Gibbons and McHugh 1966; Gibbons et al. 1960; Kocsis et al.
1984; McClure 1966; Rothschild et al. 1993; Sachar 1967; Sachar et al.
1973; Stokes et al. 1984). In the study of depression, through the appli-
cation of increasingly sophisticated measurements of HPA activity—such
as the dexamethasone suppression test (DST), described by Carroll and
co-workers in 1981—increasingly consistent observations have been re-
ported. The DST has since become one of the most widely studied mea-
surements in biological psychiatry (reviewed by Arana et al. 1985). As a
result of the isolation of corticotropin-releasing hormone (Vale et al.
1981), investigators have been able to examine more directly the state of
CNS control of adrenal activity in depressed subjects (reviewed by Gold
and Chrousos 1985; Nemeroff 1993). With the appreciation of HPA
hyperactivity in depression, interest has been focused on how this hyper-
secretion affects CNS functioning (reviewed by Rothschild et al. 1989;
Wolkowitz 1994; Wolkowitz et al. 1985, 1987, 1989, 1993a, 1993b);
this finding may contribute to the pathophysiology of the symptoms of
depression, particularly in patients with psychotic depression (reviewed
in Schatzberg and Rothschild 1988; Schatzberg et al. 1985). It has also
has led to attempts to manipulate the HPA axis for therapeutic benefit in
depressed patients (O’Dwyer et al. 1995; Rothschild and Schatzberg
1992; Ur et al. 1992; Wolkowitz et al. 1992), which could possibly fulfill
the hopes of the early researchers in psychoneuroendocrinology.
The Present and the Future
Much has happened in the field of psychoneuroendocrinology since the

1960s, as reviewed in the other chapters of this book. The number of
investigators in the field has increased at an exponential rate. Technical
advances have increased the understanding of psychoneuroendocrine
interactions to the molecular level; the level of complexity has also in-
creased, with discovery of an ever-expanding number of neurotransmit-
ters, peptides, hormones, and receptors. The promises for therapeutic
breakthroughs have never been greater. However, as Ralph Gerard is

quoted in Tower’s review of neurochemistry, “the bright area of knowledge
ever spreads and, although the dark surface of ignorance is presumably de-
creasing, the perimeter of contact with the unknown also increases”
(Tower 1981).
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Part II
Peptide Hormones
Chapter 3
Neuropeptides and Hypothalamic

Releasing Factors in
Psychiatric Illness
Dominique L. Musselman, M.D., M.S.

I n the search for the underlying pathophysiology of the major

psychiatric disorders, neuropeptides in general, and hypothalamic releasing
factors in particular, have been scrutinized closely. Undoubtedly one ratio-
nale for such intensive study in patients with primary psychiatric disorders
is the higher-than-expected psychiatric morbidity in patients with primary
endocrine disorders such as Addison’s disease or Cushing’s syndrome. How-
ever, a core assumption, the neuroendocrine window strategy, remains the
essential impetus for continuing investigation of the major endocrine axes
in psychiatric disorders. This strategy is based on a large body of literature
that indicates that the secretion of the target endocrine organ (e.g., the ad-
renal cortex or thyroid) is largely controlled by the organ’s pituitary trophic
hormone, which in turn is controlled primarily by the secretion of its
hypothalamic release and release-inhibiting hormones (Figure 3–1). There
is now considerable evidence that the secretion of these hypothalamic
hypophysiotropic hormones is controlled by the classic neurotransmitters,
including serotonin (5-hydroxytryptamine [5-HT]), acetylcholine, and nor-
epinephrine, all previously posited to play a preeminent role in the patho-
physiology of affective, anxiety, and psychotic disorders.
The authors are supported by NIH Grants DK-17298, MH-42088, MH-49523,

MH-39415, MH-40524, and 1P50MH-58922.
29
FIGURE 3–1. Relations between brain neurotransmitter systems, hypo-

thalamic peptidergic (releasing-factor) neurons, anterior pituitary, and
peripheral endocrine organs, illustrating feedback loops.
Note. Dark black line represents inhibitory signal. TRH=thyroid-stimulating hormone;
LHRH=luteinizing hormone–releasing hormone; SRIF=somatotropin release inhibitory
factor (somatostatin); MIF=melanocyte stimulating hormone release–inhibiting hormone;
CRH= corticotropin-releasing hormone; GRF= gonadotropin-releasing factor; TSH=thyroid-
stimulating hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone;
PRL=prolactin; GH=growth hormone; ACTH= adrenocorticotropic hormone.
Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts.
Kalamazoo, MI, The Upjohn Company, 1990, p. 22. Used with permission.
However, the hypothesis that information about higher central ner-

vous system (CNS) neuronal activity (for example, the activity of seroto-
nergic neurons) in a particular disease state can be obtained simply by
measuring the activity of a specific endocrine axis is far from proven and
is fraught with difficulty.
The differing behavioral and neurobiological effects of antidepressants,
anxiolytics, and antipsychotics—as well as drugs that induce or worsen de-
pression (such as reserpine), anxiety (cholecystokinin), and psychosis
(psychostimulants, phencyclidine)—have provided yet another impetus
for scrutiny of neuroendocrine pathophysiology in the major psychiatric
Neuropeptides and Hypothalamic Releasing Factors 31
illnesses. This second core assumption, the psychopharmacologic bridge

technique, posits that if a drug produces therapeutic effects and has spe-
cific biochemical actions, an etiologic relationship between the thera-
peutic effects, the biochemical changes, and the cause of the syndrome
may exist (Janowsky et al. 1993). For example, tricyclic antidepressants
block reuptake of norepinephrine and serotonin, monoamine oxidase in-
hibitors inhibit the metabolism of catecholamines, and downregulation
or decrease in the number of b-adrenergic receptors (associated with
most antidepressant treatments) occurs in association with the clinically
successful treatment of depression. Therefore, what the pharmacologic
bridge technique and the neuroendocrine window strategy provide is
1) clear evidence that alterations of a variety of endocrine axes exist
within patients with major psychiatric disorders, and 2) an appreciation of
the complexity of neuropeptide circuits in the CNS. The pharmacologic
bridge technique also provides evidence of altered neurotransmitter
transporter or receptor-mediated signal transduction in depression and
other psychiatric disorders. Whether alterations in peripheral endocrine
organ hormone secretion contribute primarily to the pathogenesis of psy-
chiatric disorders and whether altered secretion of pituitary and hypotha-
lamic hormones primarily contribute to the signs and symptoms of a
specific mental illness remain subjects of considerable controversy. In this
chapter we briefly outline the major findings concerning neuropeptides
and hypothalamic releasing factors in psychiatric diseases.
Corticotropin-Releasing Hormone
The neuroendocrine axis that has been most intensively scrutinized in

psychiatric disorders is the hypothalamic-pituitary-adrenal (HPA) axis
(Figure 3–2 and Table 3–1). There are literally hundreds of reports doc-
umenting HPA axis hyperactivity in drug-free depressed patients. In this
section we briefly review evidence for CNS (i.e., corticotropin-releasing
hormone [CRH]) involvement, pituitary (i.e., adrenocorticotropic hor-
mone [ACTH]) involvement, and adrenal (i.e., glucocorticoid) involve-
ment in the pathophysiology of the HPA axis in depression and anorexia
nervosa.
CRH, which is composed of 41 amino acids, is the primary physiolog-
ical mediator of secretion of ACTH and b-endorphin from the anterior pi-
tuitary (Vale et al. 1981). Within the hypothalamus, CRH-containing
neurons project from the paraventricular nucleus to the median eminence
(Swanson et al. 1983). Activation of this CRH-containing neural circuit
FIGURE 3–2. The hypothalamic-pituitary-adrenal axis.

Note. Dark black line represents inhibitory signal. CRH=corticotropin-releasing hor-
mone; ACTH=adrenocorticotropic hormone; MSH = melanocyte stimulating hormone.
Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts.
Kalamazoo, MI, The Upjohn Company, 1990, p. 29. Used with permission.
occurs in response to stress, resulting in an increase in synthesis and release

of ACTH, b-endorphin, and other pro-opiomelanocortin (POMC) prod-
ucts.
Convergent findings suggest that dysregulation of hypothalamic or
extrahypothalamic CRH neurons are involved in the pathophysiology of
major depression. Multiple studies of drug-free patients with major de-
pression have revealed elevated CRH concentrations in cerebrospinal
fluid (Arato et al. 1986; Banki et al. 1987, 1992b; France et al. 1988;
Nemeroff et al. 1984; Risch et al. 1992), although not all studies agree
(Geracioti et al. 1997). Postmortem CRH concentrations in cerebrospi-
nal fluid collected from the intracisternal space of depressed persons who
had committed suicide and control subjects who had died suddenly were
also revealed to be markedly greater in the depressed group than in the
control subjects (Arato et al. 1989). Elevated cerebrospinal fluid concen-
TABLE 3–1. Alterations in the activity of the limbic-hypothalamic-

pituitary-adrenal axis in depression
Increased corticotropin-releasing hormone (CRH) in cerebrospinal fluida,b
Blunted adrenocorticotropic hormone (ACTH) and b-endorphin response to
CRH stimulationa
Decreased density of CRH receptors in frontal cortex of suicide victims
Diminished hippocampal volume
Pituitary gland enlargement in depressed patientsb
Adrenal gland enlargement in depressed patientsb and suicide victims
Increased ACTH production during depression
Increased cortisol production during depressiona
Plasma glucocorticoid, ACTH, and b-endorphin nonsuppression after
dexamethasone administrationa
Increased urinary free cortisol concentrations
a
State dependent.
b
Significantly correlated to postdexamethasone cortisol concentrations.
trations of CRH are believed to be a reflection of increased synaptic con-

centrations of the peptide, likely due to central CRH hypersecretion (Post
et al. 1982).
The increase in cerebrospinal fluid CRH concentrations that occurs
during depression normalizes on recovery. In patients with major depres-
sion with psychotic features and elevated cerebrospinal fluid CRH con-
centrations, clinical recovery after electroconvulsive therapy is associated
with significant reductions in cerebrospinal fluid CRH concentrations
(Nemeroff et al. 1991). Treatment with antidepressants also results in re-
duction in cerebrospinal fluid CRH concentrations in healthy volunteers
after administration of desipramine (Veith et al. 1992) and in depressed
patients after treatment with fluoxetine (DeBellis et al. 1993) or amitrip-
tyline (Heuser et al. 1998). Therefore, elevated cerebrospinal fluid CRH
concentrations may represent a state, rather than a trait, marker of de-
pression—that is, a marker of the state of depression rather than a marker
of vulnerability to depression (Nemeroff et al. 1991). Furthermore, high
or increasing cerebrospinal fluid CRH concentrations despite symptom-
atic improvement of major depression during antidepressant treatment
may be the harbinger of early relapse (Banki et al. 1992b), as Nemeroff
and Evans (1984) have previously reported (see below) for dexametha-
sone suppression test (DST) nonsuppression (Arana et al. 1985). In the
standard DST paradigm, patients ingest 1 mg of dexamethasone, a syn-
thetic glucocorticoid, at 2100. Blood samples are obtained at 1600 and
2100 the next day for measurement of plasma cortisol concentrations.
Individuals without major depression generally “suppress” or diminish
endogenous production of cortisol as demonstrated by plasma cortisol

concentrations of less than 5.0 mg/dL.
Another method for assessing the activity of the HPA axis is the CRH
stimulation test, in which CRH (usually 100 mg or 1 mg/kg) is adminis-
tered intravenously and the ensuing ACTH (or b-endorphin) and cortisol
responses are measured (Hermus et al. 1984; S.J. Watson et al. 1988). In
drug-free depressed patients, the ACTH and b-endorphin response to
exogenously administered ovine CRH is blunted compared with non-
depressed subjects (Amsterdam et al. 1988; Gold et al. 1984, 1986b; Hols-
boer et al. 1984; Kathol et al. 1989; Young et al. 1990). Krishnan et al.
(1993) also reported that the blunted ACTH response to CRH occurs in
depressed DST nonsuppressors but not in DST suppressors. This neu-
roendocrine abnormality, like the elevation in cerebrospinal fluid CRH
concentration, is state dependent, returning to normal after successful
treatment of depression (Amsterdam et al. 1988). (See also Chapter 17
for a more detailed description of CRH testing.)
The blunted ACTH response to exogenously administered CRH in
depressed patients is likely due (at least in part) to chronic hypersecretion
of CRH from the nerve terminals in the median eminence, resulting in
downregulation of anterior pituitary CRH receptors with resultant de-
creased pituitary responsiveness to CRH. Direct evidence for hypersecre-
tion of CRH was provided by Raadsheer and colleagues (1994, 1995),
who demonstrated a marked increase in the number of paraventricular
nucleus CRH neurons and CRH mRNA expression in postmortem hypo-
thalamic tissue from depressed patients compared with nondepressed
control subjects. Such downregulation of CRH receptors in the pituitary
in response to excessive CRH secretion was previously documented in
laboratory animals (Aguilera et al. 1986; Holmes et al. 1987; Wynn et al.
1983, 1984, 1988). Moreover, in postmortem tissue from those who
have committed suicide a decrease in the density of CRH receptors was
observed in the frontal cortex (Nemeroff et al. 1988), although a discrep-
ant report does exist (Hucks et al. 1997).
On the basis of laboratory animal studies documenting corticotroph
cell hypertrophy and hyperplasia in response to CRH, as well as other
neuroendocrine alterations in depression (see below), Krishnan et al.
(1991) sought to determine whether depressed patients exhibited pitu-
itary gland enlargement. Using magnetic resonance imaging, these au-
thors demonstrated pituitary gland enlargement in depressed patients in
comparison to age- and sex-matched control subjects. In a second study,
the magnitude of pituitary gland enlargement was significantly correlated
to postdexamethasone cortisol concentrations, a measure of HPA axis
hyperactivity (Axelson et al. 1992) (see Chapter 18).
Cortisol hypersecretion in depression has been documented by ele-

vated plasma corticosteroid concentrations (Carpenter and Bunney 1971;
Gibbons and McHugh 1962), increased levels of cortisol metabolites (Sa-
char et al. 1970), and elevated 24-hour urinary free cortisol concentra-
tions. Sachar and colleagues (1970) also reported that cortisol production
is increased during depression and returns to normal in most subjects af-
ter recovery. Hypercortisolemia appears to be state dependent, like the
hypersecretion of CRH and the blunting of the ACTH response to CRH
in patients with major depression. Surprisingly, such elevations of plasma
cortisol concentrations are not proportional to increases in ACTH con-
centrations (Linkowski et al. 1985). Moreover, patients exhibit a height-
ened cortisol response to pharmacologic doses of ACTH, which appears
to be due to adrenocortical hypertrophy, not to increased adrenocortical
sensitivity (Amsterdam et al. 1983; Kalin et al. 1982; Krishnan et al. 1990)
(see below).
Based on postmortem reports of enlarged adrenal glands in suicide vic-
tims (Zis and Zis 1987) and similar findings from a computed tomographic
pilot study of depressed patients (Amsterdam et al. 1987), we conducted
a computed tomographic study of 38 depressed patients and confirmed the
findings of increased adrenal gland size (Nemeroff et al. 1992). This adre-
nal hypertrophy likely explains the fact that unlike the blunted ACTH and
b-endorphin response to CRH, the plasma cortisol response is not different
between depressed patients and healthy control subjects (Amsterdam et
al. 1987; Gold et al. 1984, 1986b; Holsboer et al. 1984; Kathol et al. 1989;
Young et al. 1990). Enlargement of adrenal glands in depressed patients
has now been confirmed using magnetic resonance imaging. It is state de-
pendent (Rubin et al. 1995), waxing and waning in parallel with exacerba-
tion and denouement of clinical depressive symptoms. Such hypertrophy
of the adrenal gland in patients with major depression may reflect current
adrenocortical capacity (Nemeroff et al. 1993), because one study has re-
ported that adrenal gland size is not correlated with plasma cortisol con-
centration, lifetime number of depressive episodes, severity of depression,
or presence of melancholia (Rubin et al. 1996) (see Chapter 18).
DST nonsuppression—like hypercortisolemia, hypersecretion of CRH,
blunting of the ACTH response to CRH, and adrenal gland hypertro-
phy—appears to be state dependent (see Chapter 6). Hypersecretion of
CRH during and immediately preceding a depressive episode with sec-
ondary pituitary and adrenal gland hypertrophy likely contributes to the
multitude of studies reporting that patients with depression manifest
HPA axis hyperactivity. Impairment of the normal negative feedback of
cortisol on HPA axis activity may exist in the particular subset of de-
pressed patients who exhibit DST nonsuppression. Indeed, elevated
cerebrospinal fluid CRH concentrations have specifically been shown to

occur in depressed patients who are DST nonsuppressors (Pitts et al.
1990; Roy et al. 1987). In healthy volunteers, however, there is evidence
that a negative correlation exists between cerebrospinal fluid CRH and
simultaneous cortisol plasma concentrations (Kling et al. 1994). Moreover,
diminished cerebrospinal fluid CRH concentrations have been docu-
mented in depressed patients with normal plasma cortisol concentrations
(Geracioti et al. 1997).
The recent refinement of the DST is the combined dexamethasone-
CRH test. Generally used within clinical research settings, this test is be-
lieved to be the most sensitive method of examining HPA axis activity.
(See Chapter 17 for details on administration of the dexamethasone-
CRH test.) If patients with depression who have been pretreated with
dexamethasone are challenged with CRH, a paradoxical increase in ACTH
and cortisol release is observed in comparison with control subjects. In
nondepressed individuals, pretreatment with dexamethasone suppresses
any major elevations of ACTH and cortisol plasma concentrations in re-
sponse to CRH stimulation. Initial reports indicate the sensitivity of the
dexamethasone-CRH test for major depression (about 80%) greatly ex-
ceeds that of either the DST (an average of 44%) or the CRH stimulation
test (Heuser et al. 1994). The dexamethasone-CRH test is thought to re-
veal subtle alterations of the negative feedback regulation of the HPA axis
(Holsboer-Trachsler et al. 1991).
Unlike with the traditional DST, the failure of dexamethasone to pre-
vent CRH stimulation of the HPA axis is not dependent on plasma con-
centrations of dexamethasone (Holsboer et al. 1987; Ritchie et al. 1990).
In contrast to the CRH stimulation test, increases in ACTH plasma con-
centrations during the dexamethasone-CRH test may demonstrate the
secretory stimulus of vasopressin on pituitary ACTH release. Neverthe-
less, the abnormally increased HPA response to a combined dexamethasone-
CRH test gradually diminishes after successful antidepressant treatment
(Holsboer-Trachsler et al. 1991) and predicts risk for relapse within
6 months of antidepressant treatment (Zobel et al. 1999). Of particular
interest are the findings of Holsboer et al. (1995), who reported that
asymptomatic first-degree relatives of patients with major depression ex-
hibit abnormalities in the dexamethasone-CRH test compared with
healthy control subjects but not as severe as patients with major depres-
sion. Future investigations will undoubtedly study relationships between
cerebrospinal fluid CRH and plasma glucocorticoid concentrations;
symptom profile studies; and volumetric measures of hippocampal, pitu-
itary, and adrenal glands in depressed patients to further elucidate the re-
lationship among these findings.
Cerebrospinal fluid CRH concentrations have been measured in a

variety of other psychiatric disorders, including the anxiety disorders,
schizophrenia, somatization disorders, and Alzheimer’s disease (Table 3–2).
TABLE 3–2. Hypothalamic-pituitary-adrenal axis activity in anxiety

and other psychiatric disorders
Posttraumatic stress disorder
Increased cerebrospinal fluid corticotropin-releasing hormone (CRH)
concentrations
Diminished adrenocorticotropic hormone (ACTH) response to CRH
stimulation
Plasma cortisol nonsuppression after low-dose (i.e., 0.5 mg) dexamethasone
administration
Normal or decreased 24-hour urinary free cortisol concentrations
Diminished hippocampal volume
Panic disorder
Normal cerebrospinal fluid CRH concentrations
Diminished ACTH response to CRH administration
Obsessive-compulsive disorder
Normal or increased cerebrospinal fluid CRH concentrations
Alcohol dependence
Increased cerebrospinal fluid CRH concentrations in acute alcohol
withdrawal
Anorexia nervosa
Increased cerebrospinal fluid CRH concentrations
Plasma cortisol nonsuppression after dexamethasone administration
Increased plasma cortisol concentrations
Increased urinary free cortisol
Alzheimer’s disease
Increased cerebrospinal fluid CRH concentrations early in the disease
Normal cerebrospinal fluid CRH concentration as the disease progresses
Diminished cerebrospinal fluid CRH concentration in the later stages of the
illness
Reduced cerebrospinal fluid CRH concentrations
Huntington’s disease
Parkinson’s disease
Spinocerebellar degeneration
Normal cerebrospinal fluid CRH concentrations
Generalized anxiety disorder
Schizophrenia
Somatization disorders
Abstinent patients with alcohol dependence
Involvement of CRH in anxiety disorders has been well documented

from both animal and human studies. As reviewed by Arborelius and col-
leagues (1999), patients with posttraumatic stress disorder (i.e., Vietnam
combat veterans) exhibit significantly elevated cerebrospinal fluid CRH
concentrations (Baker et al. 1999; Bremner et al. 1997) as well as a di-
minished response to CRH challenge (M.A. Smith et al. 1989). Unlike
patients with major depression, patients with posttraumatic stress dis-
order exhibit normal 24-hour urinary free cortisol concentrations (Baker
et al. 1999) or even reduced plasma concentrations of cortisol, especially
after dexamethasone administration (Heim et al. 1997; Yehuda 1997).
Although cerebrospinal fluid CRH concentrations are not increased in
patients with panic disorder (Fossey et al. 1996; Jolkkonen et al. 1993),
a diminished ACTH response to CRH administration has been observed
(Roy-Byrne et al. 1986). Increased (Altemus et al. 1992) or normal con-
centrations (Chappell et al. 1996; Fossey et al. 1996) of cerebrospinal
fluid CRH have been documented in patients with obsessive-compulsive
disorder, although significant decreases in cerebrospinal fluid CRH con-
centrations occur with a therapeutic response to clomipramine (Altemus
et al. 1994). Patients with generalized anxiety disorder, however, exhibit
similar cerebrospinal fluid CRH concentrations in comparison to psychi-
atrically healthy control subjects (Banki et al. 1992a; Fossey et al. 1996).
Not surprisingly, increased concentrations of cerebrospinal fluid CRH
occur in alcohol withdrawal, a condition of sympathetic arousal and in-
creased anxiety (Adinoff et al. 1996; Hawley et al. 1994). In contrast,
cerebrospinal fluid CRH concentrations are reduced (Geracioti et al. 1994)
or normal (Roy et al. 1990) in abstinent individuals with chronic alcohol-
ism who have normal cortisol plasma concentrations. In sum, although
HPA-axis hyperactivity exists in patients with certain anxiety disorders,
such perturbations do not exist in the patterns suggestive of CRH hyper-
secretion as documented in patients with major depression (Arborelius
et al. 1999).
Normal cerebrospinal fluid CRH concentrations are usually found in
schizophrenic patients (Banki et al. 1987, 1992c; Nemeroff et al. 1984;
Nishino et al. 1998), and these patients exhibit normal ACTH and corti-
sol responses to CRH (Roy et al. 1986). However, after maintenance
haloperidol was replaced by placebo, cerebrospinal fluid CRH plasma
concentrations significantly increased in male schizophrenic patients and
was unrelated to psychotic, depression, or anxiety symptoms (Forman et
al. 1994). Reductions in cerebrospinal fluid CRH concentrations are gen-
erally reported in patients with neurodegenerative brain disorders, such
as Huntington’s disease, Parkinson’s disease, end-stage Alzheimer’s dis-
ease (Edvinsson et al. 1993; Heilig et al. 1995; Suemaru et al. 1993), or
spinocerebellar degeneration (Suemaru et al. 1995). However, increased

cerebrospinal fluid CRH concentrations have been documented in pa-
tients with Alzheimer’s disease who exhibit DST nonsuppression (Mar-
tignoni et al. 1990) and in patients with dementia and depression (Banki
et al. 1992a). Elevated cerebrospinal fluid CRH concentrations have also
been reported in patients with Tourette’s syndrome in comparison to
control subjects (Chappell et al. 1996). Unfortunately, most of these
studies have failed to carefully measure dimensional indices of comorbid
depressive symptoms that would be expected to be associated with ele-
vations of cerebrospinal fluid CRH concentrations across these seemingly
disparate psychiatric and neurological disorders.
Another psychiatric syndrome with evidence of HPA axis hyperactiv-
ity and CRH hypersecretion is anorexia nervosa. In fact, many patients
with anorexia nervosa also exhibit comorbid depressive symptoms. Ele-
vated cerebrospinal fluid CRH concentrations have been reported in pa-
tients with anorexia nervosa (Hotta et al. 1986; Kaye et al. 1987). As in
individuals with depression, patients with anorexia nervosa exhibit ele-
vated plasma cortisol levels, increased secretion of urinary free cortisol,
and DST nonsuppression (Brambilla et al. 1985).
Kaye and colleagues (1987) reported that cerebrospinal fluid concen-
trations of CRH are significantly correlated with depression severity rat-
ings in patients with weight correction. Moreover, normalized pituitary-
adrenal function and cerebrospinal fluid CRH concentrations occur on
weight recovery. As in major depression, underweight anorexic patients
exhibited a blunted ACTH response after intravenous CRH administra-
tion (Gold et al. 1986a; Hotta et al. 1986). ACTH responses to CRH nor-
malize after weight gain. Hotta and colleagues (1986) report that this
normalization occurs immediately after correction of weight loss. How-
ever, the ACTH response to CRH has also been reported to normalize
only after 6 months following weight gain. In summary, underweight pa-
tients with anorexia nervosa have been observed to exhibit elevated cere-
brospinal fluid CRH concentrations and a blunted ACTH response to
CRH, and normalization of both perturbations occurs on recovery of weight.
Further research will seek to elucidate the role of CRH in anorexia ner-
vosa and to determine whether it is associated only with the frequent co-
morbid major depression.
Given the putative role of CRH in the stress response and the disease
state of major depression, multiple pharmacologic treatment strategies
have been considered, including inhibition of CRH synthesis, secretion,
and metabolism, and neutralization of CRH by antibodies (Chalmers et
al. 1996). Currently in development in multiple laboratories is another
exciting strategy, the use of small-molecule, nonpeptide CRH receptor
antagonists capable of crossing the blood-brain barrier (Deak et al. 1999).

A CRH receptor antagonist could be targeted to either of the two sub-
types of CRH receptors: the CRH1 or CRH2 receptors. CRH1 receptors
exist within the pituitary, cerebellum, neocortex, and sensory structures.
The CRH2 receptor, whose role is less well defined, is localized within
subcortical areas such as the amygdala and hypothalamus, or peripheral
organs such as cardiac and skeletal muscle, lung, and intestine (Chalmers
et al. 1995; Lovenberg et al. 1995; Perrin et al. 1995). The distinctive dis-
tribution of CRH1 receptor subserves its function as the primary neuro-
endocrine pituitary receptor responsible for the CRH-stimulated ACTH
release and its importance in cortical, cerebellar, and sensory functions.
The localization of the CRH2 receptor is considered to relay not only the
neuroendocrine actions but also autonomic and behavioral actions of
CRH (Chalmers et al. 1995; Dieterich et al. 1997). Furthermore, with
the discovery of urocortin (Vaughan et al. 1995), the preferred ligand for
the CRH2 receptor, a series of experiments must now be undertaken con-
cerning a role for this novel peptide in mood and anxiety disorders.
Certain CRH receptor antagonists diminish fear (Deak et al. 1999;
Schultz et al. 1996) or learned helplessness responses (Mansbach et al.
1997) in animals. These are in the last stages of drug development for hu-
man use and will likely produce a novel class of antidepressants or anxi-
olytics (Arborelius et al. 1999).
Endogenous Opioid Peptides
The isolation of the endogenous opioid–like neuropeptides methionine-

enkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin)
by Hughes and colleagues in 1975 and the discovery of b-endorphin in
1976 by Li and Chung were followed by determination of a third endog-
enous opioid peptide system, the dynorphins (Goldstein et al. 1979). In
the approximately 20 years since their discovery, intensive examination
of these peptides has provided evidence for their involvement in a variety
of physiological processes, including regulation of pain, mood, respira-
tion, cardiovascular function, gastrointestinal activity, satiety, and sexual
behavior. Now recognized as brain neurotransmitters, endogenous opi-
oid peptides exist within a variety of organs such as the pituitary, thyroid,
adrenal gland, gastrointestinal tract, placenta, and peripheral nervous sys-
tem (see review by A.I. Smith and Funder 1988). At the genomic level,
three genes are responsible for the precursors of opioid peptides: POMC,
proenkephalin, and prodynorphin. Consequently, there are at least three

classes of opioid peptides with different biosynthetic and neuronal path-
ways: the b-endorphins, the enkephalins, and the dynorphins. In the ad-
enohypophysis (Bloom et al. 1976), POMC is processed to yield only
ACTH and b-lipotropin. b-Lipotropin is then processed to yield at least
three compounds, including b-, g-, and a-endorphin.
The second endogenous opioid system is composed of the enkepha-
lins whose precursor is proenkephalin. This enkephalin family contains
among its opioid compounds met-enkephalin and leu-enkephalin. De-
rived from prodynorphin is the third group of endogenous opioid pep-
tides, including dynorphin A, dynorphin B, and neoendorphin, which is
located almost exclusively in the posterior pituitary.
Investigation of the role of endogenous opioid peptides in psychiatric
illness has largely focused on schizophrenia, the major mood disorders,
the eating disorders, and childhood autism and self-injurious behavior
(Frecska and Davis 1991). Clinical investigations have used various ap-
proaches, including measurement of endogenous opioid concentrations
in cerebrospinal fluid and plasma, neuroendocrine challenge tests with
determination of opioid responses, administration of opioid receptor
agonists or antagonists in clinical trials, postmortem regional brain mea-
surements, and even removal of opioid peptides from plasma of schizo-
phrenic patients via hemodialysis or peritoneal dialysis. Intensive research
conducted over two decades has produced no evidence that endogenous
opioid peptides play an important role in either the pathophysiology or
treatment of schizophrenia (see below). However, the investigations of
patients with affective illness indicate that alterations of certain endogen-
ous opioid peptides (e.g., b-endorphin) occur in conjunction with HPA
axis hyperactivity in patients with major depression. These findings are
not surprising, because b-endorphin and ACTH share a common precur-
sor, POMC, within the anterior pituitary, and both are concomitantly re-
leased during stress (Guillemin et al. 1977).
Most investigators (Black et al. 1986; Gerner and Sharp 1982; In-
turrisi et al. 1982; Naber et al. 1981; Pickar et al. 1982), but not all
(Risch 1982), have reported normal concentrations of cerebrospinal fluid
b-endorphin in patients with major depression. Because of these negative
findings and a lack of other evidence, extensive scrutiny of cerebrospinal
fluid enkephalin and dynorphin concentrations in patients with affective
disorder has not been conducted. In contrast, increased concentrations of
basal plasma b-endorphin in patients with major depression are usually
observed (Brambilla et al. 1986; Breier 1989; Gispen-de-Wied et al. 1987;
Risch 1982), although there is one discrepant report of no significant al-
terations of basal plasma b-endorphin in depressed patients (Young et al.
1990). However, depressed patients with increased urinary free cortisol

concentrations exhibit positive correlations between their urinary free cor-
tisol and cerebrospinal fluid opioid concentrations compared with healthy
individuals (Rubinow et al. 1981). Such a correlation between plasma
cortisol and b-endorphin concentrations has also been observed in de-
pressed patients (Cohen et al. 1984).
Similar to the ACTH response to intravenous CRH challenge (see
above), the b-endorphin response to exogenously administered ovine
CRH is blunted in depressed patients compared with nondepressed sub-
jects (Young et al. 1990). Moreover, nonsuppression of plasma b-endorphin
occurs in depressed patients in a manner similar to cortisol nonsuppres-
sion after dexamethasone administration. b-Endorphin nonsuppression
to dexamethasone has been observed even in patients whose baseline
b-endorphin levels were similar to those of healthy control subjects (Maes
et al. 1990; Meador-Woodruff et al. 1987; Rupprecht et al. 1988). In
these patients, postdexamethasone levels of cortisol and b-endorphin
were strongly correlated (Maes et al. 1990; Rupprecht et al. 1988). In
contrast, depressed patients have been reported to exhibit increased se-
cretion of b-endorphin in response to cholinergic stimulation (Risch et al.
1982), thyrotropin-releasing hormone (TRH), and luteinizing hormone–
releasing hormone (LHRH) in comparison with control subjects (Bram-
billa et al. 1986).
Unfortunately, neither opioid agonists nor opioid antagonists have
been found to be effective in the treatment of unipolar disorder, bipolar
disorder, or schizophrenia. The short-acting opiate antagonist naloxone
can prevent the induction of hallucination and thought disorganization
after administration of exogenous opiates (such as b-endorphin) ( Jasinski
et al. 1967; Pickar et al. 1984). Used as single agents, opioid antagonists
were ineffective in patients with schizophrenia but were initially thought
to be effective as an adjuvant treatment (Bissette et al. 1986a; Pickar et
al. 1981a, 1981b, 1982a). In the international collaborative World Health
Organization trial, neuroleptic augmentation with repeated doses of
naloxone was comparable to placebo in reducing psychotic symptoms
of schizophrenia patients (Pickar et al. 1989). A single report does exist
in which long-term administration (for more than 30 days) of the highly
potent opioid receptor antagonist nalmefene was more effective than pla-
cebo in decreasing psychotic symptoms (Rapaport et al. 1993).
Several case reports document reductions in self-injurious behavior in
patients with autism and mental retardation after administration of one
of the opioid receptor antagonists naloxone (Barrett et al. 1980; Bernstein
et al. 1984; Davidson et al. 1983; Gillman and Sandyk 1985; Richardson
and Zaleski 1983; Sandman et al. 1983, 1987; Sandyk 1985) and naltrex-
one (Campbell et al. 1989; Casner et al. 1996; Herman et al. 1987). How-
ever, there are some negative reports (Beckwith et al. 1986; Szymanski et
al. 1987). A few reports document the efficacy of naltrexone in diminish-
ing self-injurious behaviors in patients with borderline personality disor-
der as well (Roth et al. 1996). With minor exception, these reports are
generally limited by open-label design, a relatively brief duration of treat-
ment, small numbers of patients, characterization of patients by behavior
rather than etiology, or a retrospective perspective (Casner et al. 1996).
It has been hypothesized that such self-injury results in pain-induced en-
dorphin release with continued stereotyped behaviors by the patient in an
attempt to maintain increased endogenous opioid levels. In concordance
with this hypothesis, investigators have reported increased cerebrospinal
fluid endorphin concentrations in self-injurious autistic children com-
pared with autistic patients without such behaviors (Gillberg et al. 1985).
In fact, increased plasma concentrations of b-endorphin (Sandman 1988)
and met-enkephalin (Coid et al. 1983) have been detected in self-injurious,
developmentally disabled individuals in comparison with control sub-
jects. Although the aforementioned results are very preliminary, they cer-
tainly serve as an impetus for further scrutiny.
Vasopressin
Arginine vasopressin (AVP), the antidiuretic hormone, is one of the two

posterior pituitary hormones. The most well-known AVP pathway con-
sists of AVP-containing neurons whose cell bodies lie within the lateral
magnocellular subdivision of the hypothalamic paraventricular and su-
praoptic nuclei. These AVP-containing neurons terminate in the neuro-
hypophysis and secrete AVP into the systemic circulation, although they
have collaterals to the hypothalamo-hypophyseal portal system as well
(Chrousos 1992). Another group of AVP-containing neurons project
from the medial parvocellular subdivision of the paraventricular nucleus
to the median eminence. Within the median eminence, the parvocellular-
derived AVP is released from axon terminals, secreted into the hypo-
thalamo-hypophyseal portal circulation, and carried to the anterior lobe
of the pituitary gland (Swanson et al. 1983). Moreover, extrahypotha-
lamic AVP-containing neurons lie within limbic structures such as the
septum and amygdala, as well as the brainstem and spinal cord (Saw-
chenko and Swanson 1982; Swanson 1987). AVP-containing neurons
also receive afferent innervation from many different neuronal cell groups
and send axonal projections from the cerebral cortex throughout the CNS.
It is thought that AVP and the other well-known posterior pituitary hor-
mone, the nonapeptide oxytocin, play a role in modulating neural activ-
ity in hypothalamic, limbic, and autonomic circuits.
Osmotic and chemoreceptor stimulation, hemorrhage, and hypoten-
sion activate the magnocellular neurons of the paraventricular nucleus
and increase secretion of AVP from the neurohypophysis and extrahypo-
thalamic brain regions (Cunningham and Sawchenko 1991). AVP allows
the reabsorption of water back into the body by increasing the permeabil-
ity of the distal and collecting ducts of the kidney tubules. The normal,
narrow reference range of osmolality in humans is 280–295 mOsm/kg.
To protect the body from a hyperosmolar state, maximal stimulation of
AVP occurs at 295 mOsm/kg; antidiuretic hormone is not secreted as
hypo-osmolarity approaches (i.e., near 280 mOsm/kg). In humans an
increase in plasma osmolality as minute as 2% stimulates a twofold to
threefold surge in plasma levels of AVP. When plasma osmolality is nor-
mal, AVP is secreted in large amounts during hypovolemia and hypoten-
sion. However, approximately 40 times more AVP is required to increase
blood pressure compared with antidiuresis.
Chronic stress or adrenalectomy increases the activity of the parvo-
cellular AVP system (DeGoeij et al. 1992; Whitnall 1989). Interestingly,
AVP and CRH are the major hypothalamic secretagogues for ACTH re-
lease. AVP administered together with CRH produces a synergistic release
of pituitary POMC-derived peptides, that is, ACTH and b-endorphin in
humans (DeBold et al. 1984) and animals (Plotsky 1991). CRH and AVP
are co-localized in the parvocellular cells of the human hypothalamus
and may be secreted together into the human hypothalamic-hypophyseal
portal circulation (Mouri et al. 1993). The ratio of AVP to CRH in the
hypothalamic-hypophyseal portal circulation varies in different species
(Plotsky 1991) and according to the nature of the stress (Canny et al.
1989; Caraty et al. 1990).
Similar to the clinical investigations regarding CRH, a variety of pa-
tient groups have been studied. Alterations of cerebrospinal fluid AVP
have been reported in patients with major depression, bipolar disorder,
schizophrenia, anorexia, obesity, alcoholism, Alzheimer’s disease, and
Parkinson’s disease (Demitrack et al. 1989; Legros et al. 1993). Cerebro-
spinal fluid AVP concentrations in patients with major depression are
reportedly reduced in comparison with control subjects, although the
source of cerebrospinal fluid AVP is likely extrahypothalamic and not, in
contrast to its purported hypersecretion, from the paraventricular nu-
cleus in major depression (Gjerris et al. 1984, 1985; Linkowski et al.
1984). Basal plasma concentrations of AVP (secreted from the magnocel-
lular neurons of the paraventricular nucleus after osmotic or barorecep-
tor stimulation) within depressed patients have also been reported to be

decreased in comparison with age-matched control subjects (Laruelle et
al. 1990), although other researchers have found no difference (Gold et
al. 1981). Interestingly, AVP secretion in response to an infusion of
hypertonic saline is diminished in depressed patients compared with con-
trol subjects (Gold et al. 1981). A blunted ACTH response to exogenous
AVP administration in depressed patients was reported by Kathol et al.
(1989), but the finding was not replicated by two other studies (Carroll
et al. 1993; Meller et al. 1987). Remarkably, an increase in the number
of paraventricular nucleus AVP neurons co-localized with CRH cells has
been reported in depressed patients compared with control subjects
(Purba et al. 1996; Raadsheer et al. 1994). This is of interest in view of
the ability of AVP to potentiate the actions of CRH at the corticotroph.
In contrast to the findings suggestive of diminished hypothalamic-vaso-
pressinergic activity in depressed patients are the findings suggestive of
hypersecretion of AVP observed in bipolar patients in the manic phase.
Elevations in cerebrospinal fluid AVP concentrations have been docu-
mented in manic patients (Legros et al. 1983), as have significant increases
in plasma AVP concentrations in relation to patients with unipolar de-
pression and control subjects (Legros and Ansseau 1989).
AVP dysregulation has also been demonstrated in anorexia nervosa.
Underweight anorexia nervosa patients exhibit osmotic dysregulation
characterized by AVP release dissociated from gradual increases in
plasma osmolality (Gold et al. 1983) in comparison with control sub-
jects, in whom increases in plasma osmolality are accompanied by a linear
rise in plasma AVP (Robertson et al. 1976). Although the AVP response
to increased plasma osmolality may normalize with weight recovery,
some anorexia nervosa patients demonstrate persisting defects in osmo-
regulation after weight stabilization for more than 6 months. Further-
more, patients with anorexia nervosa exhibit a cerebrospinal fluid to
plasma AVP ratio greater than 1, in contrast to healthy control subjects,
who exhibit a cerebrospinal fluid to plasma AVP ratio less than 1. This
reversal of the cerebrospinal fluid to plasma AVP ratio persists well after
weight recovery for some anorexia nervosa patients.
Disturbances of AVP function have been thought to exist in aging in-
dividuals, particularly those with neurodegenerative syndromes (e.g., Par-
kinson’s disease), due to their cognitive dysfunction and associated
perturbations of fluid and electrolyte homeostasis (Leake et al. 1991).
Patients with Alzheimer’s disease were initially reported to exhibit
CNS AVP hyposecretion as evidenced by reduced AVP brain concentra-
tions (Fujiyoshi et al. 1987), diminished AVP cerebrospinal fluid concen-
trations (Bevilacqua et al. 1986; Mazurek et al. 1986a, 1986b; Raskind et
al. 1986), a blunted AVP and b-endorphin response to cholinergic chal-

lenge with intravenous physostigmine (Raskind et al. 1989), and a dimin-
ished ACTH and cortisol response to a combined intravenous CRH/AVP
stimulation test (Dodt et al. 1991). However, further investigation of
AVP-producing neurons within the paraventricular nucleus and supra-
optic nucleus of the hypothalamus revealed that the neurons expressing
AVP in the paraventricular nucleus and supraoptic nucleus do not decline
in number (and may even increase) during aging or in Alzheimer’s disease
(Van der Woude et al. 1995). During aging or in Alzheimer’s disease,
there may be increased (“activated”) peptide synthesis within the AVP-
producing neurons, as evidenced by increased plasma concentrations of
AVP and hypertrophy of AVP neurons (Vogels et al. 1990) with enlarged
nuclei and Golgi apparatus (Lucassen et al. 1993). Other investigators
have even observed that cerebrospinal fluid AVP concentrations in pa-
tients with Alzheimer’s disease are similar to concentrations seen in con-
trol subjects (Jolkkonen et al. 1989), as are postmortem brain AVP
concentrations (Leake et al. 1991; van Zwieten et al. 1996) and AVP-
mRNA levels (Lucassen et al. 1997). Another challenge study also docu-
mented that patients with Alzheimer’s disease exhibit plasma AVP re-
sponses to osmotic stimulation induced by hypertonic saline infusion that
are quite similar to those seen in healthy control subjects (Peskind et al.
1995). The discordant results within the extant literature of AVP pertur-
bations in patients with Alzheimer’s disease are no doubt due to multiple
studies with small sample sizes, assay variability, and the inherent diffi-
culties of postmortem brain studies (e.g., fixation time, postmortem de-
lay). Moreover, despite early hopes for AVP as a cognitive enhancing agent,
neither vasopressin nor its analogs have been effective in the treatment of
patients with memory disorders such as Alzheimer’s disease or Korsa-
koff’s syndrome (Legros and Timsit-Berthier 1988).
Multiple groups have investigated whether alterations of cerebro-
spinal fluid AVP concentrations exist in patients with schizophrenia.
Schizophrenic patients have been observed to exhibit increased (Linkow-
ski et al. 1984), diminished (Linkowski et al. 1984; Van Kammen al.
1981), or similar (Beckmann et al. 1985) cerebrospinal fluid concentra-
tions of AVP in comparison with healthy control subjects. However, two
so-called challenge studies—one utilizing apomorphine (a dopamine re-
ceptor agonist) and the other methylphenidate (a dopamine releasing
agent)—have provided tantalizing clues regarding alterations of AVP se-
cretion in patients with schizophrenia. Legros and colleagues (1992) ob-
served that, in comparison with healthy control subjects, schizophrenic
patients exhibit a blunted vasopressin (and oxytocin) response following
an apomorphine challenge. Moreover, after methylphenidate administra-
tion, schizophrenic patients with psychogenic polydipsia exhibit signifi-

cant increases in vasopressin plasma concentrations despite concomitant
hyponatremia compared with patients with polydipsia but not hypo-
natremia. Clearly, hypothalamic and extrahypothalamic AVP circuits are
regulated independently. Whether the perturbations of AVP secretion in
patients with neuropsychiatric disorders are state dependent or trait de-
pendent requires further elucidation.
Growth Hormone and Somatostatin
Growth hormone is synthesized and secreted from the somatotroph cells

of the anterior pituitary. Its secretion is modulated primarily by two
hypothalamic hypophysiotropic hormones—growth hormone–releasing
hormone (GHRH) and somatostatin—and secondarily by classic neu-
rotransmitters such as dopamine, norepinephrine, and 5-HT that in-
nervate the releasing factor–containing neurons (Table 3–3). Located
primarily in the arcuate nucleus of the hypothalamus, GHRH stimulates
the synthesis and release of growth hormone. Inhibition of growth hor-
mone release is mediated primarily by somatostatin, a tetradecapeptide,
which is found primarily in the periventricular nucleus of the hypothal-
amus. Somatostatin, unlike GHRH, is widely distributed in extrahypo-
thalamic brain regions, including the cerebral cortex, hippocampus, and
amygdala. Both GHRH and somatostatin are released from nerve termi-
nals in the median eminence and are transported via the hypothalamo-
hypophyseal portal system to act on the growth hormone–producing
somatotrophs of the anterior pituitary. Release of growth hormone is
stimulated by levodopa (Boyd et al. 1970), a catecholamine precursor,
and by apomorphine, a dopamine receptor agonist (Lal et al. 1973). Growth
hormone release also occurs after the administration of the serotonin pre-
cursors L-tryptophan and 5-hydroxytryptophan (5-HTP) (Imura et al.
1973; Muller et al. 1974). Serotonin receptor antagonists methysergide
and cyproheptadine interfere with the growth hormone response to hy-
poglycemia (Toivola et al. 1972). Clonidine, a central a2-adrenergic re-
ceptor agonist (Lal et al. 1975), and norepinephrine (Toivola et al. 1972)
also stimulate the release of growth hormone. In contrast, phentolamine,
a nonspecific a-adrenergic receptor antagonist, inhibits growth hormone
secretion (Toivola et al. 1972). Growth hormone secretion varies in a
daily circadian pattern that decreases in magnitude as one ages. Under
normal basal conditions, growth hormone is secreted in pulses that are
highest during the initial hours of the night (Finkelstein et al. 1972).
TABLE 3–3. Releasing and inhibiting factors for growth hormone

Growth hormone–releasing factors
Growth hormone–releasing hormone
Dopamine
Levodopa
Apomorphine (dopamine receptor agonist)
Norepinephrine
Clonidine (nonspecific a-adrenergic receptor agonist)
Serotonin
L-Tryptophan
5-Hydroxytryptophan
Factors that inhibit growth hormone release
Somatostatin
Phentolamine (nonspecific a-adrenergic receptor antagonist)
Methysergide (serotonin receptor antagonist)
Cyproheptadine (serotonin receptor antagonist)
The growth hormone response to exogenously administered GHRH

has been studied in drug-free depressed patients. At present, this test has
not been standardized to body weight, which significantly correlates with
the growth hormone response to GHRH in healthy subjects (Krishnan et
al. 1988). Further confounding factors include the influence of sex, age,
and menstrual cycle on the growth hormone response to GHRH. The ex-
isting data on responses to GHRH in subjects with depression is dis-
cordant, possibly because of the factors listed above (Nemeroff and
Krishnan 1992). However, the vast majority of studies have reported a
marked attenuation of the growth hormone response to noradrenergic
agents (e.g., clonidine, desipramine) (Charney et al. 1982; Checkley et al.
1981; Dinan and Barry 1990; Matussek et al. 1980; Siever 1987; Siever
et al. 1982) and, to a lesser extent, dopaminergic agonists (apomorphine)
(Ansseau et al. 1988) in depressed patients.
In depressed patients, dysregulation of the secretion of growth hor-
mone is also indicated by other findings (Table 3–4). Not only is nocturnal
growth hormone secretion diminished in depressed patients (Schilkrut et
al. 1975), but hypersecretion of growth hormone during the waking
hours has been reported in unipolar and bipolar patients compared with
nondepressed control subjects (Mendlewicz et al. 1985). With the char-
acterization of the genes encoding GHRH and its receptor, alterations in
the CNS of depressed patients that underlie the diminished growth hor-
mone response to norepinephrine and dopamine agonists can now be
studied in postmortem tissue.
TABLE 3–4. Growth hormone disturbances associated with major

depression
Blunted growth hormone response to noradrenergic or dopaminergic agents
Reduction of nocturnal growth hormone secretion
Hypersecretion of growth hormone during waking hours
A substantial body of literature also exists regarding alterations of so-

matostatin in patients with major depression and other neuropsychiatric
disorders such as Alzheimer’s disease and multiple sclerosis (see the ex-
tensive review by Rubinow and colleagues 1995). Somatostatin not only
inhibits growth hormone release, but it also has multiple inhibitory ef-
fects on various neuroendocrine systems, including reducing secretion of
thyroid-stimulating hormone (TSH) and CRH. Although somatostatin
does not alter ACTH concentrations in nondepressed control subjects
(Ambrosi et al. 1990; Patel 1992), somatostatin infusion diminishes
hypoglycemia-induced increases of cortisol concentration (Rubinow et
al. 1992). In preclinical studies, somatostatin influences a variety of veg-
etative functions (including appetite and locomotor activity), as well as
analgesia and learning (Rubinow et al. 1995; Vecsei and Widerlov 1990;
Walsh et al. 1985)
There are at least seven studies documenting diminished cerebrospi-
nal fluid concentrations of somatostatin in patients with major depression
(Agren and Lundqvist 1984; Bissette et al. 1986b; Gerner and Yamada
1982; Kling et al. 1993; Molchan et al. 1991; Rubinow et al. 1983, 1984,
1995). Indeed, hypercortisolemia and diminished cerebrospinal fluid
somatostatin-like immunoreactivity (SLI) have often been observed in
patients with psychiatric disorders (Wolkowitz et al. 1987). Reduced
cerebrospinal fluid somatostatin concentrations have been reported in
patients exhibiting dexamethasone nonsuppression (whether schizo-
phrenic or depressed) and are negatively correlated with the maximum
postdexamethasone cortisol plasma concentration in patients with major
depression (Doran et al. 1986). In fact, administration of supraphysiological
doses of prednisone to healthy volunteers is accompanied by significant
reductions of cerebrospinal fluid SLI (Wolkowitz et al. 1987). Although
there is some evidence of normalization of cerebrospinal fluid somatosta-
tin concentration after recovery from depression (Agren and Lundqvist
1984; Post et al. 1988; Rubinow et al. 1984), other studies have noted no
significant changes in cerebrospinal fluid somatostatin concentrations of
depressed patients despite clinical improvement with antidepressant
(Banki et al. 1992b) or electroconvulsive therapy treatment (Nemeroff
et al. 1991). Interestingly, administration of certain psychotropic medi-
cations is known to 1) decrease cerebrospinal fluid somatostatin concen-

trations (e.g., carbamazepine [Rubinow et al. 1992], diphenylhydantoin,
and fluphenazine [Doran et al. 1989]); 2) increase cerebrospinal fluid so-
matostatin concentrations (e.g., haloperidol [Gattaz et al. 1986]; or 3) have
no effect (e.g., desmethylimipramine or lithium carbonate [Rubinow et
al. 1992]).
Reductions of cerebrospinal fluid somatostatin concentrations have
also been consistently observed in patients with Alzheimer’s disease
(Bissette et al. 1986b; Oram et al. 1981; Soininen et al. 1984; Wood et
al. 1983), as have reductions in somatostatin in brain—particularly in the
frontal, parietal, and temporal cortices—on postmortem examination
(Lowe et al. 1988).
Obvious alterations of CNS growth hormone and somatostatin con-
centrations and function exist in major depression, although whether
these changes represent fundamental contributors to this syndrome or are
merely epiphenomena remains to be determined. Diminished concentra-
tions of the inhibitory neuropeptide somatostatin might plausibly allow
CRH hypersecretion and increased HPA axis activity. Further elucidation
of somatostatin receptor function and the effects and utility of somato-
statin receptor agonists and antagonists will provide important informa-
tion regarding the pathophysiology of major depression and neurodegen-
erative disorders such as Alzheimer’s disease.
Cholecystokinin
First identified in the gastrointestinal tract as a 33–amino acid peptide,

cholecystokinin (CCK) (Mutt and Jorpes 1968) was discovered in the
mammalian CNS in 1975. Utilizing a gastrin antiserum that avidly cross-
reacts with CCK, Vanderhaeghen and colleagues (1975) found abundant
gastrin-like material in the brains of many vertebrate species, including
humans. Amino acid sequence analysis determined this substance to be
the carboxyl-terminal amidated peptide CCK 8 (Dockray et al. 1978). In
the gut, CCK exists predominantly in its larger forms of CCK 22, 33, 39,
and 58, with smaller quantities of CCK 8. In the brain, its major amidated
form is CCK 8.
Interestingly, CCK is found in higher concentrations in the brain than
in the gastrointestinal tract. In the brain, only neuropeptide Y exists in
higher concentrations than CCK. CCK and high densities of its receptors
exist in areas of the mammalian brain associated with emotion, motiva-
tion, and sensory processing, such as the cortex, striatum, hypothalamus,
hippocampus, and amygdala (Dietl and Palacios 1989; Hokfelt et al.

1980; Innis and Snyder 1980; Saito et al. 1980; Tang and Man 1991).
CCK is often co-localized with dopamine in the mesolimbic and meso-
cortical areas. Of the two major subtypes of CCK receptors that exist, the
CCKA receptor is primarily found in the bowel, pancreas, and gallblad-
der, whereas the CCKB receptor predominates in the brain.
Cholecystokinin has been reported to reduce the release of dopamine
(Fuxe et al. 1980; Lane et al. 1986; Voigt et al. 1986); conversely, the re-
lease of CCK is modulated by dopamine (Meyer and Krauss 1983; Meyer
et al. 1984). Moreover, preclinical studies indicated that dopaminergic
neuronal activity may be either facilitated or inhibited by CCK (Crawley
et al. 1985; Hommer and Skirboll 1983; Vaccarino and Rankin 1989;
Van Ree et al. 1983). Therefore, initial investigation of a putative role for
CCK in the pathophysiology of neuropsychiatric disorders focused on
the potential involvement of the peptide in schizophrenia. Concentra-
tions of CCK in cerebrospinal fluid of medication-free schizophrenic pa-
tients were reported to be decreased (Garver et al. 1991a; Lotstra et al.
1985; Verbanck et al. 1984), increased (Gerner et al. 1985), or unchanged
(Gerner and Yamada 1982; Gjerris et al. 1984; Rafaelsen and Gjerris
1985) compared with control subjects. Unfortunately, the CCK analog
cerulein produced no therapeutic benefit to medication-free schizophre-
nic patients (Hommer et al. 1985), and the efficacy of ongoing antipsy-
chotic drug treatment of schizophrenic patients was not improved with
co-administration of a decapeptide closely related to CCK, ceruletide
(Hommer et al. 1985), or the CCK antagonist proglumide (Hicks et al.
1989; Innis et al. 1986). Investigation of possible perturbations of CCK
function in patients with mood disorders has also demonstrated rather
disappointing findings. There is a single report of diminished concentra-
tions of cerebrospinal fluid CCK in patients with bipolar disorder (Ver-
banck et al. 1984), but similar findings have not been made in unipolar
depression (Gerner and Yamada 1982; Gjerris et al. 1984; Lotstra et al.
1985; Rafaelsen and Gjerris 1985).
Impetus for study of the role of CCK in the pathophysiology of panic
disorder and other anxiety disorders was provided by the finding that in-
travenous injection of cholecystokinin tetrapeptide (CCK 4) induced
panic symptoms in healthy individuals (De Montigny 1989). In a subse-
quent double-blind study, patients with panic disorder experienced panic
attacks after intravenous administration of CCK but not after saline chal-
lenge (Bradwejn et al. 1990). Furthermore, compared with healthy con-
trol subjects, patients with panic disorder exhibit an increased sensitivity
to CCK 4, a preferential CCKB receptor agonist (Bradwejn et al. 1991a,
1991b, 1992), although both panic disorder patients and control subjects
experience panic attacks with increasing doses of CCK-4 (Bradwejn et al.

1991a, 1991b). These findings were extended in investigations in which
pentagastrin (another CCKB receptor agonist) provoked panic attacks in
patients with panic disorder and, to a lesser extent, in patients with gen-
eralized anxiety disorder (Brawman-Mintzer et al. 1997) and healthy
control subjects (Abelson and Nesse 1990; van Megen et al. 1994). Of
note is that patients with panic disorder exhibit diminished cerebrospinal
fluid CCK concentrations in comparison with control subjects (Lydiard
et al. 1992).
The development of CCKB receptor antagonists may be a potentially
novel treatment for panic disorder and other anxiety disorders. Certain
CCKA or CCKB receptor antagonists have demonstrable anxiolytic (Hen-
drie and Dourish 1990; Hughes et al. 1990; Ravard and Dourish 1990;
Ravard et al. 1990), antidepressant (Kelly and Leonard 1992), or memory-
enhancing (Lemaire et al. 1992) effects in animals. Moreover, in patients
with panic disorder, administration of L-365,260, a benzodiazepine-derived
CCKB receptor antagonist, blocks CCK 4–induced panic (Bradwejn et al.
1994). In control subjects without panic disorder, L-365,260 did not ex-
hibit an anxiolytic effect but did not induce adverse changes in mood, ap-
petite, or memory (Grasing et al. 1996). Another compound, CI-988,
has been studied in patients with generalized anxiety disorder but was
not more effective than placebo as an anxiolytic (Adams et al. 1995).
Nevertheless, efforts continue toward the development of an alternative,
effective anxiolytic that does not have the adverse sedative and cognitive
effects of benzodiazepines.
Neurotensin
Discovered in 1973 by Carraway and Leeman in bovine hypothalamus,

the tridecapeptide neurotensin exerts a variety of actions on endocrine
and gastrointestinal systems, in addition to its function within the CNS.
The highest concentrations of neurotensin are within the hypothalamus,
particularly the posterior hypothalamus and mammillary bodies. Signifi-
cant concentrations of neurotensin are also found within the substantia ni-
gra, ventral tegmental area, and central nucleus of the amygdala, as well
as the dorsal hippocampus, septum, dorsal pallidum, and nucleus accum-
bens (Jennes et al. 1982; Manberg et al. 1982). Although a discussion of
the anatomical localization of neurotensin is beyond the scope of this
chapter (see Bissette and Nemeroff 1995 for review), the most extensively
characterized neurotensin pathway is the mesolimbic-cortical projection
of neurotensin-containing neurons from the ventral tegmental area to the

frontal cortex and nucleus accumbens (Kalivas and Miller 1984).
Partly because of the extensive co-localization of neurotensin and do-
pamine in the rat brain and the neuroleptic-like effects of neurotensin, in-
tensive investigation of the hypothesis that this peptide is an endogenous
neuroleptic continues (Binder et al. 2001). Decreased neurotensin con-
centrations in the cerebrospinal fluid of drug-free schizophrenic patients
in comparison with healthy sex- and age-matched control subjects have
been observed in several studies (Garver et al. 1991b; Lindstrom et al.
1988; Widerlov et al. 1982). Although one study determined no signifi-
cant difference in cerebrospinal fluid neurotensin concentrations between
drug-free schizophrenic patients and control subjects (Breslin et al. 1994),
even these researchers observed a bimodal distribution of cerebrospinal
fluid neurotensin in their cohort of schizophrenic patients. Indeed, re-
ductions in cerebrospinal fluid neurotensin concentrations have not been
observed in other psychiatric syndromes, notably major depression, anor-
exia-bulimia, or premenstrual syndrome (Nemeroff et al. 1989a).
Preclinical studies have demonstrated that administration of typical
antipsychotic drugs such as haloperidol and chlorpromazine is associated
with increases in neurotensin concentrations and neurotensin mRNA ex-
pression in both the caudate nucleus and nucleus accumbens. The atyp-
ical antipsychotic clozapine increases neurotensin concentrations in the
nucleus accumbens but not in the striatum, which likely contributes to
the lower incidence of extrapyramidal side effects observed with cloza-
pine treatment (Govoni et al. 1980; Kinkead and Nemeroff 1994; Levant
and Nemeroff 1992). Microdialysis studies have revealed that these in-
creases in tissue concentrations are mirrored by increases in extracellular
fluid concentrations of neurotensin (Radke et al. 1996). Moreover, con-
centrations of neurotensin in the aforementioned brain regions are not al-
tered by tricyclic antidepressants, antihistamines, or benzodiazepines.
Antipsychotic drug treatment of schizophrenic patients is also followed
by significant increases in cerebrospinal fluid neurotensin concentrations
(Breslin et al. 1994; Widerlov et al. 1982).
Another technique that has been used to study neurotensin alterations
associated with psychopathology is postmortem brain investigation, al-
though it can be confounded by antipsychotic treatment administered
during the patient’s life, which may alter concentrations of neurotensin in
the brain. Postmortem examinations of seven subcortical brain regions of
schizophrenic patients, including nucleus accumbens and caudate nu-
cleus tissue, have not demonstrated significant alterations of neurotensin
concentrations (Kleinman et al. 1983; Nemeroff et al. 1983). In the stud-
ies examining seven areas of cortical tissue, only Brodmann’s area 32 of
the schizophrenic brain exhibited a significant group mean increase in

neurotensin concentration relative to the control group (Nemeroff et al.
1983). Bean and colleagues (1992) found no difference between schizo-
phrenic patients and control subjects in concentrations of neurotensin
mRNA or in its genomic sequence in ventral midbrain neurons. Interest-
ingly, polymorphisms have been detected in the neurotensin receptor
mRNA sequences from human brain tissue (M. Watson et al. 1993).
Whether such mRNA polymorphisms are associated with functional al-
terations of the neurotensin receptor (and in turn are associated with the
clinical psychopathology of schizophrenia) remains to be determined.
Postmortem regional CNS investigations of other neuropsychiatric
diseases, however, have revealed alterations in neurotensin concentra-
tions in brain tissue. Diminished concentrations of neurotensin in the
amygdala of Alzheimer’s disease patients have been documented (Benz-
ing et al. 1990; Nemeroff et al. 1989b). In contrast, increased neuro-
tensin concentrations have been observed in the caudate nucleus and
globus pallidus of Huntington’s disease patients (Nemeroff et al. 1983).
Although the number of neurotensin receptors on dopamine neurons in
the substantia nigra decreases as these neurons degenerate (Sadoul et al.
1984; Uhl et al. 1984), postmortem neurotensin concentrations in vari-
ous brain regions (including the caudate nucleus, nucleus accumbens,
and ventral tegmental area) in subjects with Parkinson’s disease are re-
markably similar to those found in age- and sex-matched control subjects
(Bissette et al. 1985). This may be due to the finding that neurotensin
and dopamine, though co-localized in the mesolimbic system of rodents,
is not co-localized in primates.
Development of specific neurotensin receptor agonists and antag-
onists may allow further determination of the physiological effects of
altered neurotensin receptor activity. A specific neurotensin receptor ag-
onist affords the tantalizing possibility of antipsychotic activity, whereas
a neurotensin antagonist might disrupt the actions of endogenous neuro-
tensin, thus providing even greater information of the role of this peptide
in dopamine neurotransmission and hormonal regulation within the
CNS.
Neuropeptide Y
Originally cloned from a pheochromocytoma by Minth and colleagues in

1984, neuropeptide Y is a 36–amino acid peptide whose gene is expressed
in cells derived from neural crest (Allen and Balbi 1993). Neurons dis-
playing neuropeptide Y immunoreactivity are abundant within the lim-

bic areas of the CNS (De Quidt and Emson 1986; Hendry 1993).
Neuropeptide Y is also present within neurons of the hypothalamus,
brainstem, and spinal cord. Present in most sympathetic nerve fibers,
neuropeptide Y can be detected in vascular beds throughout the body
and occurs in parasympathetic nerves as well (Sundler et al. 1993). Re-
ceptors for neuropeptide Y are also widely distributed. Not only do neu-
ropeptide Y–containing neurons innervate CRH-containing cells of the
paraventricular nucleus (Liposits et al. 1988), but administration of neu-
ropeptide Y increases hypothalamic CRH levels (Haas and George 1987,
1989) as well as its release (Tsagarakis et al. 1989). The relationship of
neuropeptide Y to CRH is further substantiated by the partial blockade
of the neuropeptide Y–stimulated ACTH response by a CRH receptor
antagonist. Moreover, neuropeptide Y potentiates the effects of exoge-
nously administered CRH in animals (Inoue et al. 1989).
Although an initial investigation (Berrettini et al. 1987) did not find
significantly diminished cerebrospinal fluid neuropeptide Y concentra-
tions in depressed patients, Widerlov and colleagues (1988) subsequently
reported that patients with major depression do exhibit decreased cere-
brospinal fluid neuropeptide Y concentrations compared with sex- and
age-matched control subjects. Negative correlations have been also ob-
served between dimensional anxiety ratings and cerebrospinal fluid neu-
ropeptide Y levels in depressed patients (Heilig and Widerlov 1990).
Furthermore, marked reductions in brain tissue concentrations of neu-
ropeptide Y were subsequently reported in suicide victims, with the most
dramatic decreases occurring in patients diagnosed with major depression
(Widdowson et al. 1992).
Preclinical investigations demonstrate the effect of neuropeptide Y in
appetitive behaviors. After intracerebroventricular injections, neuro-
peptide Y provokes excessive eating in mammals (Stanley 1993). After
starvation, the hypothalamic paraventricular nucleus concentrations of
neuropeptide Y increase; they diminish rapidly to prestarvation levels af-
ter food ingestion (Sahu et al. 1988). In humans, increased cerebrospinal
fluid concentrations of neuropeptide Y have been detected in under-
weight amenorrheal anorexic patients and in the same amenorrheal pa-
tients within 6 weeks after weight restoration. Furthermore, an inverse
relationship between cerebrospinal fluid neuropeptide Y concentration
and caloric intake is observed in healthy female volunteers (Kaye et al.
1989, 1990). Whether the symptoms of anorexia are induced by increased
neuropeptide Y secretion or whether increased cerebrospinal fluid con-
centrations of neuropeptide Y result from starvation remains to be deter-
mined.
Efforts toward development of neuropeptide Y receptor–specific ago-

nists and antagonists continue. Neuropeptide Y–ergic medications may have
significant benefit in the treatment of affective illness or eating disorders.
Substance P
In mammals, members of the rapidly acting peptide tachykinin family are

known as neurokinins (Guard and Watson 1991) and include neurokinin A,
neurokinin B, and substance P. The most abundant of the neurokinins,
the undecapeptide substance P, was discovered in 1931 by von Euler and
Gaddum but was not isolated in pure form until 1970 by Chang and Lee-
man (1970). Substance P binds to the neurokinin 1 receptor, neurokinin
A binds to the neurokinin 2 receptor, and neurokinin B binds to the neu-
rokinin 3 receptor. Within the CNS, substance P is localized within in the
limbic and stress response areas (amygdala, hypothalamus, periaqueductal
gray matter, locus coeruleus, and parabrachial nucleus) (Ku et al. 1998)
and exists within norepinephrine- and serotonin-containing cell bodies as
well (Bittencourt et al. 1991; Helke and Yang 1996; Magoul et al. 1993;
Pelletier et al. 1981). Furthermore, substance P and other tachykinins serve
as pain neurotransmitters in primary afferent neurons (J. Culman and
Unger 1995) and exert a variety of other peripheral actions, including
bronchoconstriction, vasodilatation, salivation, and smooth muscle con-
traction in the gut (Payan et al. 1984; Pernow 1983).
Preclinical studies have provided much of the impetus to continue in-
vestigation of the efficacy of substance P receptor antagonism, although
these agents have not been effective as analgesics (Nutt 1998). Adminis-
tration of substance P (or substance P agonist) to animals elicits behav-
ioral and cardiovascular effects resembling the stress response and so-
called defense reaction (Helke et al. 1990). Moreover, preclinical studies
documented reduction of behavioral and cardiovascular stress responses
by administration of substance P receptor antagonists (C. Culman et al.
1997; Kramer et al. 1998). An exciting initial study indicated that the
substance P receptor antagonist MK-869 is more effective than placebo
and is as effective as paroxetine in patients with moderate to severe symp-
toms of major depression (Kramer et al. 1998).
Future clinical investigations will determine whether brain and cere-
brospinal fluid substance P concentrations are altered in patients with
major depression (Berrettini et al. 1985; Rimon et al. 1984) and whether
there are significant changes in cerebrospinal fluid concentrations of sub-
stance P after treatment (Martensson et al. 1989).
Other Peptides
Another neuropeptide that is possibly involved in the pathophysiology of

anxiety disorders is diazepam-binding inhibitor (DBI). There has been a
great deal of interest in the isolation of endogenous ligands for benzo-
diazepine recognition sites in the CNS. DBI, an 11-kDa polypeptide, was
identified not only in animal brain tissue (Guidotti et al. 1983) but also
in human brain tissue (Ferrero et al. 1986; Shoyab et al. 1986). This en-
dogenous peptide, which avidly inhibits the binding of benzodiazepines
to brain synaptosomes, is present in high concentrations in the amygdala
and hippocampus. DBI is thought to be important in responses to stress,
particularly in regulating steroid production in both the CNS and adrenal
glands, and it may therefore play a role in modulation of depressive and
anxiety symptoms (Ferrarese et al. 1993). Indeed, intracerebroventricu-
lar injections of human DBI into animals facilitates behavioral inhibition
(Ferrero et al. 1986). Moreover, elevation of cerebrospinal fluid DBI con-
centrations has been documented in patients with major depression (Bar-
baccia et al. 1987) and has been positively correlated with cerebrospinal
fluid concentrations of CRH (Roy et al. 1989). Clinical investigations
will undoubtedly further determine the physiological function of DBI
and whether this neuropeptide can be utilized as a biochemical marker
indicative of anxiety or affective illness.
Delta sleep–inducing peptide (DSIP) may have a role in the patho-
physiology of sleep disorders. Isolated in 1977, the nonapeptide DSIP
was identified in animals after electrical stimulation of the thalamus to
induce sleep (Monnier and Hoesli 1965; Schoenenberger et al. 1978).
Circulating forms of DSIP were subsequently recognized by antisera and
were referred to as DSIP-LI for DSIP-like immunoreactivity. DSIP-LI has
been detected in various brain areas and body fluids, including adeno-
hypophyseal corticotroph/melanotropin cells, where it is co-localized
with ACTH (Bjartell et al. 1987; Vallet et al. 1988). DSIP was originally
proposed to be a sleep-inducing hormone because of its sleep-inducing
qualities after intravenous administration in animals and humans (Schnei-
der-Helmert and Schoenenberger 1983; Schneider-Helmert et al. 1981).
DSIP has been utilized in clinical trials with patients with chronic insom-
nia and narcolepsy, with both positive (Schneider-Helmert 1984a, 1984b)
and negative results (Graf and Kastin 1986).
In patients with major depression, diminished cerebrospinal fluid
DSIP levels have been detected (Lindstrom et al. 1985; Walleus et al.
1985). In depressed patients, CRH stimulation reduces plasma DSIP-LI
concentration, in contrast to nondepressed volunteers, in whom intrave-
nous CRH administration induces increased plasma DSIP-LI concentra-

tion (Lesch et al. 1988). Decreased levels of cerebrospinal fluid DSIP
have also been detected in drug-free schizophrenic patients in compari-
son with healthy control subjects (Lindstrom et al. 1985; Van Kammen
et al. 1992). Interestingly, prophylactic lithium treatment of patients
with mood disorders increases cerebrospinal fluid and plasma concentra-
tions of DSIP (Regnell et al. 1988; Walleus et al. 1985).
Obviously, the literature on DBI and DSIP in psychiatric disorders
will be further developed and extended. Future efforts will undoubtedly
reveal whether agents altering the function of these peptides can be ther-
apeutically effective in patients with anxiety, mood, and sleep disorders.
Clinical Implications
The last three decades of neuropsychophysiologic exploration have

yielded a plethora of new findings regarding the alterations of CNS
neuropeptides and hypothalamic releasing factors in certain psychiatric
disorders (Table 3–5). Not only does understanding of these findings re-
quire a sophisticated level of psychoneuroendocrine knowledge, but in-
tegration of the seemingly disparate data into a conceptual schema must
be postponed until further information is gathered. Although the balance
of evidence indicates that multiple neuropeptide systems within the
CNS are altered in major depression and anorexia nervosa, determination
of the activity or dysfunction of these systems within the brain remains
relatively difficult. Not only may there be differences between hypotha-
lamic and extrahypothalamic secretion within the brain, but disagree-
ment continues as to which compartment cerebrospinal fluid sampling
accesses (or whether it access both compartments). Furthermore, there
is discordance between CNS and more peripheral sources of a neuro-
peptide, such as neurotensin and cholecystokinin. Peripheral plasma
concentrations of a neuropeptide or hypothalamic releasing factor are de-
termined not only by the rate of release but also by local metabolic degra-
dation and by redistribution into other extravascular spaces (Linares et
al. 1988). For example, plasma CRH concentrations can be measured but
may not truly represent CNS secretion because of the CRH contribution
by the adrenal medulla and spleen.
Nevertheless, the importance of hypothalamic releasing factors in the
pathophysiology of psychiatric illness is most evident in the large body
of literature indicative of CRH hypersecretion in patients with major
depression, although not all studies are in agreement (Geracioti et al.
TABLE 3–5. Alterations of neuropeptides and hypothalamic releasing

factors in various psychiatric disorders
Major depression
Hyperactivity of the hypothalamic-pituitary-adrenal axis
Dysregulation of growth hormone secretion
Diminished somatostatin activity
Diminished neuropeptide Y secretion
Diminished delta sleep–inducing peptide secretion
Bipolar disorder—manic phase
Hypersecretion of arginine vasopressin
Anxiety disorders
Increased sensitivity to CCK-4, a preferential CCKB receptor agonist
Anorexia nervosa
Hyperactivity of the hypothalamic-pituitary-adrenal axis
Hypersecretion of neuropeptide Y
Schizophrenia
Decreased neurotensin secretion
Alzheimer’s disease
Somatostatin hypoactivity
Note. CCK=cholecystokinin.
1992). Virtually all of the neuropeptide and neuroendocrine axis alter-

ations in patients with major depression thus far studied are state depen-
dent. However, nearly all the studies noted in this chapter are “cross-
sectional” in design—that is, the psychiatric disorder and the alterations
of neuropeptide or hypothalamic releasing factors are determined at
approximately the same time. Clinical investigators of the twenty-first
century will extend understanding of whether certain neurobiological
alterations provide fundamental pathophysiological contributions to the
behavioral manifestation of particular psychiatric disorders or are merely
epiphenomena, for example, diminished cerebrospinal fluid concentra-
tions of somatostatin in patients with Alzheimer’s dementia.
Nevertheless, further cross-sectional studies are necessary to confirm
whether DBI peptide systems in depression and endogenous opioid
peptide systems in psychiatric disorders with self-mutilatory behaviors
are truly disordered. Furthermore, present efforts guided by the neuro-
endocrine window strategy and the pharmacologic bridge technique may
provide information as to whether the secretion of neuropeptides and
hypothalamic releasing factors are associated with alterations in the
activity of putative neurotransmitters—such as 5-HT, dopamine, and
acetylcholine—in particular disease states. More likely, functional brain
imaging methods, such as positron emission tomography, will provide di-

rect data of alterations in neuropeptide circuits in psychiatric disorders.
A clearer understanding of the neuroendocrinology of depression,
anxiety, and schizophrenia may well lead to the development of novel
pharmacologic agents for the treatment of these major mental disorders.
We await confirmation of an initial report documenting the effectiveness
of the substance P receptor antagonist, MK-869, in patients with major
depression. Early studies of novel CRH receptor antagonists suggest effi-
cacy in the treatment of depression. A selective CCKB antagonist with
anxiolytic activity may offer a new psychotropic modality in the treat-
ment of panic disorder. Progress during the last three decades has been
nothing short of remarkable, and the future is likely to bring further prog-
ress in treating these disorders.
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Chapter 4
Chronobiology and Melatonin
Robert L. Sack, M.D.

Alfred J. Lewy, M.D., Ph.D.
Magda Rittenbaum, M.D.
Rod J. Hughes, Ph.D.
M elatonin is a hormone produced at night by the pineal

gland. When administered exogenously, its actions are prototypical of a
new class of drugs termed chronobiotics (Dawson and Armstrong 1996).
Chronobiotics are substances that can therapeutically adjust the timing
of circadian rhythms (Simpson 1980); in other words, they can “reset”
the biological clock. The prime targets for chronobiotic treatment are the
circadian rhythm sleep disorders (American Sleep Disorders Association
1997), which include jet lag and shiftwork maladaptation, as well as some
other less common sleep disorders. Certain mood disorders, including win-
ter depression, may also involve circadian rhythm disturbances (Lewy et
al. 1987). All of these disorders have a common underlying pathophysi-
ology; that is, a desynchrony between the timing of endogenous circadian
rhythms and the timing of the environmental day-night cycle or the tim-
ing of the desired sleep-wake schedule (in some cases sleep is desired at
an atypical time; for example, during the day in night workers).
Chronobiotic drug activity should be distinguished from hypnotic
activity. Hypnotic drugs directly induce drowsiness or sleep but do not
An earlier version of this chapter (Sack RL, Lewy AJ, Hughes RJ, et al.: “Mela-
tonin as a Chronobiotic Drug”) was originally published in Drug News and Per-
spectives 9(6):325–332, 1996. Copyright 1996, Prous Science Publishers. Used
with permission.
83
necessarily shift circadian rhythms. Chronobiotics are not necessarily

hypnotic; instead, they improve sleep by optimizing the alignment be-
tween endogenous circadian sleep drive and the desired sleep time. Me-
latonin may have both chronobiotic and hypnotic actions, especially in
higher doses, but it may be possible to tease apart the two actions at
lower doses.
Perhaps the easiest circadian rhythm disorder to understand is jet lag.
After rapid transmeridian travel, there is a period lasting for several days
in which endogenous rhythms are out of phase with local time. This state
of circadian desynchrony generates symptoms of daytime sleepiness and
nighttime insomnia. In addition, there may be intense fatigue, gastro-
intestinal disturbance, and difficulty maintaining concentration. The
symptoms gradually resolve as the internal body clock “catches up” and
circadian harmony is restored. A more persistent form of circadian desyn-
chrony underlies night-shift work maladaptation. If the night worker
does not reset his or her clock, circadian rhythms will remain desynchro-
nized indefinitely. The night worker’s daytime sleep may be short and
unrefreshing. Consequently, a “sleep debt” builds up, and maintaining
alertness at night is a struggle. Disorders that may involve misalignment
of circadian rhythms are listed in Table 4–1.
TABLE 4–1. Circadian rhythm disorders

Time zone change syndrome (jet lag)
Shift work sleep disorder
Irregular sleep-wake pattern
Delayed sleep-phase pattern
Advanced sleep-phase pattern
Non-24-hour sleep-wake disorder
The potential benefits of circadian phase correction have been recog-

nized for some time. Appropriately timed bright light exposure was the
first practical treatment method for circadian phase resetting (Lewy et al.
1984) and is currently being applied in a variety of settings. Although
bright light exposure is quite potent, it is a relatively inconvenient and time-
consuming treatment compared with a safe and effective drug. Neverthe-
less, even if chronobiotic drugs are developed, planned light exposure could
be used synergistically with pharmacotherapy for the treatment of circa-
dian rhythm disorders.
The phase-resetting action of exogenous melatonin administration
was discovered quite recently, and the parameters for treatment, such as
Chronobiology and Melatonin 85
optimal timing and dosage, are currently being worked out. Meanwhile,
scientific research on melatonin has been overshadowed by a melatonin
fad in the United States, where it is sold in health food stores as a dietary
supplement. Although melatonin is not classified as a drug, those who
produce it for the health food market make implied claims that it is an
effective treatment for insomnia. Proponents of the fad also extend the
highly speculative hopes that melatonin has anti-aging effects, bolsters
the immune system, and can augment cancer therapy. We do not attempt
to review these claims in this chapter; instead we concentrate on the cir-
cadian phase-resetting and hypnotic actions of melatonin. The principles
discussed will presumably also apply to melatonin analogs and perhaps to
other chronobiotics that are under active development.
Circadian Rhythm Physiology
The word circadian is derived from the Greek roots circa, meaning
“about,” and dies, meaning “day.” Circadian rhythms have evolved as an
adaptation to the alternating light-dark cycle caused by the rotation of
the earth (for a very readable overview of circadian rhythm physiology,
see Moore-Ede et al. 1982). Circadian rhythms are not passive responses
but are actively generated by an internal pacemaker that operates to main-
tain synchrony with the light-dark cycle. The endogenous nature of these
rhythms can be demonstrated by placing an organism in an isolated envi-
ronment and then observing variations in behavior or physiology that
continue to oscillate about every 24 hours, even in the absence of any
external time cues (zeitgebers, from the German for “time-givers”). The
circadian system provides a mechanism for anticipatory adaptation to
predictable changes in the environment; for example, core body temper-
ature rises in the second half of the night, presumably preparing an indi-
vidual for activity on awakening in the morning.
In mammals, the circadian clock is located in the hypothalamus within
the suprachiasmatic nucleus (SCN) (Klein et al. 1991) (Figure 4–1). The
SCN acts as the master circadian pacemaker and controls the timing of
most circadian rhythms, including melatonin secretion, sleepiness, core
body temperature, and cortisol secretion. If this tiny area of the brain is
destroyed in laboratory animals, circadian rhythms in body temperature
and hormonal secretion are lost, and sleep occurs in short bouts evenly
distributed throughout the 24-hour day. Circadian rhythms can be re-
stored in SCN-lesioned animals by transplanting fetal SCN tissue into the
third ventricle of the brain (Ralph 1991). The intrinsic rhythm of the
FIGURE 4–1. Diagram of the major elements of the pineal interactions

with the circadian system.
The suprachiasmatic nucleus (SCN) in the hypothalamus receives photic input from the
retina via the specialized retinohypothalamic tract (RHT). This pathway is critical for light-
mediated entrainment of the circadian pacemaker located in the SCN. Multisynaptic effer-
ents descend from the SCN to the superior cervical ganglion (SCG), and postganglionic
b-adrenergic fibers ascend to terminate on the pineal gland. On receiving a signal from the
SCN, the pineal gland secretes melatonin. Circulating melatonin interacts with receptors in
the SCN, forming a feedback loop. The phase-shifting effects of melatonin administration
are most likely mediated by mimicking this arm of the loop.
Source. Reprinted from Sack RL, Blood ML, Hughes RJ, et al.: “Circadian Rhythm Sleep
Disorders in the Totally Blind.” Journal of Visual Impairment and Blindness 92:145–161,
1998. Used with permission.
SCN is not exactly a 24-hour cycle but ranges from about 23 to 25 hours
(in humans, about 24.5 hours). When subjects are isolated from all time
cues, circadian rhythms express a cycle that is slightly longer (or shorter)
than 24 hours. For circadian rhythms to be synchronized to a precise 24-
hour day, the circadian clock must be regularly adjusted (reset) by expo-
sure to 24-hour time cues. Thus, circadian phase resetting is a normal, on-
going process; the resynchronization that occurs after a challenge to the
system such as transmeridian flight is an extension of an intrinsic process
that occurs normally every day in nontravelers.
The process of adjustment through interaction with time cues in the
environment is called entrainment. In nature the primary time cue is the
solar light-dark cycle, although other timing signals may play a role. Light
information is delivered directly to the SCN via the retinohypothalamic
tract, which is anatomically distinct from the visual imaging circuitry (see
Figure 4–1).
The SCN stimulates the pineal gland to secrete melatonin during the
nighttime hours. A functional feedback loop between the pineal and the
SCN (see Figure 4–1) is mediated by highly specific melatonin receptors
(Reppert et al. 1994, 1995) concentrated in the SCN. This feedback loop
appears to regulate the timing, but not the amplitude, of melatonin se-
cretion. Melatonin receptors in the SCN are the probable target for the
clock-resetting effects of exogenously administered melatonin.
Melatonin: Basic Biology
Melatonin is a phylogenically ancient hormone that is almost ubiquitous

in the animal kingdom, including some single-celled organisms (Poeggeler
et al. 1991). It is synthesized in the pineal gland from tryptophan via se-
rotonin as an intermediate precursor (Arendt 1995). Melatonin is always
produced at night, regardless of whether an animal is active during the
day or during the night. Therefore, it is always concomitant with darkness
(Arendt 1995) but not necessarily with sleep—nocturnal species are ac-
tive at night. In nature, melatonin secretion is suppressed by light at dusk
and dawn; consequently, the duration of secretion varies with the sea-
sonal changes in the length of the day. It is useful to think of melatonin as
a hormonal signal for nocturnal darkness; the message may be used by dif-
ferent species in different ways. For example, the best-established role for
melatonin is the regulation of seasonal breeding cycles in some animals
(Tamarkin et al. 1985). When melatonin is administered exogenously, it
can mimic the effects of the short days and long nights of winter. In ham-
sters, short days are antigonadal, but in sheep they are progonadal. Thus,
the effects of melatonin on reproductive biology are species specific and
are mediated through its role as a transducer of day length.
It is likely that the phase-resetting effect of exogenous melatonin ad-
ministration is derived from its role as a signal for nighttime darkness;
that is, exogenous melatonin administration is interpreted by melatonin-
receptive areas in the hypothalamus as an early dusk or a late dawn, de-
pending on the time it is given, and the circadian pacemaker responds by
adjusting its phase accordingly.
Melatonin Phase Response Curves
Both the potency and the direction of environmental time cues are de-
pendent on the time of day they are presented. In chronobiology, this
relationship is described by a phase response curve (PRC) (Moore-Ede et

al. 1982). For example, light in the morning (early subjective day) shifts
rhythms earlier, whereas light in the afternoon (late subjective day) shifts
rhythms later. Light in the middle of the day has no effect.
The landmark experiment documenting the entraining effects of me-
latonin was conducted by Redman, Armstrong, and Ng (1983). They
tested the effects of exogenous melatonin administration on rats that were
maintained in a constant dim-light environment and that expressed non-
24-hour, free-running rhythms. Daily injections of melatonin late in the
subjective day (1–3 hours before onset of activity) entrained the animals
to a normal 24-hour cycle, but placebo treatment at the same time of the
day had no effect. The mechanism for entrainment was a daily phase ad-
vance (15–45 minutes) sufficient to counteract the free-running rhythms,
which were longer than 24 hours. In rodents, melatonin caused advances
but not delays.
McArthur et al. (1991) provided the first evidence of direct SCN re-
setting by melatonin using an in vitro brain slice preparation. The depen-
dent measures included the rate of firing in SCN neurons, which typically
peaks during midday (8–14 Hz), with slowest rates occurring throughout
the night (typically 2–4 Hz). Bath application of physiological melatonin
solution applied to rat SCN brain slices induced a phase advance of up to
4 hours in the peak firing rate when delivered late in the day. By moni-
toring the brain slice for multiple cycles, a permanent resetting of the cir-
cadian clock was documented. This observation was remarkably consis-
tent with the behavioral studies of Redman and Armstrong (Armstrong
and Chesworth 1987; Redman et al. 1983).
There appear to be considerable species differences in the phase-shifting
effects of melatonin. For example, in lizards, melatonin injections cause
larger shifts than in rodents and can delay as well as advance circadian
rhythms, depending on the time of administration (Underwood 1986).
On the other hand, hamsters are relatively immune to phase-shifting
effects (Hastings et al. 1992). In summary, animal studies have clearly
documented the ability of melatonin administration to influence the
mammalian circadian system. Presumably, this effect is related to the
physiological role of endogenous melatonin.
Melatonin Phase Resetting in Humans
In 1987, we reported our initial study of melatonin administration to to-

tally blind subjects (Sack et al. 1987), with additional data reported over
the next few years (Sack and Lewy 1988; Sack et al. 1990, 1991). The
strategy of treatment was based on the animal experiments of Armstrong
and co-workers (Armstrong and Chesworth 1987; Redman and Arm-
strong 1988; Redman et al. 1983). Five totally blind males with con-
sistent free-running (non-24-hour) melatonin rhythms were given
exogenous melatonin (5 mg by mouth at bedtime) for up to 3 weeks.
Four of the five subjects showed significant cumulative advances (7–16
hours) in the phase of melatonin rhythm compared with phase projec-
tions derived from their pretreatment rhythms (Sack et al. 1991). Corti-
sol rhythms were advanced in parallel with the melatonin rhythms. In
blind subjects, the treatment-induced phase advances were unconstrained
by the light-dark cycle and therefore accumulated over the 3-week period.
In these early studies, we were not able to entrain the subjects’ circadian
rhythms to a 24-hour cycle, perhaps because the duration of treatment
was limited to 3 weeks.
We have readdressed the issue of melatonin treatment of blind peo-
ple. Using a higher dose (10 mg), we have been able to entrain six of
seven subjects treated (Sack et al. 1999, 2000). Placebo treatment had no
effect. Figure 4–2 shows representative data from one of the blind sub-
jects. Entrainment of free-running rhythms in blind people is a clear-cut
demonstration of the clock-resetting potency of melatonin. Recently, we
found that 0.5 mg can be effective in these individuals (Lewy et al.
2001).
After our initial demonstration of phase resetting in blind people with
free-running rhythms, we proceeded with studies in sighted people. We
administered melatonin at all phases of the circadian cycle, evaluating de-
laying as well as advancing effects, and derived a PRC (Lewy et al. 1992).
For each trial, subjects were given a daily 0.5-mg dose of melatonin or
placebo at the same time each day for 4 days, and circadian phase was as-
sessed on the fifth day by measuring the timing of endogenous melatonin
rhythm (dim light melatonin onset [DLMO]). Sleep times were held rel-
atively constant. The difference in DLMO between active treatment and
placebo was used as the measure of phase shift. Figure 4–3 presents the
melatonin PRC developed by this strategy. Advance responses (shifts to
an earlier time) are most likely to occur after melatonin administration
in the late afternoon and evening (just before the onset of endogenous
melatonin secretion), whereas delay responses (shifts to a later time) are
most likely to occur after melatonin administration in the morning (coin-
cident with the decline in endogenous secretion).
The strategy for using melatonin and light to shift circadian rhythms
according to their respective PRCs is summarized schematically in
Figure 4–4. As shown in the upper panel, melatonin administration in
FIGURE 4–2. Data from entrainment of a totally blind man with free-
running rhythms by melatonin 10 mg given nightly at bedtime.
Total blindness is associated with circadian rhythms that run on a non-24-hour, “free-running”
cycle (see text). Recurrent insomnia and daytime sleepiness result when endogenous circa-
dian rhythms are out of phase with the desired sleep-wake cycle. The subject is a 57-year-
old man who was totally blinded at age 26 from trauma. His 24-hour melatonin profiles
were assessed at 2- to 4-week intervals to detect his melatonin onset (MO), the time when
concentrations rose above 10 pg/mL. His circadian period (tau) was determined by fitting
the MOs to a linear regression. MOs assessed during a diagnostic assessment (open circles)
revealed a free-running melatonin rhythm with a tau of 24.6 hours. The tau was unchanged
by placebo treatment (open squares). MOs assessed on melatonin treatment days 42 and
52 (closed squares) were at a slightly delayed but consistent phase of 1:00 and 12:45 A.M.,
6.8 hours and 13.2 hours (respectively) earlier than predicted by extrapolation of the free-
running rhythm (shown as the dotted line).
Source. Reprinted from Sack RL, Brandes RL, deJongh L, et al.: “Melatonin Entrains Free-
Running Circadian Rhythms in a Totally Blind Person.” Sleep 22(suppl):S138–S139, 1999.
Used with permission.
the evening (or light in the morning ) will shift circadian rhythms earlier
(i.e., cause a phase advance). As shown in the lower panel, melatonin ad-
ministration in the morning (or light in the evening) will shift the circa-
dian rhythms later (i.e., cause a phase delay). The most critical times for
Chronobiology and Melatonin
FIGURE 4–3. Melatonin phase response curve (PRC) derived from repeated trials of melatonin administration.
Advance responses are most likely in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses are
most likely to occur in the morning (coincident with the decline in endogenous secretion).
Source. Reprinted from Lewy et al. 1998. Used with permission.
91
FIGURE 4–4. The strategy for using melatonin and light to shift circadi-
an rhythms according to their respective phase response curves (PRCs),
shown schematically (see text for details).
Source. Reprinted from Lewy AJ, Sack RL: “The Role of Melatonin and Light in the Hu-
man Circadian System.” Progress in Brain Research 111(205):205–216, 1996. Copyright
1996, with permission from Elsevier Science.
phase shifting in nature are dawn and dusk. Melatonin given in the mid-
dle of the night and light exposure in the middle of the day (so-called
dead zones of the PRCs) have minimal phase-shifting effects.
Melatonin Treatment of Night-Shift Workers—

Some Research Findings
To test the phase-shifting actions of melatonin in the field, we conducted

a double-blind clinical trial of melatonin in night-shift workers and have
obtained some data indicating therapeutic efficacy (Sack and Lewy
1997). Our subjects were night-shift workers on a “7-70” rotating sched-
ule involving seven consecutive 10-hour shifts (9:30 P.M. to 7:30 A.M)
alternating with 7 days off. This schedule is advantageous for circadian
rhythm research because subjects have a lengthy opportunity (seven
days) to adapt to both their work and off-work schedules, and thus the
dynamics of adaptation to the alternating schedules can be investigated.
Also, subjects work precisely the same schedule every other week, so that
repeated measures can be made and the effects of treatments evaluated

in a repeated-measures design.
The subjects (nurses and hospital clerical personnel) were between
ages 21 and 55 and had worked on the 7-70 shift for at least 6 months.
All of the subjects participated in a double-blind, crossover study of me-
latonin administration. For one 2-week block they received melatonin
(0.5 mg), and for the other 2-week block they received placebo (corn-
starch) formulated in identical gelatin capsules. Subjects were given me-
latonin (0.5 mg) at their usual bedtimes—that is, between 9:00 and
11:00 P.M. during the off-work weeks and between 8:00 and 10:00 A.M.
during work weeks. Subjects were blind to the treatment condition, and
the order of treatment was randomized.
To monitor circadian phase, weekly assessments of the melatonin pro-
file were obtained so that estimates of the direction and rate of phase
shifting could be made. Just before beginning a run of night work, and
just after, subjects were admitted to the clinical research center, where
blood samples were obtained every hour for 24 hours for determination
of the DLMO, which was used as the marker of circadian phase.
We have collected data on 24 subjects to date and have formed some
conclusions. At the end of their week off, the night workers were in about
the same circadian phase as a comparison group of day-active subjects
participating in another study.
A major question of this study was the magnitude and direction of the
circadian phase shifts between the beginning and the end of the 7-night
work week without treatment (placebo condition). In brief, we found
substantial variability in both the magnitude and the direction of phase
shifting (Figure 4–5). Eight subjects showed no shift, four advanced their
DLMO, five had partial delays, and eight were delayed 6 hours or more.
Laboratory studies indicate that the congruence of sleep with the cir-
cadian sleep propensity rhythm is a critical determinant of sleep duration
and that correction of an abnormal phase relationship by a variety of
strategies can improve sleep. To address this issue, we divided the group
into definite “shifters” (more than a 6-hour phase shift) (n=10) and “non-
shifters” (less than a 3-hour phase shift) (n=7) and compared wrist acti-
graphic estimates of sleep during the placebo work and off-work weeks.
Between-group comparisons showed that time in bed was an average of
70 minutes longer per day during the work week for shifters than for non-
shifters (511±72 minutes vs. 441±83 minutes; P<0.01), and total sleep
time was an average of 100 minutes longer (441±64 minutes vs. 341±82
minutes; P<0.01). During the off-work week, there were no significant
differences in either time in bed (522±52 minutes vs. 543±24 minutes;
P = 0.32) or total sleep time (445 ± 56 minutes vs. 448 ± 58 minutes;
FIGURE 4–5. Variability in phase shifting among “7-70” night-shift

workers.
Each pair of bars represents a single subject. For each subject, the dark bar indicates the tim-
ing of active melatonin production after a week off work (sleeping at a normal time), and
the light bar, after a week at work (sleeping during the day). These data indicate that a night
worker may undergo phase advance, have no shift, or undergo phase delay in response to
the inversion of his or her sleep-wake schedule.
P=0.90) between the groups. Within-group comparisons showed that on

their work week compared with their off-work week, the nonshifters
spent almost 2 hours less in bed (406±83 minutes vs. 543±24 minutes;
P<0.01) and slept nearly 2 hours less (341±82 minutes vs. 448±58 min-
utes; P < 0.01); there were no differences between the weeks for the
shifters.
For the initial analysis of our melatonin treatment trial (the experimen-
tal design is described above), we first estimated each subject’s normal
DLMO for a day-active schedule (off-work week) and then calculated
the magnitude of the phase shift subjects were able to achieve on their
night-work, day-sleep schedule, comparing it to the shift they made with
placebo or no treatment.
Figure 4–6 shows a summary of the results. Subjects 9 through 15
could be considered specific melatonin responders; they had very little or
FIGURE 4–6. Effect of melatonin treatment on phase shifting in 7-70

workers. Each point represents the timing of a melatonin onset (ex-
plained in text).
Subject 3 was at a substantially different phase at the end of the off-work week on the two
trials, and therefore his baseline is plotted twice). Specific phase-resetting responses to me-
latonin treatment were observed in night workers who did not shift to placebo treatment
alone.
Source. Reprinted from Sack RL, Lewy AJ: “Melatonin as a Chronobiotic: Treatment of
Circadian Desynchrony in Night Workers and the Blind.” Journal of Biological Rhythms
12(6):595–603, 1997. Used with permission.
no phase shift in their DLMO with the placebo treatment, but they
shifted at least 3 hours with melatonin. Subjects 17 through 24 delayed
their DLMO substantially with placebo alone, and melatonin did not
augment the shift. Subjects 1, 2, and 4 advanced their DLMO equally
with melatonin and placebo. Subjects 5–8 had no shift with either treat-
ment. Several subjects seemed to be atypical. For example, subject 3 was
at distinctly different phases on two off-week determinations. Perhaps
because of his differing starting phase, he advanced on the placebo trial
and delayed on his melatonin trial. Subject 16 had a larger delay in her
DLMO with placebo than with melatonin. In summary, a large propor-

tion of night workers on a 7-70 schedule make substantial phase shifts at
the end of a 7-day run without treatment or with placebo; melatonin spe-
cifically augmented phase shifts in a subgroup of workers who did not
shift with placebo alone. The melatonin treatment trials in this study
provide considerable encouragement for pursuing the development of
melatonin as a phase-resetting treatment for shift workers. Simulated
shiftwork experiments conducted by other investigators have been posi-
tive (Sharkey and Eastman 2002).
Direct Sleep-Promoting (Hypnotic)

Effects of Melatonin
Melatonin may have both chronobiotic and hypnotic actions. Almost

from the time of its discovery, there has been a strong interest in the pos-
sibility that endogenous melatonin may have sleep-promoting properties,
based on the circumstantial evidence that melatonin secretion occurs at
night when people are asleep. It is also possible that melatonin may have
sedative effects that are not related to its endogenous function.
In clinical trials testing its sleep-promoting actions, the formulations
and dosages of melatonin and the target populations have varied widely.
Therefore, it is difficult to draw firm conclusions from these studies. For
example, melatonin has been administered in vastly different doses, rang-
ing from 0.1 to 2,500 mg. Doses that produce blood levels that are sub-
stantially higher than 500 pg/mL (from a dose of about 0.5 mg) can be
considered “pharmacological,” while doses that mimic endogenous mela-
tonin production (below 0.5 mg) are “physiological.” Physiological-dose
trials are presumably more relevant for explaining the action of endog-
enous melatonin. However, the effects of pharmacologic doses may be
explained not only by the higher blood levels but also by the longer du-
ration of circulating levels above a certain threshold. If this is true, then
a comparable action may be achieved by a slow-release formulation that
maintains blood levels at a steady state over a comparable period of time.
The effect of melatonin on sleep is clearly not like those of benzodiaz-
epines or barbiturates. These drugs can induce sleep in a completely alert
subject if a high enough dose is given. More refined hypotheses regarding
the effects of melatonin on sleep are suggested from the available data.
As a general rule, exogenous melatonin may promote sleep mainly (or
only) when endogenous levels are low. For example, a hypnotic action has
been demonstrated in young healthy subjects when melatonin is given dur-
ing the day (when endogenous levels are lowest) (Hughes and Badia
1997), but such an effect does not necessarily occur when it is given at
night (James et al. 1987). Furthermore, an increase in nocturnal sleep has
been reported in elderly persons with insomnia, who may have low en-
dogenous levels (Haimov et al. 1995).
Another hypothesis currently undergoing testing is that soporific ef-
fects are associated with pharmacologic doses (although some groups insist
that physiological doses are equally potent). Several studies illustrate this
conclusion: for example, in the initial trials of melatonin with healthy el-
derly subjects completed to date, a 50-mg dose improved some parameters
of sleep (Singer et al. 1995a), whereas a 0.2-mg sustained-release formu-
lation showed no benefit (Singer et al. 1995b). The numbers of subjects
were small, and, given the variability of sleep in the elderly, firm conclu-
sions await additional data. In a study of young subjects, Hughes et al.
(1995) assessed the hypnotic efficacy of three doses of melatonin (1 mg,
10 mg, and 40 mg) given at 10:00 A.M. before enforced bed rest and a sleep
opportunity from 12:00 until 4:00 P.M. Melatonin increased sleep duration
during the 4-hour nap, with a suggestion of a dose-response effect.
We have attempted to integrate the findings on melatonin and sleep
by proposing that melatonin does not produce sleepiness per se; rather, it
releases accumulated sleep drive by antagonizing the daytime alerting sig-
nal generated by the SCN. This model is schematically portrayed in
Figure 4–7. The upper panel illustrates the dynamics of the opponent
process of sleep regulation (after Edgar et al. 1993). According to this
model, sleep drive builds up during the waking hours and is discharged
at night. However, the buildup of daytime sleep drive is usually unex-
pressed, because it is opposed by an alerting process generated in the
SCN. At bedtime there is a rather sudden transition to sleepiness (some-
times referred to as the opening of the sleep gate [Shochat et al. 1997]),
which coincides with the abrupt diminution in the SCN-dependent
alerting process. The lower panel of Figure 4–7 shows how melatonin
might promote sleep by attenuating the SCN-dependent alerting pro-
cess, thereby releasing the built-up sleep drive. If melatonin is given just
before sleep time (A), this action will shorten sleep latency. If given in
the middle of the night (B), there will be little effect on sleep because
sleep drive is in the process of discharging and the alerting process is qui-
escent (i.e., the sleep gate is already open). According to the model, me-
latonin can promote daytime naps (C), depending on the amount of
underlying sleep drive.
Melatonin appears to have no anxiolytic effects. Therefore, it may be
of little benefit to persons with insomnia who cannot sleep because of
tension, anxiety, or depression.
FIGURE 4–7. Hypothesized effects of melatonin on the suprachiasmatic

nucleus (SCN) alerting process, shown schematically (see text for de-
tails).
Source. Reprinted from Sack RL, Lewy AJ, Hughes RJ, et al.: “Guidelines for Prescribing
Melatonin for Sleep and Circadian Rhythm Disorders.” Annals of Medicine 30:115–121,
1998. Used with permission.
In summary, a soporific effect of melatonin may occur only in certain

circumstances, which are currently undergoing definition. Because of its
apparent safety (see “Safety Concerns” below), it may be worth trying in
individuals who have difficulty sleeping.
Interactions Between the Chronobiotic and

Sedative Actions of Melatonin
In clinical circumstances, the chronobiotic and hypnotic (if any) actions

of melatonin may have synergistic benefits on sleep. For example, in east-
ward jet travel, there is a need to advance sleep and circadian rhythms.
Melatonin taken at local bedtime could both promote sleep and reset the
circadian clock to an earlier time. Likewise, for the night worker, mela-
tonin taken in the morning may promote daytime sleep and also shift the
circadian clock to a later time. In clinical practice, a more potent sedative
drug might be combined with melatonin. For example, in the treatment
of jet lag, it may take several days for the circadian rhythms to synchro-
nize with local time, even if melatonin administration speeds up the
adaptive process. During this transition, a hypnotic drug may help to pro-
mote sleep. Combining melatonin with a hypnotic agent might be justi-
fied in the treatment of other circadian rhythm sleep disorders as a
transitional aid. The need for a hypnotic would naturally diminish as
rhythms came into alignment with desired sleep times. Treatment rec-
ommendations using melatonin, light exposure, and hypnotic medica-
tions for jet lag are presented in Table 4–2. A clinical vignette illustrating
combination treatment for delayed sleep-phase syndrome is provided
below.
TABLE 4–2. Melatonin to counteract jet lag

To adapt to an eastward flight, the day needs to be shortened and the body clock
reset to an earlier time. To adapt to a westward flight, the day needs to be
lengthened and the body clock set to a later time.
Example: eastward flight from Portland, Oregon, to London
Several days before departure, start taking melatonin around 3 P.M. This will
start the clock-resetting process. On the day of departure, take melatonin at
3 P.M. On arrival, calculate the time to take melatonin by adding the
number of time zones crossed to 3 P.M. London is 8 time zones from
Portland, so melatonin should be taken at 11 P.M. local time the first night.
For maximum effect, the dose should be taken 1 to 2 hours earlier on the
following days.
Example: westward flight from Portland, Oregon, to Tokyo
Take melatonin at 6 A.M. on the day of departure (to delay the clock). On
arrival, calculate the time to take melatonin by subtracting the number of
time zones crossed from 6 A.M. Tokyo is 8 time zones from Portland;
therefore, melatonin should be taken at 10 P.M. local time the first night. For
maximum effect, it can then be taken later each night (e.g., during the first
awakening).
A safe hypnotic medication can prevent sleep deprivation on a long overseas
flight and during the first 3–5 nights after arrival.
A 17-year-old boy was brought to the sleep disorders clinic because he

could not wake up in time to get to school. His problems began at pu-
berty. He enjoyed staying up late on the weekends and would sleep in un-
til noon (or later) on Saturday and Sunday. He lived with his mother; she
was divorced, worked outside the home, and left early in the morning on
weekdays before he was out of bed. On weekdays, he could not fall asleep
until 2 or 3 A.M. He would set several alarm clocks but would often sleep
through the alarms. When he did not wake up in time, he missed his bus,
so he stayed home and slept until late morning. Unexcused absences re-
sulted in declining grades and demoralization about school.
A diagnosis of delayed sleep-phase syndrome was made. Considerable
time was spent with the patient and his mother explaining the circadian
system, specifically 1) how the “body clock” tended to run on a longer
than 24-hour cycle, especially in teenagers; 2) how sleeping in on the
weekend could result in a rhythm that was so delayed that it was not pos-
sible to adjust it during the school week; and 3) how appropriately timed
light exposure and melatonin administration could be used to reset and
stabilize the sleep propensity rhythm. A treatment plan was developed in
which a very specific sleep, light exposure, and medication schedule was
written out using a computer spreadsheet. The schedule started with the
patient’s current preferred wakeup time (10 A.M.). The goal of treatment
was to advance wakeup time by 15 minutes every other day. Bedtime was
set at 8 hours before wakeup time. The patient was prescribed melatonin
3 mg to take 3 hours before bedtime. If he did not fall asleep within 20
minutes, he was to get up and take zolpidem (a sedative-hypnotic) 10 mg
and go back to bed. On arising, he was to go outside in the daylight for at
least 15 minutes. He was warned not to advance the schedule any faster
than prescribed and to keep on schedule during the weekends.
At the end of 3 weeks, the patient was able to wake up in time to
make the bus. He stopped taking the zolpidem but continued to take me-
latonin and to go outside in the morning. He was able to maintain a reg-
ular schedule, and with time he was more successful at school, resulting
in improved self-esteem.
Although the sedative effect of melatonin may be desirable in certain

situations, it can also be undesirable. For example, in westward travel, a
morning dose of melatonin would be necessary to delay the clock, but
this could increase subsequent daytime sleepiness. In this situation, a low,
sustained-release formulation would be ideal.
Melatonin Analogs
Melatonin analogs, under development by several pharmaceutical com-

panies for use as chronobiotics, could someday prove to have more po-
tent chronobiotic activity than melatonin itself. For example, animal
studies with S20098 have shown effects identical to those of melatonin
(Armstrong et al. 1993), and clinical trials with this agent have begun.
However, the overall effects of these synthetic agents are more difficult
to predict, and therefore greater effort will be required to document
safety than for melatonin, which is a more natural treatment—that is, it
is not foreign to the body.
Pharmacokinetics of Melatonin Administration
Exogenous melatonin is absorbed rapidly, yielding peak serum levels

within 60–150 minutes (Vakkuri et al. 1985). A typical 3-mg melatonin
tablet can produce a spike in plasma melatonin level that can be more
than 50 times the physiological blood concentration. Oral administration
of melatonin incurs significant first-pass hepatic metabolism (Lane and
Moss 1985) and is rapidly degraded, with an elimination half-life of 45–
60 minutes (Vakkuri et al. 1985; Waldhauser et al. 1984). Thus, a 3-mg
dose is cleared in about 6–10 hours. Melatonin is metabolized by the liver
into 6-hydroxymelatonin, a biologically inactive metabolite. A smaller
proportion of melatonin is demethylated back into N-acetylserotonin, a
precursor of melatonin (Young et al. 1985). The rapid metabolism of me-
latonin may be related to its function as a hormonal timing signal; that is,
it is important for melatonin to clear rapidly once pineal secretion is ter-
minated.
For clinical use, the easily available 3-mg dose is appropriate if given
before sleep. If sedation is to be minimized, it may be advisable to use a
low dose (0.5 mg or less). There may be a role for controlled-release for-
mulations, but these are not readily available at present. Although it has
not been extensively investigated, at this time there is no evidence for tol-
erance.
Safety Concerns
Judging from animal studies, melatonin is nontoxic. An early study in

mice with doses as high as 800 mg/kg did not reveal a lethal dose (LD50)
(Barchas et al. 1967). Studies have also provided reassuring information
about the safety of melatonin administration in humans; extremely high
blood levels have not produced any acute untoward reactions. Systematic
safety studies for long-term administration have not been carried out, but
widespread use of melatonin as a dietary supplement has not resulted in
any alarming problems. Because melatonin has rather dramatic effects on
gonadal function in animals that are seasonal breeders, the question has
been raised as to whether reproductive effects occur in humans. In hu-
mans, reproductive function does not follow any clear seasonal pattern,
so it is quite possible that this action of melatonin is vestigial.
Most (perhaps all) melatonin sold in the United States is synthetic,
not extracted from pineal gland, so there is little danger of transmitting
prion disease. Therefore, unregulated use of melatonin for sleep has re-
minded some clinicians of the experience with tryptophan, in which im-
purities caused an eosinophilic syndrome; however, there is no evidence
for this problem so far with melatonin.
Summary and Conclusions
Although it may be an oversimplification, it is very useful to think of me-

latonin as a hormonal darkness signal. Melatonin can reset the circadian
clock and can be thought of as a chronobiotic drug for the treatment of
circadian rhythm disorders. Its circadian phase-shifting effects appear to
be related to its interactions with receptors in the SCN, the site of the
circadian pacemaker. To use melatonin as a chronobiotic, it is critical to
consider the timing of administration. Melatonin administration several
hours before its endogenous rise will induce phase advances (set the cir-
cadian clock earlier), whereas administration around the time of the en-
dogenous decline will induce phase delays (set the circadian clock later).
In addition to its chronobiotic activity, melatonin may have some hyp-
notic activity, which could be an advantage or a disadvantage, depending
on the clinical circumstances. We propose that the hypnotic effects are
caused by antagonism of an alerting signal generated in the SCN. Melato-
nin treatment can be synergistically combined with appropriately timed
bright light exposure to produce maximal circadian phase resetting. Al-
though melatonin has not gone through the U.S. Food and Drug Admin-
istration approval process, current evidence is that it is quite safe.
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Chapter 5
Prolactin, Growth Hormone, Insulin,

Glucagon, and Parathyroid Hormone
Psychobiological and Clinical Implications
Mady Hornig, M.D.
Jay D. Amsterdam, M.D.
A lthough it is well known that glucocorticoids, sex steroids,

and thyroid hormones are linked to psychiatric disturbances, altered
mental states can also result from changes in the anterior pituitary hor-
mones prolactin and growth hormone, the gastropancreatic hormones in-
sulin and glucagon, and parathyroid hormone. Of the endocrine disorders
that are associated with psychiatric symptoms, disorders of glucose regu-
lation are the next most frequent cause of altered mental status after dis-
orders of thyroid function. Infrequently, symptoms of mental disorders
can also occur as a manifestation of pituitary failure or hypopituitarism.
Several of these hormones have been carefully studied in research in-
vestigations of the pathobiology of psychiatric disorders. In an effort to
assess the responsiveness of distinct hypothalamic-pituitary target organ
axes, neuroendocrine stimulation tests have been devised that utilize hor-
mones such as prolactin, growth hormone, glucagon, or insulin as either
challenge agents or outcome variables. For example, the so-called insulin
tolerance test (ITT), which uses insulin as the challenge agent, has yielded
This work was partly supported by NIMH Neuropsychopharmacology Fellow-

ship PHS Grant MH 14654 (MH), a NARSAD Young Investigator Award (MH),
and The Jack Warsaw Fund for Research in Biological Psychiatry of the Depres-
sion Research Unit. The authors thank Dr. Elissa Epel for her helpful review and
comments.
107
important information in several psychiatric conditions. Hormones such

as prolactin and growth hormone are more typically used as outcome
variables in such investigations; the challenge agent that is administered
is typically a pharmaceutical with effects on neurotransmitters that are
thought to control or modulate such hormones. For instance, the assess-
ment of prolactin response after administration of a serotonergic agent is
based on the knowledge that the central 5-hydroxytryptamine (5-HT)
(serotonin) system (in addition to other neurotransmitter systems such as
the dopamine system) partly controls prolactin secretion. The impor-
tance of prolactin and other hormonal responses in this type of testing is
more as a window into central neurotransmitter functioning rather than
a direct interest in the hormone level itself.
The varied psychiatric presentations associated with disturbances in
the levels of these hormones are considered below. The application of
these hormones in stimulation tests, with a focus on the biological cor-
relates of psychopathological states, is also briefly reviewed in this
chapter.
Prolactin and Psychopathology

Psychiatric Effects of Hyperprolactinemia
Hyperprolactinemia is most often related to a benign pituitary prolacti-
noma or to the administration of medications with serotonin agonist or
dopamine antagonist effects. The regulation of prolactin is unique among
the pituitary hormones in that it is under inhibitory control, primarily by
dopamine neurons in the hypothalamus. Other neurotransmitters such
as serotonin and acetylcholine promote prolactin secretion, as do thyro-
tropin-releasing hormone (TRH), estrogens, endogenous opiates, nipple
stimulation, and physical or emotional stressors (Rafuls et al. 1987). The
only known function of prolactin in humans is to promote milk produc-
tion, but distress, depression, anxiety, hostility, increased irritability, and
decreased libido are frequent symptoms of hyperprolactinemia (Rafuls et
al. 1987; Reavley et al. 1997), in addition to the common manifestations
of galactorrhea and oligomenorrhea.
The role of prolactin in inducing psychiatric symptoms is unclear. Hy-
perprolactinemic women with no evidence of pituitary microadenoma
seen on computed tomographic scans display more anxiety than women
with definite microadenomas seen on computed tomography despite
similar levels of hyperprolactinemia, raising the possibility of stress-
related or “functional” hyperprolactinemia (Reavley et al. 1997). Major
Hormones: Psychobiological and Clinical Implications 109
depressive disorder (MDD) occurs fairly frequently in hyperprolactine-

mic females but occurs less commonly in males (Fava et al. 1993); how-
ever, the relationship between prolactin excess and the pathogenesis of
mood disturbances in these cases is not clear. In amenorrheic women
with depression, anxiety, or hostility—especially when associated with
additional complaints of decreased libido or galactorrhea—the possibility
is great that the MDD-like syndrome may derive from elevated prolactin
levels. Such clinical presentations should be promptly pursued with appro-
priate laboratory tests and subsequent pituitary imaging if elevated serum
prolactin levels are persistent and unexplained. Depression associated
with hyperprolactinemia often responds specifically to dopamine ago-
nists such as bromocriptine (Fava et al. 1993) (with clinical improvement
increasing in parallel with decreases in prolactin levels), but it responds
poorly to antidepressants such as amitriptyline (Fava et al. 1987). In con-
trast, psychotic disturbances occur much more rarely than mood distur-
bances in patients with hyperprolactinemia (Brambilla 1992).
Gender-related effects may mediate certain aspects of hyperprolac-
tinemia-associated symptoms. Women appear to have greater sensitivity
than men to dopamine blockade in the tuberoinfundibulum (Szymanski
et al. 1995). In male patients, prolactinoma may be more commonly
misdiagnosed as an affective disorder because of the low incidence of ga-
lactorrhea and gynecomastia in men (Martin et al. 1977). Apathy, asex-
uality, adiposity, and headache were the most common symptoms among
16 male prolactinoma patients (Cohen et al. 1984). Curiously, in some
cases of severe hyperprolactinemia, patients may be asymptomatic. Con-
versely, there are no known psychiatric or physical correlates of prolactin
deficiency other than absence of postpartum lactation. However, re-
duced basal prolactin level or diminished response to pharmacologic
challenge may serve as a biological marker of occult disorders of the hy-
pothalamus and pituitary.
Prolactin Abnormalities Associated

With Psychiatric Disorders
Prolactin levels are influenced by a variety of physiological and pharma-
cologic stressors. Hypoglycemic challenges—as with the ITT and TRH
and dopamine receptor blockade—are examples of factors that normally
increase prolactin. Various studies of prolactin levels at baseline and in
response to stimulation by hypoglycemia, TRH, electroconvulsive ther-
apy, serotonin agonists, and dopamine antagonists have been undertaken
in psychiatric populations.
Major Depressive Disorder

Most studies indicate a normal basal level of prolactin in patients with
MDD, although impaired prolactin responses to insulin (Amsterdam et
al. 1987), TRH (Winokur et al. 1983), and intravenous tryptophan (Henin-
ger et al. 1984) have been noted. Basal prolactin levels may be decreased
in patients with bipolar disorder in comparison with patients with uni-
polar MDD (Mitchell et al. 1990). In healthy control subjects, the ad-
ministration of serotonin agonists such as fenfluramine has been shown
to reliably induce increased prolactin levels (Yatham and Steiner 1993).
In contrast, administration of serotonin agonist to patients with MDD
typically reveals blunted prolactin responses, lending support to the se-
rotonergic hypothesis of depression (O’Keane et al. 1992). This appears
to be related to the state of depression and is not a consequence of anti-
depressant medications (Shapira et al. 1993). Some studies with seroto-
nin type 1A (5-HT1A) agonists (Moeller et al. 1994; Sevincok and Erol
2000), but not all (Meltzer and Maes 1994; Reidel et al. 2002), have
found blunted prolactin responses in patients with MDD relative to con-
trol subjects. The study by Sevincok and Erol (2000) evaluated subjects
with poststroke depression. Pharmacologic specificity and selectivity of
the challenge agent at the neurotransmitter receptor in question, dosage
administered, and associated damage to neurocircuitry may influence the
results of neuroendocrine stimulation tests in different psychiatric popu-
lations.
Schizophrenia
Although basal prolactin levels are within the normal range in most non-
medicated schizophrenic patients, some studies have shown an inverse re-
lationship between prolactin concentrations and positive symptoms (T.J.
Crow et al. 1986). Basal prolactin level in nonmedicated patients with
acute schizophrenia is also slightly greater compared with basal levels in
patients with chronic schizophrenia or control subjects (Garver 1988).
Hyperprolactinemia and associated findings of galactorrhea, menstrual
dysfunction, decreased libido, and infertility occur commonly in women
responding to typical antipsychotic agents (Canuso et al. 1998). With the
exception of risperidone, newer atypical antipsychotic agents appear to
avoid elevation of prolactin level (Goodnick et al. 2002; Remington and
Kapur 2000). The prolactin-increasing effect is partly related to the potency
of blockade at the dopamine type 2 receptor in the tuberoinfundibulum.
Although the majority of evidence indicates that such side effects do not
appear to interfere with therapeutic response, patient compliance with
medication regimens associated with such consequences may be compro-
mised, increasing risk of relapse (Hamner et al. 1996). Some investigators

have attempted to relate endocrine responses to antipsychotic drugs to
the risk of tardive dyskinesia in schizophrenic populations, but the evi-
dence for a positive correlation between the severity of antipsychotic-
related tardive dyskinesia and serum prolactin level is inconsistent (Fer-
rier 1987).
Anxiety Disorders
Very little information has been collected regarding changes in prolactin
level in simple and social phobia, and most of this information does not
show a correlation (Curtis and Glitz 1988). Support for serotonergic
hypersensitivity, as evidenced by prolactin hyperresponsiveness to sero-
tonin agonists such as m-chlorophenylpiperazine (mCPP), has been seen
in some studies of patients with panic disorder (Klein et al. 1991). How-
ever, central serotonergically mediated prolactin responses in obsessive-
compulsive disorder (OCD) seem to be more similar to the blunted re-
sponses seen in patients with MDD, even after accounting for depressive
comorbidity (Lucey et al. 1992), and may correlate with response to in-
travenous clomipramine treatment in patients with treatment-refractory
OCD (Mathew et al. 2001).
Growth Hormone and Psychopathology

Psychiatric Effects of Growth Hormone Overproduction
Pulsatile secretion of growth hormone (an anterior pituitary hormone)
normally occurs in response to decreasing blood glucose levels, exercise,
early phases of sleep, stress, and a2-adrenergic agonists and is inhibited
by b-adrenergic agonists. The plasma level of growth hormone is regu-
lated by the balance between hypothalamic stimulatory influences such
as growth hormone–releasing hormone and inhibitory influences such as
somatostatin; the pulsatile secretory pattern and brief half-life (about 20
minutes) of growth hormone result in highly variable plasma levels.
Growth hormone acts indirectly to stimulate growth by inducing insulin-
like growth factor I (IGF-I). The most common cause of growth hormone
excess is pituitary adenoma, which results in gigantism in children and
acromegaly in adults. In patients with acromegaly-gigantism, psychiatric
symptoms are rare, except in cases where enlargement of a growth hor-
mone–producing adenoma causes mass effects in the sellar space. The
most common combination of symptoms is sweating, headache, weak-
ness, and fatigue. A depressive syndrome, sometimes with psychotic fea-
tures (Fava et al. 1993; Ferrier 1987), or a schizophrenia-like illness

(Brambilla 1992) may be seen infrequently. Psychological consequences
relating to compromised quality of life may occur (Fava et al. 1993)
Psychiatric Effects of Growth Hormone Deficiency

In children, growth failure and short stature resulting from uncorrected
relative or absolute growth hormone deficiency may produce psycholog-
ical sequelae such as impaired self-esteem and distorted body image.
Other behavioral and learning problems—including somatic complaints,
anxiety, depression, social phobia, and attentional dysfunction—also oc-
cur at an increased rate in children with growth hormone deficiency and
short stature compared with control children (Stabler et al. 1996a, 1998).
Although it is not clear whether growth hormone plays a direct role in
inducing these symptoms, the effect does not appear to be directly tied
to short stature (Nicholas et al. 1997), and many of these symptoms im-
prove during growth hormone treatment in children (Stabler et al. 1998)
and adults (Stabler et al. 1996b). Severe psychosocial stress may also re-
sult in functional growth hormone deficiency, known as psychosocial
dwarfism, a condition that may be corrected with proper environmental
improvements (Fava et al. 1993).
More recently, attention has been drawn to the cognitive and psycho-
social difficulties associated with growth hormone deficiency in adults,
including social isolation, decreased interest and pleasure, fatigue, and ir-
ritability (Deijen et al. 1996). Unemployment rates are higher and mar-
riage rates are lower than in the general population (Deijen and van der
Veen 1999). The rate of social phobia in adults with childhood-onset
growth hormone deficiency is reported to be as high as 38%, far higher
than the 10% rate in subjects of short stature without growth hormone
deficiency (Nicholas et al. 1997). Improvements in cognitive function-
ing, depressive symptoms, and quality of life have been reported with ad-
ministration of recombinant growth hormone in some (Burman et al.
1995; Cuneo et al. 1998; Degerblad et al. 1990; Soares et al. 1999), but
not all (Baum et al. 1998), double-blind, placebo-controlled trials in
growth hormone–deficient adults. Decreased activation along the growth
hormone–IGF-I axis may also be responsible for some of the catabolic
changes of normal aging, and some of the psychiatric sequelae. Growth
hormone deficiency may be associated not only with reduced muscle
mass and decreased exercise tolerance, but possibly also with impaired
rapid eye movement (REM) sleep (Steiger et al. 1994; van Cauter et al.
1998) and sense of well-being (Holmes and Shalet 1995). In one study of
41 patients with growth hormone deficiency, a 32% frequency of MDD
was noted, compared with a frequency of 10% among diabetic patients

(Lynch et al. 1994).
Specific trials of growth hormone administration in elderly individu-
als with relative hyposomatotropinemia are associated with reversal of
both the neuropsychiatric impairments and the catabolic influences of
growth hormone deficiency (Hoffman et al. 1992; Holmes and Shalet
1995). Further studies are needed to determine whether the effects of
growth hormone deficiency are related to the absence of actions of growth
hormone itself on the central nervous system (CNS), the associated re-
duction in IGF-I secretion caused by the relative growth hormone defi-
ciency, or impaired functioning of organ systems outside the CNS (Hoff-
man et al. 1992).
Growth Hormone Abnormalities Associated

With Psychiatric Disorders
Changes in growth hormone secretion may be evaluated after adminis-
tration of oral glucose, after administration of the ITT, or in response to
a2-adrenergic agonists such as clonidine. Cholinergic mechanisms appear
to mediate basal growth hormone levels and the secretion of growth hor-
mone during sleep. Anticholinergic agents can decrease basal growth hor-
mone secretion (Davis et al. 1983) or sleep-dependent growth hormone
secretion (Mendelson et al. 1978), whereas cholinergic agonists stimulate
growth hormone secretion.

Basal daytime growth hormone secretion has been reported to be either
normal (Antonijevic et al. 1998) or elevated (Mendleweicz et al. 1985)
in patients with depression. Decreased cerebrospinal fluid concentration
of somatostatin may mediate increases in basal daytime growth hormone
level, leading to growth hormone hypersecretion by reducing inhibitory
input (Ferrier 1987). Growth hormone secretory patterns can also be dis-
rupted by the hypercortisolemia commonly observed in patients with
MDD (Rupprecht et al. 1989; Wiedemann et al. 1991). Despite the find-
ing of increased basal daytime growth hormone level in some studies,
growth hormone secretion associated with early phases of sleep may be
reduced in depression (Sakkas et al. 1998; Voderholzer et al. 1993). A
low nocturnal growth hormone level during adolescence may also be a
harbinger of later episodes of depression in the following decade (Coplan
et al. 2000). Also, responses of growth hormone to a wide variety of
CNS modulators are often reported to be blunted in patients with major
depression. Growth hormone responses to dexamethasone, for instance,

are reported to be subnormal (Dinan 1998; Thakore and Dinan 1994).
In addition, growth hormone responses to the a2-adrenergic agonist clon-
idine are blunted in some (Mitchell et al. 1988) but not all (Gann et al.
1995) studies, suggesting subsensitivity of a2-adrenergic receptors in pa-
tients with MDD; such subsensitivity may be reversible with effective
antidepressant treatment (Lesch et al. 1990).
Disturbances along the hypothalamic-pituitary-somatotropic axis
may be further related to the subtype of affective disorder. In one study
(Amsterdam and Maislin 1991), although a significantly decreased cu-
mulative growth hormone response was found in hypomanic bipolar
patients compared with depressed bipolar patients and healthy control
subjects, cumulative growth hormone responses were significantly in-
creased in bipolar patients compared with unipolar depressed patients.
Anxiety Disorders
Panic disorder, OCD, and social phobia have been linked to disturbances
of the growth hormone system. Basal growth hormone levels are elevated
in some studies of patients with panic disorder (Nesse et al. 1984). In addi-
tion, blunted growth hormone responses have been consistently observed
in patients with panic disorder following administration of a2-adrenergic
agonists (Charney and Heninger 1986; Coplan et al. 1995). As with ma-
jor depression, the reduced growth hormone response to clonidine is
thought to reflect reduced sensitivity of a2-adrenergic receptors in the
CNS, especially in the hypothalamus. This fits with the hypothesized
overactivation of presynaptic noradrenergic neurons in the locus coeru-
leus in panic disorder, which theoretically contributes to downregulation
of postsynaptic a2 receptors (Curtis and Glitz 1988).
The assessment of neuroendocrine function in patients with OCD is
complicated by frequent comorbidity with depressive disorders. Up to
50% of patients with OCD have coexisting MDD, but neuroendocrine
findings, though often similar to those seen in depressed populations, can
also occur in patients with OCD uncomplicated by any depressive symp-
toms. Blunted growth hormone response to clonidine in patients with
OCD, a nonspecific finding also occurring in MDD and panic disorder,
reflects reduced a2-adrenergic receptor responsiveness (Insel et al. 1984;
Siever et al. 1983).
Schizophrenia
Although basal growth hormone levels have been noted to be normal in
acute and chronic schizophrenia (Ferrier 1987), abnormal responses to
pharmacologic challenges are noted and may relate to clinical variables.

Growth hormone responses to dopamine agonists such as apomorphine
are noted by several groups to be blunted in patients with chronic psy-
chosis who were either drug naive or poorly responsive to antipsychotic
agents (Pandey et al. 1977; Rotrosen et al. 1976). However, studies of
apomorphine-induced growth hormone response in schizophrenic pa-
tients with a less chronic course and increased drug responsivity reveal an
apparent bimodal response curve, with increased growth hormone re-
sponse variability in comparison with control subjects (Pandey et al.
1977). Increased growth hormone responses to apomorphine, reflecting
heightened sensitivity of hypothalamic dopamine receptors, may have
some value in predicting relapse (Brown et al. 1988; Cleghorn et al. 1983;
Lieberman 1993).
Alzheimer’s Disease
Although two studies of patients with Alzheimer’s disease suggested ab-
normal growth hormone system functioning (Christie et al. 1987; Thien-
haus et al. 1986), the vast majority of studies in this population indicate
little change in growth hormone responses (Davidson et al. 1988; Davis
et al. 1985; Heuser et al. 1992; McKhann et al. 1984). Effects of gender
and severity of illness may account for the few studies in which dif-
ferences in growth hormone responses to a2-adrenergic or cholinergic
agonists were observed between patients with Alzheimer’s disease and
control subjects without dementia (Davidson et al. 1988; Heuser et al.
1992).
Insulin and Psychopathology

Psychiatric Effects of Hyperglycemia and Diabetes
The psychiatric complications of diabetes mellitus, whether related to
deficiency of insulin production or impaired sensitivity of insulin receptors,
are in large part linked to the well-known neurological consequences of
acute and chronic hyperglycemia and hypoglycemia. Surprisingly few
systematic studies have been performed regarding the psychiatric comor-
bidity of diabetes, despite much interest in the role of abnormal glucose
regulation in psychiatric disorders in the first half of the twentieth cen-
tury (Craig 1927; Kooy 1919). Yet it is quite common in psychiatric
settings: in a prospective study of psychiatric admissions by Hall et al.
(1981), diabetes mellitus was found in 5% of patients, whereas hypo-
glycemia was evident in 4%. The overall estimated prevalence of diabetes
in the general population is between 2% and 4% (Andreoli et al. 1986;

Harris et al. 1987). In a study of patients with diabetes (both type 1 and
type 2), 71% were found to have a lifetime history of at least one criteria-
defined psychiatric illness; affective and anxiety disorders were the most
common diagnoses in this study (Lustman et al. 1986). The psychologi-
cal adaptation to life with a serious and chronic illness, the effects of
psychosocial stressors on glycemic control, and the possible increased
vulnerability of diabetic individuals to disorders of mood and anxiety are
important factors mediating the relationship between diabetes and psy-
chiatric symptoms.
Early age at onset of diabetes is associated with multiple psychological
complications, ranging from dependence on family members, to rebel-
liousness (often taking the form of noncompliance with insulin regimens
or dietary restrictions, especially in adolescents), to hostility (Gath et al.
1980; Sterky 1963; Swift et al. 1967). However, these behavioral mani-
festations are likely related, at least in part, to the developmental conse-
quences for children and adolescents who are forced to adapt to very
significant lifestyle changes imposed on them by their illness.
The psychological consequences of adapting to a chronic disease likely
play a role in individuals with adult onset of diabetes as well. In addition
to necessary restrictive changes in diet and weight control, psychosexual
and physical complications (fatigue, peripheral neuropathies, ocular se-
quelae, and vascular problems) introduce further interference into the
lifestyle of the diabetic individual. Impotence and ejaculatory distur-
bances in diabetic men and anorgasmia in diabetic women occur at high
rates (Fairburn et al. 1982; Kolodny 1971; Kolodny et al. 1974). Simi-
larly, moderate to severe problems with fatigue were noted in 20 of 50
patients with insulin-dependent diabetes in one study (Surridge et al.
1984).
The older literature has put forward several hypotheses regarding the
possible causative influence of physical or emotional stress (Hinkle and
Wolf 1952) or personality factors (Treuting 1962) on the initial onset of
diabetes. Although stressful circumstances are unlikely to induce an ac-
tive case of diabetes in an individual who is not biologically vulnerable,
psychosocial factors are generally acknowledged to influence the course of
latent or established diabetes (Hinkle and Wolf 1952). Such mediation
by psychosocial factors may occur indirectly—such as through inatten-
tion to dietary restrictions, alcohol consumption, or failure to self-moni-
tor glucose levels or administer insulin regularly when under duress—or
through more direct, centrally mediated effects on glucose regulation.
Hinkle and Wolf (1952), for instance, found that psychologically stressful
topics could induce elevations in glucose excretion and ketones, whereas
Baker and Barcai (1970) noted a relationship between emotional arousal

and ketoacidosis that was thought to reflect an exaggerated response to
circulating catecholamines. Thus, regular and close attention to the psy-
chosocial milieu of the person with diabetes may greatly improve control
over the disorder.
There is evidence of an association of diabetes mellitus with MDD
(Goodnick et al. 1995) and other affective syndromes (Cassidy et al.
1999; Lilliker 1980). The relationship appears to be somewhat specific,
as the prevalence of diabetes does not appear to be increased in elderly
patients with schizophrenia or organic disorders (Adamis and Ball 2000);
however, the lifetime history of anxiety disorders may also be increased
in the diabetic population (Wells et al. 1989), and children with school
refusal and anxiety have been shown to have increased blood glucose lev-
els after an oral glucose tolerance test, with relative suppression of insulin
secretion (Iwatani et al. 1997). An increased point prevalence rate of
MDD of 8.5%–10.7% has been found in several controlled studies of pa-
tients with diabetes (Popkin et al. 1988; Robinson et al. 1988; Wells et
al. 1989) compared with a prevalence of 4.8%–8.6% for MDD in the
general population, using structured diagnostic techniques. There may
also be a particular association between manic-depressive illness and di-
abetes; in one study, 10% of individuals with bipolar illness also had dia-
betes, as opposed to only 4% of patients with other psychiatric diagnoses
and only 2% of the general population (Lilliker 1980). Similarly, in hos-
pitalized patients with bipolar disorder, the adjusted rate of diabetes mel-
litus was 9.9%, significantly higher than the expected frequency of 3.5%
for an age-, sex-, and race-matched comparison group (Cassidy et al.
1999). Consistent with this specificity of affective and anxiety disorder
comorbidity in patients with diabetes, the prevalence of eating disorders
does not appear to be increased in diabetic patients in well-controlled
studies, although the co-occurrence of eating disorders and diabetes does
warrant specific interventions to achieve optimal glycemic control (S.J.
Crow et al. 1998).
Comorbidity of diabetes with depression may predict a worse psychi-
atric outcome, with one study estimating an eightfold increase in relapse
rate in depressed diabetic patients compared with depressed healthy
patients (Lustman et al. 1997a). Similarly, a 5-year follow-up study of
diabetic patients previously treated for depression found that 92% of
patients had recurrent or persistent depression (Lustman et al. 1997c).
Furthermore, depressed diabetic patients may have worse outcomes with
regard to their diabetic management. One study found that severity of
depression, incidence of physical complaints, and level of hyperglycemia
were directly related in patients with type 1 diabetes (Sachs et al. 1991).
In contrast, glycemic control did not appear to be influenced by a lifetime

history of major depression in patients with type 2 diabetes (de Groot et
al. 1999). Nevertheless, microvascular and macrovascular complications
of diabetes are reported to be increased in non–insulin-dependent dia-
betic patients with depression (see Leedom et al. 1991; Lustman et al.
1998). Crammer and Gillies (1981) and Kronfol et al. (1981) both report
cases of increased insulin requirements in patients with known diabetes
during the depressive phase of their bipolar illness. The risk of developing
type 2 diabetes also appears to be increased in patients with a history
of depression (Eaton et al. 1996; Kawakami et al. 1999; Okamura et al.
1999). Therefore, aggressive management of depressive episodes and
maintenance antidepressant treatment in diabetic patients may improve
glycemic control and reduce vascular complications (Lustman et al.
1998).
For diabetic individuals with comorbid depression, the impact of an-
tidepressants on glucose regulation needs to be considered. In this regard,
it is important to note that different neurotransmitter systems may in-
fluence glucose levels in different ways. Serotonin may act to decrease
plasma glucose, possibly by mechanisms other than insulin release (Eren-
memisoglu et al. 1999); furthermore, selective serotonin reuptake inhib-
itor (SSRI) antidepressants decrease blood glucose by about 20% without
affecting plasma insulin levels (Erenmemisoglu et al. 1999; G.A. Wilson
and Furman 1982). The hydrazine group present on certain monoamine
oxidase inhibitors (MAOIs) such as phenelzine and isocarboxazid has
long been known to produce more hypoglycemia than the nonhydrazine
MAOIs such as tranylcypromine (Cooper and Ashcroft 1966; Feldman
and Chapman 1975). In contrast, drugs with more prominent catechol-
amine effects, such as the tricyclic antidepressants (TCAs), have consid-
erable stimulatory effects on plasma glucose (Erenmemisoglu et al. 1999;
Kaplan et al. 1960; Lustman et al. 1997b) and inhibitory effects on insu-
lin secretion (Aleyassine and Lee 1972; Erenmemisoglu et al. 1999).
MAOIs, TCAs, and certain SSRIs (Amsterdam et al. 1997) are associated
with the risk of weight gain, which can further interfere with glycemic
control. Therefore, specific SSRIs such as fluoxetine, which have benefi-
cial effects in reducing blood glucose but only infrequently cause weight
gain in long-term use (Michelson et al. 1999), may be advantageous an-
tidepressant agents for the diabetic population. Sertraline, another SSRI,
has been specifically studied in patients with comorbid diabetes and de-
pression and was found to be effective for depressive symptoms as well
as reducing levels of glycosylated hemoglobin A1c, indicating better over-
all glycemic control (Goodnick et al. 1997b). Furthermore, sertraline is
capable of improving neuropathy in diabetic patients without depression
(Goodnick et al. 1997a). Because the effects of other recently introduced

antidepressants on glycemic control have not been widely studied, more
research is necessary to determine their potential impact.
The long-term effects of repeated or prolonged episodes of hyper-
glycemia or hypoglycemia in the diabetic patient, or the increased pro-
pensity to develop atherosclerotic vascular disease, may also produce
permanent neurological damage or a dementia-like picture. There is sub-
stantial support for the impact of abnormal glucose levels on brain func-
tion. Elevated plasma glucose level can result in hyperosmolality with its
associated irreversible neuronal damage (Reske-Nielsen and Lundbaek
1963). Several studies have found support for an association of diabetes
with intellectual impairment in both children (Ack et al. 1961) and adults
(Bale 1973; Wilkinson 1981). Overly tight control over glucose levels in
children with type 1 diabetes through intensive management, compared
with more conventional treatment, may be detrimental to cognition,
with impairments noted in motor speed and in memory tasks relying on
medial temporal lobe function (e.g., spatial declarative memory task)
(Hershey et al. 1999). A study by Bale (1973) found a significant re-
lationship between test performance on a new word learning task and
apparent severity of previous hypoglycemic episodes, but no obvious as-
sociation with cerebrovascular disease; in fact, 17 of 100 diabetic patients
with illness duration of at least 15 years showed test performance in the
brain-damaged range; no matched control subjects performed in the
same range. In contrast, in another report only 8 of 50 patients with type 1
diabetes had cognitive complaints such as poor concentration and mem-
ory; these complaints were of mild severity and had unclear association
to current complaints of depressed mood (Surridge et al. 1984). Prospec-
tive controlled studies are needed to determine the relationship between
control of diabetes and depressive and cognitive symptoms.
Psychiatric Effects of Hypoglycemia or

Insulin Overproduction
Increased insulin secretion, as occurs with pancreatic beta cell tumors
(insulinomas), or conditions that increase glucose utilization (e.g., growth
hormone deficiency) or decrease glucose production (e.g., glycogen stor-
age diseases or glucagon insufficiency) can contribute to neuropsychiatric
symptoms by inducing hypoglycemia. Other frequent causes of hypo-
glycemia are poorly regulated diabetes mellitus or reactive hypogly-
cemia. Idiopathic, reactive forms of hypoglycemia typically produce
neuropsychiatric symptoms after ingestion of food (but not after fasting),
thus representing an exaggeration of normal physiological responses to
carbohydrate ingestion. Reactive hypoglycemia is marked by normal in-

sulin secretion but increased insulin sensitivity and reduced glucagon re-
sponses to acute hypoglycemia (Leonetti et al. 1996). Symptoms of
hypoglycemia that relate to depressed CNS activity in the context of low
absolute levels of glucose range from headache, mental dullness, confu-
sion, amnesia, and visual system abnormalities to hypothermia, seizures,
and coma. Anxiety, restlessness, lightheadedness, weakness, tremor, ta-
chycardia, palpitations, pallor, perioral and finger tingling, perspiration,
irritability, and hunger constitute the adrenergic symptoms of hypo-
glycemia and may reflect the increased epinephrine secretion induced by
an acute drop in glucose levels (Brown 1984; Davidson 1986). There
may be varying amnesia for activities during the hypoglycemic episode
following recovery (Rafuls et al. 1987). An abnormal oral glucose toler-
ance test cannot be used to establish the diagnosis; appropriate diagnosis
of idiopathic postprandial hypoglycemia instead requires the demonstra-
tion of a low plasma glucose concentration and appropriate symptoms
occurring in temporal relationship following a mixed meal, with relief
of symptoms as plasma glucose concentration rises (J.D. Wilson et al.
1998).
In insulinoma, symptoms may be present for years before diagnosis,
with up to 20% of cases misdiagnosed as either a neurological or a psy-
chiatric disorder. Although no consistent psychiatric difficulties are seen,
there are multiple case reports of bipolar-type symptoms, decreased
memory and concentration, psychosis, organic brain syndromes, and de-
mentia in association with insulin overproduction (Body and Cleveland
1967; De Muth and Taft 1964). In one large series of insulinoma cases,
85% of patients experienced weakness, blurry or double vision, sweating,
or palpitations; 80% exhibited confusion or abnormal behavior; 53% had
periods of amnesia or disturbances of consciousness; and 12% had grand
mal seizures (Service 1985).
Although the symptoms of acute hypoglycemia are notably similar to
the symptoms experienced during panic attacks, several studies have
failed to find evidence of a relationship between hypoglycemia and the
occurrence of panic attacks in patients with panic disorder (Gorman et
al. 1984; Uhde et al. 1984).
Abnormal Insulin Responses in Psychiatric Disorders

Insulin is used as a challenge agent in the ITT, during which the resulting
hypoglycemia should induce an increase of growth hormone (to >8 mg/
mL) and an increase in cortisol (to twice the baseline value or >18 mg/
dL). Disturbances in growth hormone secretion following insulin chal-
lenge tests are discussed in the section on growth hormone above. Abnor-
malities in hypoglycemic responses to insulin tolerance testing in various
psychiatric populations are discussed briefly below.

Blunted hypoglycemic responses to insulin have been reported by nu-
merous investigators studying depressed patients, suggesting a relative in-
sulin receptor subsensitivity in this population (Mueller et al. 1968).
Other studies, however, have not confirmed this finding (Amsterdam et
al. 1987). In further contrast to findings of hypoglycemic reactions, sev-
eral groups have found evidence of diminished glucose utilization in de-
pression both at baseline and following an oral glucose tolerance test (van
Praag and Leijnse 1965; Winokur et al. 1988). Patients with seasonal
affective disorder also demonstrate a more rapid rise in blood glucose
and insulin levels during winter depression than when euthymic (Krau-
chi et al. 1999). Intriguingly, hypothalamic-pituitary-adrenal (HPA) axis
responses to insulin challenge appear to be blunted in patients with major
depression but not in patients with schizophrenia (Kathol et al. 1992),
which is consistent with the hypothesis that the glucocorticoid system
abnormalities frequently linked to affective disorder pathophysiology
may serve to drive glucoregulatory abnormalities in this population.
Whether serotonin system dysfunction further contributes to distur-
bances of glucose metabolism in affective populations remains to be de-
termined.
Eating Disorders
Bulimic patients were found to have increased depression, fatigue, anxiety,
and bewilderment as assessed by self-report following glucose challenge in
a double-blind, placebo-controlled trial, whereas control subjects did not
differ in symptoms reported after glucose challenge. These mood changes
were correlated with blood glucose level in the bulimic group but not in
the control subjects, although no differences in insulin response could be
detected between groups (Blouin et al. 1993).
Personality Disorders and Aggressive Behavior

Violent alcoholic criminal offenders were noted to have an increased rate
of abnormal hypoglycemic responses following oral glucose tolerance
testing in several studies (Benton 1988; Benton et al. 1982; Linnoila and
Virkkunen 1992; Roy et al. 1988; Virkkunen et al. 1994). This phe-
nomenon is correlated with depressed concentrations of the serotonin
metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid (Lin-

noila and Virkkunen 1992; Virkkunen et al. 1994); it is thought that a
“low serotonin syndrome” may impair glucose metabolism. Other studies
demonstrated blunted cortisol and prolactin responses following oral glu-
cose loading in substance abusers with antisocial personality disorder and
aggressive behavior, but failed to confirm hypoglycemia (Fishbein et al.
1992). A large study of fasting blood glucose and personality factors in
psychiatric outpatients confirmed an inverse relationship between blood
glucose and extroverted, impulsive, acting-out, and antisocial behavior in
men, but found a positive relationship between glucose levels and histri-
onic personality traits in women (Svanborg et al. 2000). Intriguingly, a
recent study has demonstrated that both patients with type 1 diabetes
and nondiabetic subjects report more feelings of anger, even in an innoc-
uous context, after insulin-induced hypoglycemia, independent of the
degree of hypoglycemia produced (McCrimmon et al. 1999). Thus, the
role of glucoregulatory disturbances in the pathogenesis of antisocial and
other personality disorders deserves further evaluation in controlled pro-
spective studies.
Glucagon and Psychopathology
Severe hyperglucagonemia occurs most commonly in association with

glucagon-producing pancreatic alpha cell tumors (typically located in the
tail of the pancreas and often malignant), although moderate elevations
of glucagon level may occur in conditions such as hepatic cirrhosis and
chronic renal failure. The occurrence of psychiatric symptoms in associ-
ation with glucagonomas is rare and is typically related to the degree of
glucose intolerance and hyperglycemia (as reviewed in the section on di-
abetes above). Glucagon, a product of both pancreas and gut, has a wide
spectrum of metabolic effects, such as glycogenolysis, gluconeogenesis,
ketogenesis, and lipolysis. Pancreatic glucagon plays an important role in
stimulating secretion of water and electrolytes by the small intestine and
inhibiting the release of insulin and somatostatin. In glucagonomas, hy-
perglycemia, gastrointestinal upset, weight loss, fatigue, anemia, and
erythematous dermatitis are commonly observed. Glucagonomas may
infrequently be found in conjunction with parathyroid adenomas and pi-
tuitary tumors (as in multiple endocrine neoplasia [MEN] type I; see
section on MEN below). No specific symptoms (either psychiatric or
medical) have been reported to occur in association with glucagon defi-
ciency.
Parathyroid Hormone and Psychopathology

Psychiatric Effects of Hyperparathyroidism
Parathyroid hormone synthesis and release are stimulated by low levels
and inhibited by elevated levels of serum calcium. Additional factors in-
fluencing parathyroid hormone secretion include elevated serum phos-
phorus (as in renal failure), which increases parathyroid hormone release
by decreasing serum calcium; a- and b-adrenergic hormones; neurotrans-
mitters; histamine; and prostaglandins. The most common cause of pri-
mary hyperparathyroidism is a benign parathyroid adenoma. Parathyroid
adenomas can also occur in association with pancreatic and pituitary tu-
mors (as in MEN type I) or in association with pheochromocytoma and
thyroid carcinoma (MEN type II; see section on MEN below). Other
contributory factors include lithium treatment, which can increase par-
athyroid hormone secretion and thereby increase serum calcium; vitamin
D intoxication; hyperphosphatemia; certain malignancies; acute adrenal
insufficiency; and hyperthyroidism.
Parathyroid hormone abnormalities can be associated with impressive
psychopathology. In one meta-analysis, two of three case-control studies
of patients with primary hyperparathyroidism accompanied by mild
hypercalcemia found a substantially increased rate of psychiatric distur-
bances (Okamoto et al. 1997). Other studies indicate that up to two-
thirds of patients with hyperparathyroidism exhibit some psychiatric
symptoms (Petersen 1968). The most common symptoms include de-
pression with anergia (Lishman 1998; Petersen 1968); roughly 10% of
patients have evidence of psychosis, whereas an additional 10% have or-
ganic mental symptoms (Petersen 1968). Symptoms can range from lack
of initiative, memory impairment, lethargy, depression, and personality
changes to confusion, aggression, delirium, and unconsciousness, espe-
cially in parathyroid crisis, and appear to be most closely linked to the de-
gree of hypercalcemia induced by the elevated parathyroid hormone level,
rather than the parathyroid hormone level itself.
Elevations of serum calcium are also associated with mania or psy-
chotic agitation (Carman and Wyatt 1979). Whereas impairments of
memory and concentration occur infrequently at lower calcium levels, at
levels of 16 mg/100 mL or above features consistent with organic delir-
ium appear along with perceptual aberrations, sometimes progressing to
coma (Rafuls et al. 1987). This is consistent with the critical role that
calcium plays in neurotransmission mechanisms. However, even mild
hypercalcemia may cause significant neuropsychiatric changes in suscep-
tible individuals, whereas other individuals may tolerate very high cal-
cium levels without evidencing any behavioral or physical disturbances.

Up to 50% of patients are asymptomatic at diagnosis (Brickman 1986).
Diffuse electroencephalographic abnormalities may be seen. Associated
physical symptoms include anorexia, nausea, vomiting, headache, anos-
mia, fatigue, and weakness; gastrointestinal symptoms may be the first
signs of the disorder (Rafuls et al. 1987). Bone demineralization, kidney
stones, restless leg syndrome, arthralgias, and hypertension are additional
findings. Among the most common clinical symptoms are thirst or poly-
uria (occurring in about a third of patients) and fatigability or back pain
(each occurring in about a fifth of patients). Another fifth of patients
were asymptomatic (Kobayashi et al. 1997). Thus, in patients who pre-
sent with depression and fatigue along with symptoms such as thirst,
polyuria, or back pain, screening for hyperparathyroid disease might be
warranted.
Psychiatric Effects of Hypoparathyroidism

Hypoparathyroidism occurs most commonly after inadvertent or un-
avoidable dissection of the parathyroid glands during thyroidectomy (up
to 50% of postthyroidectomy patients). Rare causes include the autoim-
mune multiple endocrine deficiencies. In addition to its effects on serum
calcium, parathyroid hormone deficiency leads to increased reabsorption
of inorganic phosphate by the renal tubules; laboratory findings therefore
include hypocalcemia and a corresponding hyperphosphatemia. The rate
of decrease in serum calcium and the degree of hypocalcemia will influ-
ence the symptoms seen. About 70% of hypoparathyroid individuals
present with tetany; other clinical signs and symptoms include presenile
cataracts, perioral tingling and numbness, muscle spasms, seizures, pro-
longed QT interval on electrocardiogram, and macrocytic anemia (Brown
1984). Extrapyramidal syndromes may occur, presumably as a result of
calcification of the basal ganglia. The seizures resulting from hypoparathy-
roidism may be misdiagnosed as pseudoseizures because of the nonspecific
electroencephalographic changes and their relationship to emotional fac-
tors (Rafuls et al. 1987). About half of patients with hypoparathyroidism
exhibit psychiatric symptoms (see Denko and Kaelbling 1962; Lishman
1998).
Besides carpopedal spasm, psychiatric symptoms may be the only
signs of the disorder (Denko and Kaelbling 1962); dementia or delirium
may also occur in the absence of tetany or seizures (Haskett and Rose
1981). The hypocalcemia of hypoparathyroidism induces neuronal irri-
tability and is the primary mediator of the brain dysfunction observed.
Intellectual impairment occurs in about 30% of individuals with this hor-
monal abnormality, and organic brain syndromes, emotional lability, anx-

iety, depression, and irritability occur in another 30%. Depression is
thought to be a consistent psychiatric feature (Rafuls et al. 1987). Psycho-
sis was observed in 9% of patients in a series of 267 cases of hypoparathy-
roidism (Denko and Kaelbling 1962). Obsessions, phobias, derealization,
and hyperventilation have also been reported in patients with hypopar-
athyroidism (Denko and Kaelbling 1962; Fonseca and Calverley 1967).
Restoration of eucalcemia usually reverses the neuropsychiatric symp-
toms; thus, inclusion of serum calcium in the initial evaluation of psychi-
atric patients is warranted.
Multiple Endocrine Neoplasia Syndromes and

Psychopathology
Although these diseases are exceedingly rare, the practicing psychiatrist
should be aware of the potential for unusual combinations of symptoms
due to specific constellations of tumors in patients with one of the auto-
somal-dominant MEN syndromes. MEN type I and type II are marked by
histologic progression from hyperplasia to adenoma (and, in some cases,
to carcinoma) in parathyroid, pancreatic, pituitary, adrenal, and thyroid
tissues. MEN type I is characterized by the combination of parathyroid,
pancreatic islet, and pituitary hyperplasia or neoplasia. The clinical features
of MEN type IIA consist of medullary thyroid carcinoma, pheochro-
mocytomas, and, less commonly, parathyroid hyperplasia or adenomato-
sis. MEN type IIB is characterized by the association of medullary thyroid
carcinoma and pheochromocytoma with multiple mucosal neuromas on
the tongue, lips, subconjunctivae, and gastrointestinal tract. The first
clinical manifestation of MEN type IIB can be colonic obstruction or di-
latation or a colic-like childhood syndrome with associated diarrhea re-
sulting from ganglioneuromatosis of the gastrointestinal tract; occasional
physical stigmata include a marfanoid body habitus; pectus excavatum;
slipped femoral epiphysis; and long, thin extremities. (J.D. Wilson et al.
1998).
Panhypopituitarism and Psychopathology
Panhypopituitarism, also known as Simmonds’ disease, is associated with

a reduction in all pituitary hormones as well as in hormones usually pro-
duced by peripheral glands in response to these pituitary hormones (e.g.,
thyroid hormones, adrenal corticosteroids). In Sheehan’s syndrome, once
the most common cause of hypopituitarism, ischemia secondary to post-

partum hemorrhage results in pituitary necrosis. Currently, hypopituitar-
ism is more frequently due to an enlarged pituitary adenoma or surgical
ablation of the pituitary gland; more unusual causes include craniopharyn-
gioma, head injury with basilar skull fracture, infections (e.g., tuberculosis,
syphilis), sarcoidosis, and autoimmune lymphoid hypophysitis (Carlson
1986). Clinical features may include headache and visual field defects;
endocrine features depend on the extent of hormone deficiency and the
rate at which it develops.
Associated psychiatric symptoms can range from organic brain syn-
dromes to reduced memory, severe apathy, confusion, somnolence, de-
pression, mania, or psychosis (Jeffcoate et al. 1979; Kitis 1976). Sheehan
and Summers’s (1949) original paper on hypopituitarism noted psychi-
atric symptoms such as delusions, hallucinations, and depression. Physi-
cal symptoms, often nonspecific, may have been present for many years
before diagnosis; these include weakness, fatigue, cold sensitivity, de-
creased libido, amenorrhea, and weight loss. Symptoms characteristic of
other end-organ failures such as hypothyroidism, hypoparathyroidism,
and Addison’s disease can also be seen in hypopituitarism. Patients can
occasionally present with varying degrees of delirium or coma, depending
on the rate of onset of the disorder and the degree of pituitary insuf-
ficiency, and can be associated with brain damage. Diagnosis typically
relies on stimulation tests such as insulin-induced hypoglycemia and
growth hormone responses and TRH-induced prolactin secretion. Re-
covery is typically slow following coma or delirium, but replacement of
the end-organ hormones usually results in a good course (Lishman 1998).
Conclusion
Aside from diabetes, the endocrine syndromes described in this chapter

occur fairly infrequently. In diabetes, mood disturbances are particularly
common. However, even in the less commonly occurring endocrinopa-
thies, psychiatric symptoms can often be observed. In a psychiatric set-
ting, concerns regarding possible dysregulation of hormones such as
insulin, glucagon, parathyroid hormone, growth hormone, and prolactin
may increase when the onset or course of symptoms is unusual or inter-
mittent, somatic complaints are severe, physical or laboratory findings
consistent with endocrinopathy are present, or the patient simply does
not improve despite seemingly adequate psychopharmacologic treat-
ment.
When a suspected endocrinopathy is confirmed, definitive treatment

should be directed toward correction of the primary hormonal distur-
bance rather than toward amelioration of the secondary symptoms caused
by the endocrine disorder. However, affective, cognitive, and behavioral
symptoms associated with an endocrinopathy may not always reverse de-
spite successful treatment of the hormonal disturbance, suggesting either
permanent damage from the period of hormonal imbalance or a multifac-
torial pathophysiology underlying the psychiatric symptoms.
The high degree of nonspecific and often inconsistent findings on
neuroendocrine stimulation testing as reviewed here in brief suggest that,
with few exceptions (as noted), these types of tests should generally be
reserved for research into the biological mechanisms underlying psychi-
atric disorders. Multiple neuroendocrine, neurotransmitter, and neuro-
peptide systems are likely to interact in extraordinarily complex ways to
produce the myriad of clinical presentations seen in association with hor-
monally influenced psychiatric syndromes; simple hypotheses of hor-
monal deficiency or overproduction are clearly not adequate to explain
the broad spectrum of clinical presentations possible with disturbances of
the hormones reviewed here.
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Part III
Adrenocortical
Hormones
Chapter 6
The Hypothalamic-Pituitary-Adrenal
Axis and Psychiatric Illness
I n 1913, Harvey Cushing described the syndrome that bears his

name (Cushing 1913), showing the relationship between hyperadrenalism
and the presence of sleeplessness, inability to concentrate, visual distur-
bances, and “fits of unnatural irritability [alternating] with periods of de-
pression” (Cushing 1932, p. 138). (For more on Cushing’s disease see
Chapter 7 in this volume.) In 1955, it was observed that the administration
of adrenocorticotropic hormone and cortisone was often associated with
behavioral changes and in some cases psychosis. It is now generally accepted
in medicine that too much (or too little) cortisol can be deleterious and that
the brain is both a source and a target of adrenal and other steroid hormone
activity (McEwen et al. 1979). And yet today, the role cortisol plays in the
pathophysiology of psychiatric disorders remains unclear and is the subject
of much debate. The purposes of this chapter are to summarize the evi-
dence for corticosteroid dysregulation in psychiatric illness, to address the
question of whether elevated cortisol levels may be harmful to patients re-
gardless of diagnosis, and to discuss interventions that focus on decreasing
cortisol levels or blocking cortisol receptors as a treatment strategy.
Measurement
Dexamethasone Suppression Test
The cortisol response after a challenge with an exogenous glucocorticoid,
dexamethasone, distinguishes many psychiatrically ill (particularly de-
139
pressed) patients from psychiatrically healthy control subjects. These pa-

tients either are unable to suppress their cortisol levels or escape from
suppression abnormally early. The most widely used procedure to assess
this condition is the dexamethasone suppression test (DST), administered
according to the protocol proposed by Carroll (1982; Carroll et al.
1981b): 1.0 mg of dexamethasone is taken at 11:00 P.M. On the day after
administration of dexamethasone, blood samples for determination of
plasma cortisol concentration are most commonly drawn at 8:00 A.M.,
4:00 P.M., and 11:00 P.M. (see Chapter 17 in this volume for more details).
Sampling Times
For convenience, often only an afternoon sample is obtained from outpa-
tients, but this does result in a loss of test sensitivity (APA Task Force on
Laboratory Tests in Psychiatry 1987; Rush et al. 1996). The combination
of 4:00 and 11:00 P.M. samples provides greater sensitivity than the combi-
nation of 8:00 A.M. and 4:00 P.M. samples (Rush et al. 1996). The greatest
sensitivity is obtained if all three samples are collected (Rush et al. 1996).
Definition of Nonsuppression
The criterion level to define normal plasma concentration of cortisol
under the test conditions described earlier was defined in Carroll’s 1981
paper (Carroll et al. 1981b) as 5.0 mg/dL, using a modified Murphy com-
petitive protein binding technique (Murphy 1968) (see Chapter 17 in
this volume). Rubin and colleagues (1987) suggested a cutoff of 3.5 mg/
dL when using the more specific radioimmunoassay techniques. Others
have suggested a cutoff of 4.0 mg/dL, citing data showing that the speci-
ficity of the DST is 96% at this threshold (Rush et al. 1996). The APA
Task Force on Laboratory Tests in Psychiatry (1987) argued that using a
cutoff of 7 mg/dL would enhance the utility of the DST in the clinical set-
ting. In 1982, our group (Rothschild et al. 1982) suggested a threshold of
15 mg/dL might be more specific and predictive for psychotic depression
(see below), an observation that has been noted in several other studies
(Meyers et al. 1993; J.C. Nelson and Davis 1997). It also remains unclear
whether the cortisol abnormality (as determined by the DST) is perhaps
better viewed as a spectrum of cortisol levels rather than a binary, all-or-
none, nonsuppression versus suppression classification.
Plasma Dexamethasone Concentrations

The bioavailability of dexamethasone may be a factor influencing DST
results. Postdexamethasone cortisol levels show a significant inverse rela-
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 141
tionship with plasma dexamethasone concentrations (Arana et al. 1984,

1988; Baumgartner et al. 1986; Carson and Halbreich 1987; Poland et al.
1987; Ritchie et al. 1990; Walsh et al. 1987), and patients with major de-
pression whose DST results show them to be cortisol suppressors have
higher plasma dexamethasone concentrations than cortisol nonsuppres-
sors (Carson et al. 1988; Holsboer et al. 1986a). Dexamethasone levels
may also rise with treatment (Baumgartner et al. 1986; Devanand et al.
1991; Holsboer et al. 1986a; Maguire et al. 1990).
These observations raise the intriguing question of whether psychiatric
illness and clinical recovery are associated with changes in dexamethasone
metabolism. Holsboer et al. (1986a) suggested a possible induction of
hepatic enzymes in response to stress and hypercortisolemia. Other ex-
planations have focused on central nervous system control of hepatic
metabolism. Several regions of the brain, including the anterior periven-
tricular hypothalamic areas and the suprachiasmatic nucleus, are involved
in hepatic steroid metabolism in male rats (Gustafsson et al. 1980). It has
also been hypothesized (Holsboer et al. 1986b) that exaggerated activity
of the pituitary-adrenocortical unit may affect the enzymes that metabo-
lize dexamethasone. The importance of dexamethasone plasma levels has
prompted some (Johnson et al. 1984; Ritchie et al. 1990) to define dexa-
methasone plasma “windows” for each postdexamethasone collection
point. Only those cortisol values with concurrent dexamethasone plasma
levels falling within the defined window are considered valid.
Clinical Use of the Dexamethasone

Suppression Test
Despite the dysregulation of the hypothalamic-pituitary-adrenal (HPA)

axis that can be measured by the DST and its importance in research stud-
ies, the test has generally not been useful in the clinical setting. However,
the DST can be useful in the differential diagnosis of psychotic depression
(in which the rate of nonsuppression is high) from schizophrenia (in which
the rate of nonsuppression is considerably lower) (APA Task Force on Lab-
oratory Tests in Psychiatry 1987). The differential diagnosis of psychotic
depression from schizophrenia can be particularly difficult in a young,
first-episode patient who is too psychotic to give an adequate history.
Salivary Cortisol
The measurement of salivary cortisol has been shown to provide an ac-
curate and valid measure of biologically active free cortisol (Kirschbaum
and Hellhammer 1994). The ease of sampling is one of the most obvious
advantages of the saliva cortisol test. Although whole saliva sampled in
wide disposable containers provides adequate material for analysis, some
investigators have used swabs that the subjects chew on to stimulate sa-
liva flow to a rate that provides sufficient material within 30–60 seconds
(Kirschbaum and Hellhammer 1994). Salivary cortisol measurements are
closely correlated with cortisol levels in serum and plasma before and af-
ter administration of exogenous cortisol or dexamethasone (Kirschbaum
and Hellhammer 1994).
Salivary cortisol levels normally range from 1 to 25 nmol/L. Different
cutoff values on the DST for salivary cortisol levels have been used, often
leading to conflicting results. Mean salivary cortisol levels at a specific
time of day (due to diurnal variation) are usually used when reporting re-
sults.
Urinary Free Cortisol

Urinary free cortisol (UFC) excretion in a 24-hour urine sample very
closely reflects the circulating unbound plasma cortisol production and is
a useful indication of adrenal cortical activation (Carroll et al. 1976a). Pa-
tients are instructed to collect their urine in containers that are kept on
ice during the collection period. After collection, the urine is divided into
aliquots and is stored at -70°C for measurement of creatinine and UFC.
Results are expressed either as micrograms of UFC per 24 hours or micro-
grams of UFC per milligram of creatinine. The UFC excretion of normal
subjects is approximately 40–50 mg/24 hours; in nonpsychotic depressed
patients it rarely exceeds 90 mg/24 hours (Anton 1987) to 100 mg/24
hours (Carroll et al. 1976a).
Other Measures of HPA Axis Activity

Several other methods to measure HPA axis activity have been used in
research, although all involve greater complexity, making them of less
practical use in the clinical setting. Posener and colleagues (2000), using
24-hour monitoring of plasma cortisol in a clinical research center set-
ting, observed distinct profiles of HPA axis dysregulation in psychotic
and nonpsychotic depressed patients compared with control subjects.
Halbreich et al. (1985) demonstrated that the measurement of plasma
cortisol every half hour between 1:00 P.M. and 4:00 P.M. correlates strongly
with measurement of plasma cortisol every half hour over 24 hours,
making the measurement of plasma cortisol somewhat more practical.
Finally, Deuschle and colleagues (1998) observed that the combined
dexamethasone–corticotropin-releasing hormone challenge test is more

closely associated with activity of the HPA system than the standard DST
in nondepressed and depressed subjects. Although each of these tests has
important applications in research studies, their complexity makes them
difficult to use in the clinical setting. The role of the DST and other tests
in the endocrine evaluation of psychiatric patients is further reviewed in
Chapter 17 of this book.
Commentary on Cortisol Measurements

Measurement of salivary cortisol has been increasingly used in recent
years because of its convenience. As discussed above, measurement of
salivary cortisol correlates strongly with cortisol levels in plasma and se-
rum. UFC measurements provide the best-integrated sample, but the
sample collection method for UFC is the most difficult for the patient to
comply with. Some investigators (Rubinow et al. 1984) have observed
that neither the DST nor UFC uniformly identified all patients with HPA
axis hyperactivity. These studies suggest that postdexamethasone cortisol
concentration only partly reflects the endogenous production rate of cor-
tisol over 24 hours. Therefore, the best method for assessment of the
HPA axis (particularly for research studies) may be to use more than one
modality simultaneously.
Age
Several studies have reported increased rates of nonsuppression on the
DST with age (Baumgartner et al. 1986; Davis et al. 1984; Halbreich et
al. 1984; D.A. Lewis et al. 1984; W.H. Nelson et al. 1984; Stokes et al.
1984; Weiner 1989; Whiteford et al. 1987), whereas others have not ob-
served a relationship (Aguilar et al. 1984; Carroll et al. 1981b; Ferrier et
al. 1988; Greden et al. 1986; Schweitzer et al. 1991; Tourigny-Rivard et
al. 1981). Rush and colleagues (1996) suggested that the apparent in-
crease in DST nonsuppression in depressed patients older than age 69 (or
younger than age 20) may be due to a higher proportion of endogenous
patients in this age range. However, in healthy older subjects an associa-
tion between advancing age and higher cortisol levels on the DST has
been observed (O’Brien et al. 1994).
Age may play a key role in the effects of cortisol hypersecretion on
cognitive functioning. Rubinow and colleagues (1984) observed a signif-
icant relationship between performance on the Halstead Category Test
and mean UFC excretion in depressed patients but not in control sub-
jects. Although an even more robust correlation was observed between
age and test errors in the depressed patients, it appeared that age and
depression interacted to produce severe cognitive impairment. Other
studies (e.g., Lupien et al. 1997) have reported significant relationships
between stress-induced declarative memory impairment and cortisol in
healthy elderly subjects.
Mood Disorders
There is substantial evidence for cortisol hypersecretion in patients with

mood disorders (Carroll et al. 1976b, 1976c; Ettigi and Brown 1977; Ru-
bin 1989; Sachar et al. 1970). There is less agreement about whether the
DST separates endogenous from nonendogenous patients. Several stud-
ies have observed higher rates of nonsuppression on the DST in endoge-
nously depressed patients compared with nonendogenously depressed
patients (Brown and Shuey 1980; Calloway et al. 1984; Carroll et al.
1976b, 1976c, 1980, 1981b; Davidson et al. 1984; Kumar et al. 1986;
Rush et al. 1996). However, many of these studies included patients with
psychotic depression, who are known to have high levels of cortisol (see
below). In a meta-analysis (J.C. Nelson and Davis 1997) evaluating the
four studies that explicitly excluded psychotic patients (all inpatient
studies), rates of nonsuppression did not differ significantly in the 103
patients with endogenous depression (39%) and the 140 with nonendog-
enous depression (36%).
Psychotic Depression
It is in patients with psychotic depression (PD) that one of the most rep-
licable findings in the HPA axis literature exists: high rate of DST non-
suppression, markedly elevated postdexamethasone cortisol levels, and
high levels of 24-hour UFC. In 1983, our group (Schatzberg et al. 1983)
reported that patients with major depression and very high plasma corti-
sol levels (15 mg/dL or more at 4:00 P.M.) had a propensity for exhibiting
mood-congruent psychotic features at the time of study. For example, of
the 9 patients with major depression who had plasma cortisol levels of 15
mg/dL or more, 7 showed psychotic features, and all 6 with plasma cor-
tisol levels of 17 mg/dL or more at 4:00 P.M. were psychotic. In contrast,
of the remaining 36 patients with major depression whose plasma corti-
sol levels were less than 15 mg/dL, only 7 showed psychotic features
(c2 =11.4; df=1; P<0.001). (Schatzberg et al. 1983). In this study the fre-
quency of nonsuppression (10 of 14, or 71.4%) was higher in the PD
patients than in the nonpsychotic patients with major depression (18 of

31, or 58.1%) (Schatzberg et al. 1983).
We then compared these PD patients with a group of schizophrenic
patients to ascertain whether the high postdexamethasone cortisol levels
in the patients with PD reflected a nonspecific effect due to psychosis
(Rothschild et al. 1982). Eight of the 14 psychotic patients with major
depressive illness had a 4:00 P.M. postdexamethasone cortisol level above
14 mg/dL. In contrast, none of the psychotic schizophrenic patients had
a 4:00 P.M. postdexamethasone cortisol level above 14 mg/dL (Rothschild
et al. 1982). The mean postdexamethasone cortisol level for the unipolar
psychotic depressed patients (13.0±8.1 mg/dL) was significantly higher
than that for the psychotic schizophrenic patients (2.4±2.8 mg/dL; P<0.05)
(Rothschild et al. 1982). We concluded that the high cortisol levels seen
in our patients with unipolar psychotic depression was not due to the
psychosis per se, but rather to the presence of psychosis in the context of
an affective disorder.
Since these early reports, the vast majority of studies point to signifi-
cantly greater HPA axis activity in PD than in nonpsychotic depression,
although not all studies agree (Schatzberg and Rothschild 1992). The lit-
erature does not support the notion that the greater HPA activity seen in
patients with PD is merely the result of greater severity of depression or
the presence of endogenous features (Schatzberg and Rothschild 1992).
A meta-analysis of 14 studies that compared DST results in psychotic
and nonpsychotic depression (Nelson and Davis 1997) found the non-
suppression rate to be substantially higher in patients with PD (64%) than
in nonpsychotic patients (41%) (c2 =47.43; df=1; P<0.001). The differ-
ences between psychotic and nonpsychotic depressed patients in rates of
nonsuppression on the DST could not be explained by severity (Nelson
and Davis 1997). Our group (Schatzberg and Rothschild 1988; Schatz-
berg et al. 1985) hypothesized that hypercortisolemia may enhance do-
pamine activity in some depressed patients, leading to the development
of psychosis.
Bipolar Disorder, Manic Phase

The reported frequencies of nonsuppression on the DST in mania have
ranged from 0% to 70% (Cassidy et al. 1998). Comparisons of these
studies are complicated by many methodological differences, including
dose of dexamethasone and time of blood sampling. In addition, few stud-
ies have reported the percentage of patients in mixed and pure manic
states, which may also explain differences in reported rates of nonsup-
pression.
Evans and Nemeroff (1983) studied 7 patients who met DSM-III

(American Psychiatric Association 1980) criteria for mixed bipolar disor-
der and 3 patients who met criteria for manic bipolar disorder. All 7 of
the patients with mixed bipolar disorder were nonsuppressors, whereas
the 3 patients with manic bipolar disorder were suppressors. Krishnan
and colleagues (1983) described 10 bipolar patients with depressive fea-
tures who were all nonsuppressors. Godwin (1984) reported a nonsup-
pression rate of 60% for 35 subjects who met DSM-III criteria for manic
bipolar disorder and 5 subjects who met DSM-III criteria for mixed bi-
polar disorder. Swann and colleagues (1992) reported that 3 of 9 medi-
cation-free patients with mania and 5 of 7 medication-free patients with
mixed mania were nonsuppressors at 8:30 A.M. after a 1-mg dose of dexa-
methasone. Cassidy and colleagues (1998) reported that dexamethasone
plasma levels were lower and cortisol levels higher in patients who were
diagnosed with mixed bipolar disorder compared with patients with manic
bipolar disorder. When subjects were retested after remission, dexa-
methasone levels were higher and cortisol levels lower than during the
manic and mixed states.
Dysthymic Disorder
Several studies have investigated the rate of nonsuppression on the DST
in dysthymic disorder. Generally, the rate of DST nonsuppression is less
than in major depression and is similar to what is observed in control sub-
jects without dysthymic disorder. For example, in a meta-analysis of 10
studies that used DSM-III criteria comparing DST results in dysthymic
disorder, major depression, and other psychiatric disorders in adults
(Howland and Thase 1991), the rate of nonsuppression on the DST in
subjects with dysthymic disorder (14%) was found to be lower than in
subjects with major depression (59%) and not significantly different from
the rate in psychiatrically healthy control subjects (6%). In a more recent
study (Ravindran et al. 1994), primary dysthymic patients had a rate of
nonsuppression on the DST of 7%. In contrast, another study (Rihmer
and Szadoczky 1993) reported a 50% rate of abnormal response on the
DST in patients with dysthymic disorder, similar to that reported in pa-
tients with major depression. Our group reported a rate of DST non-
suppression in patients with either dysthymic disorder or borderline
personality of 16% compared with a rate of DST nonsuppression of 61%
in the major depression group (Schatzberg et al. 1983). We also found
that the mean (±SD) 4:00 P.M. postdexamethasone cortisol level for pa-
tients with major depression (8.8±6.7 mg/dL) was significantly higher
than that seen in the dysthymic disorder–borderline personality group
(2.9±1.0 mg/dL; P<0.05). We did not observe any significant differences

between the dysthymic disorder–borderline personality group and the
control group on mean (±SD) 4:00 P.M. postdexamethasone cortisol lev-
els (Schatzberg et al. 1983).
However, at least one group (Rihmer et al. 1983) reported both a
high incidence of DST nonsuppression in dysthymic patients and a cor-
relation between nonsuppression on the DST and treatment response
(Rihmer et al. 1983). In a study by Ravindran and colleagues (1994), pa-
tients with dysthymic disorder who were responders to fluoxetine treat-
ment showed significantly higher postdexamethasone cortisol levels than
did nonresponders. Although nonsuppression on the DST may not be
useful for predicting antidepressant response in dysthymic disorder, it
may be that the actual plasma cortisol levels following dexamethasone
administration are useful in identifying subgroups of patients with dys-
thymic disorder who may be good responders to antidepressant treat-
ment (Ravindran et al. 1994).
Posttraumatic Stress Disorder
Numerous studies have demonstrated that male combat veterans with

posttraumatic stress disorder (PTSD) have differences in HPA axis func-
tioning compared with healthy control subjects. Combat veterans with
PTSD have been shown to have lower 24-hour urinary cortisol excretion
(Mason et al. 1986; Yehuda et al. 1990) and lower plasma cortisol levels
in the morning (Boscarino 1996) and at several points throughout the cir-
cadian cycle (Yehuda et al. 1994). Combat veterans also exhibit greater
suppression of plasma cortisol in response to low doses of dexamethasone
(Yehuda et al. 1993b, 1995a). Similarly, male and female Holocaust sur-
vivors with PTSD have been shown to have lower 24-hour urinary cortisol
levels (Yehuda et al. 1995c). These observations have led Yehuda and col-
leagues (1993a, 1995b) to propose that enhanced negative-feedback reg-
ulation of cortisol is an important feature of the pathophysiology of PTSD.
Yehuda (1993b, 1995a) has hypothesized an increased density of gluco-
corticoid receptors in patients with PTSD. Evidence in support of this hy-
pothesis is the observation that combat veterans with PTSD (Yehuda et al.
1991, 1995a) and adult women with a history of childhood sexual abuse
(Stein et al. 1997) have a greater density of glucocorticoid binding sites on
lymphocyte membranes than psychologically healthy control subjects.
These studies suggest that abnormalities in HPA axis activity in pa-
tients with PTSD are the opposite of those observed in patients with
major depression, raising interesting questions for future research. For ex-
ample, would there be an HPA axis abnormality (and of what type?) in
patients who concurrently have major depression and PTSD or major de-
pression with psychotic features and PTSD? In the clinical setting, there
are often patients in whom the specific diagnosis is unclear. For example,
some patients have major depression with psychotic features and also
have a history of abuse or trauma. Should they be considered PTSD patients
who exhibit psychotic symptoms, or should they be treated as patients
with major depression with psychotic features who happen to have a his-
tory of trauma? The low-dose DST (i.e., 0.5 mg instead of 1.0 mg) may
be a potentially useful clinical and research tool for distinguishing what
is primarily a PTSD disorder from major depression with psychotic fea-
tures.
Schizophrenia
Studies of the DST in schizophrenia have yielded rates of nonsuppression

ranging from 0% to 73% (Yeragani 1990). Higher rates of DST nonsup-
pression in schizophrenia have been associated with depressive symptoma-
tology (Munro et al. 1984; Sawyer and Jeffries 1984), negative symptoms
(Coppen et al. 1983; Shima et al. 1986; Tandon et al. 1989, 1991), and
the nonparanoid subtype (Banki et al. 1984).
Reviews of the DST literature in patients with schizophrenia suggest
that variances in DST results may be due to the phase of the illness and
the medication status of the patient when the test is performed (Tandon
et al. 1991). Several groups (Herz et al. 1985; Holsboer-Trachsler et al.
1987; Moller et al. 1986; Tandon et al. 1989, 1991; Wik et al. 1986) have
observed reductions in the rates of DST nonsuppression in patients with
schizophrenia after 3–4 weeks of neuroleptic treatment. Furthermore,
rates of DST nonsuppression are higher in drug-free schizophrenic pa-
tients than in medicated schizophrenic patients (Tandon et al. 1991). Al-
though antipsychotic medications are believed to have no effect on the
DST (Carroll et al. 1981b), other groups (Devanand et al. 1984; Kraus
et al. 1988) have suggested that withdrawal of neuroleptics and anticho-
linergics may produce DST nonsuppression lasting up to 21 days.
The pathophysiology of the hypercortisolemia in schizophrenia is un-
clear. Some investigators have suggested that concurrent depression is the
major determinant of DST nonsuppression in schizophrenia (Addington
and Addington 1990). Depression is common in schizophrenia, affecting
approximately one-third of patients (Roy 1981), and suicide accounts for
10% of deaths in this population (Miles 1977). Jones and colleagues

(1994) found that nonsuppression on the DST may be related to suicidal
behavior in a sample of 57 patients with schizophrenia; specifically, non-
suppression on the DST differentiated between those who had attempted
suicide and those who had not. However, other studies have not been
able to replicate this observation (C.F. Lewis et al. 1996). Some studies
have reported higher rates of nonsupression on the DST in depressed
schizophrenic patients (Addington and Addington 1990; Munro et al.
1984; Sawyer and Jeffries 1984). However, other investigators have found
no differences in the rate of nonsuppression between depressed and non-
depressed schizophrenic patients when the depression is measured using
the Hamilton Rating Scale for Depression (Ham-D) (Mina et al. 1990;
Whiteford et al. 1988; Yeragani 1990).
The possibility that nonsuppression is associated with negative symp-
toms of schizophrenia has also been studied. Coppen and colleagues
(1983) reported that DST nonsuppression was associated with negative
symptoms. In another study (Saffer et al. 1985), the same researchers
found that a higher proportion of patients with Crow’s type II schizo-
phrenia (patients with affective flattening, poverty of speech, loss of
drive, and often evidence of cognitive impairment) had abnormal DST
results. However, neither study measured depression. Altamura and col-
leagues (1989) also reported higher rates of nonsuppression on the DST in
patients with schizophrenia with higher scores on the Scale for Assessment
of Negative Symptoms (SANS), but again depression was not measured.
McGauley and colleagues (1989) observed that mean postdexametha-
sone cortisol level correlated with the SANS score, whereas depression as
measured by the Ham-D did not. In a study of 21 medication-free pa-
tients with schizophrenia, Newcomer and colleagues (1991) observed
significant correlations between postdexamethasone cortisol levels and
both negative symptoms (as measured by the Brief Psychiatric Rating
Scale [BPRS] subscale) and cognitive deficits. However, several studies
did not demonstrate a relationship between SANS score and nonsuppres-
sion on the DST (Addington and Addington 1990; Mina et al. 1990; White-
ford et al. 1988).
Interpretation of DST studies in schizophrenia is complicated by the
fact that negative symptoms and depression may not be mutually ex-
clusive (Andreasen 1982). In one study (Ismail et al. 1998) involving 64
patients with schizophrenia diagnosed according to DSM-IV criteria
(American Psychiatric Association 1994), postdexamethasone cortisol
levels correlated significantly with Ham-D and BPRS scores but not with
SANS scores. Overall, the rate of nonsuppression in the patients with
schizophrenia was very low (less than 2%). In an interesting study by
Goldman and colleagues (1993) comparing DST results of polydipsic and

nonpolydipsic patients with chronic schizophrenia who were stabilized
on psychotropic regimens, it was found that those with polydipsia had a
higher rate of DST nonsuppression (38%) than those without polydipsia
(5%). The authors hypothesize that hippocampal dysfunction could
cause both the polydipsia and cortisol dysregulation in these patients.
Hypercortisolemia and Specific Symptoms
Most studies using the DST have focused on the frequency of nonsup-
pression within a specific diagnostic category. Certainly within a specific
diagnosis some patients exhibit hypercortisolemia and some do not, lead-
ing to confusion as to the relevance of the elevated cortisol levels to the
pathophysiology of the illness. And yet, why do some patients have this
measurable abnormality? Using an interesting approach to this question,
Reus (1982) examined whether suppression and nonsuppression on the
DST was associated with specific behavioral symptom clusters indepen-
dent of diagnosis. Nonsuppressors on the DST exhibited an increase in
classic endogenous signs of depression—including increased symptoms of
anxiety, sleep disturbance, attentional difficulty, and anergy—compared
with suppressors on the DST (Reus 1982). In patients with schizophre-
nia (as discussed above), higher cortisol levels were associated with a
greater frequency of negative and depressive symptoms in most studies.
Hypercortisolemia and Its Relationship to Outcome
Because it has been known for many years that endogenous hypercorti-
solemia or the administration of exogenous glucocorticoids can be dele-
terious for animals and human beings, one would expect that chronic
hypercortisolemia may play a role in the pathophysiology and outcome
of psychiatric illness. Prolonged elevation of cortisol levels in depressed
patients, as evidenced by failure to convert to normal suppression on the
DST (even after an apparently adequate initial clinical response to treat-
ment), has been reported in many studies to be a warning sign of in-
creased risk for relapse (Ribeiro et al. 1993). In a meta-analysis of studies
of the long-term outcome of depressed patients who were nonsuppres-
sors of cortisol on the DST at posttreatment evaluation, a significantly
poorer outcome was observed in the nonsuppressors compared with the
suppressors (c2 =32.54; df=1; P<0.0001) (Ribeiro et al. 1993). We have
observed significant correlations between measures of cortisol activity

(DST, UFC) at 1 year and measures of social and occupational function-
ing at 1 year (Rothschild et al. 1993). Patients with UFC values greater
than 100 mg/24 hours at 1 year had significantly poorer functioning, as
measured by total score on the self-report version of the Social Adjust-
ment Scale (Weissman et al. 1978), than did patients with UFC values
less than 100 mg/24 hours at 1 year. A similar relationship was observed
between DST nonsuppressor status at 1 year and poorer social and occu-
pational functioning at 1 year (Rothschild et al. 1993). We have hypoth-
esized that the association between higher levels of cortisol at 1 year and
poorer social and occupational functioning is secondary to subtle cogni-
tive deficits caused by the higher cortisol levels seen in depressed patients
(Rothschild et al. 1993). Our hypothesis is based on observations that in-
creased HPA axis activity in depressed patients is associated with larger
ventricle-to-brain ratios (Kellner et al. 1983; Rao et al. 1989; Rothschild
et al. 1989) and cognitive disturbances (Brown and Qualls 1981; Deme-
ter et al. 1986; Reus 1982; Rothschild et al. 1989; Rubinow et al. 1984;
Sikes et al. 1989; Winokur et al. 1987; Wolkowitz et al. 1990, 1997).
Sheline and colleagues (1996) reported that patients with a history of
major depression had significantly smaller left and right hippocampal
volumes than did nondepressed control subjects, although no differences
in cerebral volumes were observed. The degree of hippocampal volume
reduction correlated with the total duration of major depression. Taken
together, these studies suggest possible associations among cognitive dis-
turbances, cortisol hypersecretion, enlarged ventricles, and hippocampal
atrophy.
Similar observations of relationships between cortisol and outcome
have been reported in patients with schizophrenia. Tandon and colleagues
(1991) reported that persistent DST nonsuppression in patients with
schizophrenia was associated with greater negative symptom severity at
4 weeks and poorer outcome at 1 year. Conversely, conversion of DST
nonsuppression at baseline to normal suppression after 4 weeks of neu-
roleptic treatment was associated with significantly greater improvement
in both negative symptoms and global severity at 4 weeks. This observa-
tion is consistent with previous reports by the same group (Tandon et al.
1989) and others (Holsboer-Trachsler et al. 1987). Analogous to obser-
vations by our group in patients with depression (Rothschild et al. 1989),
persistent DST nonsuppression in patients with schizophrenia was asso-
ciated with greater ventricle-to-brain ratios and poorer 1-year outcome
(Tandon et al. 1991).
These observations of an association between chronic hypercortisol-
emia and poorer outcome in patients with psychiatric disorders is of con-
cern in light of animal studies that have demonstrated the neurotoxic

effects of corticosteroids. Throughout the animal literature, there is a
consistent finding across the mammalian species that the hippocampus is
the principal target for neurosteroidal activity (McEwen 1991; Sapolsky
1992; Uno et al. 1994). Lesions in this area produce severe memory and
attention deficits with serious affective and behavioral disturbances (Co-
hen and Eichenbaum 1993; Milner 1972; Papez 1937). Chronically ele-
vated glucocorticoid levels have been shown to be associated with loss of
neurons in the hippocampi of mammals such as rats and monkeys (Sapol-
sky 1992; Sapolsky et al. 1985, 1990). Hippocampal volume has also
been found to be reduced in Cushing’s syndrome (Sapolsky 1992; Stark-
man 1992) (see Chapter 7 in this volume).
Further studies are needed to explore, in a systematic way, the rela-
tionships among increased HPA activity, cognition, brain scan abnormal-
ities, and social and occupational functioning in patients with depression,
schizophrenia, and other psychiatric disorders. It may be that elevated
cortisol levels, which were once thought to be simply a biological marker
or an epiphenomenon, may be playing a key role in the pathophysiology
and long-term outcome of several serious psychiatric disorders.
Antiglucocorticoid Strategies
Several years ago our group hypothesized that the development of de-
lusions in depressed patients is secondary to the effects of hyper-
cortisolemia (Schatzberg et al. 1985) and that acute improvement in
psychotic symptoms in major depression with psychotic features may oc-
cur after cortisol levels are lowered or the effects are blocked with corti-
sol receptor antagonists in the brain (Schatzberg and Rothschild 1988).
The hypothesis that endogenous hypercortisolemia may play a role in
the pathophysiology of psychiatric illness can be tested by the adminis-
tration of antiglucocorticoid medication. Several studies (Amsterdam et
al. 1994; Anand et al. 1995; Arana et al. 1995; Chouinard et al. 1996;
Ghadirian et al. 1995; Iizuka et al. 1996; Murphy 1991; Murphy and
Wolkowitz 1993; O’Dwyer et al. 1995; Raven et al. 1996; Sovner and
Fogelman 1996; Thakore and Dinan 1995; Wolkowitz et al. 1992, 1996a,
1996b) have reported antidepressant effects in some patients when anti-
glucocorticoid medication was administered. Antiglucocorticoid medi-
cations used in these studies include the cortisol synthesis inhibitors
aminoglutethimide, metyrapone, and ketoconazole. The use of antigluco-
corticoid strategies in the treatment of depression have been superbly
reviewed by Murphy and Wolkowitz (1993) and Wolkowitz and Reus

(1999). Wolkowitz and colleagues (1999) reported on a sample of de-
pressed patients treated with ketoconazole in a double-blind, placebo-
controlled paradigm. Ketoconazole was found to be superior to placebo
in alleviating depressive symptoms in patients with hypercortisolemia
but not in eucortisolemic patients. Another interesting strategy is the
progesterone receptor antagonist mifepristone (RU 486), which at high
concentrations is an effective antagonist of glucocorticoid action in vivo
and in vitro (Lamberts et al. 1984; Proux-Ferland et al. 1982). Mifepris-
tone has been observed to be useful in rapidly reversing psychotic depres-
sion secondary to Cushing’s syndrome (Nieman et al. 1985; Van Der
Lely et al. 1991) and in patients with psychotic major depression (Bel-
anoff et al. 2001; Rothschild and Belanoff 2000). Studies of mifepristone
for the treatment of psychotic major depression using a double-blind,
placebo-controlled paradigm are currently in progress at our center and
several others across the country.
In addition to studies of antiglucocorticoid medications in depression,
other investigators have examined the use of these medications in other
psychiatric illnesses. Ravaris and colleagues (1994) reported the success-
ful treatment of a patient with previously refractory bipolar II depression
by adding ketoconazole to the existing regimen of lithium and phenel-
zine. Improvement was correlated with decreases in UFC levels, and dis-
continuation of the ketoconazole resulted in relapse, which was preceded
by increasing UFC levels. Chouinard and colleagues (1996) described a
case of severe refractory obsessive-compulsive disorder that was success-
fully treated by adding aminoglutethimide to the previously ineffective
fluoxetine. Finally, Wolkowitz and colleagues (1996b) studied ketocona-
zole augmentation of neuroleptics in patients with schizophrenia and
schizoaffective disorder in a double-blind paradigm. Although ketocona-
zole had no effect on psychotic symptoms, it was associated with a highly
significant antidepressant effect consistent with the hypothesis (Reus 1982)
that corticosteroid activity may moderate depressive symptoms across
psychiatric diagnoses.
Conclusion
The DST, as one of the first laboratory tests introduced in psychiatry,

represents an important milestone in the history of psychiatry. The rate
of nonsuppression of cortisol following dexamethasone administration is
dependent on diagnosis and also on certain symptoms (anxiety, sleep dis-
turbance, attentional difficulty, anergy) that cut across diagnostic groups,

as well as many technical and physiological factors. Although the use of
the DST in the clinical setting is not common, the test may have utility
in certain situations such as the differentiation of major depression with
psychotic features (high nonsuppression rate) from schizophrenia (low
nonsuppression rate)—a diagnosis that can be clinically difficult, partic-
ularly in a young person with a first episode of psychosis. The DST may
also be of use in predicting likelihood of relapse.
Attempts to correlate abnormalities observed on administration of
the DST with specific psychiatric disorders (with the exception of psy-
chotic depression) has met with limited success. However, it is important
to remember that diagnostic classification systems undergo frequent up-
date and revision. If results on measurements of HPA axis activity do not
precisely match up with the current diagnostic criteria, it does not nec-
essarily mean that the biological test does not have validity. There must
be some reason why many patients with psychiatric disorders have hy-
percortisolemia, and it may be important for the treatment and outcome
of these patients that the hypercortisolemia be monitored and treated. At
present, we are left with the observation that many psychiatric patients
have these abnormalities on measurements of HPA axis activity and with
the knowledge that cortisol is just one of the 100 different adrenal steroid
hormones and hormone metabolites that may have pathophysiological or
diagnostic significance. By further exploring the reasons for and the con-
sequences of HPA axis abnormalities, we hope to learn more about the
pathophysiology and treatment of many psychiatric disorders.
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Chapter 7
Psychiatric Manifestations of
Hyperadrenocorticism and
Hypoadrenocorticism
(Cushing’s and Addison’s Diseases)
A substantial percentage of patients with major depressive

disorder (MDD) secrete excessive amounts of cortisol, and many escape
early from the normal feedback inhibition by administered steroids such
as dexamethasone. Thus, hypercortisolemia and dysregulation of the hy-
pothalamic-pituitary-adrenal (HPA) axis have become of major interest
in psychiatry (see Chapter 6 in this volume for further discussion).
Cushing’s disease, the major type of spontaneous Cushing’s syndrome,
is the classic endocrine disease characterized by hypersecretion of cortisol
and diminished suppression of cortisol by dexamethasone. Intriguingly,
emotional disturbances were already recognized as a feature of the dis-
ease in Harvey Cushing’s original description (Cushing 1932). This asso-
ciation was later confirmed by retrospective chart reviews (Trethowan
and Cobb 1952). More recently, evaluations of patients with Cushing’s
syndrome before treatment have shown that the majority manifest many
of the clinical features seen in patients with a primary depressive disor-
der, such as depressed mood, irritability, decreased concentration, de-
creased libido, and middle and late insomnia (Cohen 1980; Starkman et
This chapter was adapted from Starkman MN: “The HPA Axis and Psychopa-
thology: Cushing’s Syndrome.” Psychiatric Annals, 23:691–701, 1993. Used with
permission.
165
al. 1981). In fact, the majority of patients with Cushing’s syndrome were
found to meet DSM-III (American Psychiatric Association 1980) criteria
for MDD (except for the exclusion of an organic mental disorder) (Has-
kett 1985; Starkman et al. 1981).
From a theoretical point of view, defining and exploring the clinical
and biochemical similarities between patients with spontaneous Cush-
ing’s syndrome and patients with primary depression provides a unique
opportunity to examine in greater detail the relationship between HPA
axis dysregulation and abnormalities in mood and cognition. For the cli-
nician, however, these similarities may lead to a problem in differential
diagnosis, particularly early in the course of Cushing’s syndrome when the
characteristic physical stigmata are less prominent.
Similarly, the converse condition exists: primary adrenal insufficiency
(Addison’s disease) also produces behavioral symptoms that can lead to
difficulties in distinguishing this condition from primary psychiatric ill-
ness. This chapter examines the behavioral effects of abnormalities in
adrenal steroid secretion and points out parameters that may assist in dif-
ferential diagnosis.
HPA Axis Physiology
Under normal conditions, the secretion of cortisol from the adrenal gland
is regulated by a system extraordinarily sensitive to changes within the or-
ganism and changes in its environment. Hypothalamic neurosecretory
cells produce corticotropin-releasing hormone (CRH), and neurotrans-
mitter pathways modulate its release. CRH, in turn, acts on the adreno-
corticotropic hormone (ACTH)–producing cells of the anterior pituitary,
and ACTH is secreted into the systemic circulation acting on the adrenal
cortex to elicit the secretion of corticosteroids, including cortisol. (Regu-
lation of the HPA axis is discussed in greater detail in Chapter 3.)
Regulatory mechanisms are present at various levels along the axis.
Cortisol feedback occurs at pituitary, hypothalamic, and suprahypotha-
lamic brain levels. An endogenous timer superimposes a circadian and ul-
tradian pattern on CRH, and thereby on ACTH and cortisol secretion.
The suprachiasmatic nucleus is a major anatomical component of the
timer, regulating the periodicity of other physiological functions such as
body temperature, eating, drinking, and activity. In addition, central ner-
vous system centers regulate CRH release in response to environmental
and endogenous inputs such as emotional and physical stress, infection,
and the metabolic milieu.
Cushing’s and Addison’s Diseases 167
Plasma ACTH and cortisol concentrations fluctuate over the 24-hour

period. Highest concentrations are present just before and at the time of
awakening, whereas the lowest ones occur before and during the early
part of sleep. With a normal sleep cycle, cortisol secretion is virtually ab-
sent between midnight and 4:00 A.M. This is followed by a period of in-
creasing HPA activity in the form of seven to nine short secretory
episodes until around 9:00 A.M. (Krieger 1979)
b-Endorphin, an opiate-like peptide, is also secreted by the pituitary
gland. Pro-opiomelanocortin (POMC), the precursor of ACTH, con-
tains the entire sequence of both ACTH and b-lipotropin, from which
b-endorphin is derived. When an ACTH-releasing stimulus is given, both
ACTH and b-endorphin are secreted concomitantly (Guillemin et al.
1977).
Addison’s Disease
Etiology
Insufficient secretion of corticosteroids may arise in two different ways.
Secondary adrenal insufficiency results when ACTH secretion by the pitu-
itary is inadequate, and the normal adrenal gland responds by decreasing
its secretion accordingly. Primary adrenocortical insufficiency, referred
to as Addison’s disease, results from destruction of the adrenal gland. In
the past, tuberculosis was the most frequent cause of this disorder. Cur-
rently, 80% of new cases are idiopathic, and most are thought to arise
from autoimmune destruction of the adrenal gland. Many such patients
also manifest autoimmune attack on other endocrine glands as well, lead-
ing to multiple endocrine deficiencies such as hypothyroidism, hypopar-
athyroidism, and premature ovarian failure. Additional causes of adrenal
insufficiency include fungal disease (such as histoplasmosis), blood-borne
bacterial infections, disorders such as sarcoidosis, and adrenal hemorrhage
due to anticoagulant treatment. Patients with acquired immunodefi-
ciency syndrome (AIDS) can also develop primary adrenal insufficiency,
possibly as a result of cytomegalic virus infection of the adrenal gland. In
contrast to Cushing’s disease, which occurs primarily in women, men and
women are equally affected with Addison’s disease.
Somatic Effects of Insufficient Adrenal Hormones

Because the entire adrenal cortex is affected, there is a deficiency of cor-
tisol, aldosterone, and androgens. As a consequence of the aldosterone
deficiency, patients develop hyponatremia, hyperkalemia, and volume

depletion with orthostatic hypotension and dizziness. The cortisol defi-
ciency leads to fasting hypoglycemia. Profound generalized weakness and
fatigue are cardinal symptoms. Patients develop loss of appetite, together
with an intense craving for salt. They have nausea, vomiting, abdominal
pain, and weight loss. Joint and muscle aches are often present, and loss of
body hair occurs. In primary adrenal insufficiency, patients develop skin
color changes, ranging from mild pigmentation to marked bronzing. This
occurs because the normal pituitary responds to insufficient cortisol pro-
duction by increasing synthesis of POMC; cleavage of POMC yields a
and b melanocyte-stimulating hormone (MSH), both of which stimulate
skin melanocytes and cause pigmentation.
Because the disease symptoms are nonspecific and insidious, an acute
presentation after a relatively minor infection, or loss of consciousness
due to hypoglycemia, is frequently the event that leads to diagnosis. Full
addisonian crisis is a medical emergency. It can occur either in undiag-
nosed patients as the degree of adrenal insufficiency increases or in diag-
nosed patients during an acute stress such as systemic illness or injury
that raises the need for corticosteroids. Patients in addisonian crisis have
severe hypotension, pallor, cyanosis, a rapid and weak pulse, and tachy-
pnea. Delirium may occur, with disorientation, confusion, and psychotic
thinking. Without immediate medical assistance, death will occur.
Neuropsychiatric Symptoms and

Problems of Differential Diagnosis
There is a paucity of recent research on the behavioral manifestations of
Addison’s disease. Most existing studies predate contemporary criteria
for the description and diagnosis of psychiatric disorders and are retro-
spective reviews rather than prospective studies (Cleghorn 1951; Engel
and Margolin 1942). However, there is a consensus that the major defin-
ing behavioral features of the disease are lethargy and apathy. Other be-
havioral manifestations include irritability, crying, and impaired sleep.
Cognitive difficulties, particularly problems with memory, decreased con-
centration, and episodic confusion, may occur.
The course of the disease is often insidious, and the patient shows
vague and nonspecific signs and symptoms that wax and wane over an ex-
tended period of time; therefore accurate diagnosis is often delayed. Be-
cause periods of stress exacerbate symptoms as the adrenal gland is called
on to increase secretion, and symptoms decrease when the stress abates,
the undiagnosed patient is often considered to have a psychiatric condi-
tion. The combination of anorexia, weight loss, and lethargy can lead to
a diagnosis of depressive disorder. Tachycardia, dizziness, and trembling

legs may be seen as signs of an anxiety disorder, as may the description
addisonian patients give that their muscles feel leaden. (Muscle weakness
and heaviness are often described by patients with anxiety; in fact, this is
a good symptom to use in discriminating between patients with pheo-
chromocytoma and those with anxiety [Starkman et al. 1985]). Addiso-
nian patients have also been diagnosed with hypochondriasis, conversion
disorder, and anorexia nervosa.
Although many of the symptoms of Addison’s disease are nonspecific,
the salt craving, the increased pigmentation of the skin, and the loss of
body hair are major clues pointing to the correct diagnosis.
Diagnosis
Once Addison’s disease is suspected, diagnosis is readily established. Lab-
oratory abnormalities include hyponatremia and hyperkalemia, although
these may be normal in the earlier phase of the disease. Hypercalcemia
occurs in 10%–20% of patients. Patients with adrenal insufficiency sec-
ondary to primary hypothalamic or pituitary abnormalities do not exhibit
hyperkalemia.
The diagnosis is supported by a low 8:00 A.M. serum cortisol concen-
tration and by decreased 24-hour excretion of urinary free cortisol or
17-hydroxysteroids. The diagnosis is further strengthened by using exog-
enous synthetic ACTH to stimulate the adrenal glands. A normal re-
sponse to a rapid stimulation by ACTH excludes the diagnosis of primary
or secondary adrenal insufficiency. An abnormal response must be con-
firmed by a more extended ACTH infusion. Radioimmunoassays for
ACTH are now commercially available. These assays can document the
elevated serum ACTH levels that exist in primary adrenal insufficiency.
(A detailed description of tests of HPA axis function is provided in Chap-
ter 17 of this volume.)
Treatment
Correction of the electrolyte imbalance alone does not alter psychiatric
symptoms appreciably. Treatment requires replacement of both gluco-
corticoids and mineralocorticoids. Recently, it has been shown that re-
placement of dehydroepiandrosterone (which is also low in patients with
untreated Addison’s disease) confers added benefit, improving well-
being, mood, energy, and libido in women (Arlt et al. 1999). Because pa-
tients remain extremely sensitive to declines in blood levels of steroids,
multidose administration of steroids throughout the day is preferable to
single-dose administration. Patients respond with improvements in

symptoms within a period of days. Treated patients are at risk of becom-
ing relatively adrenal insufficient with stress, particularly when taking
medications that cause hypotension or volume depletion. Therefore, if
psychotropic medications are required for treating a psychiatric disorder
in addisonian patients, neuroleptics and antidepressants that are less
likely to lower blood pressure (such as selective serotonin reuptake inhib-
itors) are preferable.
Cushing’s Syndrome and Cushing’s Disease
In spontaneous Cushing’s syndrome, adrenocortical hyperfunction de-

velops in one of two ways: 1) excessive ACTH is secreted, which then
stimulates the adrenal gland; or 2) pathology, such as a neoplasm, exists
in the adrenal gland, leading directly to the overproduction of cortisol.
Thus, Cushing’s syndrome is divided into two types: ACTH dependent
and ACTH independent.
In the most common form of ACTH-dependent illness (Cushing’s
disease), excessive ACTH is produced by the pituitary gland. In addition
to excessive secretion of ACTH, the normal circadian rhythm of ACTH
release is blunted, and the sensitivity of the feedback control system to
levels of circulating cortisol is diminished.
Much more rarely, ACTH-dependent Cushing’s syndrome is caused
by an ectopic CRH- or ACTH-producing tumor such as a bronchial car-
cinoid, a malignant thymoma, or a small-cell carcinoma of the lung.
These nonpituitary neoplasms have the capacity to synthesize and release
peptides resembling CRH and ACTH that are physiologically active. The
ACTH produced by the tumor leads to excessive stimulation of cortisol
secretion by the adrenal cortex, which appropriately suppress ACTH re-
lease from the normal pituitary gland. Thus, the high ACTH levels in
these patients come from the neoplasm and not from the patient’s own
pituitary gland. Small-cell carcinoma of the lung is the most common of
these neoplasms.
Patients with excessive ACTH secretion derived from either the pitu-
itary or an ectopic tumor may also secrete sufficient amounts of a-MSH
as well as b-MSH, both of which have melanotropic activity, leading to
hyperpigmentation of the skin and mucous membranes.
ACTH-independent Cushing’s syndrome occurs when a tumor devel-
ops in the adrenal cortex with a capacity to secrete cortisol in an auton-
omous fashion. The elevated cortisol concentration suppresses ACTH
secretion by the normal pituitary gland. Adrenocortical tumors leading to

Cushing’s syndrome may be benign adenomas or malignant carcinomas.
In comparison with pituitary ACTH-dependent disease, adrenal ade-
nomas and carcinomas are quite rare.
Etiology of Cushing’s Disease

The etiology—or etiologies—of spontaneous pituitary ACTH-dependent
Cushing’s syndrome, known as Cushing’s disease, is still controversial.
There are currently several major hypotheses:
• The primary disorder is in the neoplastic pituitary cells that constitute

the pituitary microadenoma seen in a large percentage of patients with
Cushing’s disease. The exaggerated ACTH secretory response of many
of these patients to stimulation by administered CRH (Gold et al.
1984) is consistent with this hypothesis.
• The primary disorder is in the central nervous system. Abnormality in
the limbic system, in particular, may lead to an overproduction of
hypothalamic CRH, which drives the pituitary to increased secretion
of ACTH and thence drives the adrenal gland to secrete cortisol
(Krieger 1972, 1975). The disordered circadian periodicity of ACTH,
growth hormone, and prolactin secretion and the remission of a small
percentage of patients treated with cyproheptadine, a serotonergic
blocking agent, are considered consistent with this view.
• There may be two forms of Cushing’s disease, one involving CRH
hypersecretion and one not. Studies analyzing episodic cortisol secre-
tion support this hypothesis (Van Cauter and Refetoff 1985).
• The idea of a continuum of HPA axis abnormalities has been proposed
in which Cushing’s disease and MDD lie on one endocrinologic spec-
trum, separated by an overlapping “gray zone” (Krystal et al. 1990).
• Decades ago, a psychosomatic hypothesis was proposed: namely,
Cushing’s disease is a pathophysiological reaction to bereavement that
occurs in predisposed individuals with lifelong disturbances in per-
sonality structure, homeostatic self-regulation, and neuroendocrine
responsiveness (Gifford and Gunderson 1970). More recently, the oc-
currence of a greater number of stressful life events in the year before
onset of Cushing’s syndrome has been reported, suggesting that such
stress may be part of a multifactorial model of pathogenesis (Sonino
et al. 1988). Other investigators have not found a greater frequency of
adverse life events within the 2 years preceding the onset of Cushing’s
disease than that seen in patients with pituitary adenomas secreting
growth hormone or prolactin (Kelly 1996).
Somatic Effects of Excess Glucocorticoids in

Patients With Cushing’s Syndrome
Glucocorticoids have catabolic and antianabolic effects on protein. There
is loss of protein from tissues such as skin, muscles, blood vessels, and
bone. Clinically, the skin atrophies and breaks down easily, and wounds
heal slowly. Rupture of elastic fibers in the skin causes purple stretch
marks, or striae. Muscles atrophy and become weak. Thinning of blood
vessel walls and weakening of perivascular supporting tissue result in easy
bruising. The protein matrix of bone becomes weak, causing osteoporo-
sis. Bones become brittle and develop pathological fractures. Osteoporo-
sis occurs most frequently in the spine, leading to vertebral collapse with
back pain and loss of height.
Carbohydrate metabolism is affected by abnormally high levels of
glucocorticoids. Glucocorticoids stimulate gluconeogenesis and interfere
with the action of insulin in peripheral cells. Although some Cushing’s
syndrome patients compensate by increasing insulin secretion and subse-
quently normalizing glucose tolerance, others with diminished insulin-
secreting capacity (diagnosed as prediabetic or subclinical diabetic) de-
velop abnormal glucose tolerance, fasting hyperglycemia, and clinical
manifestations of overt diabetes.
Excessive glucocorticoid levels affect the distribution of adipose tissue
that accumulates in the central areas of the body. Patients develop truncal
obesity, round face (moon facies), supraclavicular fossa fullness, and cervi-
codorsal hump (buffalo hump). Truncal obesity occurs together with thin-
ning of the upper and lower extremities as a result of muscular atrophy.
Although glucocorticoids normally have minimal effects on serum
electrolytes, in very large concentrations they may cause sodium reten-
tion and potassium loss, leading to edema, hypokalemia, and metabolic
alkalosis.
Glucocorticoids inhibit the immune response. They impair humoral
antibody production and the induction and proliferation of immunocom-
petent lymphocytes. They also suppress delayed hypersensitivity reac-
tions, so the skin tests for tuberculosis may convert from positive to
negative. Clinically, these patients have an increased susceptibility to in-
fectious disease.
Diagnosis of Cushing’s Syndrome

The diagnosis of Cushing’s syndrome is confirmed by the measurement
of abnormally high levels of cortisol in plasma and urine, impairment of
a sensitive feedback control mechanism, and diminution or absence of
circadian rhythm of cortisol secretion (see Chapter 17 of this volume).

Not all patients demonstrate the full picture of these abnormalities, how-
ever. Diminished or absent sensitivity of the feedback control system is
demonstrated by lack of suppression of cortisol following administration
of the synthetic steroid dexamethasone. To define the subtype of Cush-
ing’s syndrome, metyrapone, an inhibitor of adrenal corticosteroid
synthesis that lowers cortisol levels, can be used to test hypothalamic-
pituitary responsiveness to the removal of the strong inhibitory feedback
exerted by cortisol. More recently, CRH has been used to demonstrate
the exaggerated secretion of ACTH seen in patients with Cushing’s dis-
ease. (A detailed description of tests of HPA axis function is provided in
Chapter 17 of this volume.)
Neuropsychiatric Symptoms in Patients With

Spontaneous Untreated Cushing’s Syndrome
The majority of patients with spontaneous Cushing’s syndrome do not
have very severe neuropsychiatric disturbances of a psychotic or confu-
sional nature, as patients receiving exogenous corticosteroids sometimes
may. Less than 10% of patients with Cushing’s syndrome manifest a
thought disorder or confusional state that may present as depression or
mania with paranoid ideation (Starkman et al. 1981).
This observation can be understood by considering that patients with
spontaneous Cushing’s syndrome differ from those receiving high-dose
exogenous steroids in several respects. The level of circulating cortisol in
the former is not as high as the equivalent amount of steroid adminis-
tered to the latter. The mean cortisol secretion rate of 35 Cushing’s syn-
drome patients studied was 73 mg/day, an amount equivalent to 20 mg
of prednisone (Starkman and Schteingart 1981). The Boston Collabora-
tive Drug Surveillance Program, reporting on administration of high
doses of prednisone to hospitalized patients, noted a dose-response rela-
tionship between prednisone and acute major psychiatric reaction (psy-
choses or euphoria). This correlation was not present for other adverse
reactions such as gastrointestinal side effects (Boston Collaborative Drug
Surveillance Program 1972). The probability of developing an acute psy-
chotic reaction to steroids is highest when dosages of more than 40 mg/
day of prednisone or its equivalent are administered (Hall et al. 1979). It
is of interest that patients with Cushing’s syndrome who did have a very
severe psychiatric disability with delusional or confusional symptoms had
a mean cortisol secretion rate of 157 mg/day, an amount that is equiv-
alent to 40 mg/day of prednisone (Starkman and Schteingart 1981).
Patients with Cushing’s syndrome also differ from those receiving exog-
enous steroids in that they are exposed to sustained elevated cortisol lev-
els for months to years and are less subject to sudden acute shifts and
rapid rates of change of steroid levels that occur during short-term treat-
ment with high-dose corticosteroids. (Neuropsychiatric effects of pred-
nisone and other exogenous glucocorticoids are further discussed in
Chapter 8.)
What patients with Cushing’s syndrome do manifest is a consistent
constellation of symptoms that includes impairments in affect (irritabil-
ity and depressed mood), vegetative functions (decreased libido and mid-
dle insomnia), and cognitive functions (decreased concentration and
memory) (Starkman et al. 1981). Some authors view the symptom pro-
file as being characteristic of endogenous depression (Haskett 1985),
whereas others consider that the profile represents atypical depression
(Dorn et al. 1995).
Mood and Affect

Irritability, a very frequent symptom seen in close to 90% of patients, is
often the earliest behavioral symptom to appear (Starkman et al. 1981).
It begins close to the onset of weight gain and before the appearance of
other physical manifestations of Cushing’s syndrome. Patients describe
themselves as having become overly sensitive and unable to ignore minor
irritations and feeling impatient with or pressured by others. Because
some patients reported that external noises bothered them excessively,
this may reflect a generalized hypersensitivity to stimuli. In addition, an
overreactivity and easy development of anger were reported. Patients
described feeling that they were often on the verge of an emotional ex-
plosion and that the intensity of anger experienced was also increased.
Although most could restrain themselves, patients were frightened by
their irritability and potential for verbal or physical loss of control. They
described being on guard for a flare-up of anger and fleeing from confron-
tations to avoid a feared loss of control.
Depressed mood is reported by 60%–80% of patients (Cohen 1980;
Haskett 1985; Starkman et al. 1981). There is a range in the intensity of
depressed mood. Some patients describe short spells of sadness; others
experience feelings of hopelessness and giving up. Suicide attempts are
infrequent but may occur. Some patients describe hypersensitivity and
oversentimentality as determinants leading to crying spells. For some,
crying is experienced as their only available behavioral response to anger,
frustration, and feeling unable to respond effectively. Patients also expe-
rience spontaneous onset of depressed mood or crying in the absence of
any preceding upsetting thought or event.
The time course of the mood disturbances is noteworthy. Most pa-

tients report that their mood disturbances are intermittent rather than
sustained (Starkman et al. 1981). Sometimes they wake up depressed
and remain depressed throughout the day and perhaps the next day as
well. Alternatively, the onset of depressed mood or crying might occur
during the day, sometimes suddenly, with a rapid shift. Although there
are intervals when they might not experience pleasure, these patients did
not describe persistent anhedonia. That is, most do not experience the
unrelenting, unremitting inability to experience pleasure that is charac-
teristic of patients with endogenous major depressive illness (Starkman
et al. 1981). There are intervals when they retain the capacity for plea-
sure and could still find enjoyment in hobbies and interpersonal relation-
ships. At times, some patients find it difficult to initiate such activities,
although once others mobilize them, they enjoy them. The duration of
each depressive episode is usually 1–2 days and is rarely longer than 3 days
at a time. A frequent weekly total of dysphoria is reported as being 3 days.
There is no regular cyclicity, however, so that patients cannot predict
when a depressive day would occur. Some patients do have constant de-
pressed mood.
Social withdrawal is often related to shame because of physical ap-
pearance, as well as a decreased sense of focus, alertness, and clarity in
unstructured group settings. Most patients report an increased desire to
have contact with significant family members. However, sporadic with-
drawal might occur because of the patient’s need to remove himself or
herself from a situation of overstimulation that elicits the fear of im-
pending emotional dyscontrol. Guilt is infrequent, if present, and is not
excessive, self-accusatory, or irrational. Instead, it is related primarily to
remorse about the uncontrollable angry outbursts and inability to func-
tion well at work and in the family. Hopelessness, if present, is attrib-
uted to the existence of a chronic illness with increasing physical and
emotional disability that so far had proved undiagnosable and untreat-
able.
A minority of patients experience episodes of elation-hyperactivity
early in the course of the disease (Starkman et al. 1981). As the disease
progresses and new physical signs of Cushing’s syndrome begin to appear,
this type of episode becomes rare or disappears entirely. The quality of
these episodes of elation is described as a “high.” Patients are more ambi-
tious than usual and might attempt to do more than their ability and
training make reasonable. Increased motor activity is present, with rest-
lessness and rapidly performed activities. Patients report embarrassment
that their speech is both loud and rapid. In an unusually severe presenta-
tion, one patient with ectopic ACTH-secreting thymoma presented with
a typical full-blown manic syndrome, with increased pressure of speech,

rhyming of words, and paranoid ideation.
A substantial percentage of patients report generalized anxiety
(Starkman et al. 1981). New-onset panic disorder has also been observed
in patients with Cushing’s syndrome (Loosen et al. 1992). In addition,
even patients who do not experience psychic anxiety describe episodic
symptoms of autonomic activation such as shaking, palpitations, and
sweating.
Biological Drives
Abnormalities in four areas of basic biological vegetative drives are
present:
• Fatigue. This is reported by 100% of patients.

• Libido. A decrease in libido was very frequent, and was reported by
close to 70% of patients (Starkman et al. 1981). In fact, this is one of
the earliest manifestations of Cushing’s disease, beginning when the
patient is experiencing the first onset of weight gain.
• Appetite and eating behavior. More than 50% of patients have an al-
teration in their appetite: In 34%, appetite is increased; in 20%, it is
decreased (Starkman et al. 1981).
• Sleep and dreams. Difficulty with sleep, particularly middle insomnia
and late insomnia (early-morning awakening), is found in more than
50% of patients (Starkman et al. 1981). Difficulty with early insomnia
(not falling asleep at bedtime) is not as frequent. One-third of patients
report an alteration in the frequency or quality of their dreams: in-
creased in their frequency, intense, bizarre, and very vivid. Some pa-
tients report they have lost the ability to wake themselves out of a
nightmare.
Cognition
Cognitive symptoms are a prominent part of the clinical picture. Inatten-
tion, distractibility, difficulty with concentration, and shortened atten-
tion span are reported by most patients (Starkman et al. 1981). Difficulty
with reasoning ability, comprehension, and processing of new informa-
tion is often reported. Some patients report episodes of rapid scattered
thinking, whereas others complain of slow and ponderous thinking.
Thought blocking may occur in more severe instances. Patients complain
of using incorrect words while speaking and of misspelling simple words.
Impairment of memory is one of the most frequent symptoms, re-
ported by 80% of patients (Starkman et al. 1981). Patients report prob-
lems with registration of new information, which could be related in part

to impaired concentration. They commonly repeat themselves in ongo-
ing conversations. They easily forget items such as appointments, names
of people, and location of objects. Difficulty occurs with recall of impor-
tant dates in their personal or medical histories.
On mental status evaluation, difficulties with serial 7 subtractions and
recall of presidents are seen in close to 50% of patients, and difficulty
with recall of three cities is seen in more than 30% of patients (Starkman
et al. 1981). Despite this, the great majority of these patients have no
disorientation or overt clouding of consciousness, and the electroenceph-
alographs of only 5% are characteristic of delirium (Tucker et al. 1978).
Detailed neuropsychological studies reveal that individuals vary in the se-
verity or degree of cognitive dysfunction, ranging from minimal to mod-
erate and extending to the severe deficits in a wide variety of subtests
seen in close to one-third of patients (Whelan et al. 1980). Verbal learn-
ing and other verbal functions seem more vulnerable than do visuospatial
functions (Starkman et al. 2001). Magnetic resonance brain imaging re-
vealed that lower scores on verbal learning and memory tests are associ-
ated with reduced volume of the hippocampal formation, a brain region
key to learning and memory, which has an abundant concentration of
glucocorticoid binding sites (Starkman et al. 1992). Volume of the hip-
pocampal formation was also negatively correlated with serum cortisol
level.
Pathogenesis of Psychiatric Symptoms

Overall, the psychiatric symptoms that develop in Cushing’s syndrome
and their quality argue for a pathogenesis over and above a nonspecific
response to severe physical illness. Irritability and decreased libido occur
early, often before patients are aware that they have any physical prob-
lems other than a steady increase in weight. Later in the course, when de-
pressed mood makes its appearance, it is experienced not simply as the
demoralization common to patients with medical illness, but as episodic
sadness and crying, sometimes occurring in the absence of depressive
thought content. The difficulties with memory and concentration seen in
these patients appear in the absence of disorientation or overt clouding
of consciousness, and the electroencephalographs in almost all cases
are not characteristic of delirium (Starkman et al. 1981; Tucker et al.
1978). The incidence of depressive disorders is greater than in compari-
son groups of patients with other types of pituitary tumors (66% versus
8%; Kelly et al. 1980) or with Graves’ disease (62% versus 23%; Sonino
et al. 1993).
Cushing’s Syndrome After Treatment: Improvement in

Neuropsychiatric Symptoms
Cushing’s syndrome is treated in a variety of ways. In patients with pitu-
itary ACTH-dependent disease, a transsphenoidal resection is usually
performed after a magnetic resonance imaging study of the pituitary has
revealed a defined pituitary microadenoma. If there is evidence of pitu-
itary hyperfunction but such a microadenoma tumor is not found or
completely removed, cobalt irradiation of the pituitary gland is per-
formed, although several years may pass before an effect on ACTH se-
cretion is seen. Until such an effect on ACTH occurs, cortisol increase
can be controlled by chemical agents capable of blocking (such as keto-
conazole) or of blocking and destroying (such as mitotane) the cortisol-
secreting adrenocortical cells. Adrenal adenomas and carcinomas are
treated by surgical removal, followed by chemotherapy in patients with
carcinoma.
In patients with Cushing’s syndrome due to nonmalignant causes, im-
provement in hypertension occurs promptly after treatment. Remission
of other physical signs and symptoms takes place over a period of 6–12
months. Similarly, in patients with adrenal adenomas (Haskett 1985) or
pituitary ACTH-dependent Cushing’s syndrome (Starkman et al. 1986),
certain neuropsychiatric symptoms such as irritability improve rapidly,
whereas other symptoms such as lowered libido require a delay of months
to years from the correction of elevated cortisol levels for remission or
improvement.
In treated patients, improvements in depressed mood are mani-
fested by a decrease in the frequency of days when the patient feels de-
pressed. In addition, each episode lasts a shorter period of time, perhaps
only a few hours instead of 1 or 2 days. The patients also describe a
change in the quality of the depressive mood: they no longer experience
total depression or such a deep or all-encompassing depression. They
also no longer feel depressed without some external precipitating rea-
son. A mood change comes on gradually and abates gradually, rather
than appearing suddenly as before. Crying becomes less frequent, is less
easily elicited by environmental upsets, occurs only with some identifi-
able external precipitant, and is of shorter duration (Starkman et al.
1986). Rating scales for depression improve significantly (Kelly et al.
1996).
Patients also report improvements in cognitive function. The degree
of improvement in concentration is significantly associated with the de-
gree of decrease in cortisol level (Starkman et al. 1986). After treatment,
the volume of the hippocampal formation increases, and this increase is
significantly associated with the magnitude of decrease in urinary free

cortisol (Starkman et al. 1999).
The time course of improvement in depressed mood compared to im-
provement in other neurovegetative symptoms is of interest. In patients
with Cushing’s disease who manifest depressed mood at initial evaluation
and are subsequently studied during the first 12 months after treatment,
improvement in symptoms other than depressed mood occurs before im-
provement in depressed mood (Starkman et al. 1986). Depressed mood
is less likely than irritability and sleep, for example, to be among the first
cluster of symptoms to improve. Interestingly, this lag is similar to that
seen in patients with major depressive episodes treated with antidepres-
sants, in whom improvements in sleep and psychomotor activity often
occur before improvement in depressed mood.
Antidepressant medications, particularly the tricyclics, produce little
or no improvement in the depressive syndrome when administered to pa-
tients with active, untreated Cushing’s syndrome (Sonino et al. 1993).
There is less experience with the newer selective serotonin reuptake in-
hibitors, which can be administered safely (if not necessarily effectively).
After treatment, antidepressants may prove helpful when depressed
mood lingers after treatment has lowered cortisol levels or is exacerbated
because steroid levels have declined rapidly and sharply.
Relationship of Hormone Levels and Depression

The association between pretreatment cortisol levels and the degree of
severity of depressive symptoms is complex and has not yet been fully
clarified. On the one hand, individuals with greatly elevated urinary free
cortisol levels (1,000 mg/day and above) have been shown to have the
highest depression severity score, using a modified version of the Hamil-
ton Rating Scale for Depression (Ham-D; Hamilton 1967), a standard
measure of the multiple components of the depressive syndrome. On the
other hand, depression severity scores in several series of patients show
either no correlation or only a trend for correlation with urinary free cor-
tisol levels. For example, scatter plots show that at the higher levels of
24-hour urinary free cortisol, higher scores on the Ham-D occur more
consistently, but at lesser levels of 24-hour urinary free cortisol elevation,
Ham-D scores can be either high or low (Starkman et al. 1986).
In the milieu of elevated cortisol levels before treatment, low or nor-
mal ACTH levels are associated with mild rather than pronounced de-
pressed mood, whereas moderately to highly elevated ACTH levels are
equally likely to be associated with mild or pronounced depressed mood
(Starkman et al. 1981).
Because patients with adrenal adenoma constitute the major pro-

portion of Cushing’s syndrome patients with low ACTH levels, it is in-
formative to examine them as a separate group. Results of such studies,
however, do not provide a uniform answer, partly because this condition
is extremely rare, and therefore sample sizes are often small. Some stud-
ies report no difference in incidence or severity of depressive symptoms
compared with pituitary ACTH-dependent Cushing’s disease (Kelly
1996; Sonino et al. 1993). Other studies do report such differences. In a
series examining 29 patients with Cushing’s syndrome, of the 4 who were
“mentally unaffected,” 3 had adrenal tumors (Cohen 1980). In another
study, of 5 patients with adrenal tumors, 4 were only mildly depressed
(Jeffcoate et al. 1979). In a retrospective review of 78 cases of Cushing’s
syndrome reported in the literature, although two-thirds of patients with
pituitary ACTH disturbance had a problem with depression, one-fourth
of patients with Cushing’s syndrome secondary to an adrenal tumor had
depression, a highly statistically significant difference (Carroll 1972).
These latter studies, taken together, would suggest that elevated cortisol
levels in the absence of elevated ACTH levels in patients with adrenal ad-
enomas may be less frequently associated with severe depressed mood.
Several studies have investigated the relationship of improvement in
depression with the decrease in cortisol level induced by treatment. Sig-
nificant improvement in Ham-D scores clearly occurs after treatment
produces decreases in cortisol levels (Kelly et al. 1983; Starkman et al.
1986). In fact, normalizing cortisol levels can improve depressed mood
and the depressive syndrome despite the continuation of elevated ACTH
levels. In one study, 23 patients with Cushing’s disease were treated with
mitotane, an adrenal gland inhibitor that reduces cortisol levels without
reducing (and even increasing) ACTH levels. More than 60% of Cush-
ing’s disease patients with depressed mood before treatment who subse-
quently achieved normal cortisol levels but continued to have elevated
ACTH levels showed improvement in scores evaluating depressed mood
despite the continuing elevation of ACTH levels (Starkman et al. 1986).
Other investigators, using different treatments that lower cortisol but not
ACTH (bilateral adrenalectomy or metyrapone), also observed improve-
ments in depression subsequent to cortisol normalization (Cohen 1980;
Jeffcoate et al. 1979).
In summary, the data from these studies indicate that patients with
elevation of ACTH alone (as in mitotane-treated patients) are less likely
to have severe depressed mood. In contrast, patients with elevation of
both cortisol and ACTH levels may be more at risk for developing and
sustaining severe depressed mood. If so, one hypothesis suggested is that
abnormally elevated cortisol levels destabilize important psychoneuro-
physiological systems and make the central nervous system more vulner-
able to the effects of increases in ACTH and other neuroactive substances
(Starkman 1987). Currently, evidence indicates that relevant neuroactive
substances include excitatory amino acids such as glutamic acid (Sapol-
sky 1990).
Behavioral Effects of ACTH and Cortisol

The studies reviewed above lend support to the hypothesis that the neu-
ropsychiatric changes seen in Cushing’s syndrome are related, at least in
part, to the effect of elevated levels of cortisol. Further support for the
role of cortisol in eliciting neuropsychiatric abnormalities comes from re-
search with patients with primary MDD, as reviewed in Chapter 6 of this
volume. Studies in patients with primary psychiatric disorders also indi-
cate that increased cortisol levels are associated with behavioral abnor-
malities. Psychiatric inpatients with high 8:00 A.M. values of plasma
cortisol, regardless of whether they had primary endogenous depression
or some other psychiatric diagnosis, were more symptomatic on admis-
sion, and on discharge had more symptoms of sleep disturbance and de-
creased ability to think, than patients with normal values of plasma
cortisol (Reus 1982). Several investigators have reported extremely high
urinary free cortisol levels in subgroups of depressed patients who sub-
sequently attempted suicide (Bunney et al. 1969; Ostroff et al. 1982).
Cerebrospinal fluid cortisol levels are elevated in depressed patients com-
pared with nondepressed subjects, and there is a correlation between
cerebrospinal fluid cortisol level and the severity of depression (Gerner
and Wilkins 1983).
Possible mechanisms for the effect of cortisol on behavior include a
direct effect of the steroid on the cells of the central nervous system; on
neurotransmitter synthesis or function; on glucose and electrolytes, and
on increasing the sensitivity of the brain to other neuroactive substances.
Cortisol has effects on a wide variety of enzymes important in neuro-
chemistry, and one mechanism of its action may be to induce alterations
of mood-regulating neurotransmitter systems within the brain. For exam-
ple, glucocorticoids increase liver tryptophan pyrrolase, with a subse-
quent decrease in brain tryptophan and serotonin (Green and Curzon
1968). In tissue culture, hydrocortisone and dexamethasone stimulate
tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthe-
sis, and inhibit choline acetyltransferase, markedly inhibiting the synthe-
sis of acetylcholine (Schubert et al. 1980). In rat brain, corticosteroids
altered the sensitivity to norepinephrine of the norepinephrine receptor–
coupled adenylate cyclase system (Mobley and Sulser 1980). Cortico-
steroids also interact with the g-aminobutyric acid (GABA) receptor

complex, altering neuronal excitability (Majewska 1987). Exposure to
increased glucocorticoids increases intracellular calcium and extracellular
excitatory amino acids (glutamate) (McEwen 1997) and inhibits glucose
utilization of the brain, particularly in the hippocampus (Brunetti et al.
1998; de Leon et al. 1997; Kadekaro et al. 1988).
ACTH, too, has potent behavioral effects. ACTH fragment 4-10 in-
creases the state of arousal in limbic midbrain structures (DeWied 1977).
Microinjection of ACTH fragment 1-24 into the periaqueductal gray
matter of rats produces a syndrome of fearful hyperactivity in which the
animals shriek shrilly and jump repetitively on exposure to mild auditory
and visual stimuli that are normally neutral to the rat (Jacquet 1983).
Interestingly, microinjection of b-endorphin elicits the opposite effect:
sedated immobility. Because normal levels of ACTH and b-endorphin
apparently do not cross the blood-brain barrier, it is currently unclear
how the increased ACTH and b-endorphin produced by the pituitary in
patients with Cushing’s disease directly affect the brain. There are areas
of the brain where the blood-brain barrier, in fact, does not exist. Alter-
natively, the increased levels of pituitary ACTH and b-endorphin pro-
duced by the pituitary may diffuse by retrograde flow back up the portal
vein to the hypothalamus and thus regulate the brain’s production of its
own b-endorphin, which occurs in the hypothalamus.
Immunoreactive CRH levels in cerebrospinal fluid are significantly
lower in patients with Cushing’s disease than in patients with MDD and
in healthy subjects (Kling et al. 1991; Tomori et al. 1983). CRH has be-
havioral effects in animals, being primarily anxiogenic. Its role in human
behavior is still insufficiently understood.
It is important to note that this discussion has focused primarily on a
single adrenal steroid, cortisol, and a single pituitary peptide, ACTH.
This reflects the current state of knowledge. However, other adrenal glu-
cocorticoids as well as sex steroids produced by the adrenal gland, such
as testosterone, are also often increased in patients with Cushing’s disease
(Schoneshofer et al. 1986), as are the pituitary peptides b-lipotropin and
its product, b-endorphin. These substances likely contribute to the psy-
chopathology of Cushing’s disease—and possibly to the psychopatholo-
gies of primary psychiatric disorders such as MDD—and remain to be
studied.
Problems of Differential Diagnosis

Differentiation of patients with Cushing’s syndrome from other patients
with a cluster of similar physical signs and symptoms (obesity, hirsutism,
menstrual irregularities, hypertension, diabetes mellitus) is difficult in

the early stages of the disease. Manifestations of protein catabolism (mus-
cle weakness and atrophy, thinning of skin, and easy bruising) are the
clinical features of greatest discriminatory value in distinguishing these
patients from those with obesity.
Deciding whether a patient with hypercortisolemia has primary de-
pression or early Cushing’s syndrome may be difficult. (In fact, there is
some evidence for somatic effects of glucocorticoid excess even in patients
with MDD when Cushing’s disease is not a possible alternate diagnosis;
MDD patients who were abnormal responders on the dexamethasone
suppression test showed hematologic and blood chemistry findings con-
sistent with the effects of hypercortisolemia [Reus and Miner 1985] and
had significantly more hypertension [Pfohl et al. 1991] than patients who
suppressed normally.) Some patients who eventually have a full-blown
picture of Cushing’s syndrome begin with only intermittent elevations of
cortisol level and symptoms of a major affective disorder (Gold et al.
1984). Conversely, patients have been reported in whom the physical
presentation and hypercortisolemia are suggestive of Cushing’s disease,
yet the clinical course and response to psychotropic medication favor pri-
mary psychiatric illness (Krystal et al. 1990).
Although it is similar in many respects to the major depressive disor-
ders, the depression seen in Cushing’s syndrome does have certain distin-
guishing clinical characteristics that may aid in differential diagnosis. To
summarize these characteristics, irritability is a prominent and consistent
feature, as are symptoms of autonomic activation such as shaking, palpita-
tions, and sweating. Depressed affect is often intermittent, with episodes
of 1–3 days’ duration, recurring very frequently at irregular intervals. Pa-
tients usually feel their best, not their worst, in the morning. Psycho-
motor retardation, although present in many patients, is usually not so
pronounced as to be clinically obvious and is usually apparent only in
retrospect after improvement with treatment. The majority of these
patients are not withdrawn, monosyllabic, unspontaneous, or hopeless.
Their guilt, when present, is not irrational or self-accusatory and is pri-
marily related to their realistic inability to function effectively. Sig-
nificant cognitive impairment, including disorders of concentration and
memory, is a consistent and prominent clinical feature of patients with
Cushing’s syndrome.
Are there any procedures currently available that may aid in the dif-
ferential diagnosis? Sleep electroencephalographic studies indicate that
there are many similarities between patients with Cushing’s disease and
patients with MDD, which is theoretically interesting but makes such
studies not diagnostically helpful. Both groups showed a significantly
longer sleep latency, less total sleep time, and lower sleep efficiency than
did the healthy subjects. In both Cushing’s disease patients and MDD pa-
tients, rapid eye movement (REM) latency was significantly shortened,
and REM density in the first REM period was significantly increased
compared with control subjects (Shipley et al. 1992a, 1992b).
One procedure that holds some promise as a possible tool for helping
to distinguish between patients with Cushing’s disease and those with
MDD is the administration of CRH to stimulate ACTH secretion (Gold
et al. 1986). (See also Chapter 17 in this volume.) At present, however,
there is still a substantial overlap in the ACTH secretory responses be-
tween the two groups, impairing the clinical utility of the test. Further
refinements will be required. One modification includes taking both the
pre-CRH plasma cortisol level and the peak ACTH response to CRH into
account (Gold et al. 1987). Further improvement in diagnostic accuracy
is achieved when CRH is administered 2 hours after completion of the
classic endocrine 2-day low-dose dexamethasone suppression test (Yan-
ovski et al. 1993). As research continues to provide greater understand-
ing of HPA axis pathophysiology and its associations with the depressive
syndromes, the development of better tools to provide the discriminatory
power necessary can be anticipated.
Some patients with MDD continue to have an abnormal overnight
1-mg dexamethasone suppression test after treatment. Although this
may reflect an increased risk of poor outcome or relapse, if any clinical
manifestations consistent with Cushing’s disease develop, such patients
should receive endocrine evaluation, including the standard 2-mg and
8-mg dexamethasone suppression tests (Schlechte et al. 1986).
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Chapter 8
Psychiatric Effects of Glucocorticoid

Hormone Medications

T he introduction of corticosteroids to medical treatment in

1949 was accompanied almost immediately by an awareness of their pos-
sible behavioral side effects (Clark et al. 1952; Fox and Gifford 1953; Frey-
berg et al. 1951; Ritchie 1952; Rome and Braceland 1952). By 1956, even
the general public appreciated the potential liabilities of the new “wonder
drug” through Hollywood director Nicolas Ray’s movie Bigger Than Life,
in which James Mason portrayed a family man progressing into paranoia
and mania because of his addiction to cortisone. Although the dosages em-
ployed have markedly decreased over time, drug-induced changes in mood
and cognition are still observed, perhaps at a lower incidence, although de-
finitive epidemiological data are lacking. Remarkably, considering the time
that has elapsed, the state of knowledge continues to be based principally
on retrospective case series, anecdotal reports, and a few prospective in-
vestigations that differ from each other in their rigor and approach to be-
havioral assessment (Reus and Wolkowitz 1993; Wolkowitz et al. 1997).
Frequency and Character of Behavioral Symptoms
The majority of individuals receiving corticosteroids will experience a

change in their behavior, most commonly in the direction of a short-
lived, mild euphoria or anxiety state. Subtle changes in sleeping pattern
and sensory and thought processes may also become apparent. Although
189
such effects are generally regarded as unwanted, some investigators have

suggested that glucocorticoids should be investigated as possible thera-
peutic antidepressants (Arana 1991; Arana et al. 1995; Beale and Arana
1995; DeBattista et al. 2000; Dinan et al. 1997; Goodwin et al. 1992;
Mitchell 1996; Plihal et al. 1996). In a minority of patients, more pro-
found alterations in mood, ranging from frank mania to paranoid psycho-
sis, may emerge, whereas in others the initial elevation in mood can
progress to a sustained major depression over a period of weeks (Cam-
eron et al. 1985; Dawson and Carter 1998; Kershner and Wang-Cheng
1989; Ling et al. 1981; Naber et al. 1996; Plihal et al. 1996; Reckart and
Eisendrath 1990). Suicidality can emerge in rare cases (Braunig et al.
1989; Wolkowitz 1990). However, there is no pathognomonic symptom
complex or progression in symptoms, and precipitation of obsessive-
compulsive behavior, fugue states, catatonia, and frank dementia-like
states have been linked to corticosteroid treatment in individual case re-
ports (Bick 1983; Gifford et al. 1976–1977; Quarton et al. 1955; Varney
et al. 1984; Wolkowitz et al. 1997). Estimates of the actual incidence of
the more severe behavioral changes vary and depend in large part on the
nature of the population studied, the approach to behavioral assessment,
and the length and intensity of treatment provided (Pies 1995).
In the largest study to date, the Boston Collaborative Drug Surveil-
lance Program (1972), 718 consecutively hospitalized medical patients
who received prednisone were studied. Twenty-one of these patients, re-
ceiving an average of 60 mg/day of prednisone, developed what were
termed “acute psychiatric reactions,” defined by the investigators as ei-
ther psychosis or inappropriate euphoria. This undoubtedly represented
an underestimate of risk, because patients who were considered to be
emotionally unstable before treatment were excluded from the study.
Furthermore, of patients prescribed 80 mg/day of prednisone in that
study, 18.4% developed steroid psychosis (Boston Collaborative Drug
Surveillance Program 1972).
Surveys of steroid treatment in more defined populations have gener-
ally reported significantly higher incidences of mental disturbance (Bo-
bele and Bodensteiner 1994; Gift et al. 1989; Soliday et al. 1999), the
highest figures (around 50%) occurring in patients with systemic lupus
erythematosus who received prednisone (Cade et al. 1973; Goolker and
Schein 1953; Sergent et al. 1975). Interpretation of this finding, how-
ever, is complicated by the use of extremely high doses of steroids (up to
500 mg/day) and by the central nervous system changes associated with
the disease process itself (Denburg et al. 1994; Kohen et al. 1993). Dif-
ferentiation of lupus cerebritis from iatrogenic steroid-induced changes
may be aided by the observation of high levels of P ribosomal protein
Psychiatric Effects of Glucocorticoid Hormone Medications 191
antibodies in the former, but in general the differential diagnosis rests on

the timing and duration of the mental changes observed and on the re-
sponse to increases or decreases in the steroid dose (Kohen et al. 1993;
Tincani et al. 1996; Wolkowitz et al. 1997). Reviews of glucocorticoid
treatment in general have concluded an overall incidence of serious psy-
chiatric symptoms of approximately 6%, although many more patients
will experience mild, but perhaps disturbing, behavioral change (Cam-
eron et al. 1985; Reckart and Eisendrath 1990; Stiefel et al. 1989). In one
of the few prospective clinical trials using structured ratings, Naber et al.
(1996) noted a 26%–34% incidence of hypomanic reactions and a 10%–
12% incidence of depressive reactions in ophthalmologic patients receiv-
ing moderate to high short-term doses of corticosteroids.
Hall and colleagues (1979), in addition to describing more classic syn-
dromes, also underscored transient emotional lability, distractibility,
memory impairment, and alteration in sensory perception, particularly
an increase in sensory intensity, which they termed “sensory flooding.”
Subjectively rated increases in sensory intensity were confirmed in a pro-
spective double-blind trial of prednisone in healthy volunteers (Wolkow-
itz et al. 1990a). The feeling of being overwhelmed by sensory stimuli
had previously been observed in some of the original case reports pro-
vided by Glaser (1953), Goolker and Schein (1953), and Clark et al. (1952),
but it deserves emphasis in light of the otherwise undifferentiated symp-
tom picture and clinical experience that reduction in sensory stimulation
helps alleviate symptoms of steroid psychosis (Ducore et al. 1983). The
memory-impairing effects of corticosteroid medication in medically ill
patients are reviewed in Wolkowitz et al. (1997).
Attempts to identify reliable clinical predictors of risk have met with
mixed success. Several investigators have identified female gender as one
possible factor, although this may be an artifact of the marked gender dis-
parity in the prevalence of autoimmune diseases that are commonly
treated by corticosteroids, and a prospective study did not confirm a dif-
ferential gender susceptibility (Naber et al. 1996). Evidence for a dose-
response effect is more clear-cut. Investigators in the Boston Collabora-
tive Drug Surveillance Program (1972) found a statistically significant
increase in incidence with increase in daily dose, a finding that has been
supported by many of the case series and reports that have followed
(Carroll 1977), but not by all (Drigan et al. 1992). Lewis and Smith
(1983), for example, found that only 23% of patients who experienced
psychiatric symptoms received less than 40 mg/day of prednisone.
Corticosteroid dosage does not, however, seem to predict onset, in-
tensity, or character of steroid-induced behavioral symptoms (Hall et al.
1979; Ling et al. 1981). Low dosages may precipitate unusual behavioral
responses. In one case a 21-year-old woman became psychotic on a regi-

men of 7.5 mg of prednisolone a day in divided doses (Greeves 1984),
whereas in another otherwise stable patient mania was apparently pre-
cipitated by short-term usage of a steroid nasal spray (Goldstein and
Preskorn 1989). In some patients even one-time administration of doses
as low as 1 mg of dexamethasone may provoke “amphetamine-like” reac-
tions (Sovner 1983). Several studies have shown that older patients tend
to be overrepresented, but this again is confounded by the age penetrance
of the diseases studied. Keenan et al. (1996), however, did find an in-
creased incidence of steroid-related cognitive difficulties in older but not
in younger patients with arthritis. Previous history of psychiatric disorder
has likewise not been shown to reliably relate to corticosteroid-induced
mental change, although it is quite possible that it contributes to shaping
the symptom picture once a drug-induced effect occurs (Hall et al. 1979;
Ling et al. 1981). However, Minden et al. (1988) reported that past his-
tory or family history of major depression did predict the development
of manic or hypomanic symptoms in patients with multiple sclerosis
treated with adrenocorticotropic hormone (ACTH) or prednisone. It is
still not clear whether a history of mood change or psychosis following a
previous course of corticosteroids predisposes an individual to similar ex-
periences on retreatment later.
The average time for onset and overall duration of symptoms has been
reported to vary widely. Lewis and Smith (1983) noted a mean duration
of symptoms of 21 days in their sample and compared it to a range of
1–150 days in their survey of the literature. Symptoms usually present
within days of the introduction of treatment or of the increase in dosage
and usually remit promptly with appropriate diagnosis and discontinua-
tion of drug, but delayed onset (after 4 weeks) and more prolonged and
progressive courses have also been reported (Pies 1981; Wolkowitz et al.
1997). In one published case report, a 28-year-old woman developed de-
pression, and then mania, after a single course of corticosteroids and went
on to have repetitive, autonomous cycles of mood change despite discon-
tinuation of the corticosteroid therapy (Pies 1981). Particularly clear-cut
evidence for a cause-and-effect relationship between corticosteroid ther-
apy and behavioral abnormalities may be evident in patients who un-
dergo long-term alternate-day steroid regimens. Sharfstein and colleagues
(1982) reported several patients whose mood fluctuated on a regular ba-
sis in a manner akin to rapid mood cycling, becoming more euphoric and
hyperverbal on the day of dose increase and more withdrawn, lethargic,
and psychomotorically impaired on the day of dose decrease.
The mood-altering effects of corticosteroids may sometimes lead to
their intentional abuse by patients (Flavin et al. 1983). In several cases
reported by Goldberg and Wise (1986–1987), patients reported experi-

encing an unusual sense of well-being even on low doses of prednisone
(10 mg) and a rather rapid decrease in mood when they attempted to
lower the dose below this point. A history of substance abuse was not ap-
parent, but each of the subjects had a history suggestive of prior depres-
sive episodes. Accordingly, clinicians should be aware of the potential for
drug dependence in patients whose medical symptoms do not correlate
with physical or laboratory examination and should use a protocol for ta-
pered withdrawal in all patients who have been maintained on cortico-
steroids for a significant length of time (Dixon and Christy 1980; Kimball
1971; Stelzner et al. 1990). In patients who experience incipient depres-
sive symptoms on attempted withdrawal from steroid therapy, antide-
pressants may prove useful (Goldberg and Wise 1986–1987).
It is not generally appreciated that the cognitive effects of corticoster-
oids may result in as much dysfunction as their mood-altering properties
(Wolkowitz et al. 1997, 2001). Such cognitive disturbances can occur in
the presence of an otherwise clear sensorium (Naber et al. 1996; Varney
et al. 1984) and are not necessarily correlated with the severity of the af-
fective changes (Naber et al. 1996). In one particularly well-controlled
study, 32 children with chronic severe asthma were studied through a
course of short-term alternating-dose prednisone treatment (Bender et
al. 1991). During their high-dose (61.4 mg) days, children reported in-
creased anxiety and depression and demonstrated decreased verbal mem-
ory, in comparison to their low-dose (6.97 mg) days.
Clinical effects on cognition have been verified in empirical para-
digms. Keenan et al. (1996) found that medically ill patients treated with
prednisone displayed significant impairments in explicit memory func-
tion, while Wolkowitz and colleagues (1990b) showed that healthy
volunteers given a single 1-mg dose of dexamethasone—or alternatively,
80 mg of prednisone daily for 5 days—made significantly more errors on
verbal memory tasks than did subjects who received placebo. Similar re-
sults have been obtained by Newcomer et al. (1994, 1999), who reported
that synthetic glucocorticoids as well as hydrocortisone (in stress-level
doses for 4 days) impaired verbal declarative memory performance in
healthy subjects. Acutely administered hydrocortisone, however, was not
found to impair memory in healthy subjects (Beckwith et al. 1986). The
types of memory function that seem most susceptible to corticosteroid
impairment are the ones dependent on the hippocampus, such as explicit
and declarative memory; procedural and implicit memory function,
which are largely independent of hippocampal activity, do not seem to be
similarly affected (Keenan et al. 1996; Naber et al. 1996; Wolkowitz
1994; Wolkowitz et al. 1990b). Executive function and working mem-
ory, which are mediated by the frontal cortex, may also be affected by
steroid treatment (Lupien et al. 1999). In rare cases, steroid-induced cog-
nitive impairment can be so severe as to mimic a stupor or dementia-like
syndrome (Doherty et al. 1991) and can be a source of considerable mor-
bidity (Reckart and Eisendrath 1990; Wolkowitz and Rapaport 1989;
Wolkowitz et al. 1997, 2001). In six patients studied by Varney et al.
(1984), the steroid-induced dementia was characterized by deficits in
memory retention, attention, concentration, mental speed and efficiency,
IQ, and occupational performance.
Steroid Withdrawal Syndrome
Apart from the acute behavioral reactions seen during steroid treatment,
a “steroid withdrawal syndrome,” during steroid withdrawal or after dis-
continuation of steroid treatment, has been described in approximately
21% of patients (Freyberg et al. 1951). This syndrome may occur even
in the absence of biochemical evidence of deficient adrenal secretion
(Miller and Tyrell 1995). Symptoms of this syndrome may include low-
ered sense of well-being, discouragement, depression, irritability, leth-
argy, malaise, anorexia and weight loss, nausea, arthralgias and myalgias,
skin desquamation, headache, fever, depersonalization, confusion, poor
concentration, and impaired memory (Freyberg et al. 1951; Glaser 1953;
Hassanyeh et al. 1991; Judd et al. 1983; Miller and Tyrell 1995; Wolko-
witz and Rapaport 1989; Wolkowitz et al. 1997, 2001). Vomiting, pos-
tural hypotension, psychosis, obsessiveness, and suicidality also occur,
but less commonly.
In medically ill patients, it is important to differentiate such symp-
toms from a recurrence of the condition for which the steroids were
being prescribed and from symptoms of frank adrenal insufficiency. Al-
though prolonged adrenal insufficiency lasting more than a few days is
rare after short-term steroid treatment, long-term or high-dose steroid
treatment may impair adrenal function for months to a year or longer.
Persistent adrenal suppression is often discernible with the ACTH stim-
ulation test. An excellent clinical and laboratory approach to the diagno-
sis and treatment of adrenal insufficiency is presented by Miller and
Tyrell (1995).
The causes of the steroid withdrawal syndrome are unknown (Wolko-
witz and Rapaport 1989). Steroid withdrawal–related symptoms typi-
cally resolve by 6–8 weeks (Freyberg et al. 1951; Wolkowitz and Rapa-
port 1989), but they may persist for considerably longer periods in some
patients (Lewis and Smith 1983; Wolkowitz et al. 1997, 2001). If

withdrawal-related symptoms do not spontaneously subside, it may be
necessary to reintroduce the steroid and withdraw it more gradually
(Hassanyeh et al. 1991; Miller and Tyrell 1995). Pharmacotherapy and
electroconvulsive therapy have also been used (Glaser 1953; Judd et al.
1983).
Treatment of Steroid-Induced Psychopathology
Decrease in corticosteroid dosage or discontinuation of treatment is usu-

ally sufficient to result in remission of steroid-induced adverse behavioral
symptoms; specific protocols for steroid taper are described by Miller
and Tyrell (1995). Psychopharmacologic intervention is sometimes re-
quired, however (Seifritz et al. 1994). Both tricyclic antidepressants and
electroconvulsive therapy have been used to treat steroid-precipitated
behavioral syndromes. However, in one series, tricyclic agents exacer-
bated the psychopathology even more, precipitating visual and accusa-
tory auditory hallucinations that remitted only with discontinuation of
the antidepressant and the addition of a phenothiazine (Hall et al. 1978;
Sutor et al. 1996). Antidepressants may be of greater utility in the more
rare pure depressive reactions (Stiefel et al. 1989). It is unknown how se-
rotonin-specific antidepressants compare to tricyclics in the treatment of
steroid psychosis, but one case report has suggested efficacy (Beshay and
Pumariega 1998). Phenothiazines have also been used with apparent
success prophylactically in situations where patients have had prior psy-
chotic experiences on high-dose glucocorticoid regimens (Ahmad and
Rasul 1999; Bloch et al. 1994), although, as mentioned above, it is un-
known if such patients would have developed psychotic reactions on re-
treatment with steroids. Anecdotal clinical reports suggest the possible
usefulness of the atypical antipsychotic olanzapine in treating steroid
psychosis.
The fact that steroid-induced mood changes are reminiscent of those
naturally occurring in bipolar mood disorder has led to the empirical us-
age of lithium carbonate, both acutely and prophylactically. In an initial
report, Siegel (1978) found that lithium ameliorated part of the symp-
tomatology associated with corticosteroid usage in a patient who carried
diagnoses of both bipolar disorder and non-Hodgkin’s lymphoma. Addi-
tional reports since have been supportive of the potential utility of lith-
ium (Alcena and Alexopoulos 1985; Reus et al. 1991; Terao et al. 1994,
1997). In a controlled study, Falk et al. (1979) found that lithium pre-
vented the development of psychotic symptoms in patients who were re-

ceiving ACTH therapy for treatment of multiple sclerosis. The serum
lithium levels found to be effective are equivalent to those used routinely
in the treatment of bipolar disorder (i.e., 0.8–1.2 mEq/L). Lithium has
been found to blunt the circadian fluctuation of serum cortisol in hu-
mans, possibly by altering the secretory pattern of ACTH (Halmi et al.
1972), and has been found to block corticosterone-induced increases in
brain dopamine activity in rat brain (Reus et al. 1991). In a similar vein,
although less well documented, other mood stabilizers such as valproic
acid and lamotrigine may provide prophylaxis against steroid psychosis
(Abbas and Styra 1994; Preda et al. 1999). The use of mood stabilizers
in medically complicated patients has been reviewed by Greenberg et al.
(1993) and Stiefel et al. (1989).
Last, small-scale trials suggest that administration of another adrenal
corticosteroid, dehydroepiandrosterone, may allow tapering of the pred-
nisone dosage in some patients with systemic lupus erythematosus (van
Vollenhoven et al. 1994) and bronchial asthma (Koo et al. 1987) without
worsening the overall medical conditions. Anecdotally, such cotreatment
may enhance energy and memory in prednisone-treated patients. The
clinical place of this strategy, if any, remains to be determined.
There are no convincing studies that clearly discriminate among avail-
able steroid compounds in terms of their risk of inducing behavioral
change. There are some suggestions that methylprednisolone may be as-
sociated with less risk (Coirini et al. 1994) or that changing from pred-
nisone to hydrocortisone plus fludrocortisone may be useful (Seifritz et
al. 1994). These strategies have not been adequately tested, however.
Potential Etiologic Mechanisms
The parallels between corticosteroid-induced behavioral changes and

those observed naturally in the course of primary psychiatric and endo-
crine disorders associated with pituitary-adrenal dysfunction have led to
increasing consideration of the roles of corticosteroids in central nervous
system function (Kawata 1995; Wolkowitz 1994; Wolkowitz et al.
2001). McEwen (1992) has outlined how adrenal steroid hormones may
mediate the ways in which environment shapes the structure and func-
tion of the brain during early development, as well as during active adult
life and in aging. The hormonal effects may be both immediate and tran-
sient when mediated at the membrane level, or they may be longer last-
ing through modulating genomic transcription.
Steroids can have particularly prominent effects as well on neuronal

function (Landfield 1994). The highest density of corticosteroid recep-
tors in the central nervous system is found in the hippocampus, an area
critically involved in memory and behavioral learning (Joels and de Kloet
1992). Corticosteroids have effects on neurotransmitter and peptide re-
ceptors, second messengers, ion transport, G proteins, neurotrophin ac-
tivity, and membrane integrity (Lesch and Lerer 1991; Sapolsky 1996),
and any or all of these may be relevant to the drugs’ effects on behavior.
Administration of high doses of corticosteroids to healthy human volun-
teers is associated with changes in brain electrical activity, particularly in-
creases in theta waves, and with decreases in cerebrospinal fluid levels of
corticotropin, norepinephrine, b-endorphin, b-lipoprotein, and soma-
tostatin (Wolkowitz 1994; Wolkowitz et al. 1990b, 1993). No significant
prednisone-induced changes in the cerebrospinal fluid levels of metabo-
lites of dopamine or serotonin were found by Wolkowitz et al. (1990a),
but levels of 3-methoxy-4-hydroxyphenylglycol, the norepinephrine me-
tabolite, significantly decreased. Other human and animal studies have
shown that dexamethasone increases plasma free dopamine and plasma
homovanillic acid in healthy volunteers (Rothschild et al. 1984, 1985;
Wolkowitz et al. 1986). In animal studies, corticosteroid administration
has been found to produce significant changes in a variety of neurotrans-
mitter systems, enhancing acetylcholine release, reducing dopamine re-
uptake, and modulating g-aminobutyric acid (GABA) receptor activity
(Gilad et al. 1987; Nausieda et al. 1982). The hippocampus is particu-
larly rich in 5-hydroxytryptamine (serotonin) type 1A (5-HT1A) recep-
tors, and there is evidence that corticosterone modulates 5-HT1A receptor
binding density and messenger RNA levels in the CA1 region (Beck et al.
1996; Farabollini et al. 1986). Because most antidepressants modulate
serotonergic transmission by selectively regulating 5HT1A receptors, it is
possible that the mood changes observed in clinical usage of corticoster-
oids are mediated through these pathways (Meijer and de Kloet 1998).
Several studies have also suggested an alteration of 5-HT activity via ad-
ditional mechanisms (Biegon 1990; Chauloff 1993; Joseph et al. 1984;
Lesch and Lerer 1991; McEwen 1987).
Neuronal atrophy (especially in the hippocampus) or neuronal en-
dangerment has been seen in some animal models employing long-term
exposure to high levels of corticosteroids (Sapolsky 1996). Such effects
may be secondary to intracellular glucose deprivation (with subsequent
elevations in intracellular calcium levels and excitotoxicity) (Sapolsky
1996) or to steroid-induced decreases in levels of brain-derived neu-
rotrophic factor (Duman et al. 2001). Such effects remain to be defini-
tively proved in humans, however. Some of the alterations brought about
by corticosteroids may be reversible, whereas others represent potentially

permanent changes in neural circuitry. In a recent study, Lucassen et al.
(2001) found that a small proportion of steroid-treated patients showed
signs of hippocampal neuronal apoptosis as well as heat shock protein 70
staining (an index of response to oxidative damage and cellular stress) at
autopsy.
Conclusion
Any patient receiving a course of corticosteroids should be informed of

the risk of behavioral side effects. Major psychiatric side effects are rela-
tively uncommon; however, mild hypomanic-like activating or sleep-dis-
rupting side effects and difficulties with concentration or memory are
quite common. In the absence of reliable predictors of risk, patient and
family education and close objective monitoring of the patient emerge as
central components of treatment. If significantly adverse behavioral
symptoms occur, dosage reduction or discontinuation of treatment should
be considered, although rapid withdrawal is generally ill advised, because
symptoms may be exacerbated. In situations where complete discontin-
uation is infeasible, and with patients who have developed serious mental
changes during previous courses of corticosteroids (or, perhaps, with pa-
tients who have strong histories of affective illness), prophylactic treat-
ment with either lithium carbonate or low doses of an antipsychotic may
be useful. Tricyclic antidepressants should be used only with caution, and
there is preliminary evidence that selective serotonin reuptake inhibitors
and mood-stabilizing anticonvulsants may be effective in certain cases.
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Chapter 9
Dehydroepiandrosterone in
Psychoneuroendocrinology

Whether diandrone [dehydroepiandrosterone] turns out to be of

therapeutic value in psychiatric practice remains to be seen. . . .
However, we appear to have at our disposal a chemical agent that
can exert a direct and prolonged action on the mental state.
Strauss and Stevenson (1955)
D ehydroepiandrosterone (DHEA) is an abundantly pro-

duced adrenal steroid hormone (Figure 9–1) whose physiological role re-
mains a mystery. Nonetheless, it has been evaluated as a treatment for
psychiatric disorders for nearly half a century (Sands and Chamberlain
1952; Strauss et al. 1952). Several positive uncontrolled reports were
published in the 1950s (Strauss and Stevenson 1955; Strauss et al. 1952),
but large-scale interest in this potential therapy languished until the early
1990s. At that time, a rapidly expanding body of preclinical data, plus
We gratefully acknowledge the following individuals who provided stimulating

discussions and ideas about the role of DHEA in human illness, although the
ideas presented in this article do not necessarily reflect their own: Eugene Roberts,
Ph.D.; Louann Brizendine, M.D.; William Regelson, M.D.; Joe Herbert, M.D.;
Kristine Yaffe, M.D.; Joel Kramer, Psy.D.; Ray Sahelian, M.D.; David Rubinow,
M.D.; and Steven M. Paul, M.D.
This research was partially funded by grants to O.M.W. from the National Al-
liance for Research in Schizophrenia and Affective Disorders, the Stanley Foun-
dation, the Alzheimer’s Association (Grant 1 1RG-95–174), and the National
Institute on Aging (Grant R41-AG13334–01).
205
206
PSYCHONEUROENDOCRINOLOGY
FIGURE 9–1. Biosynthetic pathway of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S).
Dehydroepiandrosterone in Psychoneuroendocrinology 207
the first adequately controlled clinical trial (Morales et al. 1994), fostered
the hope that DHEA might increase well-being in humans and the hope
(or the wish) that it could extend life, protect the brain, and retard the
ravages of aging.
Coincident with this burst of scientific activity, consumer interest in
DHEA was enlivened by the passage, in the United States, of the Dietary
Supplement Health and Education Act of 1994 (P.L. 103-417), which al-
lowed the marketing and sale of DHEA as a “food supplement” (not sub-
ject to the usual U.S. Food and Drug Administration regulations) rather
than as a hormonal medication. Shortly thereafter, popular mass-market
books began promoting DHEA with titles such as The DHEA Break-
through: Look Younger, Live Longer, Feel Better (Cherniske 1998) and
DHEA: The Miracle Hormone That Can Help You Boost Immunity, Increase
Energy, Lighten Your Mood, Improve Your Sex Drive, and Lengthen Your
Lifespan (Callahan 1997). Such claims, as well as the widespread unreg-
ulated use of DHEA, have concerned many medical investigators and
practitioners, because preclinical data may not readily extrapolate to
clinical situations, and because the full risk-benefit ratio of long-term
DHEA usage remains unknown (Katz and Morales 1998; van Vollen-
hoven 1997).
The purpose of this chapter is to put into scientific context the possi-
ble role of DHEA as a psychotropic agent and to review clinical data re-
garding its use in neuropsychiatric illnesses. The main focus is on clinical
efficacy, feasibility, and safety in neuropsychiatric conditions. More exten-
sive discussions of pertinent preclinical studies are available elsewhere
(Baulieu 1997; Baulieu and Robel 1996, 1998; Majewska 1992, 1995; Re-
gelson and Kalimi 1994; Regelson et al. 1990; Roberts 1990; Roberts et al.
1987; Svec 1997; Svec and Porter 1998; Wolkowitz and Reus 2000;
Wolkowitz et al. 2000, 2001), as are reviews of the possible uses of DHEA
in nonpsychiatric conditions (Arlt et al. 1999; Katz and Morales 1998; van
Vollenhoven 1997) and in healthy aging individuals (Barnhart et al. 1999;
Flynn et al. 1999; Hinson and Raven 1999; Kroboth et al. 1999).
DHEA as a Neurosteroid
DHEA and its metabolite DHEA sulfate (DHEA-S) are the most plenti-
ful adrenal corticosteroids in humans, yet their physiological roles remain
uncertain. Important actions in the central nervous system, however, have
been inferred from the fact that DHEA and DHEA-S are synthesized in
situ in the brain; indeed, it has been termed a neurosteroid for this reason
(Baulieu 1997; Zwain and Yen 1999). Highlighting the potential impor-
tance of DHEA and DHEA-S for brain functioning, accumulation of
DHEA and DHEA-S in rat brain is largely independent of adrenal and
gonadal synthesis, remaining constant after gonadectomy, adrenal-
ectomy, and dexamethasone administration and increasing in response to
acute stress independently of changes in plasma levels (Corpechot et al.
1981a; Robel and Baulieu 1995).
Decreases in DHEA and DHEA-S Levels as a

Function of Aging, Chronic Stress, and Illness
Perhaps the most remarkable and well-replicated observation about

DHEA and DHEA-S in humans is that their circulating levels (in both
plasma and cerebrospinal fluid) peak in the mid-20s and then progres-
sively decline with age, approaching a nadir (about 20% of peak levels)
at approximately 65–70 years, the age at which the incidence of many
age-related illnesses steeply increases (Azuma et al. 1993; Guazzo et al.
1996; Regelson and Kalimi 1994). Levels of DHEA and DHEA-S also
decrease with chronic stress and medical illness (Nishikaze 1998; Ozasa
et al. 1990; Parker et al. 1985; Spratt et al. 1993; Wolkowitz et al.
2001). Glucocorticoids do not show a similar pattern of decrease with
age, illness, or stress. In fact, cortisol levels typically rise or do not change
in these conditions, and there is a highly significant decrease in plasma
ratios of DHEA and DHEA-S to cortisol with age and chronic stress
(Fava et al. 1989; Goodyer et al. 1998; Guazzo et al. 1996; Hechter et
al. 1997; Leblhuber et al. 1992, 1993; McKenna et al. 1997; Nishikaze
1998; Oberbeck et al. 1998; Ozasa et al. 1990; Parker et al. 1985; Reus
et al. 1993; Wolkowitz et al. 1992, 2001). Because DHEA and DHEA-S
may physiologically buffer the deleterious effects of excessive gluco-
corticoid exposure (see the later section “Neurotrophic Potential of
DHEA and DHEA-S”), decreasing ratios of DHEA and DHEA-S to cor-
tisol may prove especially problematic in hypercortisolemic states, in-
cluding aging, depression, dementia, and other conditions (Dubrovsky
1997; Ferrari et al. 2001; Hechter et al. 1997; Herbert 1998; Leblhuber
et al. 1992, 1993; Wolkowitz et al. 2001). Indeed, Lupien et al. (per-
sonal communication, 1995) noted greater cognitive deterioration in el-
derly men and women who showed larger decreases in ratios of DHEA-
S to cortisol over a 2-year period, whereas changes in DHEA-S levels
alone were not significantly correlated with cognitive change.
Behavioral Effects of DHEA and DHEA-S in Animals
By necessity, much of the data about the effects of DHEA and DHEA-S
derive from animal or tissue culture–based studies. Species typically
studied, such as rats and mice, have significant concentrations of brain
DHEA and DHEA-S, but minimal peripheral (adrenally derived) levels,
challenging the relevance of such preclinical data to effects in humans.
Nonetheless, such studies have provided valuable leads for designing
clinical trials and have suggested possible mechanisms of the behavioral
effects of DHEA and DHEA-S.
DHEA and DHEA-S generally have memory-enhancing effects in an-
imals. They can restore learning performance in old male mice and rats
to the levels seen in young animals (Flood and Roberts 1988; Tejkalova
et al. 1998) and can reverse pharmacologically induced amnesia in mice
(Flood et al. 1988; Melchior and Ritzmann 1996; Roberts 1990). DHEA-
S can reverse amnesia induced by scopolamine, an anticholinergic drug,
and by anisomysin, a protein synthesis inhibitor (Flood et al. 1988; Rob-
erts 1990).
DHEA-S also has antidepressant-like effects in mice tested in the Por-
solt forced swim test, significantly decreasing immobility time (Reddy et
al. 1998). The nonsulfated parent compound, DHEA, also has antide-
pressant effects in this test, but interestingly, only in high-anxiety rats
(Prasad et al. 1997). Anti-anxiety effects of DHEA and DHEA-S have
also been demonstrated in mice using the elevated plus maze test (Mel-
chior and Ritzmann 1994). However, whereas DHEA augments the anx-
iolytic effect of ethanol in this model, DHEA-S blocks it (Melchior and
Ritzmann 1994). Consistent with possibly different effects of DHEA
versus DHEA-S in animal models of anxiety, DHEA-S has been found to
be anxiogenic in the mirrored chamber test, another test of anxiety in
mice (Reddy and Kulkarni 1997). Administration of DHEA, but not
DHEA-S, also decreases mouse aggressive behavior in certain paradigms
(e.g., the attack by group-housed triads of castrated male mice on lactat-
ing female mouse intruders) (Robel and Baulieu 1995). The specificity of
DHEA versus DHEA-S in these models of depression, anxiety, and
aggression may be related to differential effects of the two hormones at
brain g-aminobutyric acid A (GABA-A) receptors (with DHEA-S having
a stronger antagonist or inverse agonist effect) (Corpechot et al. 1981b;
Demirgoren et al. 1991; Robel and Baulieu 1995), although, physiologi-
cally, DHEA and DHEA-S are readily interconvertible in the circulation.
DHEA-S also affects eating behavior, producing hypophagia in food-
deprived male mice (Reddy and Kulkarni 1998). This effect may, at least
partly, involve an N-methyl-D-aspartic acid (NMDA) receptor mechanism,

because it is blocked by dizocilpine, a NMDA receptor antagonist (Reddy
and Kulkarni 1998). DHEA also decreases feeding in obese Zucker rats;
this effect may be related to DHEA-induced increases in hypothalamic se-
rotonin or dopamine activity (Abadie et al. 1993; Porter et al. 1995).
Neurotrophic Potential of DHEA and DHEA-S
Several studies have suggested that DHEA and DHEA-S have neuro-
trophic potential. For example, DHEA and DHEA-S enhance neuronal
and glial survival and differentiation in dissociated cultures of mouse em-
bryo brain (Bologa et al. 1987; Roberts et al. 1987) and induce the for-
mation of hypertrophic cells in hippocampal slice cultures derived from
orchiectomized adult male rats (Del Cerro et al. 1995). These hyper-
trophic cells appear similar to the reactive astroglia that may be involved
in restorative events following brain injury (Del Cerro et al. 1995).
DHEA and DHEA-S also modulate the astrogliosis that usually accom-
panies myelin breakdown, lessening the formation of astroglial scar
(Muntwyler and Bologa 1989). DHEA and DHEA-S have also been
shown to prevent or reduce hippocampal neurotoxicity induced by the
glutamate agonist NMDA (Kimonides et al. 1998), by corticosterone
(Kimonides et al. 1999), by the oxidative stressors hydrogen peroxide
and sodium nitroprusside (Bastianetto et al. 1999), and by transient but
severe forebrain ischemia (Li et al. 2001). In a provocative recent study
using explants of adult human cortical brain tissue (obtained from neu-
rosurgical samples), DHEA-S, in synergy with recombinant fibroblast
growth factor, significantly improved neuronal survival (Brewer et al.
2001). It is possible that decreased levels of DHEA and DHEA-S con-
tribute to the increased vulnerability of the aging or stressed human brain
to neurotoxic damage, because 1) glutamate release has been implicated
in neural damage resulting from cerebral ischemia and other neuronal in-
sults; 2) excessive corticosterone exposure has been linked to hippocam-
pal atrophy; and 3) oxidative stress has been implicated in degenerative
changes in the hippocampus (Bastianetto et al. 1999; Hechter et al.
1997; Herbert 1997, 1998; Kimonides et al. 1998, 1999; Leblhuber et al.
1992; Wolkowitz et al. 1992). Such effects may be related to the obser-
vations that in normal aging and in Alzheimer’s disease, hippocampal
perfusion (Murialdo et al. 2000b) and volume (Magri et al. 2000) are
positively related to serum levels of DHEA and DHEA-S and to the
ratios of DHEA and DHEA-S to cortisol.
Correlation of DHEA and DHEA-S Levels With

Mood, Memory, and Functional Abilities in Humans
Correlational studies have provided indirect evidence of an effect of

DHEA on mood, memory, and functional abilities in humans, but it is
important to consider numerous caveats (outlined more fully elsewhere;
see Wolkowitz et al. 2000) before ascribing causality in these relation-
ships. For example, DHEA and DHEA-S levels often decrease nonspe-
cifically with chronic illness. This may confound studies examining
differences in DHEA and DHEA-S levels in clinical populations, because
the lowered hormone levels may reflect chronic illness, stress, or incapac-
ity rather than having diagnostic specificity or direct pathophysiological
significance (Kroboth et al. 1999).
Many, but not all, studies have reported lowered levels of DHEA and
DHEA-S in patients with depression, poor life satisfaction, psychosocial
stress, and functional limitations (Barrett-Connor et al. 1999b; Berr et al.
1996; Furuya et al. 1998; Legrain et al. 1995; Nagata et al. 2000; Scott
et al. 1999; Tode et al. 1999; Yaffe et al. 1998a). In one of the largest
cross-sectional, population-based studies, Barrett-Connor and colleagues
(1999b) assessed depression ratings in relation to plasma levels of several
steroid hormones (total and bioavailable estradiol, testosterone, estrone,
androstenedione, cortisol, DHEA, and DHEA-S) in 699 non-estrogen-
using, community-dwelling, postmenopausal women (ages 50–90 years).
These researchers found that only DHEA-S levels were significantly and
inversely correlated with ratings of depressed mood; this association was
independent of age, physical activity, and weight change. Furthermore,
women in that study with categorical diagnoses of depression had signif-
icantly lower DHEA-S levels compared with age-matched nondepressed
women. In another study, partially or completely remitted depressed pa-
tients had DHEA levels intermediate between the currently depressed
patients and control subjects, and, in the currently depressed patients,
morning DHEA levels were inversely related to depression ratings (Michael
et al. 2000). Low DHEA levels have also been reported in child and ado-
lescent patients with depression (Goodyer et al. 1996).
Several groups have found that ratios of DHEA to cortisol more ac-
curately discriminate between depressed and nondepressed individuals
than do levels of either hormone alone (Ferrari et al. 1997; Osran et al.
1993; Michael et al. 2000), with lower morning ratios seen in the depres-
sive individuals (Michael et al. 2000; Osran et al. 1993). Goodyer et al.
(1996) found that morning DHEA hyposecretion and evening cortisol
hypersecretion were significantly and independently associated with ma-

jor depression in 8- to 16-year-olds, and that patients who remained de-
pressed several months after the initial assessment had lower ratios of
DHEA to cortisol at baseline (Goodyer et al. 1998). The authors specu-
lated that, in the presence of adequate DHEA concentrations, high cor-
tisol concentrations alone may not inhibit recovery (Goodyer et al.
1998). In assessing whether premorbid steroid levels predicted the sub-
sequent development of major depression, these researchers found that
high DHEA levels predicted its development in high-risk adolescents
of both genders (Goodyer et al. 2000a, 2000b) but not in adult women
(T. O. Harris et al. 2000). They suggested that contribution of DHEA to
the onset of depression may be different from its contribution to current
or persistent depression (Goodyer et al. 2000a).
Low levels of DHEA and DHEA-S have also been associated with
higher ratings of perceived stress (Labbate et al. 1995), trait anxiety
(P. Diamond et al. 1989), and Type A behavior, cynicism, and hostility
(Fava et al. 1987, 1992; Littman et al. 1993; R.H. Schneider et al. 1989),
whereas higher levels of DHEA and DHEA-S have been associated with
greater amount, frequency, and enjoyment of leisure activities (Fava et al.
1992); greater sexual gratification and frequency of masturbation (in
females) (Persky et al. 1982; van Goozen et al. 1997); healthier psycho-
logical profiles (Fava et al. 1992); more “expansive” personality ratings
(characterized by self-centeredness, high activity drive, and high capacity
for work) (Hermida et al. 1985); and greater “sensation-seeking” and
“monotony avoidance” attributes (Klinteberg et al. 1992). However,
“disruptive behavior” ratings were found to be directly correlated with
DHEA-S levels in children with conduct disorder (Dmitrieva et al.
2001).
Buckwalter and colleagues (1999) examined hormonal correlates of
mood and cognitive function in pregnancy and in the postpartum period.
They reported a very consistent pattern of associations of plasma DHEA
levels with mood and memory. During pregnancy and after delivery,
higher DHEA levels were correlated with lower ratings of depression, in-
terpersonal sensitivity, and tension and anxiety and with better executive
control processes and free recall. The authors proposed that DHEA en-
dogenously regulates mood and cognitive function during pregnancy, and
that postpartum depression may be exacerbated by declines in DHEA
level. As such, they suggested that DHEA supplementation might be a
viable option for treating postpartum mood disturbances (Buckwalter et
al. 1999), although this remains to be empirically tested. Perhaps in a re-
lated vein, postmenopausal women experiencing a climacteric syndrome
(including symptoms of anxiety, depression, fatigue, and insomnia) have
half the circulating DHEA-S levels of matched postmenopausal women

without such symptoms and have significantly higher cortisol to DHEA-S
ratios (Tode et al. 1999).
The remaining literature examining endogenous serum or urinary
DHEA and DHEA-S levels in major depression is inconsistent, with re-
ports of increased (Hansen et al. 1982; Heuser et al. 1998; Maayan et al.
2000; Takebayashi et al. 1998; Tollefson et al. 1990), decreased (Fergu-
son et al. 1964), and unaltered (Fava et al. 1989; Reus et al. 1993; Shul-
man et al. 1992) levels. The reasons for this disparity are unclear. In one
of the studies showing high DHEA-S levels in depressed patients, the lev-
els were positively correlated with depression severity ratings (Tollefson
et al. 1990), but in another study (Takebayashi et al. 1998) hormone lev-
els tended to be inversely correlated with depression severity ratings
(P<0.10). Finally, in one of the studies showing increased DHEA and
DHEA-S levels in depressed patients, markedly elevated basal DHEA-S
levels predicted poor response to electroconvulsive therapy (ECT); ECT-
responsive patients had relatively lower levels at baseline, and therapeutic
responses to ECT were associated with significant treatment-associated
increases in DHEA-S levels (Maayan et al. 2000).
DHEA and DHEA-S levels have also been examined in other psychi-
atric illnesses. Increased, rather than decreased, ratios of DHEA-S to cor-
tisol have been reported in patients with panic disorder (Fava et al.
1989). Possibly consistent with this, Herbert and colleagues (1996)—the
same group that reported low morning DHEA levels in depressed adoles-
cents (Goodyer et al. 1996)—found that depressed adolescents with co-
morbid panic or phobic disorder did not show low morning DHEA levels.
Patients with anorexia nervosa reportedly have low DHEA and
DHEA-S levels (Gordon et al. 1999; Winterer et al. 1985) as well as very
low ratios of DHEA to cortisol (Zumoff et al. 1983). These abnormalities
revert to normal with partial clinical recovery (Zumoff et al. 1983).
However, women without anorexia nervosa who are self-described “small-
eaters” have significantly higher DHEA-S levels than do women who are
self-described “large-eaters” (Clark et al. 1995).
Patients with schizophrenia reportedly have low serum levels of
DHEA (Dilbaz et al. 1998; Erb et al. 1981; Oertel et al. 1974; Tourney
and Erb 1979), but levels of DHEA-S (which has been examined less
frequently than DHEA in this disorder) may be elevated (Oades and
Schepker 1994). In a small study comparing 13 patients who had acutely
exacerbated paranoid schizophrenia with matched control subjects, low
DHEA and high DHEA-S levels were observed in the schizophrenic
group, but these differences were not statistically significant (Brophy et
al. 1983). However, in accord with a diagnostic cutoff DHEA level of
470 ng/dL, proposed by Erb and colleagues (1981), Brophy and col-
leagues determined the mean serum DHEA level in their sample of
schizophrenic patients to be 405 ng/dL compared with 506 ng/dL in
their sample of control subjects. In a recently completed study, D. S.
Harris and colleagues (in press) noted that morning serum DHEA levels
and ratios of DHEA to cortisol were directly correlated with aspects of
memory performance and were inversely correlated with ratings of
psychosis and parkinsonian movements in medicated, institutionalized
patients with chronic schizophrenia. These findings cumulatively raise
the possibility that low DHEA levels (or low ratios of DHEA to cortisol)
identify a particularly impaired subgroup of chronic schizophrenic pa-
tients.
Three recent studies have also demonstrated low basal or stimulated
DHEA and DHEA-S levels in patients with chronic fatigue syndrome
(CFS) (De Becker et al. 1999; Kuratsune et al. 1998; Salahuddin et al.
1997). De Becker et al. (1999) found no basal difference in DHEA levels
in CFS patients but found a blunted DHEA response to intravenous in-
jection of adrenocorticotropic hormone (ACTH). Scott et al. (2000)
found no difference in DHEA response to a low-dose ACTH stimulation
test but found evidence for a divergence in DHEA versus cortisol re-
sponses in comparison with a control group. Kuratsune and colleagues
(1998) speculated that decreases in DHEA and DHEA-S levels are di-
rectly responsible for the neuropsychiatric aspects of this condition. Such
a hypothesis would be consistent with reports that exogenous DHEA ad-
ministration alleviates fatigue in healthy subjects (Morales et al. 1994) as
well as in medically ill patients (Calabrese et al. 1990). To our knowl-
edge, DHEA has not been formally tested as a treatment for CFS, al-
though infusions of DHEA along with high doses of vitamin C have been
reported to alleviate CFS in a series of uncontrolled studies in Japan
(Kodama et al. 1996a, 1996b).
Many studies have also assessed the relationship of DHEA and
DHEA-S levels to overall well-being and cognitive and general function-
ing. In many population-based studies, cognitive and general functional
abilities have been shown to be positively correlated with DHEA and
DHEA-S levels in elderly persons (Abbasi et al. 1998; Berkman et al.
1993; Berr et al. 1996; Cawood and Bancroft 1996; Kalmijn et al. 1998;
Morrison et al. 1998; Ravaglia et al. 1996, 1997; Reus et al. 1993; Rud-
man et al. 1990) as well as in the young (Klinteberg et al. 1992), but in
some studies, the relationships were gender specific. Based on the data in
elderly populations, some investigators have proposed that DHEA and
DHEA-S play a role in “successful aging” (Ravaglia et al. 1996, 1997) as
well as in “brain aging” (Magri et al. 2000).
Other studies, however, have reported no significant relationship be-

tween DHEA-S levels and cognitive performance in women (Yaffe et al.
1998a) or have reported inverse relationships between DHEA and
DHEA-S levels and cognitive test performance in men and women with
Alzheimer’s disease (Miller et al. 1998) and in female (but not male)
nursing home residents (Morrison et al. 1998). The latter authors con-
cluded that contradictory relationships exist between DHEA-S levels and
neuropsychiatric function and that these relationships may be gender
specific (i.e., direct relationships in men and inverse or no relationships
in women). Adding to the uncertain nature of the relationship of DHEA
and DHEA-S to cognitive function in demented individuals, patients
with Alzheimer’s disease or multi-infarct dementia have been variously
reported to exhibit DHEA and DHEA-S levels that are decreased (Azuma
et al. 1999; Bernardi et al. 2000; Ferrari et al. 2000; Murialdo et al. 2000a;
Nasman et al. 1991; Solerte et al. 1999; Sunderland et al. 1989; Yanase
et al. 1996), increased, or unchanged (Birkenhager-Gillesse et al. 1994;
Cuckle et al. 1990; Ferrario et al. 1999; Legrain et al. 1995; L. S.
Schneider et al. 1992; Spath-Schwalbe et al. 1990). As with depression,
Alzheimer’s disease may be characterized more strongly by decreases in
DHEA-S to cortisol ratios than by decreases in DHEA-S levels alone
(Ferrari et al. 2001; Leblhuber et al. 1992, 1993).
Other studies have evaluated whether low DHEA and DHEA-S lev-
els at an index time point predict the subsequent development (Barrett-
Connor and Edelstein 1994; Berr et al. 1996; Yaffe et al. 1998a) or pro-
gression (Miller et al. 1998) of dementia or cognitive decline. Two of
these studies failed to ascertain a significant predictive relationship, al-
though the studies may have had methodological limitations (Barrett-
Connor and Edelstein 1994; Miller et al. 1998; see Wolkowitz et al. 2000
for discussion). One prospective study with sufficient control for con-
founding factors did note significantly lower plasma DHEA-S levels in
healthy elderly patients who developed Alzheimer’s disease over the en-
suing 3 years compared with those who did not (Hillen et al. 2000).
Cumulatively, then, the descriptive and epidemiological data in hu-
mans raise the possibility of a direct relationship between DHEA and
DHEA-S levels and functional abilities, memory, mood, and sense of
well-being, although direct correlations may be stronger in men than in
women, and many inconsistencies exist in the literature. Furthermore, ab-
normalities in patients with depression and dementia have not been uni-
formly replicated. Nonetheless, even if endogenous DHEA and DHEA-S
levels are not decreased in depression and dementia, it is possible that
pharmacologic increases in their levels may have mood- and memory-
enhancing effects. This possibility is reviewed in the next section.
Effects of DHEA Treatment on Well-Being,

Mood, and Memory in Humans
In early clinical trials, DHEA was found to rapidly improve energy, in-
sight, self-confidence, emotionality, vitality, adjustment to the environ-
ment, and school and occupational performance and to decrease anxiety,
depression, apathy, and withdrawal in patients with schizophrenia, inad-
equate personality, or emotional immaturity (Sands 1954; Sands and
Chamberlain 1952; Strauss and Stevenson 1955; Strauss et al. 1952) and
in patients with phobic-obsessive psychoneuroses, neuropsychasthenia,
psychopathic personality, involutive syndromes, and depressive psycho-
ses (Pelliccioni et al. 1981; Scali et al. 1980; Serra 1953). Although these
studies were largely uncontrolled, in several cases the improvements
dissipated on single-blind crossover to placebo and returned with single-
blind crossover back to DHEA. In the first double-blind, placebo-
controlled clinical trial of DHEA, eight patients with depression, anxiety,
social phobia, shyness, lack of confidence, hyposexuality, and so forth
(classified by the authors as having vulnerable personalities) showed
slightly more global positive assessments and slightly fewer negative glo-
bal assessments when taking DHEA compared with placebo, but these
improvements were not interpreted as being significant by the authors
(Forrest et al. 1960).
After a 30- to 40-year hiatus, clinical trials with DHEA resumed. Pa-
tients with multiple sclerosis and systemic lupus erythematosus, for
example, showed increased energy, libido, and sense of well-being in
open-label trials (Calabrese et al. 1990; Roberts and Fauble 1990; van
Vollenhoven et al. 1994). In another study, DHEA was administered to
healthy middle-aged and elderly subjects in a randomized, placebo-
controlled, double-blind crossover study (Morales et al. 1994). Subjects,
ages 40–70 years old, received 50 mg of DHEA or placebo every evening
for 3 months. This dosing schedule restored DHEA and DHEA-S levels
to youthful levels within 2 weeks, and levels were sustained for the entire
3-month period. DHEA-treated subjects showed significant increases in
perceived physical and psychological well-being with no change in li-
bido. Reported improvements included increased energy, deeper sleep,
improved mood, feeling more relaxed, and having enhanced ability to
handle stressful events. These results generated considerable interest in
the possible behavioral effects of DHEA, but the global subjective
measure used to assess behavioral change in this study was relatively
crude.
Labrie and Diamond and colleagues (P. Diamond et al. 1996; Labrie
et al. 1997) treated women ages 60–70 with daily percutaneous appli-
cations of a 10% DHEA cream for 12 months. This was preceded or
followed by 6 months of placebo cream, although it is not stated if the
protocol was open label, single blind, or double blind. These researchers
noted, as did Morales and colleagues (1994), that 80% of the women re-
ported improved “well-being and an increase in energy” during DHEA
treatment. Unfortunately, these behavioral changes were assessed via
nonstandardized daily diaries. Vogiatzi and colleagues (1996) adminis-
tered micronized DHEA (40 mg) or placebo twice daily sublingually in
a double-blind manner to 13 morbidly obese adolescents. The researchers
reported no change in sense of well-being in these subjects, but their as-
sessment method was not specified, and the sample size was too small to
meaningfully gauge this effect. Piketty and colleagues (1998) adminis-
tered DHEA, 50 mg/day for 4 months, to patients with advanced HIV
disease in a randomized, controlled study. They found significant im-
provement in ratings of mental function in the DHEA-treated patients
compared with the placebo-treated patients. An additional double-blind
study examined the effects of 2 weeks’ treatment with DHEA, 50 mg/
day, compared with 2 weeks of placebo in healthy elderly men and
women (Kudielka et al. 1998; Wolf et al. 1997b). Only women tended
to report an increase in well-being (P=0.11) and mood (P=0.10), as as-
sessed with questionnaires. They also showed better performance in one
of six cognitive tests (picture memory) after DHEA treatment. However,
after post hoc correction for multiple comparisons, this difference was no
longer significant. No such trends were observed in the male subjects
(P>0.20). This study employed reliable neuropsychological test instru-
ments and had an adequate sample size, but the duration of treatment
was likely too short for behavioral changes to be manifested (Polleri et al.
1998).
Most recently, Baulieu and colleagues (2000) reported preliminary
results of a 1-year double-blind trial of DHEA (50 mg/day) versus pla-
cebo in a large group of healthy elderly patients recruited from a geriatric
clinic. Most of these patients were being seen for problems such as mild
anxiety, memory complaints, pain, and asthenia but did not qualify for
diagnoses of major depressive or dementing disorders. Significant im-
provements in libido, sexual function, and sexual satisfaction were noted
in the women but not in the men; effects were more prominent after 12
months of treatment compared with 6 months of treatment. Data from
this study on changes in cognitive performance and quality of life had not
been presented at the time of this writing. In another recent study, peri-
menopausal women with complaints of “altered mood and well-being”
were treated with DHEA (50 mg/day) or placebo in a blind manner for
3 months (Barnhart et al. 1999). DHEA had no significant effects on per-
imenopausal symptoms, mood, dysphoria, libido, cognition, memory, or
well-being, but, as suggested by Baulieu et al. (2000), such effects may
progressively develop over more extended periods of time. Consistent
with this possibility, a recent study in which postmenopausal women
were treated with DHEA (50 mg/day) for 6 months found significant im-
provements in a measure of psychological and vasomotor symptoms
(Stomati et al. 2000).
Perhaps the strongest evidence to date of an improvement in well-
being with DHEA replacement (at least in individuals with pathologi-
cally low levels of DHEA and DHEA-S at baseline) comes from a study
utilizing well-validated psychological outcome measures in women with
adrenal insufficiency secondary to Addison’s disease (Arlt et al. 1999).
Twenty-four patients were treated daily with DHEA (50 mg orally) or
placebo for 4 months in a double-blind crossover study. Treatment with
DHEA, but not placebo, resulted in significant improvements in well-
being, mood, anxiety, obsessive-compulsive traits, hostility, and exhaus-
tion. These improvements were seen after 4 months of treatment but not
after 1 month, supporting assertions that the psychological effects of
DHEA may take several months to develop (Baulieu et al. 2000; Polleri
et al. 1998). In a similar study, men and women with Addison’s disease
showed significant improvements in self-esteem, mood, and fatigue, but
not in cognitive function, with 3 months of DHEA treatment (Hunt et
al. 2000).
Other studies have specifically assessed the effect of DHEA on mood
in depressed or dysthymic subjects. In an initial small-scale (N=6) open-
label pilot study, Wolkowitz and colleagues (1997) reported antidepres-
sant effects of DHEA in middle-aged and elderly patients with major de-
pression. Dosages of DHEA were individually adjusted between 30 and
90 mg/day for 4 weeks to achieve circulating DHEA and DHEA-S levels
in the mid-to-high normal range for healthy young adults. Subjects demon-
strated highly significant improvements in scores on the Hamilton Rating
Scale for Depression (Ham-D) and the Hopkins Symptom Checklist–90
and showed a significant improvement in “automatic” cognitive process-
ing at week 3 of DHEA treatment. Mood improvements were signifi-
cantly related to increases in circulating levels of DHEA and DHEA-S
and to their ratios with cortisol; changes in cortisol concentrations alone
were not correlated with behavioral changes. One subject from this
study, an elderly woman with previously treatment-resistant depression,
received extended open-label treatment with DHEA (60 mg/day for
4 months followed by 90 mg/day for an additional 2 months). Her
depression ratings improved by approximately 50% and her access to se-

mantic memory improved by 63% during DHEA treatment and returned
to pretreatment levels after discontinuation of DHEA treatment. In-
creases in DHEA-S levels over time in this patient were also directly cor-
related with improvements in depression ratings and with improvements
in recognition memory (Wolkowitz et al. 1997).
These open-label studies were followed by a double-blind, placebo-
controlled trial in which 22 depressed patients received either DHEA
(60–90 mg/day) or placebo for 6 weeks (Wolkowitz et al. 1999). Some
patients were free of medication at the time of entering the study; others
remained depressed despite being prestabilized (more than 6 weeks) on
antidepressant medication. In the former group, DHEA or placebo was
used alone; in the latter group, DHEA or placebo was added to the stabi-
lized antidepressant regimen. In the group as a whole, DHEA, compared
with placebo, was associated with significant antidepressant responses; 5
of 11 DHEA-treated patients showed more than 50% improvement in
depression ratings and had end-point Ham-D scores below 10, compared
with none of the 11 placebo-treated patients. These results remain to be
replicated in larger studies, but they raise the possibility that DHEA,
used alone or as an adjunct to antidepressant medication in patients with
refractory depression, has significant antidepressant effects in some pa-
tients.
Bloch and colleagues (1999) conducted a 12-week double-blind, pla-
cebo-controlled study in unmedicated patients with midlife dysthymia
(one patient concurrently had major depression). Subjects received, in
randomized order, DHEA (90 mg/day for 3 weeks, followed by 450 mg/
day for 3 weeks) or placebo for 6 weeks. Compared with placebo, DHEA
produced a robust antidepressant response at both dosages. No changes
were noted in cognitive function.
Gordon and colleagues (1999) treated young women with anorexia
nervosa with DHEA (50, 100, or 200 mg/day for 3 months). Although
the specific DHEA dosage group assignment was double blind, there was
no placebo control group. The researchers noted that, despite patients
having significant levels of depression and anxiety at baseline, DHEA
treatment had no significant effects on self-ratings of either symptom.
This study should be interpreted cautiously because there was no placebo
control group, the sample size was small, the subjects may have been spo-
radically noncompliant with the study drug regimens (per the authors’
estimation), and the psychological measures employed were all self-
ratings. Self-ratings in patients with anorexia nervosa may be less reliable
than corresponding observer ratings (Johnson-Sabine et al. 1984; Kennedy
et al. 1990).
Another important area of clinical investigation is the possible cogni-

tion-enhancing effects of DHEA. In 1990, a single case was reported of a
47-year-old woman with low serum DHEA and DHEA-S levels and with
a 20-year history of treatment-refractory learning and memory dysfunc-
tion. She was treated openly with very high daily doses of DHEA ranging
from 12.5 mg/kg to 37 mg/kg for 2 years, and she demonstrated im-
proved verbal recall and recognition along with a normalization in elec-
troencephalography and P300 brain electrophysiology (Bonnet and
Brown 1990). A recent small-scale study also suggested benefits in cog-
nitive function in patients with systemic lupus erythematosus treated
with DHEA, 200 mg/day, for 7–12 months (van Vollenhoven 2002).
Recent studies by Wolf and others in Germany (Kudielka et al. 1998;
Wolf et al. 1997a, 1997b, 1998a, 1998b) have failed to detect major cog-
nitive effects of short-term DHEA administration in healthy volunteers,
although conclusions are limited by the short duration of DHEA admin-
istration used in those studies (Polleri et al. 1998). Single-dose DHEA
administration (300 mg dissolved in 5 mL of ethanol) to healthy young
adults failed to alter memory performance, despite significantly lowering
cortisol levels (Wolf et al. 1997a). In another study (Wolf et al. 1997b)
(described above), 2 weeks of double-blind DHEA administration to
healthy elderly control subjects produced only a trend toward improve-
ment in picture memory in women, but this was not significant after ad-
justing for the number of tests administered. Event-related potentials
(ERPs) were assessed in the male subjects but not in the female subjects
in this treatment paradigm (Wolf et al. 1998b). Certain significant ERP
changes were induced by DHEA treatment, indicating changes in central
nervous system stimulus processing, but these changes were apparently
insufficient to significantly alter memory performance in these men
(Wolf et al. 1998b). If DHEA exerts memory-enhancing effects via anti-
glucocorticoid actions, such benefits might be apparent only under con-
ditions of hypercortisolemia or stress. To test this hypothesis, the same
group of investigators tested cognitive performance before and after a
laboratory stressor in subjects treated with either DHEA or placebo.
DHEA treatment yielded opposing effects on memory performance: it
decreased the poststress recall of visual material learned before the stres-
sor, but it enhanced poststress attentional performance (Wolf et al.
1998a).
DHEA has also been studied as a possible memory enhancer in pa-
tients with Alzheimer’s disease and other dementias. A great deal of ex-
citement followed the initial reports of low serum DHEA and DHEA-S
levels in patients with Alzheimer’s disease (Sunderland et al. 1989) and
multi-infarct dementia (Azuma et al. 1999; Yanase et al. 1996). Although
these reports were only inconsistently replicated (as reviewed above),

they raised the possibility that increasing DHEA and DHEA-S levels in
such patients to the physiological levels seen in healthy young adults
might have salutary cognitive effects. An initial small-scale study address-
ing this possibility yielded negative findings. Dukoff et al. (1998) re-
ported that DHEA (1,600 mg/day orally for 4 weeks) had no significant
cognitive or mood effects in demented or nondemented elderly indi-
viduals. This negative report should be interpreted cautiously, however,
because the sample size was small, the demented population was hetero-
geneous, and the trial duration may have been too short to see cognitive
change in this population. Furthermore, very high doses of DHEA were
used; these may have exceeded a therapeutic window, as suggested by
prior preclinical and clinical data (Bologa et al. 1987; Lee et al. 1994;
Roberts and Fauble 1990; Roberts et al. 1987; Svec and Porter 1998).
Wolkowitz and colleagues (in press) recently treated 58 unmedicated
patients with Alzheimer’s disease with either DHEA (50 mg orally twice
daily) or placebo for 6 months in a between-groups design. At these
doses, DHEA treatment restored serum DHEA and DHEA-S levels to
(or slightly above) levels seen in healthy young adults. Relative to placebo,
DHEA treatment was not associated with significant improvement on the
cognitive scale of the Alzheimer’s Disease Assessment Scale (ADAS-
Cog), a cognitive performance test, at month 6 (P=0.10). Transient im-
provement was noted at month 3 (P=0.014), but this was not statistically
significant after correction for multiple comparisons. No significant dif-
ference between treatments was seen on the Clinician’s Interview-Based
Impression of Change with Caregiver Input (CIBIC-Plus), a global rating
measure, at either time point.
Finally, Azuma et al. (1999) reported that open-label administration
of DHEA-S (200 mg/day intravenously for 4 weeks) improved psycho-
metric test performance in four of seven patients with multi-infarct de-
mentia. In three of these cases, the improvements were judged to be
clinically significant, and in two cases, electroencephalographic patterns
showed improvement with DHEA-S treatment.
Review of the DHEA treatment literature cumulatively suggests that,
in certain situations, DHEA administration enhances mood, energy, sleep,
sense of well-being, functional capabilities, and memory. Such effects
may be more likely in elderly, depressed, or infirm patients or in patients
with markedly low DHEA levels (e.g., patients with Addison’s disease or
adrenal insufficiency) than in young, healthy individuals. They may also
be more likely to emerge after 1 or more months of treatment, and they
may continue to evolve over 6 months or longer (Baulieu et al. 2000; van
Vollenhoven et al. 1998; Wolkowitz et al., in press). Effects in individuals
with dementia have not been consistently demonstrated, and larger-scale

double-blind trials are required in these patients. Cognitive and mood ef-
fects in healthy individuals after short-duration treatment (2 weeks or
less) seem unlikely or else are quite mild. In any event, the findings re-
viewed here await larger-scale, placebo-controlled replication.
Possible Mechanisms of the

Neuropsychiatric Effects of DHEA
A full review of the postulated mechanisms underlying the neuropsychi-

atric effects of DHEA (see Wolkowitz and Reus 2000, 2001; Wolkowitz
et al. 2000, in press) is beyond the scope of this chapter, but the most
salient possibilities are listed in Table 9–1 and are briefly reviewed here.
Although DHEA or its metabolites may regulate gene transcription (Bru-
der et al. 1997; Nephew et al. 1998; Rupprecht 1997), most research has
focused on its nongenomic, membrane receptor–based effects. Electro-
physiological and neurochemical data suggest that DHEA and DHEA-S
have GABA-A receptor antagonistic (Friess et al. 1995; Majewska 1992;
Spivak 1994; Steffensen 1995; Yoo et al. 1996) and NMDA and s recep-
tor potentiating (Bergeron et al. 1996; Monnet et al. 1995; Urani et al.
1998) properties. DHEA-S has stronger GABA-A receptor antagonist or
inverse agonist effects than does DHEA; the latter may even secondarily
increase levels of certain GABA agonist neurosteroids (Friess et al. 1995;
Majewska 1992). Excitatory effects of DHEA and DHEA-S may facili-
tate memory function via enhancement of neuronal depolarization and
excitation (Carette and Poulain 1984; D.M. Diamond et al. 1995; Meyer
and Gruol 1994; Spivak 1994). DHEA-S treatment elicits excitatory
postsynaptic potentials in rat dentate gyrus and can fully counteract the
decrements in long-term potentiation caused by corticosterone in that
structure, consistent with its “antiglucocorticoid” effect (Kaminska et al.
2000). Importantly, DHEA-S also increases hippocampal cholinergic
function (Rhodes et al. 1996, 1997).
DHEA and DHEA-S could have antidepressant effects by increasing
brain serotonin and dopamine activity (Abadie et al. 1993; Murray and
Gillies 1997; Porter et al. 1995), as well as by potentiating NMDA-induced
hippocampal norepinephrine release (Majewska 1995; Monnet et al.
1995), but direct effects of DHEA administration on biogenic amine lev-
els in humans have yet to be assessed. Actions on the hypothalamic-pitu-
itary-adrenal axis are also likely to be involved in the mood and other
neuropsychiatric effects of DHEA and DHEA-S (Dubrovsky 1997; Her-
TABLE 9–1. Some possible mechanisms of the neuropsychiatric

effects of dehydroepiandrosterone (DHEA) and
DHEA sulfate (DHEA-S)
g-Aminobutyric acid–A receptor antagonistic (and perhaps weakly agonistic)
effects
N-Methyl-D-aspartic acid and s receptor potentiating effects
Increased brain regional serotonin and dopamine activity
Increased hippocampal primed burst potentiation and cholinergic function
Metabolized to testosterone and estrogen
Antiglucocorticoid activity
Protection against excitatory neurotoxicity
Increased production and release of amyloid precursor protein and secretion of
nonamyloidogenic isoforms (which are neuroprotective) and decreased
production and deposition of amyloid b protein
Inhibited production of proinflammatory cytokines, interleukin-1a,
interleukin-6, and tumor necrosis factor a and scavenging of free radicals
Increased levels and bioavailability of insulin-like growth factor I
Note. References are cited in the text.
bert 1997; Holsboer et al. 1994; Leblhuber et al. 1992; Svec and Lopez
1989; Wolkowitz et al. 1992, 1997). Antagonism of glucocorticoid ef-
fects by DHEA or by certain of its metabolites has been demonstrated in
multiple model systems in peripheral tissue (Attal-Khemis et al. 1998;
Ben-Nathan and Feuerstein 1990; Blauer et al. 1991; Browne et al. 1992;
Fleshner et al. 1997; Loria 1997; Morfin and Chmielewski 1997; Padgett
et al. 1997; Riley et al. 1990; Svec and Lopez 1989) and in brain (Kimo-
nides et al. 1999). Antiglucocorticoid effects could, in theory, account for
both antidepressant (Dubrovsky 1997; Goodyer et al. 1998; Hechter et
al. 1997; Herbert 1997; Murphy and Wolkowitz 1993; Reus et al. 1997;
Wolkowitz et al. 2001) and neuroprotective (Herbert 1998; Kimonides
et al. 1999; Leblhuber et al. 1992; Sapolsky 1986; Wolkowitz et al. 1992)
effects of DHEA.
Miscellaneous other mechanisms that could contribute to the neuro-
psychiatric effects of DHEA include increased serum levels and bioavail-
ability of insulin-like growth factor I (Morales et al. 1994); inhibition of
the formation of proinflammatory brain cytokines (e.g., interleukin-1,
interleukin-6, and tumor necrosis factor a) and free radicals, which have
been implicated in neurodegeneration (Aragno et al. 1997; Danenberg
et al. 1992; Daynes et al. 1993; Griffin et al. 1989; Solerte et al. 1999;
Straub et al. 1998; Tamagno et al. 1998); elevation of a kB-dependent
transcription factor (which has been associated with neuroprotection)
(Mao and Barger 1998); and increases in brain calcium-ATPase activity
(Zylinska et al. 1999), leading to lower intraneuronal calcium concentra-

tions.
Finally, of course, DHEA could have neuropsychiatric effects second-
ary to its conversion to estradiol and testosterone, both which have sig-
nificant behavioral and central nervous system actions (Barrett-Connor et
al. 1999a; Morrison 1997; Yaffe et al. 1998b).
Side Effects of DHEA
With news of the effects of DHEA entering the lay media and with the
ready availability of commercial DHEA in health food stores nationwide,
many consumers are already purchasing and self-prescribing this hor-
mone. Many medical authorities and researchers in this field, including
ourselves, believe this enthusiasm remains premature until more is learned
about the benefit-risk ratio of long-term DHEA supplementation (Gold-
berg 1998; Katz and Morales 1998; Svec 1997; van Vollenhoven 1997).
This admonition may change as additional studies emerge in the near fu-
ture.
Human studies to date—typically involving 6–12 months or less of
treatment with DHEA—suggest that DHEA treatment is generally well
tolerated and not associated with significant group mean changes in phys-
ical examination; hepatic, thyroid and hematologic tests; urinalysis and
prostate-specific antigen levels; or prostatic or urinary function (Baulieu
et al. 2000; Morales et al. 1994; Reiter et al. 1999; van Vollenhoven
1997; Wolkowitz et al., in press). Long-term and other unforeseen side
effects remain possible, however, and DHEA cannot yet be recommended
for clinical use (van Vollenhoven 1997), with the possible exceptions of
treating Addison’s disease (Arlt et al. 1999; Hunt et al. 2000) or systemic
lupus erythematosus (van Vollenhoven et al. 1998) or as an adjunctive
therapy in certain patients receiving long-term glucocorticoid therapy
(Straub et al. 2000). Relatively common minor side effects that are seen
with DHEA treatment (even with treatment periods less than 6 months)
include acne, oily skin, nasal congestion, and headache. Less commonly
reported side effects include insomnia, overactivation (including disinhi-
bition, aggression, mania, or psychosis), hirsutism, increased body odor,
itching, irregular menstrual cycles, and voice deepening (Dean 2000;
Strauss et al. 1952; van Vollenhoven 1997; Wolkowitz et al., in press).
Proarrhythmogenic and antiarrhythmogenic effects (Sahelian and Borken
1998) have also been reported, as have (in animal models) pro-tumor and
antitumor effects. Tumorigenic effects in humans remain controversial
(McNeil 1997), but because DHEA may be converted to testosterone

and estradiol, individuals with hormone-sensitive tumors should proba-
bly not receive this hormone. It would also seem prudent for any indi-
viduals taking DHEA for a long period to have regular physical and
laboratory examinations, including (as appropriate) liver function tests,
prostate-specific antigen, digital prostate examination, Pap smear, uterine
ultrasound, mammography, blood tests for levels of DHEA-S, bioavail-
able (free) testosterone and estradiol, and possibly electrocardiography
(van Vollenhoven 1997).
Clinical Considerations
For patients who are interested in trying DHEA, and for physicians inter-
ested in prescribing it, despite the cautions just listed, the following rec-
ommendations seem prudent; additional recommendations are outlined
by van Vollenhoven (1997). Most of the following recommendations are
derived from an informed reading of the scientific literature and from
common sense and anecdotal experience rather than from empirical clin-
ical studies:
• The current state of knowledge about the effects of DHEA and about
its potential side effects should be reviewed with patients, with partic-
ular emphasis on diminishing any unrealistic expectations about its
anti-aging effects.
• Patients should be monitored for the occasional development of hy-
pomanic, aggressive, psychotic, or disinhibited behavior (Dean 2000;
Howard 1992; Markowitz et al. 1999; Strauss and Stevenson 1955;
Strauss et al. 1952; Wolkowitz et al., in press).
• Patients at increased risk for hormonally sensitive tumors (e.g., cancer
of the breast, ovary, uterus, cervix, or prostate or malignant mela-
noma) should be advised not to take DHEA (until more is known
about its potential risks), although certain antitumor as well as pro-
tumor effects have been reported in animal studies (Comstock et al.
1993; Dorgan et al. 1997; Goldberg 1998; Jones et al. 1997; McNeil
1997; Schwartz et al. 1986). For other patients, baseline and follow-up
assessments, such as prostate-specific antigen measurements (Goldberg
1998), mammograms, uterine ultrasounds, and Pap smears, may be pru-
dent (van Vollenhoven 1997). For nonhysterectomized women con-
templating long-term DHEA treatment (e.g., more than 3 months),
periodic progesterone treatment aimed at shedding the uterine lining
(which may have hypertrophied under the estrogenic influence of

DHEA) may also be a prudent precaution.
• Periodic assays of serum testosterone (in particular, bioavailable or free
testosterone) and estradiol levels should be performed to preclude ex-
cessive increases in levels of either.
• Baseline serum levels of DHEA-S should be measured to assess the rel-
ative appropriateness of DHEA “replacement” and to establish a base-
line against which the treatment-induced increases can be compared,
although it is unknown if baseline levels predict clinical response.
• Although few clear relationships have yet been demonstrated be-
tween exogenously augmented serum DHEA and DHEA-S levels and
therapeutic outcome (van Vollenhoven 1997; Wolkowitz et al., in
press), it seems reasonable on purely theoretical grounds to assay
serum DHEA-S levels after each dosage adjustment to guide the
achievement of levels in the normal or high-normal range for young
adults (although for some disease conditions, supraphysiological lev-
els may be more efficacious [Barry et al. 1998; Svec 1997; Svec and
Porter 1998]). It remains to be determined if, as suggested by preclin-
ical and some clinical studies, certain of the biological and clinical ef-
fects of DHEA bear an inverted-U-shaped relationship to DHEA and
DHEA-S concentrations (Bologa et al. 1987; Flood and Roberts 1988;
Flood et al. 1988; Kroboth et al. 1999; Lee et al. 1994; Roberts 1990;
Svec and Porter 1998), raising the possibility of a therapeutic win-
dow.
• Dosages for most of the neuropsychiatric conditions reviewed here
have been in the general range of 25–100 mg/day, although there have
been few studies that have systematically compared the efficacy and
tolerability of differing doses. Indeed, clinical trials have used dosages
as low as 5 mg/day to as high as several grams/day. Due to the rela-
tively short half-lives of DHEA-S and, especially, DHEA, we have
generally divided the total daily doses into twice-daily or three-times-
daily dosing in our studies, with the larger portion of the dose being
given in the morning to mimic the endogenous circadian rhythm (Svec
1997). Doses given late in the evening (e.g., after 6:00 or 8:00 P.M.)
may be overly activating and may cause insomnia in some patients.
However, a study demonstrating positive effects on well-being em-
ployed only nightly dosing (Morales et al. 1994).
• If no benefit is observed after approximately 3–6 months of treatment,
it seems unlikely that additional benefit will accrue, and discontinua-
tion of DHEA seems appropriate. Few studies have investigated the
effects of abrupt DHEA withdrawal, but after prolonged DHEA ad-
ministration, gradual tapering of the dose may be prudent.
• As noted, DHEA can be procured widely without prescription in the

United States. There is no federal regulatory control over the purity
and bioavailability of these uncontrolled commercial preparations, and
the actual DHEA content of over-the-counter preparations reportedly
varies from 0% to 150% of the claimed content (Parasrampuria et al.
1998). In particular, preparations advertising “natural DHEA” derived
from Mexican wild mountain yams are composed of diosgenin, a man-
ufactured source of steroid products that is, by itself, ineffective in
vivo (Araghiniknam et al. 1996). Pharmaceutical-grade DHEA is
available by prescription in the United States from various compound-
ing pharmacies.
Conclusion
Despite the meteoric rise in research in DHEA and DHEA-S in recent

years, their role in human neuropsychiatric diseases and their possible
place in clinical therapeutics remain uncertain. It is to be hoped that this
situation will be remedied in the near future. The provocative clinical
and preclinical leads reviewed in this chapter should bolster enthusiasm
for exploring the neuropsychotropic potential of DHEA and DHEA-S.
In our opinion, DHEA supplementation is not yet ready for unsuper-
vised clinical use, because its benefits and safety with long-term use, as
well as the optimum parameters for its administration, have yet to be
clearly established. Individuals wishing to undertake DHEA supplemen-
tation, nonetheless, should obtain DHEA from a reputable source and
take it under medical supervision, with appropriate laboratory and clini-
cal monitoring.
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Part IV
Gonadal Hormones
Chapter 10
Menstrual Cycle–Related and

Perimenopause-Related
Affective Disorders
David R. Rubinow, M.D.

Peter J. Schmidt, M.D.
A s part of a growing recognition of the impact of gonadal ste-

roids on central nervous system function, increased attention has been paid
recently to the possible role of the menstrual cycle and the perimenopause
in disorders of mood and behavior. This increased attention represents the
latest expression of a continuing discussion between those observing mood
disturbances during these periods of reproductive endocrine change and
those cautioning against unwarranted statements about causality.
For centuries medical observers have reported that the changes in re-
productive hormones occurring during the normal menstrual cycle or the
perimenopause may influence mood and behavior. In fact, some early re-
ports suggested that changes in reproductive hormones not only could
modulate behavior but could actually result in the de novo appearance of
disturbances in mood and behavior. In keeping with this early suggestion
that reproductive endocrine function might affect mood in various ways,
it is important to understand that although the behavioral effects of go-
nadal steroids are not uniform, this fact does not imply that these hor-
mones are irrelevant to behavior.
In this chapter we focus on two conditions that suggest a possible re-
lationship between changing gonadal steroid levels and changes in mood
and behavior: menstrually related mood disorders and perimenopause-
related depression. After briefly describing the endocrinologic character-
istics of the normal menstrual cycle and of the perimenopause, we discuss
245
each of these conditions separately and pose questions that help define
the possible relationships between mood changes, the menstrual cycle,
and the perimenopause. Finally, for each condition, we provide several
recommendations for evaluation and treatment.
Normal Cycling
The first day of menstruation is, by convention, the first day of the men-
strual cycle. Gonadotropin-releasing hormone (GnRH) is secreted in a
pulsatile fashion from the hypothalamus and stimulates the secretion of
follicle-stimulating hormone (FSH) from the pituitary. FSH stimulates
the secretion of estrogen from the ovarian follicles, resulting in the pro-
liferation of the uterine lining. At the end of the first menstrual cycle
week, one follicle is selected and becomes the predominant follicle. That
follicle undergoes maturation and secretes increasing amounts of estro-
gen. The release of the egg from the follicle, ovulation, marks the end of
the follicular phase.
After ovulation and under the influence of luteinizing hormone (LH)
stimulation, the corpus luteum (the remains of the ovarian follicle) se-
cretes large amounts of progesterone (P4) and, to a smaller extent, estra-
diol (E2). This phase of the menstrual cycle is the luteal phase. If fertili-
zation and implantation of the egg do not take place, the corpus luteum
atrophies. Progesterone levels precipitously decline, and that decline ini-
tiates the shedding of the uterine lining—menstruation—within approx-
imately 14 days of ovulation.
Perimenopause and Menopause
The menopause has been defined as the permanent cessation of menstru-

ation resulting from loss of ovarian activity and is characterized endocri-
nologically by tonically increased gonadotropin (FSH, LH) secretion,
persistently low levels of ovarian steroids (estradiol and progesterone),
and relatively low (50% decrease compared with younger age groups) an-
drogen secretion (see Figure 10–1) (Adashi 1994). The perimenopause
has been defined as the transitional period from reproductive to nonrepro-
ductive life (Reame 1997; Seifer and Naftolin 1998). As the perimeno-
pause progresses, ovarian follicular depletion occurs, the ovary becomes
less sensitive to gonadotropin stimulation, and a state of relative hypo-
estrogenism occurs; gonadotropin secretion is increased across the men-
Menstrual Cycle–Related Affective Disorders 247
FIGURE 10–1. Levels of the ovarian steroids estradiol (E2) and proges-
terone (Prog) and the pituitary gonadotropic hormones follicle-stimulating
hormone (FSH) and luteinizing hormone (LH) at three phases of repro-
ductive life.
The illustrated hormonal patterns for the climacteric do not reflect intraindividual and in-
terindividual variability in frequency of ovulation and length of menstrual cycle during this
phase. Ov=ovulation; M=menses.
Source. Reprinted from Schmidt PJ, Rubinow DR: “Menopause-Related Affective Disor-
ders: A Justification for Further Study.” American Journal of Psychiatry 148:844–952, 1991.
Copyright 1991, American Psychiatric Association. Used with permission.
strual cycle, ovulatory cycles are fewer, and menstrual cycle irregularity
ensues (Judd and Fournet 1994). However, in contrast to the postmeno-
pause, episodic (not tonic) gonadotropin secretion is present and both
ovulation and normal (or at times increased) estradiol secretion may occur
(Burger et al. 1995; Santoro et al. 1996). The late perimenopause is char-
acterized endocrinologically by persistent elevations of plasma FSH levels,
sustained menstrual cycle irregularity with periods of amenorrhea, and hy-
poestrogenism. However, the levels of several other hormones that may
impact mood and behavior also decrease with aging (concomitant with
changes in reproductive function): androgens (testosterone and andros-
tenedione) (Adashi 1994; Burger et al. 1995; Davis and Burger 1996);
dehydroepiandrosterone (Morley et al. 1997); and insulin-like growth fac-
tors and binding proteins (Klein et al. 1996; Morley et al. 1997).
Menstrual Cycle–Related Mood Disorders

(MRMD)
MRMD refers to cyclic mood disorders with symptoms (e.g., irritabil-

ity, sadness, mood swings, anxiety) that interfere with daily function
and that are confined to the luteal phase of the menstrual cycle, with
symptom remission occurring within a few days of the onset of menses.
The term MRMD was chosen to emphasize the affective symptoma-
tology in the cyclic disorder that is otherwise most commonly called
premenstrual syndrome (PMS). More recently the term premenstrual
dysphoric disorder (Table 10–1) has been applied to women in whom
the affective and behavioral symptoms are prominent and are a source
of impairment. As such, women with premenstrual dysphoric disorder
can be viewed as a subset of the women identified as having PMS by
the criteria of the International Classification of Diseases, 9th Revision
(World Health Organization 1977), or as the equivalent of women
with MRMD or PMS as operationally defined in a variety of publica-
tions (Freeman et al. 1990; Mortola et al. 1991; Schmidt et al. 1998)
(i.e., affective symptoms confined to the luteal phase and causing im-
pairment). A representative case of a woman presenting with PMS fol-
lows:
A 30-year-old married mother of four was referred to the National Insti-

tute of Mental Health for a cyclic mood disorder. She noted that during
the preceding 7 years she had experienced mood and somatic symptoms
that were seemingly related to her menstrual cycle. Approximately 9 days
before her menses, she would become sad and cry, want to be alone, and
experience sensitivity to rejection, guilt, self-criticism, and occasional sui-
cidal ideation. These symptoms were not responsive to expressed concern
from others. Rather, she attempted to isolate herself because she became
profoundly irritable around others and demonstrated anger, impatience,
“meanness,” overreactivity, and verbal outbursts. Her verbal loss of con-
trol caused problems at work and in her relationships with her family.
Other symptoms included a decrease in her general level of interest and
energy; an inability to initiate activities or to experience pleasure; fatigue;
disturbed sleep; distractibility; indecisiveness; and increased appetite and
food intake with cravings for chocolate and carbohydrates. Somatic symp-
toms included swelling of the hands, abdomen, and breasts. Symptoms
gradually increased in intensity during the 9 days before her menses but
disappeared “within minutes” at or immediately following its onset. The
patient had attempted a number of treatments—including magnesium, B
vitamins, diuretics, and progesterone suppositories—without success. On
standardized diagnostic interview, she did not meet the criteria for cur-
rent or past psychiatric disorder.
TABLE 10–1. Research diagnostic criteria for premenstrual dysphoric

disorder
A. In most menstrual cycles during the past year, five (or more) of the
following symptoms were present for most of the time during the last week
of the luteal phase, began to remit within a few days after the onset of the
follicular phase, and were absent in the week postmenses, with at least one
of the symptoms being either (1), (2), (3), or (4):
(1) markedly depressed mood, feelings of hopelessness, or self-
deprecating thoughts
(2) marked anxiety, tension, feelings of being “keyed up,” or “on edge”
(3) marked affective lability (e.g., feeling suddenly sad or tearful or
increased sensitivity to rejection)
(4) persistent and marked anger or irritability or increased interpersonal
conflicts
(5) decreased interest in usual activities (e.g., work, school, friends,
hobbies)
(6) subjective sense of difficulty in concentrating
(7) lethargy, easy fatigability, or marked lack of energy
(8) marked change in appetite, overeating, or specific food cravings
(9) hypersomnia or insomnia
(10) a subjective sense of being overwhelmed or out of control
(11) other physical symptoms, such as breast tenderness or swelling,
headaches, joint or muscle pain, a sensation of “bloating,” weight gain
Note: In menstruating females, the luteal phase corresponds to the period

between ovulation and the onset of menses, and the follicular phase begins
with menses. In nonmenstruating females (e.g., those who have had a
hysterectomy), the timing of luteal and follicular phases may require
measurement of circulating reproductive hormones.
B. The disturbance markedly interferes with work or school or with usual
social activities and relationships with others (e.g., avoidance of social
activities, decreased productivity and efficiency at work or school).
C. The disturbance is not merely an exacerbation of the symptoms of another
disorder, such as major depressive disorder, panic disorder, dysthymic
disorder, or a personality disorder (although it may be superimposed on any
of these disorders).
D. Criteria A, B, and C must be confirmed by prospective daily ratings during
at least two consecutive symptomatic cycles. (The diagnosis may be made
provisionally prior to this confirmation.)
Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Man-
ual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). Washington, DC, Amer-
ican Psychiatric Association, 2000. Copyright 2000, American Psychiatric Association.
Used with permission.
Defining Questions
Are There Luteal Phase–Specific Mood Disturbances?
If women’s daily moods are studied over three or more cycles, a subgroup
can be identified in which mood clearly varies in a menstrual cycle–
dependent fashion, with increasing symptoms during the luteal phase and
elimination of symptoms at or soon after the onset of menses. (See
Figure 10–2 for three examples of women’s self-ratings.) The fact that
fewer than 50% of women presenting with a history of PMS will show a
cycle-dependent pattern, however, illustrates the need to obtain longitu-
dinal ratings in addition to a history of PMS before making a diagnosis.
This requirement for prospective ratings has been incorporated into both
sets of diagnostic guidelines for PMS: those for premenstrual dysphoric
disorder, a diagnosis appearing in Appendix B of DSM-IV-TR (American
Psychiatric Association 2000) (Table 10–1), and those of the National In-
stitute of Mental Health (NIMH Premenstrual Syndrome Research Work-
shop Guidelines. Rockville, MD, National Institute of Mental Health,
unpublished, 1983). According to these criteria (which also contain an
impairment requirement), about 5% of women of reproductive age
would be diagnosed with PMS (Rivera-Tovar and Frank 1990). In an at-
tempt to operationalize the definition of PMS, the National Institute of
Mental Health PMS Research Workshop (in Rockville, MD, 1983) spec-
ified the degree of change (30%) in symptom severity during the luteal
phase required for a syndromal diagnosis. These and other operational
criteria for PMS are reviewed and compared by Schnurr (1989).
For our studies, PMS is operationally defined as follows: Each woman
has an increase of at least 30% (relative to the range of the scale em-
ployed) in her mean self-ratings of negative moods (depression, anxiety,
and irritability) in the 7 days before menses, compared with the ratings
for the 7 days afterward, in at least two of three cycles during the
3-month baseline. As described by Schnurr (1988, 1989), this method
correlates highly with the effect-size method used to establish that sever-
ity criteria for PMS have been met. Women are excluded from the study
if they have mood symptoms during the follicular phase of the cycle, that
is, postmenstrual mean mood ratings beyond the midpoint of the rating
scale. All women with PMS come to our clinic or are referred by their
personal physician because their PMS symptoms interfere with daily
function. Additional criteria include the following: regular menstrual
cycles (e.g., 22–34 days), normal gynecologic examinations, and do not
meet criteria for a current DSM-IV Axis I diagnosis. Approximately 30%
of the women presenting to our clinic with symptoms of PMS meet these
diagnostic criteria.
FIGURE 10–2. Depression self-ratings of three women with premenstru-

al syndrome.
Source. Reprinted from Rubinow DR, Roy-Byrne PP, Hoban MC, et al.: “Prospective As-
sessment of Menstrually Related Mood Disorders.” American Journal of Psychiatry 141:684–
686, 1984. Copyright 1984, American Psychiatric Association. Used with permission.
Are These Mood Disturbances Associated

With Abnormal Physiological Events?
Once women with PMS are identified, the question is whether menstrual
cycle–related mood changes are accompanied by abnormal physiological
events. For obvious reasons, attention has been focused largely on the
reproductive endocrine system. Despite many investigations of basal
hormone levels in patients with PMS compared with control subjects, no
diagnosis-related differences in gonadal steroids, gonadotropins, or sex
hormone–binding globulin have been consistently observed. Therefore,
both the levels of reproductive endocrine hormones (including estra-
diol, progesterone, FSH, LH, and ovarian and adrenal androgens) and
their pattern of secretion over the menstrual cycle do not appear to be
disturbed in PMS (Figure 10–3). Similarly, most (Bicikova et al. 1998;
Schmidt et al. 1994; Wang et al. 1996), but not all (Rapkin et al. 1997),
examinations of the levels of the progesterone metabolites (and neu-
rosteroids) allopregnanolone and pregnanolone, which modulate the
activity of the receptor for the neurotransmitter g-aminobutyric acid
(GABA), have found no differences between women with PMS and con-
trols.
Because much of the regulatory information of the endocrine system
is conveyed by the pattern of pulsatile secretion, dynamic elements of the
hypothalamic-pituitary-ovarian axis have been studied. In a study of 15
patients with PMS and 15 control subjects, the FSH and LH responses
to GnRH were similar (P.J. Schmidt, MD, et al., unpublished data, May
1993). Data from LH pulsatility studies are conflicting: some studies
show no differences in pulsatility (Reame et al. 1992), and others dem-
onstrate increased frequency and decreased amplitude of pulses
(Facchinetti et al. 1990) in patients with PMS compared with control
subjects. In sum, there is no consistent or convincing evidence that PMS
is related to abnormal circulating levels of gonadal steroids or gonado-
tropins.
Even if group differences in gonadal steroid–related factors were iden-
tified, the following questions posed by Reid (1986) would have to be ad-
dressed before any biochemical abnormality is accepted as etiologically
relevant in PMS: What percentage of patients and control subjects show
such a premenstrual alteration? What degree of alteration constitutes ev-
idence for PMS? Is the alteration reproducible in patients from month to
month? Does the severity of PMS correlate with premenstrual change
observed in a circulating factor? Are changes in a factor pathognomonic
of the premenstrual mood state or epiphenomenal to depressive states in
general?
Several nonreproductive endocrine factors have also been examined.

Although there is no consistent evidence for abnormal levels or patterns of
secretion of any hormone in PMS, it is striking that recently reported
(Rubinow and Schmidt 1999) diagnosis-related differences in biological
factors (which remain to be confirmed) are not confined to the luteal
phase but rather appear in both follicular and luteal phases. These biolog-
ical differences include increased prevalence of abnormal thyroid-stimu-
lating hormone responses to thyrotropin-releasing hormone (Roy-Byrne et
al. 1987), decreased slow-wave sleep (Lee et al. 1990), phase-advanced
temperature minima and cessation of melatonin secretion (Parry et al.
1989, 1990), decreased red blood cell magnesium concentration (Rosen-
stein et al. 1994; Sherwood et al. 1986), blunted growth hormone and cor-
tisol responses to L-tryptophan (Bancroft et al. 1991), and increased
cortisol response to corticotropin-releasing hormone infusion (Rabin et al.
1990). If any of these findings are relevant, they must be related to the sus-
ceptibility to PMS symptoms, but they cannot by themselves explain this
cyclic phenomenon. Luteal phase decreases in both plasma b-endorphin
(Chuong et al. 1985; Facchinetti et al. 1987) and platelet serotonin uptake
(Ashby et al. 1988; Taylor et al. 1984) have been reported in PMS,
although neither the diagnostic group–related decreases nor their confine-
ment to the luteal phase is consistently observed (Bloch et al. 1998; Hamil-
ton and Gallant 1988; Malmgren et al. 1987; Tulenheimo et al. 1987;
Veeninga and Westenberg 1992).
Is the Luteal Phase Necessary for the Occurrence of PMS?

If there are no basal or stimulated reproductive endocrine abnormalities
or luteal phase–specific biological abnormalities in PMS, is the luteal phase
even necessary for its expression? This question was answered in a study
by Schmidt et al. (1991), in which women with prospectively confirmed
PMS were blinded to menstrual cycle phase by administering the proges-
terone receptor antagonist mifepristone (RU 486) in combination with
either human chorionic gonadotropin (hCG) or placebo. Seven days af-
ter the LH surge, women with PMS were randomly administered placebo
or mifepristone, a progesterone receptor blocker that causes a sudden de-
crease in plasma progesterone and the onset of menses within 48–72
hours. Patients also received hCG or placebo. Patients receiving mifepris-
tone and hCG had menses within 48–72 hours, but normal luteal phase
progesterone levels were maintained by the stimulatory effects of hCG
on the ovary, and a second menses occurred about 9 days later with in-
volution of the corpus luteum. Thus, hCG preserved the luteal phase de-
spite the induction of menses by mifepristone. Alternatively, patients
Menstrual Cycle–Related Affective Disorders
FIGURE 10–3. Menstrual cycle–related changes in levels of estradiol, progesterone, follicle-stimulating hormone, and luteiniz-
ing hormone in patients with premenstrual syndrome and in control subjects.
No significant diagnosis-related effects were observed. Data presented are group means plus standard deviation.
Source. Reprinted from Rubinow DR, Hoban MC, Grover GN, et al.: “Changes in Plasma Hormones Across the Menstrual Cycle in Patients With Menstrually
Related Mood Disorder and in Control Subjects.” American Journal of Obstetrics and Gynecology 158:5–11, 1988. Used with permission.
255
receiving mifepristone and placebo entered the follicular phase after the
mifepristone-induced menses. Results demonstrated that women with
prospectively confirmed PMS experienced their characteristic premen-
strual mood state after the mifepristone-induced menses, at a time when
the peripheral endocrine profile was that of the early follicular phase
(Figures 10–4 and 10–5).
The observation that, as a group, women with prospectively con-
firmed PMS showed no alterations of their symptoms despite the re-
setting of the menstrual cycle could support either of two conclusions.
Premenstrual syndrome may represent an autonomous, cyclic disorder
that is linked to, but can be dissociated or desynchronized from, the
menstrual cycle. Alternatively, symptoms may be triggered by hormonal
events before the late luteal phase, consistent with reports that the sup-
pression of ovulation results in a remission of PMS symptoms (Casson et
al. 1990). To test the latter possibility, we suppressed ovarian steroid pro-
duction and created a temporary, reversible menopause by administering
the GnRH superagonist leuprolide acetate (Lupron). Suppression of the
ovarian cycle prevented the appearance of PMS symptoms, a finding that
was also observed in other studies (Bancroft et al. 1987; Muse et al.
1984).
To determine whether gonadal steroids were the factors that when re-
moved resulted in the elimination of PMS, we added back estradiol and
progesterone separately to women who continued to take leuprolide and
for whom leuprolide alone successfully eliminated symptoms of PMS.
Both estradiol and progesterone were associated with the return of symp-
toms typical of PMS (Schmidt et al. 1998) (Figure 10–6). It does appear,
therefore, that gonadal steroids can trigger symptoms of PMS, an obser-
vation that at first glance appears discordant with the lack of differences
in gonadal steroid levels between women with PMS and control subjects.
In the second part of this study, women with confirmed absence of PMS
received the same protocol of leuprolide and hormone addback. The con-
trol women showed no perturbation of mood during leuprolide-induced
hypogonadism and, significantly, no perturbation of mood during hormone
addback with either progesterone or estradiol, despite achieving hor-
mone levels comparable to those seen in the women with PMS. Women
with PMS, therefore, are differentially sensitive to gonadal steroids such
that they experience mood destabilization with levels or changes in go-
nadal steroids that are absolutely without effect on mood in women lack-
ing a history of PMS. These results indicate that gonadal steroids are
necessary but not sufficient for PMS. They can trigger PMS, but only in
women, who, for undetermined reasons, are otherwise vulnerable to ex-
periencing mood state destabilization (Schmidt et al. 1998).
FIGURE 10–4. Absence of the effect of truncation of the late luteal phase
with RU 486 on the appearance of premenstrual syndrome symptoms.
Data show group means plus standard deviation. Analysis of variance with repeated mea-
sures showed significant increases in anxiety symptoms from day 5 through day 11 after the
administration of RU-486 or placebo (open bars) compared with the ratings from the 7 days
before the luteinizing hormone (LH) surge (the follicular phase) (shaded bars). No signifi-
cant effects in the treatment group were observed. hCG=human chorionic gonadotropin.
Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of
Induced Menses on Symptoms in Women With Premenstrual Syndrome.” New England
Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Soci-
ety. Used with permission.
258
FIGURE 10–5. Appearance of premenstrual syndrome (PMS) symptoms during an RU 486–induced follicular phase in one
woman.
Sadness ratings ranged from 1 (none) to 6 (extreme). After the administration of RU 486, the woman had typical PMS symptoms during the drug-induced
follicular phase of the menstrual cycle, confirmed by the plasma levels of gonadal steroids shown. LH=luteinizing hormone.
Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of Induced Menses on Symptoms in Women With Premenstrual Syn-
drome.” New England Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Society. Used with permission.
Premenstrual syndrome, then, may represent a behavioral state that is

triggered by an undefined biological stimulus related to the menstrual cycle
in those who may be rendered susceptible to changes in behavioral state by
antecedent experiential events (e.g., history of physical or sexual abuse)
(Paddison et al. 1990) or biological conditions (e.g., hypothyroidism)
(Schmidt et al. 1990). This hypothesis would be consistent with data from
studies showing the successful treatment of PMS with surgical or medical
oophorectomy (Casper and Hearn 1990; Muse et al. 1984) (addressing the
trigger) as well as with nonreproductive modalities (e.g., fluoxetine) (Steiner
et al. 1995; Stone et al. 1990) that may address the underlying susceptibility.
The Menstrual Cycle and Psychiatric Disorders
There are various ways in which the menstrual cycle may modulate
mood and behavior disturbances independent of the presence of PMS:
1) the menstrual cycle may modify the severity of appearance of certain
psychiatric illnesses; 2) the menstrual cycle may trigger the recrudes-
cence of a previously experienced psychiatric illness. In general, these
phenomena may be readily distinguished from PMS during longitudinal
confirmation of the diagnosis.
Menstrual Cycle–Related Events May Modulate

Preexisting Psychopathology
A series of observations have suggested that normal menstrual cycle func-
tion may influence or alter the expression of the symptoms of primary
psychiatric disorders. First, phase-related symptom exacerbation has
been noted, with several reports of psychiatric patients (with mania or
schizophrenia) whose symptoms increased in severity before menses and
improved after menses. For example, Malikian et al. (1989) reported the
premenstrual worsening of the symptoms of depression in a sample of
women with chronic depressive illness.
Second, the potential influence of the menstrual cycle on the expres-
sion of the symptoms of psychiatric illness has been inferred from numer-
ous reports of the disproportionate occurrence of suicide attempts and
psychiatric admissions during the premenstrual phase (Dalton 1959; Jan-
owsky et al. 1969; Mandell and Mandell 1967; Tonks et al. 1968). How-
ever, a postmortem study employing endometrial biopsies as a method of
dating menstrual cycle phase found no increased proportion of suicides
occurring during the premenstruum (Vanezis 1990).
FIGURE 10–6. Sadness ratings for 10 women with premenstrual syndrome (upper panel) and 15 control subjects (lower panel),
showing minimal mood and behavioral symptoms during administration of leuprolide.
In contrast, women with premenstrual syndrome but not the control subjects had a significant increase in sadness during administration of either estradiol (E2)
or progesterone (P4). Histograms represent the mean (± standard error) of the seven daily scores on the Daily Rating Form Sadness Scale for each of the 8
weeks preceding hormone replacement (leuprolide alone) and during the 4 weeks of estradiol (plus leuprolide) and progesterone (plus leuprolide) replacement.
A score of 1 indicates that the symptom was not present, and a score of 6 indicates that it was present in the extreme.
261
In contrast, the menstrual cycle may be associated with the episodic

improvement of a coexisting psychiatric illness. Figure 10–7 illustrates the
pattern of dysphoric symptoms in a woman initially presenting to our clinic
with PMS and who had the diagnosis of PMS confirmed prospectively. Af-
ter the onset of menstrual cycle irregularity, she developed a pattern of
chronic dysphoria punctuated by symptom-free intervals during the men-
strual and postmenstrual phases of the menstrual cycle. Thus, instead of
PMS, it appeared that this patient experienced a brief, postmenstrual-
related remission of the symptoms of a chronic affective disorder.
Menstrual cycle phase may influence the appearance (as opposed to
the severity) of symptoms of a concurrent psychiatric disorder. Suther-
land (1892) noted that 99 of 162 women with mania characteristically
experienced their mania during (88 women) or within 1 day to 1 week
before (11 women) their menses. The episodic symptoms of certain psy-
chiatric disorders (e.g., bulimia and panic disorder) have been reported
anecdotally as being disproportionately frequent during the premenstrual
phase. Although several authors have noted premenstrual increases in
food cravings and appetite in women with and without PMS (Both-Orth-
man et al. 1988; Cohen et al. 1987; Fankhauser et al. 1989; Smith and
Sauder 1969), no consistent premenstrual increase in bulimic episodes
has been observed. Similarly, studies have failed to identify a menstrual
cycle phase–related exacerbation or clustering of the symptoms of panic
or anxiety in patients with panic disorder (Cameron et al. 1988; Cook et
al. 1990; Stein et al. 1989).
Menstrual Cycle–Related Events May Trigger the

Recrudescence of Previously Experienced Psychiatric Illness
The menstrual cycle may also influence the reappearance of characteristic
symptoms of a psychiatric disorder that otherwise appears to be in remis-
sion. In 1868 Isaac Ray stated that “in female patients, the menstrual pe-
riod may produce an abnormal excitement after convalescence appeared
to be firmly established” (Evans 1893). Brockington et al. (1988) reported
this phenomenon in three cases of postpartum psychosis in which a remis-
sion was disturbed by a time-limited recrudescence of the original symp-
toms during the premenstruum. This relationship between the menstrual
cycle and postpartum illness is of particular interest given the reports of a
higher-than-expected prevalence of a history of postpartum depression in
some patients with PMS (Warner et al. 1991). These reports suggest that
hormonal changes such as those seen during the postpartum period and
the premenstrual phase of the normal menstrual cycle may trigger the re-
currence of a previously experienced mood or behavioral disturbance.
FIGURE 10–7. Daily self-ratings of sadness in a woman with prospectively confirmed PMS.
After the onset of menstrual cycle irregularity (hatched histogram), the patient’s ostensible premenstrual dysphoria became a chronic dysphoria punctuated
by symptom-free intervals during the menstrual and postmenstrual phase of her infrequently occurring menstrual cycles.
263
Treatment Approaches
Until recently, the ability of medical professionals to help women with

PMS was limited and for the most part was confined to unproven thera-
pies (e.g., progesterone) or to lifestyle and dietary manipulations. Some
nutritional, behavioral, and cognitive approaches—such as the initiation
of regular exercising, restriction of caffeine consumption, and education
regarding sleep hygiene—may benefit some women.
Our approach to treatment is founded on the principle that the cor-
nerstone of effective treatment is a careful evaluation. A complete med-
ical and psychiatric history and review of systems is required to rule out
medical disorders (e.g., hypothyroidism) that may masquerade as an ep-
isodic mood disorder as well as psychiatric disorders, the symptoms of
which may or may not vary according to the phase of the menstrual cycle.
The patient is then told that, both for purposes of evaluation and to es-
tablish a baseline against which the efficacy of treatment can be mea-
sured, it will be necessary for her to rate the intensity of her symptoms
on a daily basis for the next few cycles. Either 100-mm line scales or six-
point severity scales can be used to track the appearance and intensity of
commonly experienced symptoms or of symptoms that the patient iden-
tifies as most characteristic of her syndrome. For practical purposes, the
Daily Rating Form (Endicott and Halbreich 1982) permits the patient
and physician to determine at a glance the relationship between symp-
tom appearance and menstrual cycle phase. These daily ratings serve sev-
eral functions. First, they establish whether symptoms appear during the
luteal phase and are confined to that phase, whether they occur chroni-
cally with premenstrual exacerbation, or whether they lack menstrual
cycle–related variation (e.g., depression or recurrent brief depression).
Second, they provide considerable information about the life and symp-
tom determinants of the patient, irrespective of the diagnosis. Third, they
provide considerable therapeutic benefit: the patient not only develops
self-observational skills that can assist her treatment but additionally may
experience relief in response to the validation, predictability, and control
that are conferred by the rating process.
For most women with PMS (as defined in this chapter), manipula-
tions of lifestyle are not sufficient, and some form of medication is usually
prescribed. A multitude of vitamins and minerals—such as pyridoxine
(vitamin B6), vitamin E, vitamin A, magnesium, and calcium—have been
studied as treatment modalities for PMS. All of these agents have shown
inconsistent results and have not been proved to be superior to placebo.
Other agents—such as diuretics, b-blockers, prostaglandin inhibitors, and
prolactin inhibitors—may have some beneficial effects for specific symp-

toms but are not overall effective treatments for PMS (Altshuler et al.
1995; Rausch and Parry 1993; Rubinow and Schmidt 1995; Steiner et al.
1995; Yonkers et al. 1997). However, the two options that at this time
are associated with replicable efficacy are the selective serotonin reup-
take inhibitors (SSRIs) (Steiner et al. 1995; Stone et al. 1991; Su et al.
1997; Sundblad et al. 1992; Wood et al. 1992; Yonkers et al. 1997) and
ovarian suppression (Bancroft et al. 1987; C.S. Brown et al. 1994; Free-
man et al. 1993; Hammarback and Backstrom 1988; Hussain et al. 1992;
Mezrow et al. 1994; Mortola et al. 1991; Muse et al. 1984; West and
Hillier 1994). As such, one can easily justify a trial of an SSRI in someone
with PMS, with either continuous therapy or the intermittent adminis-
tration of medication from (approximately) ovulation until the onset of
menses. SSRIs are effective in only 50%–60% of patients with PMS, with
predictors of efficacy currently undetermined. In most studies the effec-
tive dose of an SSRI in PMS is lower than that required for the treatment
of major depression and may additionally require adjustment of dosage
(up or down) or time of administration (morning or evening) to assess ef-
ficacy or manage side effects (particularly sleep disturbance). For those
who are unresponsive or for whom side effects (e.g., sexual dysfunction)
may limit treatment, any of the other putative therapeutic agents may be
employed, albeit with even less of a guarantee of success. Use of ovarian
suppression should be reserved for women with severe PMS and for whom
oophorectomy would be a potential option (i.e., women who will not
wish to have additional children). Although they require application of
both the art and the science of medicine, menstrual cycle–related mood
disorders are treatable conditions.
Perimenopause-Related Depression
Defining Questions
How Is the Perimenopause Defined and Characterized?
In the past, several different criteria have been employed to define the
reproductive status of women participating in studies of the relationship
between menopause and mood. First, an age window of 45–55 years has
been used to select perimenopausal subjects. Although the average age
of the menopause is 51 years, there is considerable individual variation in
the age at onset of the menopause, ranging from the early 40s to the late
50s. Adopting an age window as the sole selection criteria will inevitably
result in the selection of a heterogeneous sample of women in different
phases of reproductive life: some premenopausal, some perimenopausal,

and some postmenopausal. Second, investigators have employed age
combined with retrospective or prospective self-reports of menstrual
cycle history and have defined the menopause as 6 months to 1 year of
amenorrhea and the perimenopause as menstrual cycle irregularity. How-
ever, self-reports of menstrual cycle irregularity cannot be used to reliably
define reproductive status. Treolar (1981) observed that menstrual cycle
irregularity is not confined to the perimenopause and may occur fre-
quently during other periods of reproductive life. Moreover, Kaufert et
al. (1987) observed that, among a sample of middle-aged women with
menstrual cycle irregularity, as many women returned to normal men-
strual cycle function as entered the menopause (defined by 6 months of
amenorrhea) during a 3-year period of follow-up. The third criterion
commonly used to define reproductive status has been the presence of el-
evated plasma gonadotropin levels in the context of low plasma estradiol
levels. However, perimenopause-related elevations in gonadotropins
may be reversible, and, again, the sole reliance on elevated gonadotropin
levels may result in the selection of heterogeneous samples of women un-
less gonadotropin levels are subsequently measured to prospectively con-
firm group assignment. For example, we have observed several women
who presented with a history of either menstrual cycle irregularity or
amenorrhea and with elevated gonadotropin levels but whose mood
symptoms and hot flushes improved over a 2-month period associated
with a resumption of normal estrogen production and a return of plasma
gonadotropin levels to the premenopausal range (Daly et al., unpub-
lished data, June 1992). Thus, a combination of both menstrual cycle his-
tory and elevated gonadotropin levels may be the best method for
selecting and characterizing the reproductive status of perimenopausal
women, but it is not necessarily predictive of future reproductive func-
tion.
Do Disturbances of Mood Occur During the Perimenopause?

Studies attempting to determine whether mood disturbances are associ-
ated with the perimenopause have been complicated by several method-
ologic issues. First, problems have arisen when investigators attempted
to measure specific depressive symptoms by using rating scales designed
to measure the severity of depressive syndromes and which may, therefore,
fail to sample relevant symptoms or be sufficiently sensitive to changes in
target symptoms. A second problem in studies examining the possible oc-
currence of depression during the perimenopause has been the failure to
distinguish between instruments designed to measure the severity of an
affective syndrome (a rating scale) and those established to diagnose an

affective syndrome (a structured diagnostic interview). A third methodo-
logical problem, present in most investigations of the linkage between
the perimenopause and disturbances in mood and behavior, has been the
overly restrictive supposition on the part of investigators about the na-
ture of the mood disturbance.
Debates over the phenomenology of perimenopausal affective disor-
ders date back more than a century. In a paper by William Conklin (1889),
a form of neurasthenia or mixed anxiety–depressive illness was described
in relation to the perimenopause. In addition to case reports verifying
Conklin’s description of neurasthenia-like disorders during the peri-
menopause, medical observers such as Maudsley in England (Merson
1876) and Kraepelin in Germany (Kraepelin 1896/1975) also suggested
that a special form of melancholia occurred during the perimenopause,
commencing a controversy in psychiatry that continues to date and has
overshadowed attempts to further explore other perimenopause-related
affective syndromes.
Several influential studies have not confirmed the existence of invo-
lutional melancholia (Weissman 1979; Winokur and Cadoret 1975), and
some studies have not identified an increased prevalence of major depres-
sive disorder during the perimenopause. Perimenopause-related depres-
sion, in contrast to postpartum depression, is therefore not recognized as
a distinct condition in DSM-IV-TR. Nonetheless, studies have not dis-
proved a relationship between depression and the perimenopause in
women who experience depression in this context. In particular, the oc-
currence of a neurasthenia or atypical depression associated with the
menopause, described in early case reports, has been largely ignored. In
fact, the symptoms of 40 women presenting to our clinic with depression
associated with the perimenopause were consistent with minor depres-
sion (as determined by the Schedule for Affective Disorders and Schizo-
phrenia [Spitzer et al. 1978]), with an increased frequency of symptoms
such as irritability, tearfulness, anxiety, disturbed sleep, difficulty concen-
trating, and food cravings (Table 10–2). Furthermore, some studies sug-
gest that the perimenopause in some women may interact with and alter
the course of primary affective disorder (Angst 1978; Kukopulos et al.
1980).
What Are the Possible Relationships Between

Mood Disturbances and the Perimenopause?
Several possible relationships exist between the onset of disturbances of
mood and behavior and the perimenopause. First, several investigators
TABLE 10–2. Presenting symptoms of depression during the

perimenopause (N=40)
Percentage showing
Symptom symptom
Irritability 70
Tearfulness 70
Excessive worry 67
Anxiety 67
Mood more fragile; easily upset by life events 64
Depressed mood 61
Mood instability 61
Increased appetite, cravings 58
Unmotivated 56
Decreased energy 53
Poor concentration 53
Early-morning waking 50
Interrupted sleep 50
Emotionally detached from important people in life 50
Note. Subjects met criteria for major or minor depression after administration of the
Structured Clinical Interview for DSM-IV (Spitzer et al. 1990) and the modified Schedule
for Affective Disorders and Schizophrenia—Lifetime Version (Spitzer et al. 1978), respec-
tively.
have suggested that it is a purely coincidental relationship and that there

is no specific etiologic connection between reproductive endocrine
events and the experience of a change in mood and behavior during this
phase of a person’s life. Second, the perimenopause may act as a nonspe-
cific stress related to midlife and the vicissitudes of aging, whereby a
change or a loss of self-esteem (or depression) is precipitated in response
to stressful life events in someone who is predisposed to experience these
symptoms. Third, the perimenopause causes specific somatic symptoms
such as hot flushes, which may produce a secondary sleep disturbance
that is sufficient to result in daytime somnolence, decreased energy, and
other mood and behavioral symptoms. Certainly, some women with se-
vere nocturnal hot flushes may present with disturbances of mood and
behavior; however, hot flushes by themselves are neither necessary nor
sufficient for the production of mood and behavioral disturbances in
perimenopausal women. A fourth possible relationship is that the peri-
menopause may result in the de novo appearance of mood and behav-
ioral symptoms or may modulate mood and behavioral disorders. This
relationship implies that the endocrine-related events of the peri-
menopause may alter candidate neurotransmitter systems associated
with psychiatric illness. This possibility suggests the potential importance

of either estrogen withdrawal/deprivation or perimenopause-related un-
opposed estrogen exposure (due to more frequent anovulatory cycles) in
the development of mood and behavioral disturbances in the perimeno-
pause.
The Perimenopause and Affective Disorders

Causal Relationship
The manifold interactions between gonadal hormones and neurotrans-
mitters and neuromodulators suggest a possible neurobiological basis for
the effect of alterations in reproductive hormone activity on mood and
behavior. The extent to which interactions between gonadal hormones,
gonadotropins, catecholamines, neuropeptides, and neurosteroids actu-
ally influence the development of climacteric-related and menopause-
related mood and behavioral disorders is purely a matter for speculation
(McEwen and Alves 1999; Roca et al. 1999; Rubinow et al. 1998). None-
theless, it seems clear that changes in reproductive endocrine function
would be accompanied by discrete alterations in central nervous system
neurotransmitter activity that may constitute relevant mechanisms in the
pathophysiology of mood disorders. Furthermore, the rate of hormonal
changes may be an important regulatory variable, perhaps conveying a
differential behavioral sensitivity to sudden (surgically induced meno-
pause) versus gradual (natural menopause) decline of ovarian function
(Kaufert et al. 1992; Kritz-Silverstein et al. 1993).
Despite the inferred potential of perimenopausal changes in gonadal
steroids to alter human behavior, several epidemiological studies have
suggested that in fact there is no relationship between the onset of de-
pression and changes in reproductive function during the perimeno-
pause. In general, the types of evidence that have been adduced to refute
the existence of involutional melancholia are epidemiological and phenom-
enological. Weissman (1979) studied a sample of 422 women consecu-
tively admitted as outpatients with diagnoses of major nonbipolar
depression. Using an age criterion of 45–55 years for defining meno-
pausal status, Weissman found no difference in symptom patterns and
number of previous depressive episodes between the 347 women
younger than age 45 (presumed premenopausal) and the 75 women older
than age 45 (presumed menopausal or postmenopausal). Weissman con-
cluded there was not sufficient evidence to consider involutional-onset
depression as a distinct entity. In agreement with Weissman’s findings,
studies have not demonstrated an increased risk of suicide or psychiatric

hospitalization in women during the perimenopause or postmenopause
years. Furthermore, despite a generally higher prevalence rate of de-
pression in females compared with males, several studies reported a
slightly lower 6-month prevalence rate of depression during the pre-
sumed menopausal-climacteric years than in younger age groups (Weiss-
man et al. 1988).
However, this evidence is far from conclusive in refuting the existence
of a perimenopause-related affective syndrome. Despite similar or lower
point prevalence rates and similar clinical presentations of depression
during the menopause and at other times of life, one cannot infer that
these syndromes share identical etiologies. At least two investigators re-
ported involutional-onset depression to be associated with a lower family
history of depression than that observed in patients with early-onset de-
pression (R.P. Brown et al. 1984; Stenstedt 1959). Thus, while peri-
menopausal major depression (as opposed to minor depression) does not
appear to be phenomenologically distinct, there is some evidence sug-
gesting that it may differ from earlier-onset depression with respect to
family history and age at index depressive episode (R.P. Brown et al.
1984). It is not unusual in medicine for phenomenologically similar dis-
orders to have different precipitants or causes; for example, meningitis in
both the neonate and the infant may present with fever, vomiting, and
drowsiness, yet different pathogenic organisms are typically involved
with each age group.
Some epidemiological studies have suggested, in contrast to the con-
clusions described above, that the perimenopause may be a period of life
that increases the vulnerability of a woman to experience depression
(Kessler et al. 1993). For example, some studies report that during
midlife, compared with other periods of reproductive life, the sex ratio
for depression increases from 2:1 to 3–4:1 (female to male) (Kessler et
al. 1993; Myers and Weissman 1980). In addition, although Winokur
(1973) concluded that his data did not support the idea of menopause as
an important precipitating factor in episodes of affective disorder, he ob-
served that the postmenopausal women in his sample described a high
frequency of symptoms of depression (38%) and nervousness (75%);
consequently, he elected to use more stringent diagnostic criteria for de-
pression (e.g., need for hospitalization) during the 3 years after meno-
pause. Thus, although Winokur concluded that there is no increase in risk
of depression during the 3 years after the menopause, his risk rates were
decreased spuriously by employing more stringent diagnostic criteria for
depression during the 3 years after the menopause compared with de-
pression during other periods of life. Similarly, studies have reported a
high prevalence of mood and behavioral symptoms in women after

oophorectomy (Oldenhave et al. 1993), which in some studies exceeds
the prevalence of symptoms reported by women after natural menopause
(Kritz-Silverstein et al. 1993). In multinational preliminary data, Weiss-
man et al. (unpublished data, May 1995) observed an increased hazard
rate for onset of depression in their older cohort of women (but not men)
during ages 45–50. Finally, some clinic-based treatment trials report the
improvement of mood and behavioral symptoms in perimenopausal
women with estrogen replacement, suggesting a potential role for ovarian
steroids in the treatment and possibly the development of depression
during the perimenopause (Brincat et al. 1984; Montgomery et al. 1987;
Schmidt et al. 2000; Soares et al. 2001). Thus, although the perimeno-
pause is not associated with the development of depression in the majority
of women, the endocrine changes during this phase of life may be related
to the onset of depression in some women.
Treatment Recommendations
The management of mood and behavioral disturbances during the peri-
menopause requires the determination of the symptoms experienced and
the hormonal context in which they appear. As a complement to the
usual dicta regarding careful neuropsychiatric evaluation, longitudinal
monitoring of symptoms on a daily basis may provide invaluable infor-
mation about the severity, stability, and pattern of symptom experience.
Both affective and relevant somatic symptoms (e.g., vaginal dryness, hot
flushes) should be followed up. If it was not previously done, the pres-
ence of the perimenopause and hypoestrogenism should be documented
with FSH and estradiol measures. As part of our operational criteria, we
have required three of four serial FSH levels to be greater than 20 IU/L
(depending on the laboratory) for the perimenopause and greater than 40
IU/L for the menopause. Although estradiol levels below 60 pg/mL are
consistent with decreased ovarian function, levels above 60 pg/mL may
nonetheless appear in the presence of markedly elevated FSH levels that
suggest ovarian insensitivity.
The therapy selected for a major depressive disorder during the peri-
menopause will depend on the nature and severity of the somatic symp-
toms and the presence (or absence) and type of hormone replacement
therapy. In perimenopausal women presenting with depression, the pres-
ence of distressing signs of estrogen deficiency such as vaginal dryness and
hot flushes should lead to consideration of a trial of estrogen therapy, un-
less contraindications to estrogen treatment exist (e.g., history of breast
cancer). Alternatively, if perimenopausal somatic symptoms are mild or
minimal, despite laboratory evidence of perimenopausal reproductive

status, and moderate to severe mood symptoms are present, then the
choice of hormone versus antidepressant therapy may be best informed
by such factors as personal history of depression, family history of affec-
tive disorder, severity of affective symptoms, or the presence of contra-
indications to estrogen therapy.
The relationship between the onset of mood symptoms and the initi-
ation of hormone therapy should be determined for at least two reasons.
First, mood and behavioral symptoms may appear with inadequate estro-
gen replacement and can remit with appropriate dosage adjustments or
with a change to an alternative form of estrogen therapy. Adjustment of
hormone therapy is therefore recommended before considering adjunc-
tive psychopharmacotherapy. Second, mood and behavioral symptoms
may directly result from the hormone therapy. Specifically, cyclic mood
and behavioral symptoms have been reported in association with sequen-
tial hormone replacement in some (Hammarback et al. 1985; Magos et
al. 1986), but not all (Kirkham et al. 1991; Prior et al. 1994), studies and
may remit with a change in the replacement regimen from sequential to
continuous combination therapy. Alternatively, if addition of progester-
one consistently precipitates adverse mood changes, estrogen therapy
alone may be attempted if it is accompanied by appropriate monitoring
of the endometrium. Symptoms of depression and loss of libido con-
sequent to ovarian failure may nonetheless be responsive to antidepres-
sant therapy, and this option should not be ruled out irrespective of the
strength of the association between ovarian dysfunction and affective dis-
order.
Potential roles for testosterone (Sherwin 1988; Sherwin and Gelfand
1985, 1987; Sherwin et al. 1985) or dehydroepiandrosterone (Bloch et
al. 1999; Wolkowitz et al. 1999) in the treatment of perimenopause- or
midlife-associated sexual dysfunction or depression have also been pro-
posed. The value of these proposed treatments awaits determination.
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Chapter 11
Endogenous Gonadal Hormones in

Postpartum Psychiatric Disorders
Lisa S. Weinstock, M.D.

Lee S. Cohen, M.D.
D escriptions of postpartum mood disturbance date back to

the time of ancient Greece. The Greeks attributed postpartum illness to
a “wandering uterus.” Despite the evolving understanding of brain func-
tion, the knowledge of what factors mediate the pathophysiology of post-
partum psychiatric illness remains limited. Psychiatric symptoms that
manifest at particular points across the female life cycle—such as the pre-
menstrual period, pregnancy, or the puerperium—have frequently been
attributed to changes in female reproductive physiology. This has been
the case despite an absence of systematically derived data from well-stud-
ied populations of women that might support the association between
depressive symptoms, for example, and specific changes in hormonal sta-
tus. Factors such as personal or family history of mood disorder and psy-
chosocial support appear to be more consistently associated with risk for
affective disorder at certain points in the female life cycle. This chapter
describes the spectrum of postpartum psychiatric disorders. Epidemiol-
ogy and etiology are reviewed. Risk factors for postpartum psychiatric ill-
ness as well as evaluation and treatment approaches are also discussed.
Particular attention is given to the potential role of endogenous gonadal
hormones in the modulation of postpartum psychiatric disorders.
Postpartum affective disorders are frequently classified into three
categories: postpartum blues, postpartum depression, and postpartum
psychosis. In this chapter we describe these syndromes with respect to
epidemiology, risk factors, etiology, pathophysiology, and strategies for
evaluation and treatment.
281
Overview of Postpartum Psychiatric Disorders

Postpartum Blues
Postpartum blues, also known as maternity blues, are the least severe
forms of postpartum psychiatric disorder. They are a commonly expe-
rienced phenomenon, with an estimated prevalence ranging from 26%
to 85% (O’Hara 1991). Blues occur typically in the first week after
delivery. Common features include crying spells, anxiety, mood labil-
ity, confusion, sleep and appetite disturbance, irritability, and depressed
mood. Symptoms usually appear between postpartum days 3 and 7
(Kendell et al. 1981), although they can be seen as early as postpartum
day 1 (Yalom et al. 1968). Symptoms typically remit by postpartum day
10.
Postpartum Depression
Postpartum depression represents a more severe form of puerperal mood
disturbance. Unlike blues, symptoms emerge slowly during the first few
weeks after delivery. Symptoms include those characteristic of other
major depressive episodes: dysphoric mood, loss of interest, decreased
energy and appetite, sleep changes, guilt, change in psychomotor activ-
ity, diminished concentration, and potential suicidality. Because some
symptoms of depression—such as sleep disturbance, fatigue, and appe-
tite changes—can be normative during the postpartum period, it may be
difficult to distinguish such vegetative symptoms of depression from
those more characteristic of a depressive episode. The severity of post-
partum depression ranges from mild to severe. Postpartum mood distur-
bance may also be classified as psychotic or nonpsychotic.
Prevalence rates of nonpsychotic postpartum major depression are es-
timated between 6.8% (Gotlib et al. 1989) and 16.5% (Whiffin 1988).
The extent to which pregnancy and the postpartum period constitute a
period of increased risk for affective disorder has been addressed in sev-
eral studies, with inconsistent results. Several studies have shown that the
risk of depression after delivery is higher than the risk of depression dur-
ing pregnancy (Kumar and Robson 1984; Watson et al. 1984). However,
studies that compare rates of depression during the postpartum period to
rates of depression in nonpuerperal women have not consistently shown
a significant difference in rates of mood disturbance (O’Hara 1986;
O’Hara et al. 1991). Although rates of postpartum mood disturbance
may not vary from those seen in a matched control group, other data sug-
Endogenous Gonadal Hormones in Postpartum Disorders 283
gest that women with histories of depression are at significantly increased

risk for postpartum major depression (O’Hara 1995; O’Hara et al. 1983).
In addition, depression during pregnancy appears to be a strong predictor
of postpartum depression (O’Hara et al. 1991). Postpartum depression
typically lasts between 3 and 6 months, although many women report
episodes lasting more than 1 year (Cox et al. 1982). Proposed risk factors
for postpartum depression are listed in Table 11–1.
TABLE 11–1. Risk factors for postpartum depression

History of prior episode of postpartum depression
Depression during pregnancy
History of nonpuerperal depression
Family history of depression
Marital discord
Stressful life events
Stressful newborn-related events
Source. Altshuler L, Hendrick V, Cohen L: “Course of Mood and Anxiety Disorders Dur-
ing Pregnancy and the Postpartum Period.” Journal of Clinical Psychiatry 59 (suppl 2):29–
33, 1998.
Postpartum Psychosis
Postpartum psychosis is the most severe form of postpartum mood distur-
bance. Typical symptoms include hallucinations or delusions, confusion,
and (occasionally) severely depressed mood. The incidence is estimated
at approximately 1 in 1,000 to 4 in 1,000 births (Brockington et al.
1982). Although nonpsychotic postpartum depressive episodes may typ-
ically emerge during the first 4 weeks after delivery, puerperal psychotic
episodes begin earlier in the immediate postpartum period—very often
within the first few days after delivery. Several studies suggest that the
first 30 days postpartum represent a period of increased risk for new-
onset psychosis (Kendell et al. 1987; McNeil 1987; Nott 1982). In a fre-
quently cited study by Kendell et al. (1987), it was described that the
number of psychiatric admissions in women during the first 30 days after
delivery was much higher than in a 30-day nonchildbearing period during
pregnancy or after 30 days postpartum.
Whether postpartum psychoses are distinct from psychotic episodes
that occur at other times has been debated. Many have suggested that
most postpartum psychosis is a form of affective disorder, specifically bi-
polar disorder. For example, a study by Brockington et al. (1981) deter-
mined that women with postpartum psychosis experienced higher levels
of euphoria, activity, incompetence, and confusion than women with

nonpuerperal psychosis. However, the women in the postpartum psycho-
sis group were primarily women with depression or mania, whereas the
women in the other group were primarily diagnosed with schizophrenia
or schizoaffective disorder. Kendell’s epidemiological study revealed that
women with histories of manic-depressive illness were at the highest risk
for psychiatric admissions during the postpartum period (Kendell et al.
1987). Many researchers believe that postpartum psychosis represents a
form of bipolar disorder, and women with histories of bipolar disorder
appear to be at increased risk for postpartum psychotic episodes (Dean
et al. 1989).
Etiology of Postpartum Psychiatric Disorders:

Endocrine Factors
A number of potential causes of postpartum psychiatric syndromes have

been investigated. These include both biological and psychosocial factors
that may contribute to affective worsening in the postpartum period. In
this section we describe the endocrine changes that take place during
pregnancy.
Endocrine Changes in Pregnancy and the Puerperium

Given the significant and rapid changes in the reproductive environment
characteristic of the postpartum period, a considerable focus has been
placed on the role of hormones in the etiology of postpartum affective
syndromes. Pregnancy and the puerperium are a time of significant endo-
crinologic change. Hormones that undergo changes during pregnancy in-
clude peptide hormones—such as human chorionic gonadotropin (hCG),
human placental lactogen (hPL), prolactin, gonadotropin-releasing hor-
mone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone
(LH), and b-endorphins—as well as steroid hormones such as progester-
one, estrogens, androgens, and glucocorticoids. Significant changes in the
thyroid system occur during pregnancy as well. What follows is a brief
description of the major hormonal changes seen during pregnancy and
the postpartum period, and a review of effects these hormones have on
the neural systems associated with psychiatric disorders. How these hor-
monal changes (and their impact on neuromodulating systems in the
brain) affect pregnancy and the puerperium has yet to be adequately de-
lineated.
Human Chorionic Gonadotropin

A glucoprotein produced by the placenta, hCG functions to maintain
pregnancy. Levels of hCG begin to rise 8 days after ovulation and peak
between days 60 and 90. The concentration of hormone then falls to a
constant level during the period between 100 and 130 days of pregnancy
(Cantazarite et al. 1987). Concentrations of hCG fall precipitously dur-
ing the first 48–96 hours postpartum. We know of no studies investigating
the relationship between hCG and the neurotransmitter systems associ-
ated with psychiatric disorders.
Human Placental Lactogen

hPL is a single-chain polypeptide similar to pituitary growth hormone
and prolactin. Maternal serum concentrations rise throughout gestation
and are at maximum levels in the last month of pregnancy. hPL has a
half-life of 20 minutes, and the concentration of this hormone falls pre-
cipitously after delivery, becoming undetectable by postpartum day 2. As
is the case with hCG, there is no evidence that hPL affects neurotrans-
mitter systems associated with psychiatric disorders.
Gonadotropin-Releasing Hormone
GnRH is a decapeptide produced by the hypothalamus and is responsible
for synthesis and release of LH and FSH from the pituitary. In nongravid
women, GnRH is released in a pulsatile fashion. Hypothalamic release of
GnRH is suppressed during pregnancy and early in the puerperium.
The relationship between GnRH and behavior has not been well stud-
ied. In animals, central administration of GnRH has been shown to en-
hance sexual behavior (Moss and McCann 1973). In humans, GnRH
cannot be easily measured in the systemic circulation. The extent to which
GnRH dysregulation might contribute to puerperal psychiatric disorders
has not been explored.
Follicle-Stimulating Hormone and Luteinizing Hormone

Serum concentrations of FSH and LH are low in all women during the
first 10–12 days postpartum. Levels then increase and reach follicular-
phase concentrations by postpartum week 3. Low levels of postpartum
LH and FSH are believed to be due to decreased GnRH secretion during
pregnancy and the early puerperium. Pituitary gonadotropins have no
known central nervous system actions on neurotransmitter systems asso-
ciated with psychiatric disorders; there is no evidence that changes in lev-

els of either FSH or LH are related to postpartum psychiatric illness.
b-Endorphin
Circulating levels of b-endorphins increase during late pregnancy and
reach very high levels during delivery. Levels then drop rapidly during
the first few hours after delivery (Newnham et al. 1984). However, se-
rum b-endorphin does not cross the blood-brain barrier and does not re-
flect central nervous system concentration of b-endorphin.
Prolactin
Prolactin is a peptide hormone, made in the anterior pituitary (see Chap-
ter 5, this volume). Plasma concentrations in nonpregnant women are ap-
proximately 10 ng/mL. During pregnancy, maternal blood levels rise to
concentrations of 200 ng/mL. In nonlactating women, levels decline
postpartum over a period of approximately 2 weeks. In women who
breastfeed, levels remain above the nongravid range and increase in re-
sponse to suckling. If breastfeeding occurs 1–3 times a day, prolactin
returns to nongravid levels within 6 months; if breastfeeding occurs more
than 6 times a day, levels can remain high for up to 1 year postpartum
(Novy 1987). In the hypothalamus, increasing concentrations of pro-
lactin lead to increases in dopamine release, which then inhibits further
prolactin release. Studies of the effects of prolactin on other dopamine
systems of the brain have not consistently shown any specific effects of
prolactin on dopamine binding sites. One study showed hyperprolactine-
mia increasing striatal dopamine receptor binding sites (Hruska et al.
1982), but another series of studies failed to show an effect of hyperpro-
lactinemia on dopamine receptor binding sites in the striatum (Simpson
et al. 1986). In nonchildbearing women, hyperprolactinemia has been as-
sociated with depression, anxiety, and hostility (Simpson et al. 1986).
Estrogen
Estrogens are produced by both the placenta and the fetus during preg-
nancy. Estrone and estradiol are produced by the placenta through con-
version of the androgen dehydroepiandrosterone sulfate (DHEA-S),
which is produced by fetal and maternal adrenal glands. Estriol is also syn-
thesized by the placenta, but from the precursor 16a-hydroxy DHEA-S,
produced by the fetal liver from adrenal DHEA-S (Campbell and Wino-
ker 1985). Plasma levels of estrogens rise dramatically throughout preg-
nancy, increasing in an almost linear fashion in late pregnancy (Carsten

1986). After delivery, plasma levels of estrogens decline very rapidly.
Within 3 hours after removal of the placenta, plasma concentrations of
estradiol fall to 10% of the antepartum value (Cantazarite et al. 1987).
Within 24 hours after delivery, estradiol levels in the maternal circulation
are less than 2% of prepartum levels. Estrone and estriol levels fall at
similar rates (Filer 1992). The lowest levels of estrogens are reached by
1 week postpartum, and levels do not climb back to follicular-phase
levels until approximately 3 weeks postpartum in nonlactating women.
In lactating women levels remain low anywhere from 60 to 180 days
postpartum, depending on the timing of the return of menses (Novy
1987).
In addition to their role in the feedback mechanisms associated with
control of the menstrual cycle, estrogens appear to have effects on neu-
rotransmitter systems implicated in the etiology of mood and anxiety dis-
orders. Estrogens have been shown to have neuroleptic-like effects on
dopamine systems in animals. For example, estradiol administration has
been shown to cause changes in dopaminergic receptor function in rat
striatal tissue (Hruska and Silbergeld 1980; Levesque and DiPaolo 1993).
Administration of estrogens leads to an increase in dopaminergic receptor
density (Hruska and Silbergeld 1980), and long-term administration of
estrogen leads to an effect similar to that seen with long-term administra-
tion of antipsychotics, producing dopamine supersensitivity on with-
drawal of estrogen (Gordon et al. 1980). It has also been reported that
elevated estrogen levels decrease tyrosine hydroxylase activity, thereby
decreasing dopamine synthesis (Blum et al. 1987). Resultant reduction in
synaptic dopamine after estrogen administration is hypothesized to lead
to dopamine supersensitivity (Snyder 1977). These animal findings are
consistent with the theory that the large increases in estrogen levels seen
during pregnancy, followed by rapid withdrawal of estrogen postpartum,
may cause dopamine supersensitivity. It has been theorized that this do-
pamine supersensitivity may lead to increased vulnerability to psychosis
or affective instability in certain women (Kumar et al. 1993).
Exogenous estradiol has also been associated with changes in seroto-
nin and noradrenaline receptor function in the brains of animals (Ken-
dall et al. 1981; Wagner et al. 1979). Studies have shown that estrogen
treatment decreased b-adrenoreceptor binding in rat cerebral cortex (Wag-
ner et al. 1979). Kendall et al. (1981) reported that ovariectomy prevents
antidepressant-induced downregulation of the 5-hydroxytryptamine
(serotonin) type 2 (5-HT2) receptor, and that this effect is reversed with
estradiol administration. It is unclear how the rapid withdrawal of es-
trogen seen in the early postpartum period may impact the serotonergic
and noradrenergic systems implicated in the etiology of depressive dis-

orders.
Progesterone
Progesterone is produced by the ovary during the first 6–7 weeks of preg-
nancy, and then production shifts to the placenta. At term, serum proges-
terone levels are approximately 170 times higher than levels seen in the
follicular phase of the menstrual cycle (Filer 1992). Levels fall precipitously
after delivery, and the half-life of progesterone is calculated in minutes
(Novy 1987). As the corpus luteum of pregnancy continues to produce
small amounts of progesterone during the first few days postpartum, levels
do not fall as precipitously as do estrogen levels (Filer 1992). However, by
postpartum day 3, plasma levels are lower than those observed in the luteal
phase of the menstrual cycle, and by the end of postpartum week 1, levels
are as low as those seen in the follicular phase (Filer 1992).
A progesterone metabolite, 3a-hydroxy-5a-dihydroxyprogesterone
(allopregnanolone) has been shown to bind to g-aminobutyric acid type
A (GABA-A) receptors in rat brain, mimicking the GABA-mediated in-
hibition produced by benzodiazepines and barbiturates (Majewska et al.
1986). Administration of micronized progesterone has been associated
with sedative and hypnotic effects similar to those seen with benzodiaz-
epines (Arafat et al. 1988; Freeman et al. 1992).
Androgens
Serum levels of testosterone increase throughout pregnancy and are signif-
icantly elevated in the third trimester. The increase is due to the increase
in estrogen, which causes an increase in the liver-synthesized binding
protein that binds both estrogen and testosterone. Although total test-
osterone levels increase throughout pregnancy, free testosterone concen-
trations remain stable. At delivery, testosterone levels drop secondary to
the drop in binding protein, but free levels again remain stable. Levels of
DHEA and DHEA-S decrease during pregnancy because they are uti-
lized to produce the large amounts of estrogens synthesized by the pla-
centa. After delivery there is a gradual return of DHEA and DHEA-S to
baseline levels (Filer 1992).
Thyroid Hormones
Rapid fluctuations in thyroid indices occur in the immediate postpartum
period. During pregnancy, there is an increase in total thyroxine (T4) and
triiodothyronine (T3) levels secondary to increased liver production of

thyroid-binding globulin. However, levels of free T3 and T4 remain con-
stant. During the postpartum period, total T3 and T4 levels drop, but free
levels do not change (Filer 1992). Thyroid-stimulating hormone levels do
not differ significantly between the nonpregnant, pregnant, and postpar-
tum states (Novy 1987). Thyroid dysfunction, particularly blunted thy-
roid-stimulating hormone response to thyrotropin-releasing hormone,
has been associated with many psychiatric disorders, and thyroid dys-
function is often associated with affective symptoms (Cohen 1997) (see
Chapters 14 and 15, this volume).
Corticosteroids
Plasma concentrations of both free and bound cortisol rise during late
pregnancy and peak during labor. Postpartum levels rapidly fall to those
seen in late pregnancy, and then gradually return to pregravid concentra-
tions (O’Hara 1991). By postpartum day 1, levels have returned to the
antepartum range. Return of both cortisol and 17-hydroxycorticosteroid
to nonpregnant levels occurs by the end of the first postpartum week
(Novy 1987).
Hypercortisolemia and nonsuppression with dexamethasone have
been associated with depression (see Chapter 6, this volume). In addi-
tion, a reduced metabolite of deoxycorticosterone, 3a-5a-tetrahydrode-
oxycorticosterone, has been shown to modulate the GABA-A receptor
complex, interacting at a site close to or identical with that of barbitu-
rates (Majewska et al. 1986).
Endocrine Changes and Postpartum

Psychiatric Disorders
Given the rapid fluctuations of the hormonal environment noted in the

postpartum period, and evidence suggesting that many of these hor-
mones may affect the neurotransmission systems implicated in the
pathophysiology of psychiatric disorders, it has been hypothesized that
these postpartum endocrine changes may catalyze the onset of psychiat-
ric symptoms in some women during the postpartum period. However,
there are no consistent data suggesting a particular relationship between
concentrations of most of these hormones and what is seen clinically in
women who suffer from psychiatric disorders.
Postpartum Blues
Etiology
Endocrine factors. Systematic study of the relationship between endo-
crine factors and postpartum blues has yielded conflicting and incon-
clusive results. Nott et al. measured levels of LH, FSH, estrogen and
progesterone in women during the six weeks postpartum. They found no
consistent evidence of an association between specific changes in hor-
mone levels and changes in mood. However, a correlation was noted be-
tween irritability and antepartum estrogen levels (Nott 1982). Feksi et al.
(1984) describe a relationship between maternity blues and elevated
concentrations of salivary progesterone and estrogen. A study by Heid-
rich et al. (1994), however, failed to show significant differences in free
hormone levels of estradiol and progesterone between women with and
without postpartum blues. Gard et al. (1986) also found no difference in
estrogen or progesterone in the first 5 days postpartum between women
with or without maternity blues. No consistent relationship between cor-
tisol levels and postpartum blues has been found.
A few studies have looked at b-endorphin levels and postpartum
mood, but results have been inconsistent. One investigation noted a re-
lationship between low levels of b-endorphin at 36 weeks gestation and
severe symptoms of blues (Newnham et al. 1984). Another study showed
no association between b-endorphin levels and blues (Brinsmead et al.
1985).
Nonendocrine factors. Biological factors which have been investigated
as potential causes of postpartum blues include plasma tryptophan levels,
platelet monoamine oxidase (MAO), and platelet alpha receptors. Two
studies have noted an absence of normal increase in plasma tryptophan seen
typically in the first 2 days postpartum in association with postpartum blues
(Gard et al. 1986; Handley et al. 1980). However, tryptophan supplemen-
tation during the first 10 days postpartum did not reduce the incidence of
blues. One study showed that women with postpartum blues had more
platelet alpha 2 receptors than women without blues (Metz et al. 1983).
Psychosocial and demographic factors have been investigated in the
etiology of postpartum blues. First pregnancy and past history of PMS
appear to be risk factors for postpartum blues (Nott et al. 1976; Yalom
et al. 1968).
Treatment
Postpartum blues are generally considered to be a transient, self-limited,
and normal consequence of pregnancy. There is some evidence that blues
may predict risk for later postpartum depression. However, the majority
of women with postpartum blues recover without any negative sequelae
(O’Hara 1987). Appropriate treatment includes anticipation, support,
reassurance, and follow-up to ensure that symptoms have in fact remit-
ted by 2 weeks postpartum. Symptoms that continue beyond this time
frame may reflect an evolving mood disturbance.
Consequences
There have been no studies suggesting that postpartum blues has any
long-term negative effects on mother or child.
Postpartum Depression
Etiology
Endocrine factors. As is the case for postpartum blues, there is little
consistent evidence suggesting that a specific hormonal imbalance or ab-
normality is the cause of postpartum depression. Pedersen et al. (1993)
found higher cortisol levels during the puerperium in women with post-
partum dysphoria. O’Hara et al. (1991) did not find any difference in
plasma or urinary cortisol levels between depressed and nondepressed
women in the early postpartum period. Studies of dexamethasone sup-
pression have not shown a distinction between postpartum depressed
and nondepressed women in the early postpartum period (Greenwood
and Parker 1984; Singh et al. 1986).
O’Hara et al. (1991) did find significantly lower levels of estradiol at
gestation week 36 and postpartum day 2 among postpartum depressed
women. Studies examining the relationship between postpartum depres-
sion and progesterone levels have failed to show a consistent relationship
between level of depression and levels of progesterone (Ballinger et al.
1982; Kuevi et al. 1983). A study by Harris et al. (1989) reported lower
levels of progesterone in depressed breastfeeding women than in nonde-
pressed breastfeeding women, with the opposite effect seen in bottle-
feeding women. A study by Buckwalter et al. (1999) found that although
mood disturbances during pregnancy were associated with higher levels
of progesterone and lower levels of DHEA, in the postpartum period el-
evated testosterone levels were associated with greater mood disturbance.
Studies of thyroid function and postpartum mood have produced in-
consistent results as well. One study failed to show evidence of thyroid
disturbance associated with postpartum mood disturbance (Grimmel
and Larsen 1965). Two more recent studies did show an association
between thyroid dysfunction and postpartum mood disturbance (Harris
et al. 1989; Pop et al. 1991). Pedersen et al. (1993) found that women
with higher levels of postpartum dysphoria had lower free T4 levels and
higher T3 uptake at 38 weeks of pregnancy.
Nonendocrine factors. A number of studies describe risk factors that
appear to increase risk for postpartum depression. However, these stud-
ies tend not to be particularly consistent. No data suggest that age, parity,
or marital status are consistently associated with increased risk for post-
partum depression.
The extent to which certain psychosocial factors have been impli-
cated in the etiology of (or contribute risk for) postpartum depression has
also been explored. Some studies have noted an association between neg-
ative or stressful life events during pregnancy or during the postpartum
period and increased probability of postpartum depression. For example,
poor marital relationships have been associated with depression during
the postpartum period in some but not all studies (Blair et al. 1970; Feg-
getter and Gath 1981; Hopkins et al. 1987; O’Hara 1986; O’Hara et al.
1983). In contrast, poor social support has been associated quite consis-
tently with increased risk for postpartum depression (O’Hara et al. 1983;
Paykel et al. 1980).
Most studies have suggested that history of depression is a risk factor
for postpartum depression (Martin 1977; Nilsson and Almgren 1970;
O’Hara 1986; O’Hara et al. 1983, 1991; Paykel et al. 1980; Playfair and
Gowers 1981; Tod 1964; Uddenberg 1974; Watson et al. 1984). In ad-
dition, family history of depression also appears to be a risk factor for
postpartum depression (Nilsson and Almgren 1970; O’Hara et al. 1984;
Watson et al. 1984). Although history or family history of mood disorder
appears to be highly associated with postpartum depression, a small
number of studies have failed to demonstrate this association (Blair et al.
1970; Dalton 1971; Kumar and Robson 1984; O’Hara et al. 1991; Pitt
1968).
No factor has been identified as singularly driving the risk for post-
partum depression. However, history of depression and family history of
depression appear to increase the risk of postpartum depression most
consistently in studies that have examined this issue. In addition, depres-
sion during pregnancy and poor psychosocial support do appear to con-
sistently increase the risk of postpartum depression (O’Hara 1986;
O’Hara et al. 1991).
Treatment
There are few treatment studies of postpartum depression. Research into
prevention of postpartum depression has shown that prenatal education
(including relaxation training and advice to avoid stressors and seek sup-
port) may decrease postpartum distress. Because women with histories
of depression appear to be at increased risk for postpartum depression,
prophylactic strategies to reduce the risk of postpartum depression are
indicated. In women with histories of chronic or recurrent depression,
consideration of continuation of pharmacotherapy during pregnancy and
the postpartum period is appropriate. Given evidence that depression
during pregnancy is a strong predictor of postpartum depression, avoid-
ance of recurrence of depression during pregnancy may decrease the like-
lihood of a postpartum depressive episode. Women must be informed of
the risks to the fetus of pharmacotherapy during pregnancy, and a careful
weighing of risks to the fetus against risks of untreated depression in the
mother must be undertaken to come up with appropriate treatment
strategies for individual patients. Risks to the fetus associated with use of
pharmacotherapy during pregnancy may include specific risks of certain
congenital anomalies when specific medications are used during the first
trimester, unknown risks of neurodevelopmental problems associated
with exposing the developing fetal brain to psychotropic medications
throughout the pregnancy, and potential risks of toxicity and withdrawal
associated with maternal use of medications at time of delivery (Alt-
shuler et al. 1996).
Appropriate treatment of postpartum depression is like treatment of
depression in other settings. Patients who have profound depression with
suicidality, or those who are unable to take care of themselves, benefit in
almost all cases from hospitalization. Evaluation to rule out medical
causes of depression, such as Sheehan’s syndrome or postpartum thyroid
dysfunction, is important. Treatment of postpartum depression may in-
clude pharmacotherapy in conjunction with psychotherapy and other
support when necessary. Only a few studies of the treatment of postpar-
tum depression with specific agents have been published. These agents
include antidepressants such as sertraline, venlafaxine, and fluoxetine, all
of which have demonstrated efficacy (Appelby et al. 1997; Cohen et al.
2001; Stowe et al. 1995). Estrogen, administered either transdermally or
sublingually, has been reported to have a small effect on improvement of
postpartum depressive symptoms (Ahokas et al. 1998; Gregoire et al.
1996). However, in the study of transdermal estrogen (Gregoire et al.
1996), many subjects received antidepressants in conjunction with estro-
gen, thus calling into question the effect of estrogen alone. Further inves-
tigation is needed into the possible use of estrogen in the treatment of
postpartum depression before it can be considered a first-line therapy.
Both cognitive-behavioral therapy and interpersonal therapy have
been shown to be helpful in the treatment of postpartum depression
(Appelby et al. 1997; Stuart et al. 1995). Services such as home health
aides or visiting nurses who can help with baby care, thus allowing moth-
ers to catch up on rest, are often quite helpful. Enlisting family members
to take over some of the numerous chores involved with care of a new
baby also may allow a mother with depression to recover more quickly.
If pharmacotherapy is initiated, safety of breastfeeding may be raised
as an issue of concern. The use of lithium is generally contraindicated
during breastfeeding, as breast milk levels of this drug are relatively con-
sistent and may reach 50% of serum levels (Llewellyn and Stowe 1998;
Schou and Amdisen 1973). Other psychotropic medications may be se-
creted into breast milk; however, the amount may be small or unmeasur-
able by standard laboratory tests. Mothers should be advised that if they
wish to breastfeed when using psychotropic medications, the baby’s se-
rum should be measured for presence of drug approximately 2 weeks af-
ter medication is initiated. If medication is not detected in the infant’s
plasma, then mothers may elect to continue to breastfeed. However, they
should be cautioned that standard laboratory assays may not be suffi-
ciently sensitive to detect trace amount of drug. On the other hand moth-
ers may be reassured that the likelihood of neonatal toxicity in the setting
of a nondetectable infant plasma level of drug is extremely small (Birn-
baum et al. 1999; Stowe et al. 1997).
Consequences
Follow-up studies of women who have experienced postpartum depres-
sion have shown that women with postpartum depression often continue
to experience depression up to 3.5 years after delivery (O’Hara et al.
1991). Risk for recurrent postpartum depression has been estimated to
be 50%, and risk for recurrent nonpostpartum depression is also elevated
(O’Hara 1995). Studies of children of mothers who have had postpartum
depression have shown more problems in these children than in children
of nondepressed mothers, including behavior problems, poorer cognitive
performance as toddlers, and patterns of insecure attachment with moth-
ers (Cogill et al. 1986).
Postpartum Psychosis
Etiology
Endocrine factors. There has been little research concerning the rela-
tionship between endocrine status and postpartum psychosis. A study by
Kumar et al. (1993) found that women with histories of bipolar or schizo-
affective disorder who went on to have a postpartum recurrence of illness
exhibited an enhanced growth hormone response to the apomorphine

challenge test compared with both women who remained well and con-
trol subjects. The enhanced growth hormone reflected increased dopa-
mine receptor supersensitivity in the hypothalamus in the women who
experienced a recurrence postpartum (Kumar et al. 1993). These authors
hypothesized that the dopamine supersensitivity may have been related
to an impairment in downregulation of dopamine receptors consequent
to estrogen withdrawal postpartum, although estrogen levels were not re-
ported in the study. Meakin et al. (1995) investigated the relationship be-
tween development of puerperal psychosis, growth hormone response to
apomorphine, and levels of other hormones (including progesterone, es-
trogen, and thyroid hormones) and were not able to identify any markers
for the development of puerperal psychosis.
Nonendocrine factors. Primiparous women appear to be at increased

risk for postpartum psychosis. The risk of postpartum psychosis in a first
pregnancy appears to be twice as high as that in multiparous women
(Kendell 1985). Women with a history of bipolar disorder also appear to
be at increased risk of developing postpartum psychosis. The increase in
risk has been estimated as high as 50% (Reich and Winokur 1970). Fam-
ily history of psychosis also appears to be a risk factor for postpartum psy-
chosis (Brockington et al. 1982; Kendell 1985; Tetlow 1955).
Treatment
Few studies of treatment of postpartum psychosis have been reported.
Postpartum psychosis should be considered a psychiatric and obstetric
emergency. Postpartum psychosis has been associated with infanticide
(O’Hara 1995). Treatment should include hospitalization, and accepted
somatic treatments have included antipsychotic medications and mood
stabilizers, as well as electroconvulsive therapy. In the United Kingdom,
specialized mother-baby units have been established that allow psychotic
mothers to be hospitalized along with the infant. This allows the mother
to continue to take as much responsibility as she is able for care of the
infant while she is undergoing treatment. Children hospitalized with
their psychotic mothers do not appear to be at increased risk of physical
injury (Margison and Brockington 1982).
Consequences
Women who experience a postpartum psychotic episode appear to be at
increased risk for subsequent episodes of both nonpuerperal and postpar-
tum psychosis. Estimates of risk of postpartum psychotic episodes in sub-
sequent pregnancies have ranged from 21% (Brockington et al. 1982) to

as high as 75% (O’Hara 1995).
Studies examining the long-term effects of postpartum psychosis on
children have suggested that children of psychotic mothers are at increased
risk for attentional and behavior problems, as well as childhood depression
(Cohler et al. 1977; Emery et al. 1982; Harvey et al. 1981; McKnew et al.
1979; Weintraub et al. 1978; Welner et al. 1977; Winters et al. 1981).
Conclusion
Postpartum psychiatric disorders affect a large number of women world-

wide. Clinicians should be aware of the risk factors that make certain
women more vulnerable to developing psychiatric symptoms in the post-
partum period, and careful screening for symptoms of mood disorder should
take place both before and after pregnancy to ensure that women with
mood symptoms can receive treatment. Endogenous gonadal hormones af-
fect neurotransmitter systems implicated in the etiology of mood disorders;
however, the precise role these hormones may have in the etiology of post-
partum mood disorders is not well understood. Further research into the po-
tential effects of postpartum hormonal changes on mood is necessary.
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Chapter 12
Clinical Psychotropic Effects

of Gonadal Hormone
Medications in Women
Uriel Halbreich, M.D.

Steven J. Wamback, B.S.
T he female gonadal hormones, estrogen and progesterone,

play a major role in the regulation of fertility and sexuality in women. The
emphasis in studies of these hormones, as well as in their clinical applica-
tions, has been on their use in gynecological clinics and in situations that are
associated with women’s reproductive life cycle and menopause. Since an-
tiquity, however, it has been very well known that some of the events dur-
ing a woman’s life cycle are closely associated with changes in mood and
behavior. These events include puberty, the menstrual cycle, pregnancy,
the postpartum period, and menopause. In modern times, the use of con-
traceptive pills, amenorrhea, ovariectomy, infertility treatments, hormonal
replacement therapy, and other situations were added. All of these periods,
events, and changes are associated with changes in levels of gonadal hor-
mones. Therefore, it has become quite plausible that these hormones might
be responsible for behavioral and mood changes. Furthermore, for more
than 60 years, it has been suggested that exogenous administration of these
hormones might be beneficial for treatment of dysphoric disorders.
In this chapter we selectively review the clinically relevant literature
on the effects of estrogen and progesterone on mood and behavior. The
emphasis in the discussion concerning estrogen is on its most frequent
use, namely as hormone replacement therapy (HRT) for postmenopausal
women. The emphasis in the discussion of progesterone is on its role as a
303
protective counterbalance to estrogen in HRT as well as on its role as an

oral contraceptive. The suggested actions of estrogen are further exam-
ined with a comparison of the effects of the estrogen mixed antagonist
tamoxifen, which is widely used for treatment of women with breast
cancer. Some of the distinctions between hormone-related effects and
sex-related determinations may be examined by the study of hormonal
effects in male-to-female transsexuals, even though most clinicians do
not see very many transsexuals in their daily practice.
Interaction Between Gonadal

Hormones, Brain, and Behavior
The secretion and activity of gonadal hormones are regulated via the hy-
pothalamic-pituitary-gonadal (HPG) system. Inputs and circuits from
the cortex and several internal brain regions influence the hypothalamus,
which secretes gonadotropin-releasing hormone (GnRH) in a pulsatile
fashion. GnRH causes the secretion of the pituitary hormones, follicle-
stimulating hormone (FSH) and luteinizing hormone (LH), which are in-
volved in the process leading to ovulation and which regulate the female
gonadal hormones estrogen and progesterone. A series of feedback mech-
anisms maintain a very delicate homeostasis of the HPG system and its
interactions with other hormonal and biological systems. This homeosta-
sis can be impaired in response to environmental stimuli, pharmacologic
interventions, and a variety of physical and mental disorders.
The interaction between the brain and gonadal hormones is bidirec-
tional. The peripheral gonadal hormones exert two main types of actions
on the central nervous system: organizational/genomic effects and activa-
tional/nongenomic effects (McEwen 1991). The organizational/genomic
effects are trophic and occur early during development of the brain. They
are permanent and control neural architecture and future activity. Among
other influences, organizational effects of gonadal hormones or their ab-
sence are responsible for gender differences in brain and behavior. Acti-
vational/nongenomic effects of gonadal hormones occur mostly during
postnatal life and throughout the entire life cycle. They are reversible and
include alterations of normal electrical and biochemical functions and
structure. They can add to, and support, gender-differentiated brain
functions. Activational/nongenomic effects include many functions that
are considered to be involved in the continuous regulation of behavior
and mood, are putatively impaired in mental disorders, and are in-
fluenced by psychotropic medications. These activities include receptor
Gonadal Hormone Medications in Women 305
potentiation by direct or modulatory effects, enzyme induction or inhi-

bition, potentiation of intracellular second-messenger processes, and
other transitory effects. Receptors and binding sites for gonadal hormones
are selectively distributed in the brain and in connection to different neu-
rotransmitter systems. Therefore, their effect cannot be generalized. An-
other caveat in the evaluation of effects of gonadal hormones is that
different metabolic or synthetic analogs might cause opposing behavioral
effects. For example, several progesterone metabolites and progestins are
anxiolytic, whereas some others are anxiogenic. Timing is also of impor-
tance. Priming with estrogen might change the effects of progesterone,
and cyclic administration might cause different effects than continuous
use.
Estrogen Replacement Therapy for Menopausal

Women: Effects on Mood and Cognition
HRT for menopausal women is quite prevalent. It is estimated that up to

30% of women receive HRT after menopause. The main menopausal
change is the discontinuation of ovulation and menstrual cycling, which
is accompanied by constant increased levels of LH and FSH, low levels of
estrogen, and negligible levels of progesterone. These low levels of estro-
gen result in accelerated decrease in bone mineral density and osteoporo-
sis, increased vulnerability to cardiovascular disorders, and atrophy of the
gonadal-urinary tract. HRT is approved by the U.S. Food and Drug Ad-
ministration for prevention of decreased bone mineral density (e.g., Lind-
say 1991), as well as for prevention and treatment of menopausal genito-
urinary atrophy.
However, shortly after the proposed “use of folliculin in involutional
stress” (Sevringhaus 1933), there were initial attempts to use estrogen for
treatment of postmenopausal depression (Wiesbader and Kurzrok 1938).
Mostly animal studies, but also some human trials (e.g., Best et al. 1992;
Ditkoff et al. 1991; Halbreich et al. 1995; Limouzin-Lamothe et al.
1994) suggest that estrogen should have antidepressant properties. It
increases serotonergic functions as well as norepinephrine synthesis and
activity on receptor levels. In addition, it decreases metabolism of mono-
amines by inhibiting the activity of the enzymes monoamine oxidase and
catechol O-methyltransferase. It also increases g-aminobutyric acid
(GABA) activity. Its effect on some other systems like the cholinergic one
is mixed. Estrogen shows a modulatory effect on dopaminergic systems,
which might be important for gender differences in schizophrenia, as
well as adverse effects of antipsychotic medications, which are not dis-

cussed in detail here (McEwen et al. 1997).
Nonetheless, the few reports on studies of the efficacy of estrogen for
treatment of depressed postmenopausal women were consistently nega-
tive and disappointing (Coope 1981; Coope et al. 1975; Oppenheim
1986; M.A. Schneider et al. 1977; Shapira et al. 1985). Yet a recent study
by Whooley et al. (2000), comparing current estrogen users and nonusers
among 6,602 postmenopausal women, found that current use of un-
opposed estrogen was associated with a decreased risk of depressive
symptoms. There are also clinical observations and suggestions that estro-
gen might be used effectively as an adjunct therapy for postmenopausal
women who have not responded to treatment with tricyclic antidepres-
sants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). Several
post hoc analyses of postmenopausal women with and without HRT who
participated in clinical trials suggest that women receiving HRT respond
better to antidepressants (L. Schneider et al. 1997). Regretfully, we are
unaware of double-blind, placebo-controlled prospective reports of es-
trogen efficacy in these situations, but personal communications and dis-
cussions at scientific meetings are quite numerous. Certainly, there is a
need for a well-designed scientific confirmation of this notion (which, on
a theoretical basis, would be expected to be positive). The combination
of an SSRI and estrogen might be expected to be more beneficial than a
TCA-estrogen combination because of amplification of the side effects of
TCAs (e.g., cholinergic effects) by estrogen. Estrogen probably comple-
ments and supplements SSRI activity by its inhibitory effect on mono-
amine oxidase, its postsynaptic effect on serotonin receptors, its enhance-
ment of norepinephrine activity, and its positive effect on intracellular
signal transduction. It is of interest that the clinically reported effects of
estrogen as an adjunct therapy in depressed women is similar to the re-
ported effects of thyroid hormones in the same group of patients. Be-
cause of the similarities between thyroid and estrogen receptors and re-
ceptor-mediated activities, the clinical similarities are of great heuristic
and practical interest. It is to be hoped that further studies will clarify
these issues.
As opposed to the negative results of using estrogen as an indepen-
dent antidepressant for depressed women, there were more than a dozen
reports of clinical trials showing that the administration of estrogen re-
placement to healthy, nondepressed postmenopausal women improves
their mood and general feeling of well-being (Aylward 1976; Aylward et
al. 1974; Best et al. 1992; Daly et al. 1993; Ditkoff et al. 1991; Fedor-
Freybergh 1977; Furuhjelm and Carlstrom 1977; Furuhjelm and Fedor-
Freybergh 1976; Limouzin-Lamothe et al. 1994; Michael et al. 1970;
Palinkas and Barrett-Connor 1992; M.A. Schneider et al. 1977). In addi-

tion, there are numerous case studies and uncontrolled clinical reports of
increased well-being; increased energy and libido; and improved sexual
performance, desire, and affection in elderly women who have received
HRT for long periods of time.
The influence of HRT on cognitive functions of postmenopausal women
is still under investigation. Since the early 1950s, it has been suggested
that this influence might be diversified and may depend on the cognitive
construct studied (Caldwell and Watson 1952). In most cases, when var-
ious tests of memory were studied, a positive effect of estrogen was re-
ported (e.g., Campbell and Whitehead 1977; Fedor-Freybergh 1977;
Furuhjelm and Carlstrom 1977; Hackman and Galbraith 1976; Halbreich
et al. 1995; Kampen and Sherwin 1994; Phillips and Sherwin 1992; M.A.
Schneider et al. 1977). However, this improvement is not generalized. For
example, some women who had improved immediate recall and associa-
tion learning in response to estradiol administration (Phillips and Sherwin
1992) did not show improvement of delayed recall, visual reproduction,
or digit span. In another large survey (Barrett-Connor and Kritz-Silverstein
1993) of 800 women who either were or were not taking estrogen (mostly
Premarin), verbal and visual memory were not improved by estrogen use.
In a study by Sherwin’s group (Kampen and Sherwin 1994), selective re-
minding and paragraph recall (verbal memory) were improved, whereas
spatial ability and attention span were not.
Our own studies (Halbreich 1997; Halbreich et al. 1993, 1995), with
an extensive battery of cognitive tests, showed improvement on complex
integrative cognitive tasks that require integration of several cognitive
constructs, such as recognition, interpretation, decision making, eye-
hand coordination, and reaction. These integrative tasks are reported to
be impaired in conditions that involve generalized brain impairment
(such as concussion or generalized brain trauma) and might involve dam-
age to brain circuitry. We also found positive effects of estrogen on several
short-term memory functions.
A rapidly developing area of interest is the possible positive effect of
estrogen in women with Alzheimer’s-type dementia. It has been reported
that among women receiving estrogen replacement therapy the inci-
dence of Alzheimer’s disease tended to be lower and the deterioration in
those who did develop Alzheimer’s disease was less severe than in
women of the same age who did not receive HRT (Birge 1997; Hender-
son 1997; Paganini-Hill 1994). Several studies have reported improve-
ment of dementia in women who were treated with conjugated estrogen
(e.g., Honjo et al. 1989, 1995; Mortel and Meyer 1994, 1995; Ohkura et
al. 1994, 1995). It is of interest that in several studies (Asthana et al.
1999; Ohkura et al. 1994, 1995) termination of treatment resulted in a

worsening of cognitive functions. However, a recent study by Mulnard et
al. (2000) did not find evidence that estrogen replacement therapy for
1 year enhances cognitive function or slows the progression of Alzheimer’s
dementia. It is also known that the addition of progesterone to HRT regi-
mens reduces the effect of HRT on depressed mood (Zweifel and O’Brien
1997).
The involvement of estrogen in Alzheimer’s dementia is being un-
folded at present. It is still undetermined whether estrogen replacement
therapy might be a preventive measure or whether it might also be used
as treatment for improvement of dementia and other cognitive impair-
ments once they already exist. The importance of the lack of estrogen as
a risk factor for Alzheimer’s disease and the magnitude of its contribution
to the variance of dementia is also still unknown. Considering the inten-
sified interest in the interaction between estrogen and Alzheimer’s de-
mentia, it might be expected that answers to these questions are not far
ahead. With the advent of a new class of drugs, selective estrogen recep-
tor modulators, which have differential site-specific estrogenic or anties-
trogenic effects in different target tissues, HRT will undergo a sea of
change in the coming years.
Common Estrogen Preparations and Dosages

In premenopausal women, the most significant estrogen is estradiol,
which is secreted from the ovaries and is their most potent hormone.
After menopause, women still have small amounts of estrogen in the
form of estrone, which is derived from the adrenals by metabolism of an-
drostenedione. Estradiol is also metabolized (oxidized) to estrone and
then to estriol. Pharmacologically, the two most prevalent estrogen prod-
ucts are estradiol and conjugated estrogens, even though several other
preparations are available. Estradiol is probably the most potent estro-
gen, but when given in equipotent dosages, all estrogens probably show
similar effects on bone mineral density and the cardiovascular system.
Their effect on lipids might be different. It is still unknown whether they
differ in their effects on mood and cognition because we are not aware of
any direct comparison studies to this effect.
Hence, we address only issues that might be related to mood and be-
havior in consideration of preparations that are widely and commonly
used. Oral conjugated estrogens are sulfate esters mostly of estrone and
equilin. The usual daily dosage for HRT is 0.625 mg. Because of prelim-
inary findings that positive effects of estrogen on cognitive functions
might be related to plasma levels of estrogen (Drake et al. 2000; Sherwin
2000), it might eventually be found that for improved cognition and

well-being, 1.25 mg/day is actually needed. According to the American
Medical Association’s Drug Evaluations Annual (American Medical Asso-
ciation 1995), “There have been problems with bioequivalence of generic
preparations; new manufacturing specifications to ensure conformity of
generic products to Premarin are being developed."
Our own studies initially involved estradiol delivered via a transder-
mal patch to postmenopausal women. The combination of this prepara-
tion and mode of delivery appears to be preferable because it is readily
absorbed; it is only minimally metabolized in the skin; and it results in a
close-to-physiological situation of high estradiol-to-estrone ratio com-
pared with the high estrone levels of oral preparations. Transdermal ad-
ministration also entirely bypasses the liver and therefore produces less
binding to sex hormone–binding globulin and other binding proteins (less
protein binding as well as less first-pass extraction by the liver). There-
fore, higher available estrogen levels are coupled with steady continuous
plasma levels of estrogen (estradiol) delivery; and, provided that the as-
sumption that higher levels of steady estrogen might be needed to pro-
duce favorable cognitive effects is true, transdermal patches might be
preferable to oral conjugated preparations. In our studies of postmeno-
pausal women, we used 0.1-mg patches twice weekly. Because of the
finding of a positive correlation between plasma levels of estradiol and
cognitive performance in some tests, it is still unclear whether the lower-
dose 0.05-mg patch would be sufficient, even though it provides the
usual recommended dose for HRT. Transdermal patches are prescribed
for change twice weekly and should be rotated on the trunk or buttocks.
Some women prefer to apply them on the upper thigh. An additional
side effect of transdermal patches is irritation and redness at the applica-
tion site, which in many cases is transitory.
An interesting variation of oral estrogens is a combination of esterified
estrogen (0.625 or 1.25 mg) and methyl testosterone (1.25–2.5 mg). For
purposes of mood, cognition, and libido, this combination of estrogen
and androgen should be quite effective because of the addition of the an-
drogen, which might have a positive effect on mood and cognition in its
own right. This suggestion is strengthened by the reports here (Rako
1999). After hysterectomy and subsequent ovarian failure (a conse-
quence of loss of the blood supply provided by the uterine artery) or after
oophorectomy, symptoms of estrogen deficiency and testosterone defi-
ciency are present. Symptoms of loss of libido and sexual response, lack
of general energy, and a diminished sense of well-being can be attributed
to testosterone deficiency. Too often these symptoms are misdiagnosed,
and many women are prescribed antidepressants (Rako 1999). At present,
however, there are few studies showing any direct comparison of effects
on well-being and cognition of esterified estrogen or estradiol with and
without methyl testosterone (Sherwin and Gelfand 1985). In fact, this
preparation might cause some androgenic side effects.
Regimens of Hormone Replacement Therapy:

Pros and Cons
Most clinicians prescribe HRT in a cyclic fashion—cyclic or continual es-
trogen with a cyclic addition of progesterone. However, several other op-
tions should be taken into consideration: estrogen only, cyclic estrogen
with no addition of progesterone, continual administration of estrogen
and progesterone combination, and cyclic or continual administration of
an estrogen-androgen combination. Evaluation of the mood and behav-
ioral effects of progesterone per se is discussed separately. In this section
we focus on the merits and disadvantages of the addition of progesterone
as part of HRT.
Progesterone is recommended as part of HRT to induce endometrial
shedding and bleeding, to avoid estrogen-induced endometrial hyperpla-
sia, and to decrease the risk of endometrial cancer. In women who have
had hysterectomy, progesterone is not needed, and unopposed continual
estrogen can be prescribed (Williams and Moley 1994).
Most clinicians prescribe progesterone in a cyclic sequential fashion
of HRT in women who have attained natural menopause, as well as for
oral contraception. In this way, estrogen (usually Premarin or Estraderm)
is taken for 25 days and a progesterone, usually medroxyprogesterone ac-
etate (Provera) (5–10 mg), is added during days 15–25. This is usually
followed by withdrawal bleeding, and the cyclic hormonal regimen is re-
sumed within 5 days, even if no bleeding occurs. Negative mood effects
in this regimen are quite prevalent. They appear during the period in
which progestogens are added or shortly thereafter. Actually, this sequen-
tial addition of progestogen has been used as a model for simulating pre-
menstrual syndrome (PMS) and its cyclicity (Hammerback et al. 1983).
The negative mood effects of this HRT regimen might be dose related
and may be more severe with increased dosage of the progestogen (Magos
et al. 1984, 1986a, 1986b).
It has been suggested (Halbreich 1996), though not yet confirmed,
that women who had PMS during their reproductive life might be more
vulnerable to the development of mood side effects from sequential cy-
clic HRT. The mood effects of continual administration of estrogen with
cyclic progestogen are probably similar. Symptoms might be less severe
because of no cyclic withdrawal of estrogen (see Lobo et al. 1984), but
we are unaware of actual studies to this effect. Continual administration

of combined estrogen and progesterone in low dosages produces fewer
mood and behavioral side effects than the cyclic regimen and therefore
may be a preferential HRT modality. Clinical experience is that mood
side effects might be milder or dependent on the progestogen used. A
recent study by Bjorn et al. (2000) compared side effects of medroxy-
progesterone acetate and norethindrone acetate among postmenopausal
women with and without a history of PMS. Researchers found that women
with a history of PMS had significantly more negative mood symptoms
during medroxyprogesterone treatment and had more negative daily life
effects while taking norethindrone compared with women with no his-
tory of PMS. Among women with no history of PMS, medroxyprogester-
one was associated with more positive mood symptoms compared with
norethindrone.
Because pyridoxine deficiency may be a contributing factor to depres-
sion, especially among users of oral contraceptives, 25–30 mg/day of
pyridoxine is recommended (Coukell and Balfour 1998). Patients expe-
riencing depression should be advised to discontinue the medication to
determine if the symptom is drug related. In patients with a history of de-
pressive disorder, oral contraceptives are to be discontinued if depression
recurs to a severe degree.
Our experience is that cyclic administration of estradiol patches with
no progesterone produces withdrawal bleeding within a few days after
discontinuation of the estrogen. We used this regimen for research pur-
poses for periods up to 60 days. Several other groups gave continual es-
trogen for longer periods. As is the case with other regimens, there might
be increased irritability, tension, and anxiety during the first 2 weeks of
estrogen administration, but these initial side effects usually disappear
with continuation of treatment. The reported mood side effects that are
observed with HRT regimens that include progestogens are not observed
with this pattern. For routine clinical purposes, however, the relative risk
should be evaluated by the individual clinician.
Contraindications and Adverse Effects of Estrogen

The contraindications for the prescription of estrogens are listed in
Table 12–1. In addition, close supervision is required in cases of severe
hypertension, diabetes mellitus, asthma, migraine, epilepsy, cardiac or
renal dysfunction (due to possible exacerbation or because of water re-
tention), and liver diseases (due to a possibility of decreased metabolism
of exogenous estrogen) (Drug Facts and Comparisons 2000; “Estrogens”
2000). Adverse effects of estrogen are listed in Table 12–2. It should be
TABLE 12–1. Contraindications for the use of estrogen

Breast cancer (with a possible exception of localized receptor-negative breast
cancer)
Estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Active thrombophlebitis or thromboembolic disorders
History of thrombophlebitis, thrombosis, or thromboembolic disorders during
previous estrogen use
Known or suspected pregnancy
Source. Information adapted from “Estrogens” 2000.
TABLE 12–2. Adverse effects of estrogens

Increased risk of endometrial carcinoma
Increased risk of breast cancer ??
Increased risk of gallbladder disease
Breakthrough bleeding
Thrombophlebitis
Nausea, vomiting, abdominal cramps
Bloating, water retention
Breast tenderness, enlargement, or secretion
Headache, dizziness, convulsions
During initial 2 weeks: anxiety, depression, and irritability
With Estraderm: irritation or rash at application site
Intolerance to contact lenses
Changes in libido
Teratogenic effects
emphasized that some of the side effects—such as anxiety, depression,

and irritability—might be very acute and usually disappear or improve
within 2 weeks. Therefore, if the patient complains of these side effects
immediately after initiation of treatment, their transitory nature should
be explained to her and she should be encouraged to continue medica-
tion. Some of the other adverse effects—for example, nausea, vomiting,
and weight changes—might also decline with time, although frequently
they might persist.
Hormonal Treatment of Premenstrual Syndrome: Effects of

Ovulation Suppression With GnRH Analogs and Estrogen
Premenstrual syndromes are quite prevalent and might affect up to 40%
of women of reproductive age (Andersch et al. 1986; Woods et al. 1982a,
1982b). Three to eight percent of women meet criteria for severe dys-
phoric PMS or premenstrual dysphoric disorder (American Psychiatric
Association 2000); such diagnoses require impaired functioning and war-
rant treatment (American College of Obstetricians and Gynecologists
1989; Rivera-Tovar and Frank 1990). Even though the exact etiology and
pathobiology of PMS are still obscure, most researchers in the field be-
lieve that gonadal hormones play a major role in the disorder. It is sug-
gested that the etiology of PMS involves a compilation of vulnerability
factors; environmental, social, and personality inputs; and biological de-
terminants. The biological determinants probably involve an interplay
between steroids, gonadal hormones, other hormonal systems, neu-
rotransmitters, and intraneural mechanisms (Gold and Severino 1994;
Halbreich 1995, 1996, 1999; Halbreich and Endicott 1985; Halbreich et
al. 1986, 1988, 1995; Smith and Schiff 1993). The role of ovulation or
ovulation-related mechanisms and processes in the pathophysiology of
PMS is underscored by reports that women with PMS did not have symp-
toms during anovulatory menstrual cycles (Backstrom et al. 1983, 1989).
Hysterectomy and ovariectomy were shown to eliminate PMS, whereas
symptoms continued when hysterectomy alone was performed (Back-
strom et al. 1983; Casper and Hearn 1990; Casson et al. 1990). Indeed,
one of the most effective treatments for PMS is elimination of ovulation
with GnRH analogs or with danazol (Bancroft et al. 1985, 1987; Halbreich
et al. 1991; Muse et al. 1984).
Suppression of ovulation interferes with multiple processes as well as
with their cyclicity, and even though the main change is probably in the
decreased levels and elimination of cyclicity of gonadal hormones, the in-
fluence of other parameters cannot be ignored. This is also the case when
GnRH analogs or other ovulation suppressants are administered as treat-
ment for other disorders (e.g., endometriosis or polycyclic ovaries).
Ovulation might be suppressed by danazol (Danocrine), which is a
synthetic derivative of 17a-ethinyl testosterone. It inhibits the midcycle
gonadotropin surge. It has been shown (Day 1979; Gillomere et al. 1985)
to be effective for treatment of PMS in a marginal dosage of 200 mg/day.
It is effective only when ovulation is suppressed (Halbreich et al. 1991).
Even though it has been reported that danazol is also effective when
given following ovulation at the beginning of the luteal phase, this has
probably not been confirmed. Danazol might cause a myriad of side ef-
fects, mostly androgenic, and is not well tolerated by many women. Ovu-
lation suppression by several GnRH analogs (e.g., buserelin) has been
widely shown to be effective in treatment of a wide range of premen-
strual syndromes, including dysphoric PMS (Bancroft et al. 1985, 1987;
Hammerback and Backstrom 1988). The most convenient way to sup-
press ovulation and treat PMS is by administration of leuprolide acetate

(Lupron), which is injected intramuscularly (3.75 mg) once a month.
However, leuprolide is quite expensive, and in the current market it is not
reimbursable for the indication of PMS by most third-party payers. Ad-
ministration of leuprolide and other GnRH analogs produces a lack of es-
trogen and progesterone and therefore a “pharmacologic menopause”
with possible initial menopausal symptoms. If taken without any estro-
gen supplement, leuprolide and other GnRH analogs produce long-term
effects. This state can be overcome with the addition of continual estrogen
or cyclic estrogen. If progesterone is added in a sequential cyclic regimen,
the advantages of GnRH analogs are overcome because this cyclicity in-
duces symptoms that mimic PMS (Mortola et al. 1991).
Suppression of ovulation, elimination of cyclicity, and fluctuation of
gonadal hormones can actually be achieved by sustained high levels of
estrogens. Crystalline estradiol subcutaneous implants (100 mg in the
anterior abdominal wall) have been shown to be superior to placebo for
treatment of PMS (Magos et al. 1984, 1986a, 1986b) in long-term (10-
month) treatment. Two points are of interest regarding this regimen:
first, very high placebo response (94%) was noticed during the first 2
months, but it disappeared 4 months into the study. Second, to counter-
act the endometrial building effect of estrogen and to induce bleeding,
progestin (Norethisterone) (5 mg) was administered sequentially, which
produced PMS-like effects during the progestin period, although to a
lesser degree and in a smaller number of patients. A substantial group of
women have been treated with this regimen of continual estrogen and cy-
clic progestin for many years (more than 8–10 years) with sustained relief
from PMS (Watson and Studd 1993; Watson et al. 1989, 1990).
A relatively convenient and less intensive modality of sustained estro-
gen administration is transdermal estrogen patches (Estraderm and Sys-
ten), which in high dosages of 0.2 mg twice weekly suppress ovulation.
This treatment is highly effective for PMS (Watson et al. 1989, 1990), is
sustainable, does not induce menopause-like symptoms, and is relatively
cost-effective. When given in combination with a sequential cyclic pro-
gestogen, some of its therapeutic efficacy is lost. However, estrogen with-
drawal usually induces bleeding within a few days, and therefore with
adequate long-term follow-up, cyclic (up to 60 days) administration of
transdermal estradiol patches with no addition of progesterone should be
effective and safe for long periods of time. We are unaware, however, of
any published controlled studies of the long-term efficacy and safety of
this regimen in the United States (nor of any other sustained regimen ex-
cept estrogen implants); hence this recommendation should be taken
very cautiously.
A very reliable and less dramatic alternative is symptomatic treat-

ment. In women with dysphoric PMS, several antidepressants, especially
SSRIs, have been shown to be highly effective (see reviews by Gold and
Severino 1994; Halbreich 1996). Their evaluation, however, is beyond
the scope of this chapter. The effects of progesterone and contraceptive
pills on menstrually related mood and behavioral changes, as well as their
side effects, are discussed under “Mood and Behavioral Effects of Contra-
ceptive Hormones” below.
Mood and Behavioral Effects of Contraceptive Hormones

Oral contraceptives are used very widely. Many products are available on
the market, and generalization of their effects on mood and behavior
would be misleading because they have different steroids, different com-
binations, and various modes of administration; most of them can markedly
affect the regulation of mood and behavior. Hormonal contraceptives are
marketed mainly as oral pills. However, there is increasing use of long-
acting depot preparations and intravaginal rings, which are discussed
briefly at the end of this section. Oral contraceptives are usually a com-
bination of synthetic estrogen and a progestin or, in a few cases, proges-
tin-only “minipills.” The combination pills are supplied in three main
modes of administration: 1) monophasic, in which constant amounts of
low-dose estrogen and progestin are taken for 21 days with a 7-day with-
drawal period (during which bleeding usually occurs); 2) biphasic, in
which a constant low dose of estrogen is combined with a low dose of a
progestin for 10 days, then the progestin is increased for 11 days, after
which both hormones are withdrawn; and 3) triphasic, in which the
progestin is alternately increased and decreased every 7 days with a con-
stant dose of estrogen. There are also triphasic preparations in which the
levels of both estrogen and the progestin change.
It is of interest that even though mood side effects of oral contracep-
tives were already reported a generation ago (Cullberg 1972) and up to
30% of women discontinue oral contraceptive use because of mental side
effects (Milsom et al. 1991), the knowledge about the diversified mood
and behavior affects of oral contraceptives is far from satisfactory. The re-
port that 30% of women discontinue oral contraceptive use because of
mental effect is quite consistent with other reports that 30% of women
taking oral contraceptives develop negative mood changes (Clare 1985a,
1985b; Cullberg 1972).
The mood and behavioral side effects of oral contraceptives are prob-
ably due mostly to the progestin component. As mentioned above, the
different progestin compounds used might be responsible for conflicting
reports in this field. This possibility was demonstrated by Backstrom

(1992), who found that levonorgestrel induced more mental side effects
than desogestrel.
The schedule of administration might also be of importance. It has
been documented (Bancroft et al. 1985, 1987, 1993) that triphasic oral
contraceptives induced more mental side effects than monophasic oral
contraceptives, even though the monophasic pills had higher progestin
dosages. This observation is in accord with the notion that menstrually
related symptoms might be associated with the cyclic fluctuation of go-
nadal hormones, mostly progesterone, and not necessarily with their
absolute levels. The triphasic preparations simulate and amplify the hor-
monal fluctuations, and according to the hypothesis described above
would be expected to induce higher rates of side effects.
Vulnerability to depression might play an important role in the devel-
opment of mood side effects to oral contraceptives. It has been suggested
that women who have a history of dysphoric PMS, which has been shown
to be associated with major depressive disorder and other affective disor-
ders (Halbreich and Endicott 1985), are more prone to dysphoric mood
side effects of oral contraceptives (Backstrom 1996; Backstrom et al.
1985; Cullberg 1972; Graham and Sherwin 1987; Hammerback and
Backstrom 1988). This issue is still not entirely clear, because it has been
reported that women with moderate to severe PMS were more likely to
develop negative mood symptoms while taking oral contraceptives, com-
pared with women with mild PMS who had positive mood changes when
taking oral contraceptives (Backstrom 1992). As implied by Backstrom
(1996), the latter effect might be due to a placebo effect that might be
more influential on women with mild PMS, whereas the actual drug-
related side effects are more apparent in women with severe PMS—who
might also be the women who are more vulnerable or are at higher risk
of developing affective disorders in general.
The mood effects of minipills, which contain only progestin and are
taken continually, are not well studied. They are less favorable than com-
bination pills, mainly due to menstrual irregularities and a lower degree
of contraceptive effectiveness. Dysphoria might be expected, especially
in vulnerable women, but this has not been extensively studied.
The depot contraceptives are very widely used, mostly depot medroxy-
progesterone (Depo-Provera) and, more recently, levonorgestrel (Nor-
plant). The mental side effects of these drugs remain unclear. Several
controlled studies have reported some mood side effects (Haugen et al.
1996; Kirkman et al. 1999; Sivin et al. 1998), as have two case reports
(Wagner 1996; Wagner and Berenson 1994). Westhoff and colleagues
(1998a, 1998b) undertook a prospective multicenter study to evaluate
the relationship between contraceptives and depression, focusing on

Norplant and Depo-Provera. With both Norplant and Depo-Provera, re-
lationship satisfaction was the greatest predictor of depression symptom
scores. Other multicenter studies assessing the impact of long-acting con-
traceptives like Depo-Provera and Norplant show that there is no in-
crease in depressive symptoms (Kaunitz 1999).
Mood and Behavior Effects of Tamoxifen and

Other Estrogen Antagonists
Tamoxifen is a synthetic steroidal compound that was introduced as an
antiestrogen for treatment of breast cancer in women (Richardson 1988).
It is also used as a prevention maintenance therapy for healthy women
who are at high risk to develop breast cancer (National Surgical Adjuvant
Breast and Bowel Project 1992) and is therefore administered to quite a
large population of women. It is currently acknowledged that tamoxifen
is actually a mixed estrogenic-antiestrogenic compound, and in some spe-
cies and in some tissues its estrogen-like activity prevails. Such is the case
with bone tissue, in which tamoxifen was shown to delay decreased bone
mineral density. Its activity on the central nervous system and biological
processes that are putatively involved in regulation of brain and behavior
has not yet been fully documented.
Implications from animal studies of the behavioral effects of tamox-
ifen should be viewed cautiously due to the species variability of its ef-
fects. Tamoxifen prevents lordosis in female rats (Etgen 1979), as well as
prepartum onset of maternal behavior (Ahdieh et al. 1987). It reduces of-
fensive behavior in rats (Brain et al. 1988) and aggressive behavior in
mice (Hasan et al. 1988). Tamoxifen increases estrogen-related anxiety
behavior in female rats (i.e., it acted as an estrogen antagonist) (Pellow et
al. 1985). Short-term administration of tamoxifen to ovariectomized fe-
male rats causes decreases in food intake, body weight, and adipose tissue
(Bowman et al. 1983), whereas longer-term administration transiently
increases food intake and body weight (Gray et al. 1993) in a way similar
to that of estrogen.
Information on the mood and behavior effects of tamoxifen in hu-
mans is still limited. The evaluation of the role of drug-related depression
is complicated by the fact that most patients who receive this medication
are women with breast cancer, who might be depressed due to their pri-
mary illness. In women with breast cancer, 15% of those taking tamoxifen
developed depressive symptoms, compared with 3% of women who did
not receive tamoxifen. Symptoms improved following discontinuation of
treatment (Cathcart et al. 1993). Similar observations were reported by
another group (Shariff et al. 1995), which found that 12% of breast can-
cer patients taking tamoxifen had moderately elevated scores for anxiety
and dysthymia. When given as a chemopreventive therapy to healthy
women, only 2% (3/141) reported depression, a rate that was quite sim-
ilar to that of placebo (2/138) (Powles et al. 1990). In a small study of
males taking tamoxifen, 4 of 24 patients reported depression (Anelli et
al. 1994).
Our own impression is that tamoxifen does not usually cause depres-
sion by itself. However, if a woman with a lifetime history of a major de-
pressive disorder becomes depressed again as part of her usual pattern
while taking tamoxifen, her response to antidepressants might be altered.
She might not respond to medications to which she responded well in the
past, or she might need higher dosages of these medications.
It is intriguing (and distressing) that despite the relatively extensive
use of other antiestrogens, such as clomiphene (which is used for stimu-
lation of secretion of gonadotropins and induction of ovulation) (Ameri-
can Medical Association 1994) and recently raloxifene (which is used for
HRT and breast cancer), the effects of these medications on the central
nervous system, mood, and behavior have not yet been properly studied.
However, alertness to possible alteration of mood in women treated with
these medications is advisable.
Mood and Behavior Effects of Progesterone and Progestins

Many clinically relevant aspects of progesterone and progestins (syn-
thetic preparations with progesterone-like activity) are described earlier
in the sections “Regimens of Hormone Replacement Therapy,” “Hor-
monal Treatment of Premenstrual Syndrome,” and “Mood and Behav-
ioral Effects of Contraceptive Hormones.” In this section we briefly draw
some implications from previously discussed clinical observations and
added aspects that might be related to dysphoric mood in general.
Natural progesterone is mainly available for parenteral administration
and is being used as vaginal or rectal suppositories; synthetic progester-
ones are generally administered orally. They might be derived from the
testosterone molecule or from 17-hydroxyprogesterone. They vary greatly
in their potency, progestational and androgenic effects and in their mood
and behavioral effects.
The diversity of biological and pathobiological effects is further em-
phasized by the expanded knowledge on the different effects of various
progesterone metabolites. Progesterone and its metabolites enter the cen-
tral nervous system. Levels of progesterone in the brain change through-
out the menstrual cycle, and they are not evenly distributed; they are
higher in the cerebral cortex, hypothalamus, and limbic regions. One of

the first indications that the brain is a target organ for progesterone was
the finding of progesterone receptors in selected mood-related and cog-
nition-related areas of the brain (Luine et al. 1975; Pfaff and McEwen
1983). Progesterone binding sites have been identified (in selected areas)
on neuron cell membranes as well as on its nucleus. Progesterone and
other steroids may also be metabolized in the brain itself as well as in the
periphery. Various metabolites might have opposite effects on mood;
therefore, the metabolic pathway might determine the overall effect. The
A-ring reduced metabolites of progesterone, allopregnanolone (3a-hydroxy-
5a-pregnane-20-one) and pregnanolone (3a-hydroxy-5b-pregnan-20-one),
have been shown to be potent agonists of the brain GABA-A receptor
(Paul and Purdy 1992), and as such they have anxiolytic (antianxiety)
properties. However, as GABA-A agonists with barbiturate-like modula-
tion, these metabolites might also show effects similar to those of benzo-
diazepines on several cognitive functions. This was actually discovered
when progesterone was administered to healthy women (Freeman et al.
1990, 1993), who experienced increased fatigue and confusion and de-
creased performance on immediate recall and symbolic copying (a mea-
sure of motor performance) tasks—results that are similar to the cognitive
effects of benzodiazepines. The cognitive impairment was dose related.
Similar anesthetic, anxiolytic, and antiepileptic effects of pregnanolone
and allopregnanolone, which are related to the agonist effect on GABA-A
receptors, were consistently reported by other groups (Carl et al. 1990;
Finn and Gee 1993a, 1993b, 1994; Gee 1988; Landgren et al. 1982;
Majewska 1992; Majewska and Schwartz 1987; Majewska et al. 1986;
Norberg et al. 1987).
Clinically, the memory and other cognitive impairments induced by
these progesterone metabolites might explain the observations that the
cognitive side effects of benzodiazepines are amplified by progesterone
and some other progestogens. This should be taken into consideration in
the selection and administration of specific HRT regimens or oral contra-
ceptives simultaneously with anxiolytics. A non-GABAergic anxiolytic
might be preferable, especially in women who are taking progesterone.
The interaction between GABA, benzodiazepine, and progesterone led
to the speculation that progesterone might also be beneficial to attenuate
withdrawal symptoms of benzodiazepine-dependent patients (Schweizer
et al. 1995).
As opposed to allopregnanolone and pregnanolone, some other pro-
gestogens, such as pregnenolone sulfate, and some androgen metabolites
show anxiogenic effects (Paul and Purdy 1992) and act on the GABA-A
receptor’s benzodiazepine site as “inverse agonists.”
A recent study of women with PMS (Wang et al. 1996) showed a sig-
nificant menstrually related cyclic variation of pregnenolone and preg-
nenolone sulfate, which was correlated with progesterone levels and
variation. These authors found that higher luteal-phase levels of 5a-preg-
nane-3,20-dione (5a-dihydroprogesterone [5a-DHP]) and 3a-hydroxy-
5a-pregnan-20-one (3a,5a-tetrahydroprogesterone [3a,5a-THP]) were
associated with improved PMS symptoms, whereas higher levels of preg-
nanolone sulfate and pregnanolone (as well as estradiol) were associated
with worsened negative dysphoric symptoms. This might suggest that
different metabolic pathways of progesterone might exist in different
women and in different situations, resulting in different anxiolytic or
anxiogenic effects. In women with dysphoric PMS, or any other dys-
phoric state, the dominant pathway is the one leading to the anxiogenic
metabolites. It is of interest whether these not-yet-confirmed hypotheses
are also pertinent to the central nervous system. Another interesting and
generalizable finding of the same study (Wang et al. 1996) is that dys-
phoric symptoms correlate with plasma levels of progesterone, preg-
nenolone, 5a-DHP and 3a,5a-THP, with a delay of 3–4 days between
hormonal peaks and symptoms formation. This finding confirms pre-
vious reports by Halbreich et al. (1986) and Redei and Freeman (1995)
and might have implications for the understanding of the clinical time-
line of progestogens as well as for the elucidation of their pathophysi-
ology.
Effects of Female Hormones on

Male-to-Female Transsexuals
Even though the prevalence of transsexualism is quite low (probably 1 in
30,000 men) (Meyer-Bahlburg 1994), and the likelihood of the average
clinician actually treating transsexuals or addressing their side effects is
remote, transsexualism is of interest because it provides an excellent
model for the study and understanding of the effects of gonadal hor-
mones. This is a useful model for several reasons: 1) Genetically male
subjects receive female hormones, and therefore the gender, biological,
and behavioral effects can be distinguished from gonadal hormonal ef-
fects in the same subject. 2) The same people can be studied before hor-
monal treatment, while their hormonal milieu is predominantly that of
the male gonadal hormones, and then after treatment, while they are pre-
dominantly influenced by female hormones. They can also be studied before
and after surgical castration. 3) At baseline, before hormonal treatment,
people with transgender identities (whether or not it is defined as a dis-
order) (American Psychiatric Association 2000) can be compared to men
and women in behavioral as well as hormonal and other biological pa-

rameters, as part of the search for biological underpinnings of gender and
sex.
Nevertheless, transsexuals are not a perfect model for the influences
of exogenous gonadal hormones on biology and behavior. First, many of
them are homosexuals, and as such, they might have inherent biological
differences from heterosexual men (Dorner et al. 1991, 1993). The wish
for gender and sex transformation might distinguish them even further
from other homosexual men who do not wish to change their sex (Dor-
ner et al. 1991, 1993).
Another caveat for generalizations from this work is that male-to-
female transsexuals receive estrogen dosages that are far higher than
those used for HRT and other indications in women. The usual dosage of
conjugated estrogen administered to transsexuals is 7.5–10.0 mg/day,
which is 10 times higher than the dosage normally given to postmeno-
pausal women (Meyer et al. 1986). Up to 2 years of estrogen treatment
at this high dose is necessary to achieve maximum breast development.
The effects of estrogen and antiandrogens (cyproterone acetate) on the
behavior of genetic XY transsexuals are quite pronounced (Van Goozen
et al. 1995). Anger, aggression proneness, sexual arousability, and cogni-
tive spatial ability decreased after estrogen treatment, whereas verbal flu-
ency improved, indicating that these behaviors and cognitive functions
are influenced by activational effects and are not entirely or essentially
sex-specific organizational functions. Because of their antiandrogenic ef-
fects, progestins are sometimes coadministered (continually or cyclically)
with estrogen therapy to male-to-female transsexuals, although we are
not aware of any studies that have measured the behavioral effects of
such progestin treatment. Synthetic progestins such as medroxyprogest-
erone acetate and cyproterone acetate, however, have been shown to sup-
press self-initiated aggressive sexual activity and libido for extended
periods of time in male felony sex offenders, even though when given in
appropriate doses normal sexual responsiveness is maintained in these
patients (Cooper 1986).
Behavioral studies on the response of transsexuals to administration
of female hormones are currently quite scarce. They should be evaluated
cautiously, because double-blind, placebo-controlled studies are difficult
to conduct with this population. The very high resolve of transsexual
patients to change their appearance and behavior might affect their
responses to self-reporting on female behavior and feelings, which might
be exaggerated. Objective tests of research might suggest that not all
changes are subjective, but further rigorous research is needed in this
area.
Summary and Conclusion
The female gonadal hormones estrogen and progesterone, as well as their

metabolites and other gonadal hormone agonists and antagonists, have an
extensive and significant impact on the brain and its related mood, cog-
nition, and behavioral processes. There is a substantial, growing body of
data suggesting that estrogens might be indicated for treatment and preven-
tion of Alzheimer’s dementia, as well as for protection against deteriora-
tion of cognitive function in postmenopausal women and improvement
of their well-being. Even though estrogen alone probably does not im-
prove the mood of depressed postmenopausal women, estrogen admin-
istration might augment the effectiveness of SSRIs among those diag-
nosed with depression (Amsterdam et al. 1999; L. Schneider et al. 1997,
1998).
Estrogen might also be effective in the treatment of PMS. Progester-
one often counteracts the effects of estrogen, and some of its metabolites
appear to act as anxiolytic agents, whereas others are anxiogenic. A woman’s
mental health history should be considered before administering long-
acting depot contraceptives (i.e., Depo-Provera and Norplant) until more
is known about the specific mood effects of the progestins depot medroxy-
progesterone and levonorgestrel.
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Chapter 13
Psychiatric Effects of Exogenous

Anabolic-Androgenic Steroids
Harrison G. Pope Jr., M.D.

David L. Katz, M.D., J.D.
The anabolic-androgenic steroids (AASs) are a family of

hormones that includes the natural male hormone, testosterone, together
with a large number of synthetic analogs of testosterone that have been
synthesized over the course of the last 40 years. In the body, natural tes-
tosterone is synthesized from cholesterol; its four-ring chemical structure
resembles that of cholesterol. Testosterone binds to androgen receptors
in the cytoplasm of cells; the steroid-receptor complex is then transported
to the cell nucleus, where it stimulates gene transcription and hence new
protein synthesis. Synthetic AASs generally represent small modifica-
tions to the testosterone molecule, such as addition of an alkyl group at
the 17a position of the molecule, or formation of an ester at the 17b hy-
droxyl group; the mechanism of action of these synthetic compounds is
essentially identical to that of testosterone itself.
Both testosterone and synthetic AASs produce a combination of ana-
bolic and androgenic effects. The anabolic effects—which are the effects
generally sought by illicit users of these drugs—include increased protein
synthesis, decreased nitrogen excretion, and consequent gains in muscle
size and strength. The androgenic effects are the masculinizing effects of
the drugs, such as growth of male hair patterns and male sexual charac-
teristics. The androgenic effects of natural testosterone are largely attrib-
utable to its metabolite dihydrotestosterone, which displays about 10
times the androgenic potency of testosterone itself. However, testoster-
one is also partly metabolized to the estrogenic compound estradiol. Syn-
thetic AASs are similarly metabolized in part to estrogenic compounds,
which may produce such effects as gynecomastia in some illicit users of
331
AASs. Although various AASs may differ in their relative degree of ana-
bolic versus androgenic effects, no AAS even approaches being purely an-
abolic or purely androgenic.
Since the 1970s, AASs have come into widespread use, first among
elite athletes, and subsequently among amateur bodybuilders, football
players, and other athletes seeking gains in muscle mass and strength.
However, research suggests that many men who use these drugs illicitly
do not have any particular athletic aspirations at all, but simply wish to
improve their physical appearance (Pope et al. 1988, 2000a). Epidemio-
logical studies in the United States suggest that more than 1 million
Americans have used AASs at some time in their lives (Buckley et al.
1988; Durant et al. 1993; Faigenbaum et al. 1998; Johnston et al. 2002;
Pope et al. 2000a; Radokovich et al. 1993; Yesalis et al. 1990, 1993, 1997).
Partially in recognition of the magnitude of this problem, the U.S. Con-
gress has reclassified AASs as schedule III substances (Anabolic Steroids
Control Act of 1990 [P.L. 101-647]; U.S. Senate 1990).
AASs are well known to produce important physiological side effects
in addition to their anabolic properties. These include, for example, acne,
hypertension, gynecomastia (as mentioned above), testicular atrophy,
and unfavorable alterations in the ratio of total cholesterol to high-
density lipoproteins (Brower 2002; Catlin 1998; Friedl and Yesalis 1989;
Glazer 1991; Haupt and Rovere 1984; Kouri et al. 1996; Lenders et al.
1988; Lombardo and Sickles 1992; Yesalis 2000). These effects have
been well documented in the literature and are not reviewed here. Less
extensively studied, however, are the psychiatric effects of AASs; it has
only recently been recognized that AASs may produce prominent psy-
chiatric changes in some illicit users and that these effects may represent
a public health problem. In this chapter, we review studies that have ex-
amined the psychiatric effects of AASs and offer some general impres-
sions to assist the clinician who may encounter patients who exhibit
these effects.
Studies that have examined the psychiatric effects of AASs include
1) clinical studies of AASs in the treatment of psychiatric or medical dis-
orders, 2) laboratory studies of the effects of AASs in normal volunteers,
and 3) naturalistic field studies of athletes using AASs illicitly.
Clinical Studies
Soon after the isolation of testosterone in 1935 (David et al. 1935;

Wettstein 1935), a number of investigators assessed the possible psy-
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 333
chiatric benefits of this hormone, in doses ranging from 10 mg/week to

as much as 100 mg/day, in various populations of patients (Altschule
and Tillotson 1948; Barahal 1938; Danziger et al. 1944; Davidoff and
Goodstone 1942; Guirdham 1940; Zeifert 1942). These studies most
frequently examined middle-aged men with melancholic depression,
and they generally documented a modest antidepressant effect with
AAS administration. However, with the advent of electroconvulsive
therapy and the tricyclic antidepressants, AASs rapidly lost favor as an-
tidepressant agents. As recently as 1985, however, a double-blind study
of the AAS mesterolone versus amitriptyline noted a clear antidepres-
sant effect of the former drug (Vogel et al. 1985). Few adverse effects
were noted in most of these studies, even after many weeks of treat-
ment, but one investigation found that four of five men receiving im-
ipramine for treatment of depression developed paranoid delusions
when methyltestosterone was added to their regimen (Wilson et al.
1974).
Several recent studies have renewed interest in the possible antide-
pressant effects of testosterone. Seidman and colleagues (1998) recruited
five men who remained depressed despite adequate treatment with se-
lective serotonin reuptake inhibitors (SSRIs) and added intramuscular
testosterone to their antidepressant regimen. All five men improved; four
of these subjects then underwent discontinuation of testosterone, and
three of the four relapsed within a few weeks. In a subsequent double-
blind study, Seidman and colleagues (2001) assigned 30 depressed men
to intramuscular testosterone or placebo; in this study, however, testoster-
one was administered alone rather than in conjunction with an existing an-
tidepressant. No significant difference was found between treatment
groups at 6 weeks on either the Hamilton Rating Scale for Depression
(Ham-D) or the Beck Depression Inventory. Most recently, Pope and col-
leagues (in press) conducted a placebo-controlled, double-blind study in
which testosterone transdermal gel or equivalent placebo gel was added
to the antidepressant regimen of 22 men who remain depressed in spite
of adequate antidepressant treatment. At 8 weeks, the subjects assigned
to adjunctive testosterone gel exhibited significantly greater improve-
ment on the Ham-D and the Clinical Global Inventory than did subjects
assigned to placebo.
AASs have also been used to treat various medical conditions, such as
certain anemias (Blumberg and Keller 1971; Fried et al. 1973; Shahidi
and Diamond 1961) and muscular dystrophy (Barwick et al. 1963; Bek-
eny et al. 1960; Dowben and Perlstein 1961; Griggs et al. 1989). Most of
these studies employed only physiological or modestly supraphysiologi-
cal doses of AASs (equivalent to 50–200 mg of testosterone per week)
and did not specifically assess psychiatric symptoms in their subjects.

However, in studies of replacement therapy with AASs in hypogonadal
men, psychiatric effects have been more systematically documented.
Findings in these studies have varied, with some investigations finding in-
creased irritability, improved mood, and increased energy in hypogonadal
men receiving testosterone (Luisi and Franchi 1980; O’Carroll et al. 1985;
Skakkebaek et al. 1981; Wang et al. 1996) and other groups failing to ob-
serve such effects (Davidson et al. 1979; O’Carroll and Bancroft 1984;
Salmimies et al. 1982). However, since these studies generally employed
only physiological replacement doses of testosterone, their results proba-
bly do not generalize to athletes taking massively supraphysiological doses
of AASs illicitly.
Two relatively recent applications of AASs in clinical medicine are
for treatment of postmenopausal women and for men infected with hu-
man immunodeficiency virus (HIV). In menopausal women, androgens
in small doses, often administered synergistically with estrogen, have
been shown to reduce depression and increase libido (Sands and Studd
1995; Sherwin and Gelfand 1985). In one study of surgically meno-
pausal women, androgen administration was also associated with higher
hostility scores than was administration of estrogen or placebo (Sherwin
and Gelfand 1985). In a more recent study of surgically menopausal
women, testosterone improved sexual function, depressed mood, and
sense of well-being (Shifren et al. 2000). In men with HIV infection,
hypogonadism is a common finding (Croxson et al. 1989); thus, admin-
istration of testosterone or other AASs seems justified as a potential
replacement therapy. Evidence from controlled studies in which AASs
were administered to HIV-positive men suggests that these men experi-
ence improved mood, energy, and libido (Grinspoon et al. 2000; Rabkin
et al. 2000). Again, however, it must be recognized that all of these stud-
ies investigated the effects of modest doses of AASs in specialized pop-
ulations.
A final clinical application of AASs, though uncommon, is in the
treatment of female-to-male transsexuals. An interesting finding to
emerge from this area is that androgens may increase performance on
visuospatial abilities on neuropsychological testing (Cherrier et al. 2001;
Janowsky et al. 1994; Van Goozen et al. 1994). This finding appears con-
sistent with the observation that men tend to perform better than women
on visuospatial tasks (see review in Halpern 1992). At present, however,
it remains unclear to what degree the differences between the sexes are
attributable to perinatal organizing effects of androgens on the develop-
ing brain, and to what degree these differences are due to an acute acti-
vating effect of androgens in adulthood.
Laboratory Studies Using Modest Doses of

Anabolic-Androgenic Steroids
More than 25 published laboratory studies have examined the effects of

various AASs on athletic performance; studies conducted before 1984
were reviewed by Haupt and Rovere (1984) and updated by Elashoff and
colleagues (1991); others have appeared more recently (Bhasin et al.
1996; Crist et al. 1988; Friedl et al. 1991). Most of these studies were fo-
cused almost entirely on the athletic or physiological effects of AASs and
did not systematically assess psychiatric effects in their subjects. Also,
many studies employed relatively modest doses of AASs—doses far
lower than those typically used illicitly by athletes (Pope and Katz 1988).
Nevertheless, several studies anecdotally reported psychiatric changes in
some of their subjects, such as increased libido, irritability, aggression,
and euphoria (Haupt and Rovere 1984).
In several studies, AASs were administered to healthy volunteers for
physiological or endocrinologic investigations. For example, Friedl and
colleagues (1989, 1991; Hannan et al. 1991) compared testosterone dec-
anoate (100 mg or 300 mg/week) and nandrolone decanoate (also at 100
or 300 mg/week) in 30 healthy men for 6 weeks. The men in the high-
dosage groups exhibited higher scores on the Hostility and Resentment
and Aggression subscales of the Minnesota Multiphasic Personality In-
ventory. One subject receiving 300 mg of nandrolone reported an
uncharacteristic episode of anger, and another described an episode of
confusion and crying. Similar doses of AASs were also used in a physio-
logical study by Forbes and colleagues (1992), in which the investigators
administered testosterone enanthate, at a dosage of approximately 3 mg/
kg per week, to seven healthy men for 12 weeks. No psychiatric effects
were reported, but it is not clear whether the authors were specifically
assessing such effects. In an endocrinologic investigation, Matsumoto
(1990) administered placebo or testosterone enanthate at various dosage
levels (25, 50, 100, or 300 mg/week) to 51 men for a 6-month period.
The authors noted only “minor behavioral alterations” in 3 of the sub-
jects, of whom 1 was receiving placebo, 1 was receiving 100 mg of tes-
tosterone, and 1 was receiving 300 mg of testosterone per week. Bagatell
and colleagues (1994) documented no marked psychiatric changes in a
group of 19 healthy men treated with testosterone 200 mg/week for 20
weeks. The authors concluded that “concerns of adverse effects of exog-
enous [testosterone] on male sexual and aggressive behavior have per-
haps been overstated.” However, these authors failed to note that the
dosage used in their study was far lower than that used by most athletes
in the field (Pope and Katz 1994).
Naturalistic Studies
As can be seen from the above review, most medical and laboratory stud-
ies of AASs have used only physiological or modestly supraphysiological
doses of AASs, and in addition have only rarely measured psychiatric ef-
fects in a systematic way. Therefore, these studies provide little evidence
regarding the effects to be expected of athletes who may frequently self-
administer combinations of several AASs simultaneously (a practice
known as “stacking”), such that their total weekly dosage of AASs may be
5–10 times greater than that typically administered in laboratory studies
(Brower 1991, 2002; Pope and Brower 2000; Pope and Katz 1988, 1994).
To assess these effects, one must examine naturalistic studies of actual il-
licit AAS users in the field.
Before 1988, only a few anecdotal reports had appeared describing
psychiatric effects of AASs in athletes (Annitto and Layman 1980; Fre-
inhar and Alvarez 1985; Tennant et al. 1988). Since 1988, however, many
studies have appeared in which investigators have assessed groups of
AAS-using athletes using psychiatric interviews or rating scales. These stud-
ies are summarized below.
In 1988, Pope and Katz (1987, 1988) interviewed 41 AAS users (39
men and 2 women), recruited from gymnasiums in Boston and Los An-
geles, using the Structured Clinical Interview for DSM-III-R (SCID). The
authors found that 5 (12.2%) of the subjects reported manic syndromes
during AAS use, compared with none of the subjects during periods
when they were not taking AASs (P=0.06). Five (12.2%) of the subjects
reported psychotic symptoms (paranoid or grandiose delusions, and in
one case, auditory hallucinations) during the on-AAS periods, compared
with none of the subjects during the off-AAS periods (P=0.06). Also,
5 (12.2%) of the subjects reported an episode of major depression on
stopping AASs; however, 2 of these subjects had also experienced a ma-
jor depressive episode at some other time in their lives.
Choi and colleagues (1990) compared 6 men, of whom 3 were AAS
users and three nonusers, in a longitudinal design. Subjects rated them-
selves repeatedly on several scales, including the Buss-Durkee Hostility
Inventory (BDHI), the Profile of Mood States (POMS), and the Rosen-
zweig Picture-Frustration Study. They also received unstructured in-
terviews. On both the BDHI and the POMS, users showed increased
hostility when taking AASs compared with when they were not taking
AASs or compared with nonusers. One AAS user in the study admitted
to attempted murder during a previous period of AAS use.
Lefavi and colleagues (1990) compared 13 current users of AASs, 18
former users, and 14 nonusers. On the Multidimensional Anger Inven-
tory (MDAI), users scored significantly higher than nonusers on two sub-
scales: Anger-Arousal and Hostile Outlook. The MDAI was not employed
in assessing the former users, but this group also reported increases in ag-
gression in association with their past AAS use.
Perry and colleagues (1990) compared 20 weightlifters who were
currently using AASs with a comparison group of 20 weightlifters who
had never used AASs. On the Symptom Checklist–90 (SCL-90), users
reported significantly higher scores during the periods when they were
taking AASs than did the nonusers on the Depression, Anxiety, and Hos-
tility subscales. Scores on the Depression, Somatization, and Paranoid
Ideation subscales were also significantly higher in the users while taking
AASs compared with these same users during periods when they were
not taking AASs. No significant differences were found on any subscale
when comparing the users at times when they were not taking AASs with
the nonusers. However, in contrast to these robust differences on the
SCL-90, the authors did not find an increased incidence of major psychi-
atric disorders among the AAS users when interviewing them using the
Diagnostic Interview Schedule.
Moss and colleagues (1992) sought personality pathology in 50 cur-
rent or past AAS users compared with 25 nonuser athletes, using the
Multidimensional Personality Questionnaire. No significant differences
were found on this instrument, except a trend toward slightly higher ag-
gression scores among the users compared with the nonusers. The au-
thors also used the POMS, the BDHI, and the SCL-90 to compare the 25
current AAS users with the 25 nonusers. In general agreement with the
studies of Choi et al. (1990) and Perry et al. (1990), described above,
Moss and colleagues (1992) found that current AAS users displayed sig-
nificantly higher ratings of hostility on the POMS and significantly higher
scores on the Somatization and Hostility subscales of the SCL-90. On the
BDHI, the Verbal Aggression subscale significantly differentiated users
from nonusers, and trends approaching significance were also found on
the Irritability and Guilt subscales. However, the authors reported that
they were unable to confirm the presence of specific psychiatric disorders
in association with AAS use.
Bahrke and colleagues (1992) reported almost entirely negative find-
ings in a comparison of 12 current AAS users, 14 former users, and 24
nonusers. In this study, both the current users and the former users de-
scribed subjective increases in enthusiasm, aggression, irritability, and li-

bido in association with AAS use compared with the nonusers. However,
when administered the POMS and the BDHI, the current and former
AAS users did not exhibit any significant differences from the nonusers
on any of the subscales of either instrument. The authors concluded that,
despite perceived psychological changes in association with AAS use,
these changes, if present, were too subtle to be detected with objective
testing.
In 1994 Pope and Katz published a new study, using the SCID in the
same manner as their 1988 study described above, to interview 88 cur-
rent or past AAS users and 68 nonusers recruited from gymnasiums in
Boston and Los Angeles. In this study they found that 23% of the AAS
users displayed a major mood syndrome (mania, hypomania, or major
depression) in association with AAS use. This figure was significantly
higher than the prevalence of these syndromes in these same users during
periods when they were not taking AASs (6%) or the prevalence of major
mood syndromes in the comparison group of nonusers (4%). This differ-
ence did not appear to be attributable to differences in premorbid psy-
chological characteristics of users compared with nonusers, nor did it
appear to be attributable to use of drugs other than AASs, because users
rarely abused other drugs simultaneously with AASs. The authors con-
cluded that mood disturbances associated with AAS use represented a
potential public health problem.
Burnett and Kleiman (1994) compared 24 adolescent athletes who
had used AASs, 24 comparison athletes who reported that they had never
used AASs, and 24 nonathletic adolescents, using the Millon Adolescent
Personality Inventory and the POMS. In a comparison of the 5 AAS-using
athletes currently taking AASs versus the 19 AAS-using athletes who
were not currently taking AASs, the former group exhibited significantly
higher levels of depression, anger, and vigor (P<0.05 for all comparisons)
and a trend toward significantly higher total mood disturbances (P<0.10)
than the latter group.
Parrott and colleagues (1994) examined 21 amateur athletes, attend-
ing a Welsh needle-exchange clinic, who were using high doses of ana-
bolic steroids for periods of 6–14 weeks, separated by AAS-free periods.
On the BDHI and a feeling state questionnaire, subjects reported mark-
edly and significantly higher levels of aggression, alertness, irritability,
anxiety, suspiciousness, and negativism while taking AASs compared
with periods when they were not taking AASs.
Malone and colleagues (1995), also using the SCID, compared 31
current AAS users, 46 former users, and 87 nonusers. Like Pope and Katz
(1994), these authors found that hypomania was associated with AAS
use and that major depression was associated with discontinuation of

AASs. Particularly alarming was the authors’ finding that 5 (6.5%) of the
77 current or past AAS users reported a suicide attempt during a period
of discontinuing AAS use. Interestingly, the authors found a higher prev-
alence of psychiatric diagnoses in the former users than in the current
users, suggesting perhaps that selection factors might have influenced
which subjects presented for study.
Two other naturalistic studies of AAS users have been partially re-
ported in the literature but have not been published in detail. In the first
of these, Cooper and Noakes (1994) in South Africa studied 12 AAS-using
bodybuilders over a 4-month period. Initially, subjects were hesitant to
reveal the full magnitude of AAS effects on their personal lives, according
to the authors, but these effects became more obvious as the observation
period progressed. One subject repeatedly threatened to shoot his mother
while taking AASs; another kicked car doors in a parking lot continuously
for 6 minutes. The authors noted no comparable behavioral changes in a
control group. They concluded that “the true extent of the psychiatric
and behavioral problems associated with AAS use is almost certainly un-
derestimated.” In a second study, Fudala and colleagues (1996) reported
longitudinal data on 6 paid volunteers self-administering AASs. Subjects’
reports of four effects (changes in aggression, libido, frequency of sexual
activity, and mood swings) indicated that increases in these effects were
reported 2–10 times more often than decreases when subjects were tak-
ing a “cycle” of AASs. Changes were also noted on rating scales such as
the POMS and the BDHI, but these changes were not always clearly re-
lated to periods of AAS use.
In summary, 12 naturalistic investigations, to our knowledge, have ex-
amined psychiatric symptoms and syndromes reported in association
with AAS use among athletes in the field. These studies have used either
various rating scales (such as the POMS, SCL-90, and BDHI) or various
interview instruments (such as the Diagnostic Interview Schedule and
the SCID). The findings of these studies initially appear to be somewhat
contradictory, with some studies finding virtually no psychiatric changes
in AAS users (Bahrke et al. 1992) and others describing robust changes
(Pope and Katz 1988). However, a simple explanation of the differences
seems to emerge when one examines the dosages of AASs reported by
the athletes examined in the 10 published studies. For this analysis, we
have defined a low dosage of AASs as the equivalent of 300 mg of test-
osterone per week or less; a medium dosage as the equivalent of 300–
1,000 mg/week; and a high dosage as the equivalent of 1,000 mg/week
or more. When the dosages used by subjects in the various studies are ex-
amined, it will be seen that there appears to be an association between
dosage and degree of psychopathology. For example, the earlier study of

Pope and Katz (1988), which reported a very high prevalence of psychi-
atric syndromes, also included a large number of high-dosage AAS users.
Indeed, the 8 men in this study who displayed psychotic symptoms or a
manic episode reported an average weekly dosage of 900 mg. Similarly,
among the 25 men who reported a weekly dosage of 1,000 mg or more
in the more recent study of Pope and Katz (1994), 11 (44%) reported
mania, hypomania, or major depression. At the other extreme is the
study of Bahrke and colleagues (1992), whose subjects reported a mean
weekly AAS dosage of only 318 mg, and in which even the heaviest AAS
user used only 620 mg/week. These users displayed virtually no psychi-
atric changes. Again similarly, when examining the 12 users in the recent
Pope and Katz (1994) study who reported using 300 mg or less per week,
only 1 subject (8%) reported hypomanic symptoms, and none reported
mania or major depression. Studies examining subjects reporting inter-
mediate levels of AAS use found intermediate levels of psychopathology.
In short, therefore, the literature appears to be consistent when dosage is
taken into account: dosages of 300 mg/week or less rarely produce psy-
chopathology; dosages of 1,000 mg/week or more do so frequently.
However, the naturalistic studies described above are subject to sev-
eral methodological limitations. First, they rely on subjects’ self-reports
of use of drugs obtained illicitly. Therefore, the dosage or identity of these
drugs often cannot be confirmed. Second, subjects’ retrospective ac-
counts of psychiatric syndromes may be colored by various biases, such
as influences from the gymnasium subculture or expectations regarding
the effects of AASs. Third, various forms of selection bias may operate;
for example, subjects with prominent psychopathology might be more
likely or less likely to volunteer to participate in a research study. Fourth,
in a retrospective investigation it is difficult to differentiate the psychiat-
ric effects of AASs themselves from the influences of subjects’ premorbid
personalities, use of other psychoactive substances, and other factors.
Several more recent reviews have commented on these methodological
limitations of studies examining illicit AAS users (Bahrke and Yesalis
1994; Riem and Hursey 1995; Rubinow and Schmidt 1996).
Laboratory Studies of High-Dosage

Anabolic-Androgenic Steroid Use
Four laboratory studies have appeared in which dosages equivalent to

at least 500 mg/week of testosterone were administered to normal vol-
unteers under placebo-controlled, double-blind conditions. In the first,

by Su and colleagues (1993), 20 healthy volunteers were administered
placebo, followed by methyltestosterone (40 mg/day), followed by
methyltestosterone (240 mg/day), with each treatment interval lasting
3 days. Most of the subjects exhibited few psychiatric changes; how-
ever, one man exhibited marked depressive symptoms after treatment
was discontinued; one exhibited hypomanic symptoms during treat-
ment with methyltestosterone; and one became frankly manic with
methyltestosterone—to the point where he requested to be placed in
seclusion. In the second study, Bhasin and colleagues (1996; Tricker et
al. 1996) administered testosterone enanthate (600 mg/week) for 10
weeks to 21 healthy volunteers. These investigators did not administer
psychiatric ratings to their subjects, but they asked each subject and one
of the subject’s significant others to rate the subject’s mood and be-
havior. No significant differences were found in the study between
the group administered testosterone and a similar group administered
placebo for the same period. In the third study, Yates and colleagues
(1999) administered testosterone cypionate (500 mg/week) to 18
healthy volunteers. Seventeen of these subjects exhibited few psychiat-
ric changes, but one developed a marked personality change and was
described by the authors as closely approaching the full DSM-IV crite-
ria (American Psychiatric Association 1994) for a manic episode. In the
fourth study, Pope and colleagues (2000b) administered testosterone
cypionate, in dosages increasing to 600 mg/week over a 6-week period,
to 50 healthy men in a placebo-controlled crossover design. Two of the
men in this study developed prominent hypomanic episodes, and 6 oth-
ers developed mild hypomanic symptoms. The subjects in the study by
Pope et al. (2000b) were drawn from three groups: 1) men who had
previously used illicit AASs but who had not done so within the last 3
months, 2) men who lifted weights regularly but who had never used
AASs, and 3) men who neither lifted weights regularly nor used AASs.
The authors assessed the level of the subjects’ manic symptoms in re-
sponse to testosterone, using a regression analysis that included a term
for group status. It was found that group status contributed no signifi-
cant effect to manic symptoms, regardless of whether the three groups
were treated as ordered or unordered categories. This observation sug-
gests that a biological effect of testosterone, rather than psychosocial
variables related to weightlifting or prior AAS use, accounts for the dif-
ferences observed.
Collectively, a total of 109 men received markedly supraphysiological
doses of AASs under double-blind conditions in these four studies; of
these, 5 (4.6%) displayed prominent hypomanic or manic reactions. The
95% confidence interval for this rate is 1.4%–10.4%. However, it must be

recognized that this rate may well represent an underestimate of the true
prevalence of severe psychiatric reactions in the field, for several reasons.
First, illicit AAS users may take much larger dosages of AASs per week
than can be ethically administered in the laboratory, with some taking as
much as several thousand milligrams per week at the peak of an AAS cy-
cle (Pope and Katz 1988). Second, illicit users may stack multiple AASs
together simultaneously—a practice that may augment psychiatric ef-
fects in unknown ways. Third, subjects in laboratory studies were gen-
erally selected with careful exclusion criteria, including exclusion of
subjects with a history of major psychiatric disorder or recent substance
dependence. Actual illicit users are of course not subject to such restric-
tions. For all of these reasons, it seems likely that the approximately 5%
rate in these four laboratory studies represents a “lower bound” for the
true rate of prominent hypomanic or manic reactions caused by AAS
abuse.
Probably the outstanding finding of these four laboratory studies, as
well as that of the field studies described above, is that psychiatric re-
sponses to AASs are nonuniform: a majority of users exhibit little or no
psychiatric change, whereas a minority exhibit prominent and some-
times severe psychiatric effects. The mechanism of this response re-
mains unknown; none of the studies described above has provided data
indicating why certain subjects are vulnerable to these effects, whereas
most are not. One possible hypothesis, on the basis of preliminary data
in animals, is that high doses of AASs increase dopaminergic and
5-hydroxytryptaminergic metabolism (Thiblin et al. 1999). A recent
human study (Daly et al. 2001) appears to support this hypothesis, in
that it found significantly higher levels of 5-hydroxyindoleacetic acid
(5-HIAA) in the cerebrospinal fluid of men receiving the AAS methyl-
testosterone as opposed to placebo. In this study, 5-HIAA levels corre-
lated significantly with increased energy, diminished sleep, and sexual
arousal.
Specific Syndromes Associated With

Anabolic-Androgenic Steroid Use
In addition to the hypomanic symptoms associated with AAS use and the
depressive symptoms associated with AAS withdrawal in many of the
studies described above, several specific syndromes have been described
in association with AAS use. These include AAS dependence, “muscle
dysmorphia,” violence toward others, and progression to opioid abuse or

dependence.
Anabolic-Androgenic Steroid Dependence

A series of investigations have suggested that AASs may possess depen-
dence-inducing properties. For example, in several studies, Brower and
colleagues found that a substantial number of AAS users met DSM-III-R
criteria (American Psychiatric Association 1987) for substance depen-
dence (Brower 1992, 1997, 2002; Brower et al. 1989a, 1990). The causes
for this dependence syndrome may be both physiological and psycholog-
ical. First, the withdrawal syndrome from discontinuing AASs may pre-
cipitate a period of pronounced depression, which may be associated
with suicidal ideation or even completed suicide (Allnut and Chaimow-
itz 1994; Brower et al. 1989b; Elofson and Elofson 1990; Malone et al.
1995; Pope 1990). Users who experience this withdrawal depression
may thus be tempted to quickly resume use of AASs to “self-medicate”
these symptoms. A detailed discussion of this hypothesis is presented by
Kashkin and Kleber (1989), who postulated that a delayed depressive
withdrawal syndrome, preceded by an acute hyperadrenergic withdrawal
state, may contribute to a syndrome of “addiction” to AASs.
In addition, the desire to look bigger and stronger, or to avoid losing
muscle gains previously achieved, may prompt AAS users to continue to
take these drugs repeatedly once they have first tried them. Brower and col-
leagues (1989a, 1990) suggested that individuals who felt that they were
not big enough or strong enough, and who took larger doses of AASs for
longer periods, were the ones who were most likely to become dependent.
Muscle Dysmorphia
The speculations outlined above regarding psychological mechanisms for
AAS dependence are supported by the observation that many individuals
using AASs display a sort of “reverse anorexia nervosa” in which they per-
ceive themselves to be small and weak even when they are in fact large
and muscular. In recent studies from our laboratory, we have called this
syndrome muscle dysmorphia and described its characteristics in greater
detail (Olivardia et al. 2000; Phillips et al. 1997; Pope et al. 1993, 1997).
Other investigators have also found that feeling “not big enough” may
represent a risk factor for use of AASs (Bahrke et al. 2000; Brower et al.
1994; Kanayama et al. 2001; Pope et al. 2000a). The role of this syn-
drome of body image distortion in weightlifters who use AASs clearly
deserves further investigation.
Violence
Several reports have noted that occasional users of AASs become unchar-
acteristically violent when taking these drugs (Choi et al. 1990; Con-
acher and Workman 1989; Dalby 1992; Pope and Katz 1990; Pope et al.
1996; Stanley and Ward 1994). In two of these reports (Pope and Katz
1990; Stanley and Ward 1994), the individuals displayed psychotic
symptoms apparently associated with AAS use. Although it is difficult to
confirm in retrospective observations that the violence was specifically
attributable to AAS use, many of the individuals described in these re-
ports exhibited no premorbid history of violence, no criminal record, and
no apparent history of psychiatric disorder prior to AAS use—observa-
tions suggesting that AASs represented the principal etiologic factor in
the violent behavior.
Our anecdotal experience suggests that AAS-induced violence is fre-
quently directed at women (Pope et al. 2000a). In an examination of this
hypothesis, Choi and Pope (1994) studied 23 AAS users and 14 nonus-
ers, recruited in the course of a study described earlier (Pope and Katz
1994), using the Dyadic Adjustment Scale and the Conflict Tactics Scale
to assess users’ relationships with wives or girlfriends. Although the
former scale did not detect effects of AASs, the Conflict Tactics Scale re-
vealed several significant differences between the AAS users when taking
the drug versus not taking the drug and between the users taking the drug
versus the nonusers. Several users described striking incidents of violence
toward women while taking AASs: for example, one reported that he
threw a brick at his girlfriend, and another reportedly fractured several
bones in his girlfriend’s hand by squeezing it. Neither of these subjects
reported comparable behavior toward women when they were not taking
AASs.
During the last several years, we have also consulted on approxi-
mately 20 legal cases in which individuals were charged with various vi-
olent crimes that appeared to have been committed at times when the
individuals were taking AASs. Several of these cases involved murder or
attempted murder. We described this experience, and presented an ex-
ample of a particularly striking murder case, in a paper (Pope et al. 1996).
Again, it is not possible to conclude with certainty that AASs played an
etiologic role in these crimes. It is noteworthy, however, that most of
these men reported no history of any DSM-IV psychiatric disorder before
their AAS exposure, and most also displayed no prior history of criminal
convictions or violent activity. In several of the cases, however, the indi-
vidual had used alcohol as well as AASs at the time of the crime, which
suggests a possible additive effect. In many of these cases, the role of
AASs was raised as an issue in the legal defense, either under the rubric
of “involuntary intoxication” or, less frequently, insanity. We are not
aware of any case in which an “AAS defense” has led to a verdict of not
guilty by reason of insanity, but there have been several cases in which
the evidence of AAS use may have acted as a mitigating factor, apparently
leading to a more lenient sentence. Three of these criminal cases are de-
scribed in a separate publication (Pope and Katz 1990); a more detailed
discussion of the forensic issues surrounding AASs and criminal behavior
has also appeared (Bidwell and Katz 1989).
Progression to Opioid Abuse or Dependence

AAS use may also possibly serve as a “gateway” to abuse of opioid ago-
nist/antagonists such as nalbuphine (McBride et al. 1996; Wines et al.
1999) or to ordinary opioid agonists such as heroin (Arvary and Pope
2000; Kanayama et al., in press; Wines et al. 1999). Specifically, in one
series of 227 men with opioid dependence admitted to a New Jersey
treatment facility (Arvary and Pope 2000), 21 (9%) reported a history of
AAS use. Fourteen (67%) of these 21 men reported that they were first
introduced to opioids by fellow AAS users at the gym, and 17 (81%) re-
ported that they first purchased opioids from the same individual who
had first sold them AAS. In another study of 223 male substance abusers
admitted to an inpatient treatment facility (Kanayama et al., in press),
6 (7%) of the 88 men listing opioids as their drug of choice, plus a sev-
enth man admitted for both cocaine and opioid dependence, stated that
they used AAS when younger, then first learned of opioids from AAS us-
ers at the gym, and subsequently purchased opioids for the first time
from the same person who had previously sold them AAS. Although it is
not possible to say with certainty that AAS use was a causal factor in in-
troducing these men to opioid abuse or dependence, their histories are
certainly suggestive of this hypothesis. The present authors are personally
aware of several cases of men in the last 3 years who were apparently in-
troduced to opioids in this manner and who subsequently died of un-
intentional overdoses of intravenous opioids. Thus, the gravity of this
syndrome should not be minimized.
Anabolic-Androgenic Steroid Use in Women
The previous discussion of the psychiatric effects of AASs is focused al-

most exclusively on data from men using these drugs. However, sub-
stantial data suggest that some women have experimented with AASs
as well. However, the number of women using AAS is almost certainly
much lower than the number of men. Admittedly, some anonymous
student surveys have suggested that rates of AAS use in girls may be at
least 1.5%—or about one-third the rate in boys (Durant et al. 1993;
Middleman et al. 1995), and one survey found a rate of 2.8% in girls as
opposed to only 2.6% in boys (Faigenbaum et al. 1998). However, since
these estimates were based on anonymous survey responses, they must
be regarded with some caution, because of the risk of false positive re-
sponses by students who had used either corticosteroids or nutritional
supplements that they misidentified as “steroids” (Pope et al. 2000a).
Studies in which subjects were interviewed personally, such as the Na-
tional Household Survey (1994), thus probably provide somewhat
more reliable estimates—and in that survey the ratio of women to men
is much lower. In the 1994 survey (the most recent to collect AAS
data), the number of American men estimated to have used AAS in the
past 3 years was 413,458, as compared with 31,316 women—a ratio of
13 to 1 (National Household Survey 1994). With subjects who re-
ported that they had ever used a needle to inject AAS (perhaps a better
measure of serious AAS use), the survey estimated 205,499 men versus
8,404 women—a ratio of 25 to 1. In the only large interview study that
recruited subjects of both sexes, Malone and colleagues (1995) ob-
tained 71 male AAS users and 6 female users—a ratio of 12 to 1.
Because of the relative infrequency of female AAS users, few studies
have examined the psychiatric effects of AASs in women. One anecdotal
report described 10 women athletes who had used AASs (Strauss et al.
1985); these women described various masculinizing effects and, in some
cases, increases in aggression. However, given the small sample size and
lack of a control group in this study, it is difficult to generalize from these
findings. Other more recent studies have documented adverse effects on
lipoprotein profiles (Moffat et al. 1990) and neuroendocrine measures
(Malarkey et al. 1991) in small groups of women using AASs, but they
have not systematically sought psychiatric symptoms. More recently, our
group reported a comparison of 25 women athletes who had used AASs
with 50 who had not (Gruber and Pope 2000). None of the AAS-using
women in this study described a frank episode of mania or major depres-
sion in association with AAS use or withdrawal, probably because the
doses that they used were lower than those frequently used by male us-
ers. However, a majority of these women reported increases in irritability
and aggression during AAS use and depressive symptoms after discon-
tinuing AASs.
Clinical Implications
At present, our understanding of the psychiatric effects of AASs remains

limited, so recommendations for the clinician must be tentative. How-
ever, several general impressions emerge.
First, convincing data now exist to suggest that AASs can produce
prominent psychiatric effects in some individuals who use these drugs.
These effects appear to be dose related: when AASs are administered in
physiological or modestly supraphysiological doses, as replacement ther-
apy in hypogonadal men or in treatment of disorders such as muscular
dystrophy, the incidence of psychiatric effects appears to be low. Simi-
larly, laboratory studies of subjects receiving 300 mg/week of testoster-
one or its equivalent have also rarely documented psychiatric effects. In
the field, in studies examining athletes who ingested AASs illicitly, dos-
ages of 300 mg/week of testosterone or its equivalent also rarely pro-
duced psychiatric effects. However, many athletes take much larger doses
of AASs, and it is these individuals who may be most likely to be encoun-
tered by the psychiatric clinician. Individuals taking 1,000 mg or more of
testosterone equivalent per week may display frank manic episodes, oc-
casionally accompanied by psychotic symptoms. Little has been written
about the treatment of such episodes, although individual case reports
(Annitto and Layman 1980; Freinhar and Alvarez 1985; Pope and Katz
1987, 1988; Stanley and Ward 1994) suggest that elimination of the
offending agent and temporary treatment with neuroleptics may lead
to prompt remission of the symptoms. At present, it is unclear whether
mood-stabilizing agents such as lithium, valproate, or carbamazepine
would be useful in treating AAS-induced hypomanic or manic syn-
dromes.
It is difficult to estimate the frequency of AAS-induced manic epi-
sodes that come to the attention of clinicians, because the possible etio-
logic role of AASs is often not assessed. However, the possibility of AAS
use should be considered in manic individuals who are unusually mus-
cular. Because AAS users often deny that they have used these drugs, the
patient’s history may be unreliable. If the clinician remains suspicious, a
formula for calculating normalized fat-free mass index in men has re-
cently been published by our laboratory; this formula provides an ap-
proximate method for determining whether an individual exhibits a
degree of muscularity beyond that attainable by natural means, thus
raising the suspicion of AAS abuse (Kouri et al. 1995). The reader is re-
ferred to the original paper for a full presentation of this formula. Urine
testing for AASs is available, but it is expensive and is subject to various
limitations (Aguilera et al. 1996, 1999; Catlin and Cowan 1992; Catlin
et al. 1987). A less expensive screening test that may be of some value
is to determine the plasma testosterone level. If it is well above the nor-
mal range, this finding would suggest that the patient may have been
illicitly taking exogenous testosterone. If it is well below the normal
range, then the patient may very likely have been using some other ex-
ogenous AAS, thus suppressing his own endogenous testosterone pro-
duction.
Episodes of major depression following AAS withdrawal may also re-
quire psychiatric intervention. One report described successful treat-
ment of four such episodes with fluoxetine (Malone and Dimeff 1992).
Another report described an AAS user whose withdrawal depression did
not respond to desipramine or fluoxetine but ultimately responded to
electroconvulsive therapy (Allnut and Chaimowitz 1994). Given the risk
of suicide in some individuals withdrawing from large doses or long
courses of AASs, such intervention may be important.
At present, it is not clear why some individuals develop manic or de-
pressive symptoms in association with AAS use while the majority of us-
ers do not. There is little evidence in the various retrospective studies
reviewed above to suggest that a prior history of psychiatric disorder or a
family history of psychiatric disorder increases the risk of these syn-
dromes, although further investigation is clearly required to resolve this
question. Similarly, there is little reason to assume that the prior person-
ality of the user, his history of aggressive or violent behavior, or his expec-
tations regarding the effects of AASs are particularly predictive of a
AAS-induced mood syndrome. Presumably, individuals who have dis-
played a mood syndrome in association with a previous course of AAS
use will be at increased risk to display a similar syndrome on using AASs
in the future, but even this is not certain. In the retrospective study cited
earlier (Pope and Katz 1994), we noted anecdotally that individuals dis-
playing adverse responses to AASs on one occasion were likely to do so
on another, but this was not invariably the case. Assessment of this ques-
tion is complicated by the fact that individuals may use different combi-
nations and doses of AASs on different occasions, making comparison
difficult. In short, therefore, it seems most likely that AAS-induced mood
syndromes represent an idiosyncratic response that is largely unpredict-
able, although such syndromes probably do become more likely with in-
creasing dosages.
Treatment of AAS use and dependence may be difficult in many cases,
because athletes exhibiting this syndrome rarely seek treatment (Pope et
al. 2000a). However, preliminary recommendations, based on models de-
veloped from treatment of other types of substance dependence, have
been published (Brower 1992, 1994, 2002; Corcoran and Longo 1992;
Goldberg et al. 1991, 1996a, 1996b, 2000). Pharmacotherapy for de-
pression during AAS withdrawal and pharmacotherapy or psychotherapy
to deal with body image disorders such as muscle dysmorphia (Neziroglu
et al. 1997; Phillips 2001; Phillips et al. 1997; Rosen et al. 1995) may be
useful elements in such a treatment program. It is not clear whether AAS
users will benefit from treatment in mixed groups with other types of
substance abusers, because many AAS users scrupulously avoid abuse of
other substances and pay close attention to their health while using AASs
(Pope and Katz 1994). Thus, in our experience, AAS users do not inte-
grate easily into groups of other substance abusers. Similarly, we are not
aware of a 12-step type of program that has been employed successfully
with AAS users. Individual therapy, ideally with a therapist who is famil-
iar with AASs and with the gymnasium subculture, may therefore be the
treatment of choice.
Finally, forensic psychiatrists should be aware of the possibility that
AASs may be involved in acts of violence. In cases where an athlete or
an unusually muscular individual has committed a violent crime, the
possibility of AAS use should always be considered and, if possible, as-
sessed via urine testing. The psychiatrist’s index of suspicion should be
particularly high in instances where the individual abruptly becomes
very depressed, with prominent vegetative features such as anhedonia
and psychomotor retardation, immediately after being incarcerated, but
then seems to regain his normal personality several weeks later. This
pattern, which we (Pope and Katz 1990) and others (Stanley and Ward
1994) have noted in men who were incarcerated in the midst of a course
of AAS use, likely reflects the abrupt syndrome of AAS withdrawal,
during which hypothalamic-pituitary-testicular function is grossly at-
tenuated, followed by return of more normal mood as testicular func-
tion reverts to baseline. Of course, even in cases where it is established
beyond doubt that an individual has committed violence under the in-
fluence of AASs, the forensic implications may vary, depending on pre-
vailing laws regarding “voluntary intoxication” or “diminished capacity”
caused by a substance that the individual has intentionally ingested.
In conclusion, studies regarding the clinical effects of AASs and
clinical treatment of AAS users remain limited. Virtually all of the rel-
evant literature has appeared just within the last 10 years. With in-
creased attention now being directed at the psychiatric syndromes
associated with AAS use, the understanding of the epidemiology, na-
ture, and treatment of these syndromes will doubtless expand rapidly
in the near future.
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Part V
Thyroid Hormones
Chapter 14
Thyroid Function in
David O’Connor, M.D.

Harry Gwirtsman, M.D.
Thyroid Physiology
The principal hormones of the hypothalamic-pituitary-thyroid (HPT)

axis are thyroxine (T4) and triiodothyronine (T3), the latter being the
more potent biologically (Larsen and Ingbar 1992). Although both T4
and T3 are released from the thyroid gland, about 90% of circulating T3
is derived from T4 by monodeiodination in (mainly) liver, kidney, and
other tissues by the enzyme 5¢-deiodinase type I (5¢D-I). In serum, more
than 99.5% of T4 and T3 are bound to thyroxin-binding globulin (TBG),
albumin, and thyroxine-binding prealbumin (TBPA), leaving less than
0.5% of T4 and T3 unbound and biologically active (Larsen and Ingbar
1992). Alterations in either deiodination or serum protein concentrations
(as in liver disease, starvation, or chronic illness) can therefore pro-
foundly affect thyroid hormone economy (Israel and Orrego 1984; Israel
et al. 1979).
Biosynthesis and release of T4 and T3 from the thyroid gland are pri-
marily controlled by the anterior pituitary hormone thyrotropin (thy-
roid-stimulating hormone [TSH]). In turn, biosynthesis and release of
TSH from thyrotropes are mediated principally by the tripeptide thyro-
tropin-releasing hormone (TRH). TRH is released directly into the portal
venous system, which connects the hypothalamus and the pituitary gland,
361
from hypothalamic neurons that originate in the paraventricular nucleus.

TRH also stimulates the release of prolactin from pituitary lactotroph
cells. Homeostatic control within the HPT axis is ensured through nega-
tive-feedback inhibition by T4 and T3 at the thyrotrope, leading to dimin-
ished synthesis and release of TSH. Thyroid hormones have also been
shown to selectively reduce TRH biosynthesis in the hypothalamus, which
may provide yet another means of regulation (Segerson et al. 1987). Fi-
nally, many neurotransmitters and non-HPT-axis hormones affect TRH
and TSH release (Morley 1981).
A wealth of laboratory studies provide evidence for both a neuroreg-
ulatory role of thyroid hormones (Table 14–1) and a homeostatic mech-
anism by which brain intracellular T3 concentrations are enzymatically
maintained within narrow limits ( J. L. Leonard 1990). The enzyme
5¢-deiodinase type II (5¢D-II)—found in the central nervous system, an-
terior pituitary, brown adipose tissue, and placenta—has been shown to
increase threefold to fivefold within 24 hours of thyroidectomy and to
decrease by 80%–90% within 2–4 hours after injection of a saturating
dose of T3 ( J.L. Leonard 1990). The thyroid hormone–induced changes
in 5¢D-II activity in vivo and in cell cultures are due to changes in the
half-life of the enzyme (in euthyroid animals the half-life of 5¢D-II is
about 30 minutes; it increases to 4–6 hours in hypothyroid animals) and
do not depend on transcription or translation. Moreover, T4 and reverse
T3 (rT3) are more than 100-fold more effective than T3 ( J.L. Leonard
1990). In contrast, 5¢D-I activity is decreased in thyroidectomized rats,
and at least 3–5 days of hypothyroidism are required to observe this de-
cline in activity (J.L. Leonard 1990). Taken together, these findings sug-
gest that a well-balanced thyroid economy is important for the brain to
function normally. The evidence supporting thyroid imbalance in those
with mental illness is the subject of this chapter.
Assessment of Thyroid Function
The intactness of the HPT axis can normally be evaluated by measuring

the concentrations of serum thyroid hormones, although the assays for
free T3 (FT3) and free T4 (FT4) are not without limitations in that non-
thyroidal illness can affect their performance, leading to falsely low results
(Tunbridge and Caldwell 1991). If such assessment provides ambiguous
results, or if one suspects more subtle changes in HPT axis function (e.g.,
subclinical hypothyroidism), it is necessary to assess serum TSH concen-
trations (Larsen and Ingbar 1992; Toft 1991). Additional guidelines for
Thyroid Function in Psychiatric Disorders 363
TABLE 14–1. Evidence for a neuroregulatory role of thyroid hormones

Thyroid hormone receptors are widely distributed throughout the brain
(Dratman et al. 1982).
Both thyroxine (T4) and triiodothyronine (T3) enter the brain by a high-affinity
saturable transport mechanism (Dratman et al. 1976, 1982).
Within the brain T4 and T3 are differentially distributed regionally and are
highly localized in synaptosomes (Dratman et al. 1976, 1982).
The rate of conversion of T4 to T3 is many times greater in brain than in liver
(J.L. Leonard 1990).
There is evidence that T4 may be converted into T3 within nerve terminals
(Dratman and Crutchfield 1978).
Despite extremes of T4 availability, brain T4 and T3 concentrations and brain T3
production and turnover rates are kept within narrow limits (Dratman et al.
1983; J.L. Leonard 1990), suggesting that small changes in brain thyroid
hormones may produce significant changes in behavior.
Hyperthyroidism increases striatal b-adrenoreceptors and striatal dopaminergic
activity, whereas hypothyroidism reduces striatal and hypothalamic
b-adrenoreceptors (Atterwill et al. 1984).
Hyperthyroidism increases, and hypothyroidism decreases, presynaptic
a2-adrenoreceptor function (Atterwill et al. 1984).
Hypothyroidism causes a significant increase in serotonin and substance P levels
in rat brain nuclei (Savard et al. 1983).
the laboratory evaluation of the thyroid axis are provided in Chapter 17

of this volume.
Thyroid Function in a General Psychiatric Population
The prevalence of one or more thyroid abnormalities in acutely hospital-

ized psychiatric patients ranges from 6% to 49% (Table 14–2). Most
prominent among these findings are the euthyroid sick syndrome (char-
acterized by abnormal concentrations of circulating iodothyronines in
otherwise euthyroid patients [Larsen and Ingbar 1992]) and mild, tran-
sient hyperthyroxinemia. Both findings have been observed in schizo-
phrenia and depression alike (Roca et al. 1990; Spratt et al. 1982); they
usually normalize on recovery (Chopra et al. 1990; Morley and Shafer
1982; Spratt et al. 1982). It is therefore necessary to interpret blood thy-
roid function tests with caution in all recently hospitalized patients.
The euthyroid sick syndrome, attributable largely to reduced ex-
trathyroidal conversion of T4 to T3 (Chopra et al. 1983), is common in
many acute and chronic illnesses (Larsen and Ingbar 1992). Whether
364
TABLE 14–2. Transient hyperthyroxinemia in acutely hospitalized psychiatric patients
Study N Thyroid measure Prevalence (%) Comment
Weinberg and Katzell 1977 50 T4 increased 6 Mental state improved after remission of the thyrotoxicosis.
Caplan et al. 1983 100 FT4I increased 6
Cohen and Swigar 1979 480 Estimated 18 In half of the patients, return to normal within several weeks.
FT4I increased or
decreased
Spratt et al. 1982 645 T4 increased 33 No difference between schizophrenic and depressed patients.
Thyroid function without therapy in 22 patients serially followed.
FT4 increased 18
Morley and Shafer 1982 386 FT4 or FT3I increased 19 Elevations particularly common in patients with paranoid
Total T3 increased 17 schizophrenia (38%) and in patients with amphetamine abuse
(32%). Return to normal levels on retesting 2 or 3 weeks later.
Roca et al. 1990 45 One or more thyroid 49 Significant positive correlations between psychiatric symptom
hormones increased severity and FT4I among depressed and schizophrenic patients.
Chopra et al. 1990 84 T4 increased 24 On repeat testing 7–21 days after admission, serum TSH (and/or T4)
FT4I increased 16 normalized in 3 of the 5 patients studied.
Total T3 increased 20
FT3I increased 13
TSH increased 17
Levy et al. 1981 150 Thyroid hormones 7 Euthyroid sick syndrome in 7% of patients; when blood was sampled
serially, 27%.
McLarty et al. 1978 1,206 Thyroid hormones 0.5–0.7 Hypothyroidism (0.5%), hyperthyroidism (0.7%).
Note. FT4 =free thyroxine; FT3I=free triiodothyronine index; FT4I=free thyroxine index; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.
patients with nonthyroidal illnesses with low T4 or T3 concentrations, or

both, are hypothyroid is not clear; the clinical significance of the euthyroid
sick syndrome therefore remains uncertain (Brent and Hershman 1986;
Chopra et al. 1983). Pathophysiologically, transient hyperthyroxinemia
may result from centrally mediated hypersecretion of TSH, particularly
among depressed patients in whom high TSH concentrations are found
in the face of elevated thyroid hormone levels (Roca et al. 1990)—a find-
ing that distinguishes this phenomenon from ordinary hyperthyroidism.
Being centrally mediated, transient hyperthyroxinemia may be the result
of environmental circumstances (e.g., acute hospitalization) or of being
acutely mentally ill.
Thyroid Function in Mood Disorders

Peripheral Thyroid Hormones
Depression
Peripheral thyroid hormone concentrations were assessed in acutely de-
pressed inpatients and outpatients and were compared with concentra-
tions in nondepressed control subjects, euthymic patients, or both; the
results are equivocal. Most depressed patients appear to be euthyroid
(Briggs et al. 1993; Kirkegaard 1981; Loosen 1986, 1988; Vandoolaeghe
et al. 1997). However, some investigators reported serum T4 levels in the
upper normal range (Dewhurst et al. 1968; Hatotani et al. 1974; Kirkeg-
aard and Faber 1981; Kjellman et al. 1983; Kjellman et al. 1993; Styra et
al. 1991) or found increased serum concentrations of rT3 (Kirkegaard and
Faber 1981; Kjellman et al. 1983; Linnoila et al. 1979), the hormonally in-
active analog of T3 (Larsen and Ingbar 1992). Other investigators reported
lowered thyroid function in depressed patients, including reduced mean
levels of free T4 index (FT4I) and FT4 (Custro et al. 1994; Natori et al.
1994; Rinieris et al. 1978a, 1978b; Rybakowski and Sowinski 1973) and
of T3 (Custro et al. 1994; Joffe et al. 1985; Linnoila et al. 1979; Natori et
al. 1994; Orsulak et al. 1985; Rupprecht et al. 1989; Wahby et al. 1989).
Two studies involving a total of 366 depressed outpatients who were
screened carefully for evidence of thyroid disease (Briggs et al. 1993; Fava
et al. 1995) concluded that because of the low incidence of abnormal
findings (e.g., increased serum TSH levels were found in 2% and 2.6% of
patients), routine thyroid function tests are not indicated.
Are there dynamic changes in thyroid function when the individual
patient shifts from depression into remission? If so, are these changes
related to the applied treatment or to aspects of remitting symptoms?
Although these questions cannot be answered with certainty, studies that

have addressed them have revealed remarkably consistent results. Most
(Baumgartner et al. 1988; Board et al. 1957; Brady and Anton 1989;
Brady et al. 1994; Ferrari 1973; Gibbons et al. 1960; Hoeflich et al. 1992;
Joffe and Singer 1987, 1990; Kirkegaard and Faber 1986; Kirkegaard et
al. 1975, 1977; Kusalic et al. 1993; Mason et al. 1989; Muller and Boning
1988; Southwick et al. 1989; Unden et al. 1986; Whybrow et al. 1972),
but not all (Karlberg et al. 1978; Kolakowska and Swigar 1977; Leichter
et al. 1977; Shelton et al. 1993), studies reported significant reductions
in serum T4 concentrations after remission was induced by a wide range
of somatic treatments, including various antidepressants (e.g., chlorimip-
ramine [Baumgartner et al. 1988]; maprotiline [Baumgartner et al. 1988;
Hoeflich et al. 1992]; desipramine [Baumgartner et al. 1988; Brady and
Anton 1989; Joffe and Singer 1990]; fluvoxamine [Hoeflich et al. 1992];
sertraline [McCowen et al. 1997]; imipramine [Brady et al. 1994]), lith-
ium, sleep deprivation, or electroconvulsive therapy (ECT). Four studies
(Joffe and Singer 1990; Kusalic et al. 1993; Roy-Byrne et al. 1984; South-
wick et al. 1989) documented that the T4 reduction was greater in those
who responded to treatment than in nonresponders, suggesting that re-
duction of thyroid function may facilitate treatment response. This con-
cept is further supported by a study by Joffe et al. (1992), in which six
depressed patients were treated with the antithyroid drug methimazole
(20 mg/day) for 4 weeks. Three patients responded to treatment (defined
as greater than a 50% change in score on the Hamilton Rating Scale for
Depression to a score below 10), and two patients had a partial response
(greater than a 25% change in score). These five patients showed reduc-
tions in T4 level and FT4I but not in TSH level during the 4-week trial.
Alternatively, increased thyroid function may facilitate treatment re-
sponse. This was first noted by Whybrow et al. (1972), who showed that
heightened thyroid activity before treatment was positively correlated
with a prompt clinical response to imipramine.
Bipolar Disorder
Serum concentrations of thyroid hormones have been shown to be in-
creased in some acutely ill adult (Mason et al. 1989; Muller and Boning
1988; Southwick et al. 1989; Styra et al. 1991) and adolescent (Sokolov
et al. 1994) patients with bipolar disorder. Other investigators found
reduced thyroid hormone concentrations in acutely ill bipolar patients
(Bartalena et al. 1990a; Chang et al. 1998; Rybakowski and Sowinski
1973), and normal concentrations in euthymic (Kjellman et al. 1985)
bipolar patients. In contrast to depression, changes in serum T4 concen-
trations are not common during recovery from mania (Bauer and Why-
brow 1988). The relationships between bipolar disorder and various
forms of hypothyroidism are discussed under “Thyrotropin, Subclinical
Hypothyroidism, and Antithyroid Antibodies” below.
Seasonal Affective Disorder

Serum thyroid hormone concentrations appear to be normal in patients
with seasonal affective disorder (SAD) (Bauer et al. 1993; Coiro et al.
1994; Lingjaerde et al. 1995).
Thyrotropin, Subclinical Hypothyroidism, and

Antithyroid Antibodies
Assessment of the TRH-induced TSH response and development of su-
persensitive TSH assays have allowed both identification of milder forms
of hypothyroidism and standardization of varying degrees of hypothy-
roidism (Evered 1986; Wenzel et al. 1974). Assessment of basal TSH
with a supersensitive TSH assay is now seen as providing a reliable index
of thyrotrope activity across the entire spectrum of thyroid disease; it has
therefore replaced the TRH test in both medicine (Toft 1991) and psy-
chiatry (Maes 1993; Maes et al. 1993). The diagnostic criteria for the dif-
ferent forms of hypothyroidism, including subclinical hypothyroidism,
are listed in Table 14–3.
TABLE 14–3. Grades of hypothyroidism

Grade Clinical features Serum T4 Serum T3 Serum TSH
Overt Obvious symptoms and Low Usually Very high

signs of hypothyroidism low
Mild Mild or nonspecific Low or Normal Moderately high
symptoms or signs normal
Subclinical None Normal Normal Slightly elevated
Note. T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.
Source. Adapted from Ross 1991.
Like overt hypothyroidism, subclinical hypothyroidism can arise from

a variety of causes—for example, iodine and medications containing iodine,
ablative treatment of hyperthyroidism, inadequate replacement therapy for
overt hypothyroidism, lithium therapy, and (most commonly) autoim-
mune (Hashimoto’s) thyroiditis (Larsen and Ingbar 1992). Asymptomatic
autoimmune thyroiditis (based on the evidence of circulating thyroid anti-
bodies with normal thyroid function) is common, particularly in older

women (Tunbridge and Caldwell 1991). Overt hypothyroidism develops
at the rate of 5% per year in subjects with antibodies and raised TSH level.
Whether subclinical hypothyroidism should be treated on the basis of
preventing such deterioration continues to be a matter of debate. Treat-
ment may be indicated to prevent progression to overt hypothyroidism,
especially in patients with elevated levels of both TSH and microsomal
antibody titers (Tunbridge and Caldwell 1991). The major benefits of
treatment, based on two randomized trials, appear to be improvements in
clinical symptoms and psychometric test results (Ross 1991).
Depression
The following TSH and autoimmune dysfunctions are not uncommon in
depression: a blunted TSH response to TRH, an abnormal circadian TSH
rhythm, elevated basal TSH concentrations, and elevated titers of anti-
thyroid antibodies. The latter two findings are frequently seen together
in subclinical hypothyroidism.
Abnormal circadian TSH rhythm. Depression is often associated with
disturbances in various circadian behavioral rhythms (e.g., changes in
emotional well-being during the day, frequently worsening in the early
morning) and biological rhythms (e.g., abnormalities in body tempera-
ture and cortisol secretion). To these circadian dysfunctions we can add
an abnormal diurnal TSH rhythm, most commonly a lack of the noctur-
nal TSH surge (Table 14–4). In addition to depression and anorexia ner-
vosa (discussed under “Thyroid Function in Eating Disorders” below),
this abnormality can be found in central hypothyroidism (Adriaanse et al.
1993), in euthyroid patients with suprasellar extensions of pituitary le-
sions (Adriaanse et al. 1993), and after naloxone administration (Samuels
et al. 1994). The latter, of course, suggests that endogenous opioids have
significant stimulatory effects on TSH secretion, predominantly during
the nocturnal TSH surge.
Subclinical hypothyroidism. Between 1% and 4% of patients with a
variety of affective illnesses show evidence of overt hypothyroidism, and
between 4% and 40% show evidence of subclinical hypothyroidism (see
Table 14–5).
Subtle, but not overt, thyroid dysfunctions are therefore rather com-
mon in depressed patients, and they are not clinically innocuous. Comorbid
subclinical hypothyroidism can lower the threshold for the occurrence of
both depression (Haggerty et al. 1993) and panic disorder (Joffe and Lev-
itt 1992) and can be associated with cognitive dysfunction (Haggerty et
TABLE 14–4. Circadian variation in thyroid function in depression
Study N Diagnosis Thyroid measure Comment
Weeke and Weeke 12 ED T4, T3, FT4, FT3, TSH 0200h and 2400h Absence of diurnal TSH variation and free
1978 hormones related to symptom severity
Weeke and Weeke 4 ED T3, TSH q1h for 24h No difference from control subjects
Thyroid Function in Psychiatric Disorders

1980
Golstein et al. 1980 13 ED: 5 BP, 8 UP TSH q60 min/day or q30 min/night for 24h Nocturnal TSH peak absent in UP
Kijne et al. 1982 9 ED T4, T3, TSH q4h No difference between depression and recovery
Kjellman et al. 1984 32 MDD TSH q2h for 24h 24-hour TSH secretion reduced during
depression, normalization on recovery
Unden et al. 1986 31 MDD T4, T3, TSH q4h, but q2h (2400h–0800h) TSH reduced in depression. No change in T3, T4
between depressed patients and control
subjects
Souetre et al. 1988 8 BP TSH q1h for 25h, body temperature Nocturnal body temperature increased and
nocturnal TSH surge blunted during
depression; both normalized on recovery
Souetre et al. 1989 16 ED, 15 recovered TSH q1h for 25h, body temperature Amplitude reduction during depression
significantly correlated with depression scores;
normalization of circadian rhythms on recovery
Bartalena et al. 1990b 15 ED TSH q1h (2400h–0200h) Nocturnal TSH surge abolished in 14 patients
Coiro et al. 1994 7 SAD TSH q1h (2300–0200h and 0700–0900h) No difference between spring/summer and
fall/winter tests. At both periods, patients
lacked nocturnal TSH surge
Note. BP = bipolar depression; ED = endogenous depression; FT 3 = free triiodothyronine; FT 4 = free thyroxine; MDD = major depressive disorder;
SAD=seasonal affective disorder; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone; UP=unipolar depression.
369
370
TABLE 14–5. Hypothyroidism in affectively ill patients
Study N Diagnosis Prevalence (%) Comment
Gold et al. 1981 250 Depression and/or anergia 1 (grade 1) Of the 20 patients with some degree of hypothyroidism, 6 were
4 (grade 2) later discharged after thyroid replacement alone.
4 (grade 3)
Gold et al. 1982 100 Depression and/or anergia 15 (grades 1–3) Of these 15 patients, 60% had detectable antimicrosomal antibodies.
Targum et al. 1984 21 Refractory depression 24 (grade 3) Five of 7 patients who responded to combined thyroid hormone-
antidepressant treatment had grade 3 hypothyroidism.
Haggerty et al. 1987 102 Affective disorder 10 (grade 3) Dexamethasone nonsuppressors were significantly more likely to
have elevated TSH levels than suppressors. 20% of patients had
antithyroid antibodies.
Tappy et al. 1987 157 Psychogeriatric admissiona 4 (grade 1) 15% of 27 patients with neurotic depression had grade 1
104 Medical-surgical admissions 2 (grade 1) hypothyroidism.
Joffe et al. 1992 139 Unipolar depression 14 (grade 3) Depression with grade 3 hypothyroidism differed from depression
without grade 3 hypothyroidism by the presence of a concurrent
panic disorder and a poorer antidepressant response.
Gewirtz et al. 1988 15 Refractory depression 40 (grades 2, 3) The 6 women with hypothyroidism all responded behaviorally to
thyroid substitution.
Maes et al. 1993 62 Minor depression 8.8 (grade 3) Diagnoses made by use of ultrasensitive TSH assay. Of the
101 Major depression melancholic patients, 8.8% showed some degree of subclinical
57 Melancholic hypothyroidism.
Custro et al. 1994 75 Mood disturbance (in 56 (grade 3) Five of 9 endogenously depressed women were subclinically
women) hypothyroid, but none of the 66 patients with minor depression.
All five women were positive for antithyroid antibodies.
TABLE 14–5. Hypothyroidism in affectively ill patients (continued)
Study N Diagnosis Prevalence (%) Comment
Ordas and Labbate 260 Major and minor depression 3.1 (grade 3) Eight of 260 patients showed subclinical hypothyroidism.
1995
Fava et al. 1995 200 Depression (in outpatients) 2.6 (grade 3) TSH concentration was slightly elevated in 2.6% of patients; no
relationship to response rate was found.

Howland 1993 Refractory depression 52 (grade 3) 52% (range 29%–100%) of patients showed evidence of
(review of six studies) subclinical hypothyroidism.
Note. grade 1=overt hypothyroidism; grade 2=mild hypothyroidism; grade 3=subclinical hypothyroidism; TSH=thyroid-stimulating hormone.
371
al. 1986, 1990b) or a reduced response to standard psychiatric treatments

(Haggerty et al. 1990b; Joffe and Levitt 1992). That some depressed pa-
tients with subclinical hypothyroidism respond behaviorally to thyroid
hormone replacement (Gewirtz et al. 1988; Gold et al. 1981, 1982) sug-
gests that it may be useful to intervene therapeutically and to broaden the
list of index symptoms for initiating thyroid hormone replacement to in-
clude depression and memory deficits in addition to the somatic symp-
toms of fatigue, weight gain, and cold intolerance (Haggerty and Prange
1995). Haggerty et al. (1993) demonstrated that the lifetime frequency
of major depression was significantly higher in subjects with subclinical
hypothyroidism (56%) than in those without it (20%).
TSH: sources of variance. Serum TSH concentrations (at baseline or
after TRH stimulation) can be associated with treatment response (Fava
et al. 1992; Poirier et al. 1995), anxiety (Poirier et al. 1995), insomnia
(Poirier et al. 1995), severity of illness (Maes et al. 1994; Poirier et al.
1995), and both global and regional cerebral blood flow and cerebral glu-
cose metabolism (Marangell et al. 1997). Other investigators, however,
did not find associations between TSH concentrations and treatment re-
sponse (Fava et al. 1995), levels of anxiety (Kavoussi et al. 1993), severity
of illness (Vandoolaeghe et al. 1997), or length of episode and duration
of illness (Vandoolaeghe et al. 1997).
Antithyroid antibodies. In a wide spectrum of depressed patients, prev-
alence of abnormal antithyroid antibody titers can range from 6.9% to
20% (Table 14–6), compared with the prevalence of about 5% found in
the general population (Tunbridge and Caldwell 1991).
It is not obvious whether abnormal antibody titers are clinically rele-
vant if they are accompanied by normal serum TSH concentrations (Joffe
1987; Nemeroff et al. 1985). Summarizing the experience of the Chapel
Hill group, Prange et al. (1990) concluded that in 148 patients with men-
tal disorders, the prevalence of antithyroid antibodies was 7% in schizo-
phrenia, 8% in major depression, 20% in bipolar depression, and 33% in
a mixed bipolar episode. Patients with antithyroid antibodies had a
poorer average treatment response than those without antibodies.
Bipolar Disorder
When examining thyroid function in bipolar illness, it is useful to distin-
guish between rapid-cycling and non–rapid-cycling bipolar disorder. By
definition, rapid cyclers experience four or more affective episodes per
year (American Psychiatric Association 1994). Approximately 10%–15%
of bipolar patients experience rapid cycling; although they are similar to
other bipolar patients nosologically and demographically, they tend to
TABLE 14–6. Antithyroid antibodies in affectively ill patients
Prevalence
Study N Diagnosis (%) Comment
Gold et al. 1982 100 Depression and/or 9 Of 15 patients with some form of thyroid abnormality, 60% had positive
anergia antibody titers.

Nemeroff et al. 45 Affective disorder 20 Each of the 9 patients with symptomless autoimmune thyroiditis had
1985 normal baseline serum TSH, T4, T3 uptake, and FT4I concentrations.
Haggerty et al. 102 Affective disorder 20 TSH levels were normal in 7 of these patients and were elevated in 14.
1987 Thyroid antibodies were present in 14% of the dexamethasone
nonsuppressors and 19% of the suppressors.
Haggerty et al. 99 Affective disorder 9 Although the overall frequency of positive antibody titers did not differ in
1990a 68 Non–affective disorder 10 affective and nonaffective disorders, patients with bipolar affective
disorder–mixed or bipolar affective disorder–depressed had a higher rate
of positive antibody titers than other patients.
Joffe et al. (1987) 58 Unipolar depression 9 Antimicrosomal and antithyroglobulin antibodies. The presence of detectable
antibody titers was not related to abnormal thyroid function tests.
Haggerty et al. 218 Major depression 7 Major depression was not associated with excessive rate of thyroid
(1997) 19 Bipolar depressed 16 antibodies; thyroid autoimmunity was more common in subtypes of
51 Bipolar mixed 19 bipolar disorder in which depressive symptoms are prominent.
Bipolar manic 4
80 Adjustment disorder 3
144 Medical outpatients 7
Note. FT4I=free thyroxine index; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.
373
have a longer duration of illness and a more refractory course (Dunner

and Fieve 1974). Furthermore, women are disproportionately repre-
sented, making up 80%–95% of rapid-cycling patients compared with
about 50% of non–rapid-cycling patients (Bauer and Whybrow 1988). A
variety of factors may predispose bipolar illness to a rapid-cycling course,
including treatment with tricyclic antidepressants (TCAs), monoamine
oxidase inhibitors (MAOIs), lithium, and antipsychotics (Wehr et al.
1988). To these factors we can now add comorbid hypothyroidism.
Wehr and Goodwin (1979) first reported that TCA induced rapid cy-
cling in 5 female bipolar patients; 3 had a history of thyroid disorder. Cho
et al. (1979) demonstrated that 6% of lithium-treated women developed
hypothyroidism; most (71%) were rapid cyclers. Cowdry et al. (1983), in
a retrospective chart review, found some variety of hypothyroidism in
92% of 24 rapid-cycling patients and in 32% of 19 non–rapid-cycling pa-
tients. Bauer et al. (1990) reported that 23% of 30 patients with rapid-
cycling bipolar disorder had grade 1 hypothyroidism, whereas 27% had
grade 2 and 10% had grade 3 abnormalities. Other investigators confirmed
the high prevalence of hypothyroidism of some sort in bipolar illness but
found similar rates in rapid-cycling and non–rapid-cycling patients (Bar-
talena et al. 1990a; Joffe et al. 1988; Post et al. 1997; Wehr et al. 1988).
Instead they demonstrated that spontaneous or lithium-induced hypo-
thyroidism was associated with female sex (Joffe et al. 1988) or duration
of lithium treatment (Bartalena et al. 1990a; Joffe et al. 1988). Sack et
al. (1988) demonstrated that the nocturnal TSH rise was absent in rapid-
cycling patients.
If hypothyroidism during bipolar illness predisposes to a rapid-cycling
course, what are the effects of treatment with thyroid hormones? O’Shan-
ick and Ellinwood (1982) first suggested that such treatment may be ben-
eficial. In the most extensive study to date, Bauer and Whybrow (1990)
entered 11 rapid-cycling bipolar patients whose symptoms were refrac-
tory to their current treatment into an open trial of high-dose T4. T4 was
added to the baseline medication regimen, and the dosage was increased
until clinical response occurred or until side effects precluded further in-
crease. When the patients received T4, their depressive and manic symp-
toms decreased significantly. Four patients then underwent single- or
double-blind placebo substitution; three relapsed into either depression
or rapid cycling. Treatment response did not depend on thyroid status at
intake. In 9 of 10 responsive patients, it was necessary to achieve supra-
normal levels of serum FT4 to induce clinical response; however, side
effects were minimal and there were no signs of T4-induced hypermetab-
olism. Baumgartner et al. (1994a) treated 6 patients with severe forms of
non–rapid-cycling bipolar disorder whose symptoms had previously been
refractory to all current antidepressant or prophylactic medications with

supraphysiological doses of T4 (250–500 mg/day) as “art adjuvant” to their
previous medications for an average of 28 months. The mean number of
relapses declined and the mean duration of hospitalizations shortened
significantly during follow-up. Three patients had no further relapses at
all. The side effects were negligible. However, Cowdry et al. (1983)
noted that efforts to treat rapid cycling with thyroid hormones have met
with inconsistent results.
Seasonal Affective Disorder

Bauer et al. (1993) compared thyroid function in patients in a current
major depressive episode during the course of recurrent major mood dis-
order with seasonal pattern to thyroid function of control subjects 1) be-
fore and after 4 weeks of light treatment and b) at baseline and after
4 weeks of arising early without exposure to bright light. No consistent
abnormalities in TSH, TSH response to TRH infusion, or thyroid autoan-
tibodies were seen in depressive patients at baseline. Coiro et al. (1994)
evaluated the diurnal TSH secretion in 7 SAD patients and in 8 control
subjects without SAD. Both groups were tested in the fall/winter (when
patients were suffering depressive symptoms) and in spring/summer
(when patients were euthymic). In all tests, the mean peak TSH response
to TRH was significantly lower in the SAD patients than in control sub-
jects. No significant differences were observed in either group between
the spring/summer and fall/winter tests. At both periods, SAD patients
showed normal TSH levels in the morning but did not experience a noc-
turnal TSH surge. These data point to an abnormal diurnal TSH secre-
tion in SAD, regardless of the phase of the illness. Raitiere (1992),
studying 49 consecutive SAD patients over a 21-month period, reported
that 35% had elevated serum TSH levels, and an additional 16% had an
exaggerated TSH response to TRH; both findings are consistent with
mild primary hypothyroidism.
Cerebrospinal Fluid Studies

Depression
The studies evaluating concentrations of various hormones of the HPT
axis in the cerebrospinal fluid (CSF) of affectively ill patients are summa-
rized in Table 14–7.
As shown in Table 14–7, some depressed patients show increased
CSF concentrations of T4, rT3, free rT3, or TRH. The pathophysiological
significance of these findings is currently not well understood.
376
TABLE 14–7. Thyroid hormones in cerebrospinal fluid of psychiatric patients
Study N Diagnosis Thyroid measure Comment
Linnoila et al. 1983 34 MDD rT3 increased rT3 increased in unipolar depression
11 BPD
Kirkegaard and Faber 12 MDD FT4, FrT3 increased Decrease in both hormones with recovery
1991
Kirkegaard et al. 1979 15 MDD TRH increased TRH higher in depressed patients, both before and after
20 Neurological disease recovery, than in neurological disease
Banki et al. 1988 14 MDD TRH increased TRH markedly higher in depressed patients than in the other
4 Somatization patient groups
disorder
12 Neurological disease
Gjerris et al. 1985 21 ED TRH No significant difference among patient groups
13 Non-ED
8 Mania
9 Schizophrenia
Roy et al. 1994 17 MDD TRH No significant difference between patients and control subjects
Roy et al. 1990 51 Alcoholism TRH No significant difference between patients and control subjects
Adinoff et al. 1991 13 Abstinent alcoholics TRH Inverse correlation between TRH-induced TSH response and
cerebrospinal fluid TRH concentrations
Fossey et al. 1993 45 Anxiety disorder TRH TRH levels in patients with panic disorder, generalized anxiety
disorder, or obsessive-compulsive disorder not different from
those of control subjects
Note. BPD=bipolar disorder; ED=endogenous depression; FrT3 =free reverse triiodothyronine; FT4 =free thyroxine; MDD=major depressive disorder;
rT3 =reverse triiodothyronine; TSH=thyroid-stimulating hormone.
Effects of Somatic Treatments on Thyroid Function

Lithium
Lithium has important effects on thyroid function. It potently inhibits
the conversion, by monodeiodination, of T4 to T3, and it inhibits iodine
uptake, thyroid hormone production, and thyroid hormone secretion by
the thyroid gland (Burrow et al. 1971; Carlson et al. 1973).
During lithium treatment, affectively ill patients commonly show, in
varying degrees and combinations, reduced levels of T3 and T4, increased
levels of TSH, an exaggerated TSH response to TRH, and clinical evi-
dence of subclinical hypothyroidism, overt hypothyroidism, and goiter.
Sudden onset of thyrotoxicosis has also been noted, though much less
frequently (Joffe and Levitt 1993; Loosen 1986; Myers et al. 1985).
Therefore, lithium maintenance is likely to suppress thyroid function in
a sizable portion (i.e., 6%–30%) of affectively ill patients, particularly fe-
male patients. Increases in antithyroid antibody titers are also common
during lithium therapy, especially in patients who present with positive
antithyroid antibody titers and hypothyroidism before treatment (Cala-
brese et al. 1985; Lazarus et al. 1986; Myers et al. 1985). These effects
appear to be temporary; that is, they may reverse even if lithium is contin-
ued. They are almost always fully reversed after discontinuation of lithium.
Nevertheless, it appears useful to regularly monitor thyroid function dur-
ing lithium therapy.
Although indications for frequency and type of testing remain con-
troversial, we recommend assessing thyroid function (i.e., basal TSH
and FT4) before lithium administration to identify dynamic changes
during treatment. If such assessment points to thyroid pathology, fur-
ther tests—such as assessment of T3, FT3, T3 uptake, and antimicro-
somal antibodies—may be necessary. After initiation of lithium, thyroid
function tests should be repeated during the first half year every 3 months,
and thereafter every 6 or 12 months. Such monitoring will allow early
identification of subclinical or clinical hypothyroidism—which, as dem-
onstrated in the section “Bipolar Disorder” above, is likely to predispose
patients to a rapid-cycling course, and which may be treated by supple-
menting with thyroid hormone if discontinuation of lithium is not fea-
sible.
MAOIs
To date, only one study has evaluated whether MAOIs can adversely af-
fect thyroid function. Joffe and Singer (1987) treated depressed patients
with phenelzine for 4 weeks and reported no change in thyroid function.
Although the study suggests that MAOIs do not have a noticeable effect
on thyroid function, one may caution against the use of MAOIs in the
presence of hyperthyroidism. Increased thyroid hormone concentration
results in increased myocardial sensitivity to a number of central and pe-
ripheral mediators of cardiac activity, including catecholamines and in-
doleamines. Therefore, cardiac toxicity could result from the use of
MAOIs in patients with hyperthyroidism (Larsen and Ingbar 1992).
TCAs
Although TCA toxicity is increased in the presence of hyperthyroidism
(Loosen and Prange 1984; Prange et al. 1969), there appear to be no mor-
phologic or functional changes in the HPT axis during TCA administra-
tion in healthy volunteers (Kirkegaard et al. 1977; Widerlov et al. 1978)
or in depressed patients (Coppen et al. 1974; Karlberg et al. 1978). (The
change in serum T4 concentrations during antidepressant treatment noted
above does not appear to be specific to TCAs, as it is seen during a wide
range of antidepressant treatments, including TCAs, selective serotonin
reuptake inhibitors, sleep deprivation, and ECT.) Hoeflich et al. (1992)
treated 41 depressed patients with either maprotiline or fluvoxamine for
4 weeks. Serum T4 levels and body temperature decreased and serum
TSH increased significantly during treatment, but there were no signifi-
cant differences between treatment groups or between responders and
nonresponders. Shelton et al. (1993) treated 39 depressed patients with
either desipramine or fluoxetine. Twenty-six percent showed some ab-
normality in baseline thyroid hormone levels. There were no demonstra-
ble differences for any of the thyroid indices from baseline to the 3- or 6-
week samples for the total group or for either drug. There was a signifi-
cant group-by-time interaction for total T4 between the drug treatment
groups, which was caused by a small but significant increase in T4 in the
desipramine sample. Correlations between the change in hormones over
the 6-week period and treatment response were calculated. There was a
significant association between a decline in T3 levels and response to flu-
oxetine but not desipramine.
Brady et al. (1994) assessed the comparative efficacy of fluvoxamine
and imipramine in patients with major depressive disorder. Although se-
rum thyroid hormone concentrations were normal at baseline, both T4
and T3 levels decreased significantly in the imipramine group but not in
the fluvoxamine group. In the imipramine group, decreases in depression
scores were also significantly correlated with decreases in T3 concen-
trations. McCowen and colleagues (1997) found elevated serum TSH
concentrations in nine T4-substituted patients with hypothyroidism (with
duration of the illness ranging from 1 to 23 years) who were treated with
sertraline. FT4I values decreased in all patients in whom they were mea-
sured. No patient had symptoms of hypothyroidism. The effects of ser-
traline were not due to changes in T4 absorption or serum concentrations
of TBG; sertraline may increase the clearance of T4.
Taken together, the data suggest that routine monitoring of thyroid
function in patients with major depressive disorder taking TCAs is not
necessary. However, TCAs—and, to a lesser degree, selective serotonin
reuptake inhibitors—should be used with caution in patients with overt
thyroid disease, particularly hyperthyroidism, because they may promote
tachycardia and cardiac arrhythmias in this condition. The theoretical
basis for these effects is similar to that described above for MAOIs. The
effects of sertraline in hypothyroid patients substituted with T4 described
above (McCowen et al. 1997) also need to be considered.
Carbamazepine and Valproic Acid

Carbamazepine, an anticonvulsant agent increasingly used in the man-
agement of bipolar patients, is known to decrease thyroid function in
both epileptic (Ericsson et al. 1985; Isojarvi et al. 1995; Larkin et al.
1989; Tanaka et al. 1987) and affectively ill patients. Roy-Byrne et al.
(1984) first reported that carbamazepine decreased serum thyroid hor-
mone levels in depressed patients. This decrease was greater in respond-
ers than in nonresponders and was not due to changes in mean dosage
and blood level of carbamazepine. Herman et al. (1991) observed that
during carbamazepine treatment serum thyroid hormone concentrations
decreased significantly, whereas the metabolic rate did not. Marangell et
al. (1994) documented increased CSF TRH concentrations during car-
bamazepine treatment. Carbamazepine induction of hepatic micro-
somal enzymes has been proposed as a mechanism for the enhanced
nondeiodinative clearance of thyroid hormones (Ahima et al. 1996).
However, Joffe et al. (1984) demonstrated that the TRH-induced TSH
response was reduced after carbamazepine treatment, suggesting that
carbamazepine may decrease thyroid function primarily by reducing
TSH secretion at the pituitary level. Whether the thyroid-suppressing ef-
fects of carbamazepine are related to its therapeutic effects is unknown;
however, they are of clinical importance because side effects of carba-
mazepine—such as sedation, lethargy, and fatigue—could be interpreted
as signs of early hypothyroidism. It is therefore useful to monitor thyroid
function during carbamazepine treatment. Kramlinger and Post (1990)
assessed the clinical and laboratory effects of adding lithium to carba-
mazepine in 23 patients with affective disorders. Lithium produced a ro-
bust reversal of carbamazepine-induced leukopenia, increasing white

blood cell counts, predominantly neutrophils, to levels significantly
above placebo baseline values. The combination also produced additive
antithyroidal effects, resulting in greater decreases in T4 and FT4 and a
modestly higher TSH level than with carbamazepine alone.
Valproic acid, another anticonvulsant agent increasingly used in the
management of bipolar patients, does not appear to suppress thyroid
function in epileptic adults (Ericsson et al. 1985; Larkin et al. 1989) or
children (Tanaka et al. 1987). It has been proposed that valproic acid
does not affect thyroid function because it has no influence on hepatic
microsomal enzyme induction, indicating enzyme induction as the likely
mechanism for thyroid suppression in patients receiving anticonvulsants
(Larkin et al. 1989).
ECT
The effects of ECT on hormones of the HPT axis are remarkably consis-
tent. Most (Aperia et al. 1985; Dykes et al. 1987; Papakostas et al. 1991;
Scott et al. 1989) but not all (Deakin et al. 1983) studies reported that
serum TSH levels rise acutely during ECT; the TSH rise seems to atten-
uate after a series of ECT treatments (Aperia et al. 1985; Hofmann et al.
1994). A blunted TSH response to TRH during ECT has also been re-
ported (Decina et al. 1987), although not all studies agree (Hofmann et
al. 1994; Papakostas et al. 1981). In rats, ECT can induce synthesis of
TRH in multiple subcortical limbic and frontal cortical regions, which are
known to be involved in depression (Sattin 1998).
Seizure activity (Papakostas et al. 1991; Scott et al. 1989) and seizure
duration (Dykes et al. 1987; Scott et al. 1989) are associated with these
dynamic changes in HPT axis function during ECT, but not treatment re-
sponse (Decina et al. 1987; Dykes et al. 1987; Papakostas et al. 1991),
treatment modality (i.e., unilateral vs. bilateral ECT) (Decina et al. 1987),
or psychopathology (i.e., diagnosis of depression or schizophrenia) (Pa-
pakostas et al. 1991).
Prange et al. (1990), studying 50 patients with major depressive dis-
order, first reported that baseline thyroid hormone concentrations were
inversely related to ratings of ECT-induced organicity. This finding, sug-
gesting that the course of ECT may be beneficially affected by thyroid
hormones, was confirmed when the same investigators demonstrated
that patients given a small amount of T3 required fewer ECT treatments
than patients receiving placebo, although the percentage decrease was
not different among groups (Stern et al. 1991).
Sleep Deprivation
The antidepressant effects of one night of sleep deprivation have been
well documented (Kuhs and Toelle 1991; Leibenluft and Wehr 1991).
Changes in serum thyroid hormone and TSH concentrations during par-
tial or total sleep deprivation are very common. Although study designs
and methodologies differed, all studies reported that serum TSH levels
increased significantly during total (Baumgartner et al. 1990a, 1990c;
Kaschka et al. 1989; Kasper et al. 1988, 1992; Leibenluft et al. 1993;
Parekh et al. 1998) or partial (Baumgartner et al. 1990b, 1993) sleep
deprivation; the TSH rise did correlate with clinical response in some
(Baumgartner et al. 1990a; Kaschka et al. 1989; Kasper et al. 1992;
Parekh et al. 1998) but not other (Baumgartner et al. 1990b, 1990c;
Kasper et al. 1988; Leibenluft et al. 1993) studies. Increases in serum
thyroid hormone levels during sleep deprivation have also been reported
(Baumgartner et al. 1990a, 1990b, 1990c; Kaschka et al. 1989; Kasper
et al. 1992; Parekh et al. 1998); the thyroid hormone increase did
(Kasper et al. 1992) or did not (Baumgartner et al. 1990b) correspond
with clinical response. In patients with rapid-cycling bipolar disorder,
the normal nocturnal circadian increase in serum TSH was absent, and
sleep deprivation failed to increase TSH concentration (Sack et al.
1988).
Phototherapy
There is no evidence that thyroid function plays a role in the response of
winter depressive symptoms to light treatment (Bauer et al. 1993; Joffe
et al. 1991).
Summary: Thyroid Function in Mood Disorders

Depression
Most longitudinal studies have revealed intriguing dynamic reductions in
serum T4 concentrations in depressed patients during a wide range of so-
matic treatments, including various antidepressants, lithium, sleep dep-
rivation, and ECT. There is also evidence that the T4 reduction was
greater in treatment responders than in nonresponders. However, despite
their consistency, the data need to be viewed with caution. Transient
hyperthyroxinemia was also seen in acutely ill psychiatric patients with
diagnoses other than depression (suggesting that the finding is disease
nonspecific), and T4 levels normally quickly declined, even if there was
no therapeutic intervention or notable behavioral change. It is therefore
important to control for acute hospitalization and to perform longitudi-

nal studies, ideally without treatment or at least with delayed treatment.
It has been speculated that the increased serum T4 concentrations in de-
pression, together with the blunted TSH response to TRH, reflect gluco-
corticoid activation of the TRH neuron, leading to increased TRH
secretion with resultant downregulation of the TRH receptor on the thy-
rotrope. Normalization of thyroid function after treatment may there-
fore result in part from an inhibitory response of the TRH neuron to
antidepressant treatment (Jackson 1998).
Although overt thyroid disease is rare in major depression, more
subtle forms of thyroid dysfunction are common, particularly in fe-
male patients. They include a blunted TSH response after administra-
tion of TRH, an absent or flat diurnal TSH curve, positive antithyroid
antibody titers, and evidence of subclinical hypothyroidism (the latter
two are often seen together in the same patient). Are these findings
clinically relevant? In the case of positive antibody titers (without the
clinical picture of subclinical hypothyroidism), it is not known. How-
ever, TSH blunting has shown promising clinical utility in predicting
the outcome of standard antidepressant treatment and in assessing the
risk for violent suicide attempts, although both need replication in
larger samples (Loosen 1986). Pathophysiologically, the low TSH re-
sponse to TRH in the presence of normal serum thyroid hormone lev-
els and the lack of the nocturnal TSH surge, observed in some patients
with depression or SAD, are suggestive of mild central hypothyroidism
(Coiro et al. 1994). The possible medical and psychiatric consequences
of subclinical hypothyroidism are still a matter of intense debate. Med-
ically, it is not known whether subclinical and overt hypothyroidism
share the same risk for cardiovascular disease. Often T4 replacement
therapy is now initiated in subclinical hypothyroidism because of the
risk that the condition may deteriorate into overt hypothyroidism, and
because of the evidence that such replacement may improve clinical
and behavioral symptoms. Psychiatrically, comorbid subclinical hypo-
thyroidism appears to negatively affect the clinical course of depres-
sion; replacement therapy has therefore been advocated in depressed
patients with comorbid subclinical hypothyroidism (Haggerty and
Prange 1995).
There does not appear to be a need to routinely screen for thyroid ab-
normalities in depressed patients. Two studies including a total of 366 de-
pressed patients concluded that routine thyroid function tests are not
indicated because only a very small percentage of patients showed even
such mild thyroid abnormalities as subclinical hypothyroidism (Briggs et
al. 1993; Fava et al. 1995).
Bipolar Disorder
Bipolar disorders are often associated with various forms of hypothyroid-
ism. As in depression, such comorbidity is seen more frequently in female
patients. As in depression, such comorbidity seems to negatively affect
the course of the illness (by predisposing the individual patient to a rapid-
cycling course). As in depression, substitution with T4 has proved useful
in some patients, but often high doses are necessary to induce clinical
response (Bauer and Whybrow 1988; Baumgartner et al. 1994a). Con-
ceptually, these findings have led to the hypothesis that a relative central
thyroid hormone deficit may predispose to the marked and frequent
mood swings that characterize rapid-cycling bipolar disorder. However,
there are several confounding issues in studies involving rapid cycling and
thyroid function (Bauer et al. 1990). First, because of their more severe
course, rapid-cycling patients are more likely to have received thyroid
hormone treatment and may then be erroneously classified as hypothy-
roid in retrospective studies. Second, the female preponderance in rapid-
cycling bipolar disorder may elevate the rate of hypothyroidism, because
both disorders are more common in women. Last, the use of lithium and
carbamazepine, known goitrogens, is not examined in some studies. It
also remains to be determined whether the alleged central thyroid
hormone deficit serves only as a risk factor for the development of rapid
cycling in a known bipolar patient, or whether it can predispose most af-
fectively ill patients to any major behavioral change (e.g., the switch from
depression into recovery or from depression into mania).
Thyroid Function in Alcoholism

Effects of Ethanol Administration on Thyroid Function
The short-term effects of ethanol on HPT axis function have been inves-
tigated only in nonalcoholic subjects (Leppaeluoto et al. 1975; Van Thiel
et al. 1979; Ylikahri et al. 1978). The data indicate that ethanol admin-
istration does not acutely affect serum thyroid hormone concentration or
TSH response to TRH.
Peripheral Thyroid Hormones and TSH

Acute Alcohol Withdrawal
Major manifestations of moderate to severe ethanol withdrawal include
tachycardia, tremor, diaphoresis, and increased temperature. The origin
of these symptoms has been attributed, in part, to increased sympathetic

tone with both peripheral and central components. The similarity be-
tween these withdrawal features and the clinical symptoms of hyperthy-
roidism is apparent, although overt hyperthyroidism has not been shown
to be a consequence of ethanol withdrawal.
Nine studies (Baumgartner et al. 1994b; Dackis et al. 1984; de la Fu-
ente et al. 1982; Geurts et al. 1981; Kallner 1981; Loosen et al. 1979;
Mueller et al. 1989; Roejdmark et al. 1984; Valimaki et al. 1984) assessed
baseline serum thyroid hormone concentrations during ethanol with-
drawal. Five studies found notable differences between alcoholic subjects
and healthy control subjects: an increase in FT4I and total T4 (Loosen et
al. 1979), a decrease in T4 (Geurts et al. 1981), a decrease in T3 (de la
Fuente et al. 1982; Kallner 1981), and a decrease in FT4 and FT3 (Baum-
gartner et al. 1994b). Transient changes in serum T4 concentrations can
also occur as the individual patient shifts from intoxication to withdrawal
(Geurts et al. 1981), or from withdrawal to postwithdrawal or abstinence
(Baumgartner et al. 1994b; Dackis et al. 1984; Loosen et al. 1979). Mostly,
these changes are mild; they almost never reach the magnitude observed
in overt thyroid disease.
Eleven studies (Anderson et al. 1992; Banki et al. 1984; Dackis et al.
1984; de la Fuente et al. 1982; Kallner 1981; Loosen et al. 1979; Mueller
et al. 1989; O’Hanlon et al. 1991; Pienaar et al. 1995; Thakore and Dinan
1993; Valimaki et al. 1984) assessed the TRH-induced TSH response in
acute alcohol withdrawal. All studies demonstrated a blunted TSH re-
sponse in some patients; a retrospective analysis reveals that 89 (34%) of
a total of 260 patients showed a blunted TSH response.
Abstinence Without Liver Disease

The most consistent HPT axis finding in abstinent alcoholic individuals
without liver disease is a blunted TSH response to TRH (Casacchia et al.
1985; Dackis et al. 1984; Garbutt et al. 1991, 1992; Knudsen et al. 1990;
Loosen et al. 1979, 1983; Marchesi et al. 1989; Mueller et al. 1989; Pi-
enaar et al. 1995; Radouco-Thomas et al. 1984; Sellman and Joyce 1992;
Thakore and Dinan 1993; Willenbring et al. 1990); a retrospective anal-
ysis of these studies reveals that 75 (27%) of a total of 283 patients
showed a blunted TSH response. Reduced serum concentrations of T4
(Dackis et al. 1984), T3 (Agner et al. 1986; Loosen et al. 1983), and FT3
(Baumgartner et al. 1994b) have also been reported. The blunted TSH
response in abstinent alcoholic subjects does not appear to be the result
of a disturbed feedback inhibition of thyroid hormones on TSH (Garbutt
et al. 1992).
Abstinence With Liver Disease

Cirrhosis and less severe forms of liver injury are associated with changes
in protein synthesis and with alterations in the metabolism of many sub-
stances, including thyroid hormones (Chopra et al. 1974; Nomura et al.
1975). Alcoholic individuals with liver disease therefore exhibit a differ-
ent profile of HPT axis changes than do alcoholic individuals without
liver disease. With regard to serum thyroid hormone concentrations, the
data are quite uniform. For the most part, T4 levels are not changed (Ag-
ner et al. 1986; Green et al. 1977; Hepner and Chopra 1979; Israel et al.
1979; Monza et al. 1981; Nomura et al. 1975), whereas T3 levels are de-
creased (Agner et al. 1986; Chopra et al. 1974; Green et al. 1977; He-
gedus et al. 1988b; Hepner and Chopra 1979; Israel et al. 1979; Nomura
et al. 1975; Rumilly et al. 1983; Van Thiel et al. 1979). Despite de-
creased T3 levels, overt hypothyroidism is not present. T3 reductions ap-
pear to derive from decreased conversion of T4 to T3 (thought to be
secondary to liver cell damage and loss of deiodinating capacity [Agner
et al. 1986; Hepner and Chopra 1979; Israel et al. 1979; Orrego et al.
1987]), are inversely correlated with an index of liver disease (Israel et
al. 1979) or with the general severity of the cirrhotic condition (Rumilly
et al. 1983), and can be associated with increased rates of early death
(Hepner and Chopra 1979). The data suggest that assessment of serum
T3 concentrations may be useful in gauging prognosis and complement-
ing other indices of severity. The data further suggest that manipulations
of HPT axis hormones may be useful therapeutically. Orrego et al. (1987)
reported that the administration of propylthiouracil, an inhibitor of the
conversion of T4 to T3, increased the rate of survival in alcoholic patients
with severe liver disease. Although the underlying mechanism for this
effect is not clear, it has been suggested that propylthiouracil lowers
oxygen demand in hepatocytes by decreasing thyroid hormone levels,
which in turn renders the cells less likely to experience hypoxic injury
(Israel and Orrego 1984; Israel et al. 1979).
Hegedus et al. (1988) reported that individuals with chronic alcohol-
ism and liver cirrhosis exhibit reductions in thyroid gland volume, as as-
sessed by ultrasonic examination, and an increase in thyroid gland fibrosis
at autopsy compared with control subjects, raising the question of a di-
rect toxic effect of long-term ethanol ingestion on the thyroid gland.
Notably absent in the abstinent alcoholic subjects with liver disease is
the blunted TSH response to TRH commonly seen in those without liver
disease. However, elevated basal TSH levels are rather common (Chopra
et al. 1974; Green et al. 1977; Monza et al. 1981; Nomura et al. 1975;
Van Thiel et al. 1979); it is not apparent whether they are of clinical sig-
nificance. The most likely factor contributing to elevated basal TSH lev-
els and, possibly, absence of a blunted TSH response, is the reduced
serum T3 concentration noted above. Other possible factors are a de-
creased TSH clearance, increased serum estrogen levels (which are not
unusual in patients with liver damage and which could potentiate TSH
release), or a combination thereof. Estrogens do acutely inhibit the rate
of hormone release from the thyroid in adults, but any effect appears to
be transient because thyroid function is similar in healthy women and
men (Gambert 1991), and both men and women taking long-term estro-
gen therapy have normal serum FT4, FT3, and TSH levels (Gambert
1991).
Subjects at Risk for Developing Alcoholism

The persistence of a blunted TSH response in some abstinent alcoholic
individuals raises the question of whether TSH blunting is a precursor
of alcoholism or a sequela of heavy alcohol consumption. Six studies
(Garbutt et al. 1994, 1995; Loosen et al. 1987b; Monteiro et al. 1990;
Moss et al. 1986; Radouco-Thomas et al. 1984) evaluated the TSH re-
sponse in subjects at risk for developing alcoholism; the results of these
studies, which normally compared family history–positive (FHP) and
family history–negative (FHN) young men, are not consistent. Monteiro
et al. (1990) noted no differences in TSH response between groups. In
a study of very young subjects, ages 8–17 years, Moss et al. (1986) dem-
onstrated that FHP boys exhibited a higher basal TSH and a higher peak
TSH response after TRH administration compared with FHN boys.
Girls, when compared by family history, did not differ in basal or TRH-
stimulated TSH levels. Three studies (Garbutt et al. 1994; Loosen et al.
1987b; Radouco-Thomas et al. 1984) allow the individual identification
of a blunted TSH response; analysis of these studies reveals that 18
(46%) of 39 FHP subjects and 3 (5%) of 61 FHN subjects showed a
blunted TSH response. These latter findings are consistent with the hy-
pothesis that the TRH-induced TSH response may be a marker of vul-
nerability to alcoholism. An association between the marker and the
risk for late-onset alcoholism has also been suggested (Garbutt et al.
1995).
CSF Studies in Alcoholism

Roy et al. (1990) reported that CSF TRH concentrations were not signif-
icantly different among 51 alcoholic patients and 15 nonalcoholic control
subjects. However, among the control subjects there was a significant
correlation between CSF concentrations of 5-hydroxyindoleacetic acid

and CSF concentrations of TRH. This correlation was lacking in the alco-
holic subjects. Adinoff et al. (1991) administered TRH and measured
CSF concentrations of TRH in 13 abstinent alcoholic subjects. They
found an inverse correlation between the TSH response to TRH and en-
dogenous CSF TRH concentrations. This finding supports the hypothesis
that as the concentration of CSF TRH increases, anterior pituitary TRH
receptor density decreases, resulting in a blunted TSH response to TRH
stimulation.
Summary: Thyroid Function in Alcoholism

Short-term administration of ethanol to nonalcoholic volunteers does not
produce changes in peripheral thyroid hormone levels. However, with
long-term ethanol abuse, as occurs in alcoholic patients, perturbations in
thyroid function are common, although their clinical relevance remains
unknown because they typically do not reach the level of overt thyroid
disease. There is strong evidence that alcoholic patients with liver disease
have low T3 levels and increased levels of basal TSH. The extent of T3
reduction (which usually parallels the extent of liver damage) and the
failure to increase T3 levels with recovery are indicative of a poor prognos-
tic outcome. In a related way, pharmacologic inhibition of the conversion
of T4 to T3 is associated with increased survival in alcoholic individuals
with severe liver disease, presumably by reducing the metabolic demand
on the liver—a finding that is likely to add important new components to
the management and treatment of patients with severe alcohol-induced
liver disease.
A blunted TSH response to TRH is common in patients without chronic
liver disease. A review of the literature reveals that it is present in 35% of
patients during acute withdrawal and in 27% of patients during absti-
nence. TSH blunting is also common in subjects at high risk for devel-
oping alcoholism. These findings suggest that TSH blunting may be a
precursor of alcoholism (i.e., a trait marker) rather than a sequela of
heavy alcohol consumption (i.e., a state marker). Although a blunted
TSH response is unlikely to become useful as a clinical marker due to its
low sensitivity and specificity (Loosen et al. 1987a), it nevertheless could
further the understanding of the pathophysiology of the illness and the
biology of vulnerability; it also could aid in the clarification of subtypes.
It will be necessary to perform prospective studies to confirm that the
HPT axis alterations observed in the offspring of alcoholic fathers are
truly predictive of the increased risk for developing alcoholism.
Thyroid Function in Anxiety Disorders

Panic Disorder
Orenstein et al. (1988) evaluated 144 consecutive female psychiatric pa-
tients and found that those with a lifetime history of either panic disorder
or agoraphobia with panic attacks were more likely than other patients
to report a personal or family history of hyperthyroidism or goiter. How-
ever, as noted elsewhere (Stein and Uhde 1993), the study was retrospec-
tive and did not determine whether patients with panic disorder have a
higher rate of overt thyroid dysfunction than nonpsychiatric control sub-
jects or individuals with other psychiatric disorders. Other studies have
bridged this gap by showing that patients with panic disorder have an ab-
normally high prevalence of goiter (Chiovato et al. 1998) or thyroid ill-
ness (Lesser et al. 1987). Matuzas et al. (1987) reported that 50% of 65
consecutively admitted patients with panic attacks had mitral valve pro-
lapse (according to both cardiac auscultation and echocardiography), and
that 26% of 42 women and 8% of 13 men had thyroid abnormalities.
Several studies have evaluated peripheral thyroid hormone indices in
patients with panic disorder; they found no significant difference be-
tween patients and control subjects (Chiovato et al. 1998; Lesser et al.
1987; Munjack and Palmer 1988; Stein and Uhde 1988; Yeragani et al.
1987). Stein et al. (1991) demonstrated that the QKd interval in the
electrocardiogram, a presumptive index of end-organ thyroid hormone
activity, was normal in 15 patients with panic disorder.
Other Anxiety Disorders

Studies that evaluated thyroid function in generalized anxiety disorder or
obsessive-compulsive disorder (Joffe and Swinson 1988) did not reveal
consistent abnormalities. Munjack and Palmer (1988) did not find any
abnormal values of T4 concentration, FT4I, or TSH concentration in 41
patients with generalized anxiety disorder. Lindemann et al. (1984) re-
ported that 9% of 295 phobic patients had some form of thyroid dysfunc-
tion, with women showing a higher prevalence rate (11%) than men (3%).
The difference in prevalence of thyroid illness between this sample and
the general population was significant for both women and men. How-
ever, Tancer et al. (1990) found normal concentrations of thyroid hor-
mones or antithyroid antibodies in patients with social phobia. Only one
study evaluated thyroid function in patients with posttraumatic stress
disorder (PTSD). Mason et al. (1994), studying 96 male combat veterans
with PTSD and 24 male control subjects, reported that PTSD patients
showed moderately elevated T4 levels and normal FT4 levels, marked and
sustained elevation in levels of both T3 and FT3, as well as elevated T3:T4
ratios and normal TSH levels.
Thyrotropin and Antithyroid Antibodies

Panic Disorder
Serum TSH levels, either at baseline or after TRH stimulation, were shown
to be normal (Chiovato et al. 1998; Munjack and Palmer 1988; Stein and
Uhde 1988, 1991) or reduced (Tukel et al. 1999) in patients with panic
disorder. Reductions in TSH response to TRH were especially seen in pa-
tients who presented with depressive symptoms (Gillette et al. 1989; Stein
and Uhde 1991). Positive thyroid microsomal antibody titers have also
been reported in patients with panic disorder (Chiovato et al. 1998; Matu-
zas et al. 1987), but not all studies agree (Stein and Uhde 1989).
Cerebrospinal Fluid Studies

Fossey et al. (1993) reported that CSF concentrations of TRH were not
different between nonpsychiatric control subjects and patients with panic
disorder, generalized anxiety disorder, or obsessive-compulsive disorder.
Summary: Thyroid Function in Anxiety Disorders

In contrast to depression and bipolar disorder, there is little evidence for
abnormal thyroid function in anxiety disorders. Most studies found pe-
ripheral thyroid hormones to be normal in both panic disorder and gen-
eralized anxiety disorder. Although there is preliminary evidence of an
abnormally high prevalence rate of goiter and thyroid illness in patients
with panic disorder (Chiovato et al. 1998; Lesser et al. 1987), serum
TSH concentrations and indices of end-organ thyroid hormone activity
such as the QKd interval were found to be normal. Finally, during an ex-
perimentally induced panic attack, no changes in serum thyroid hormones
or TSH were noted (Vieira et al. 1997).
Thyroid Function in Premenstrual Dysphoric Disorder

Schmidt et al. (1993) reported that 13 of 124 women (10%) with pre-
menstrual dysphoric disorder had evidence of either grade 1 or 2 hypo-
thyroidism or hyperthyroidism, and 18 women (30%) had abnormal

TSH responses to TRH, either blunted (n=6) or exaggerated (n=12).
Girdler et al. (1995) showed that although women with premenstrual
dysphoric disorder had normal thyroid hormone concentrations during
the follicular or luteal phase of their menstrual cycle, they had signifi-
cantly greater variability in TSH, T4, and FT4I than did control women.
However, other studies (R.F. Casper et al. 1989; Nikolai et al. 1990) re-
ported no evidence of thyroid dysfunction in women with premenstrual
dysphoric disorder. In three studies, patients received T4 supplementa-
tion in a double-blind design; there was no evidence for T4 being superior
to placebo (R.F. Casper et al. 1989; Myers et al. 1985; Nikolai et al.
1990).

Serum TSH concentrations in women with premenstrual dysphoric dis-
order are usually normal in both the follicular and the luteal phase of the
menstrual cycle (R.F. Casper et al. 1989; Roy-Byrne et al. 1987). Schmidt
et al. (1993) reported that 16 of 124 (13%) women with premenstrual
dysphoric disorder had elevated thyroid antibody titers.
Thyroid Function in Eating Disorders

Peripheral Thyroid Hormones and TSH
Anorexia Nervosa
It is well known that patients with anorexia nervosa demonstrate clinical
signs consistent with hypothyroidism, including cold intolerance, consti-
pation, low resting metabolic rate (RMR), bradycardia, elevated serum
levels of carotene, and slowed deep tendon reflexes. In the undernour-
ished state of anorexia nervosa, serum T4 and FT4 levels are in the normal
range (though lower than those found in matched control subjects), but
serum T3 levels are often in the hypothyroid range, occasionally as low as
T3 levels seen in acute myxedema (Moore and Mills 1979), as are FT3 and
TBG concentrations. The diminished TBG levels partially account for
the decrease in T4 and T3 levels, but not for the reduced FT3 concentra-
tions.
It appears that T3 is more sensitive than T4 to nutritional state (Table
14–8). Starvation produces acute decreases in serum T3 concentrations in
laboratory animals (where they are made more profound by hyperactiv-
ity [Brooks et al. 1990]), in healthy volunteer subjects (Gorozhanin and
TABLE 14–8. Thyroid function in anorexia nervosa
Thyroid measure Finding No. studies References
T4 AN in normal range 5 Brown et al. 1977; Burman et al. 1977; Collu 1979; Moore and Mills 1979; Moshang et al.
1975
T4 AN<matched controls 3 Kokei et al. 1986; Miyai et al. 1975; Tamai et al. 1986
FT4 AN<matched controls 2 Kokei et al. 1986; Tamai et al. 1986

FT4 AN in normal range 1 Collu 1979
T3 AN<normal range 4 Collu 1979; Croxson and Ibbertson 1977; Moore and Mills 1979; Moshang et al. 1975
FT3 AN<normal range 1 Komaki et al. 1992
TBG AN<normal range 1 Tamai et al. 1986
T4, T3, TBG ANWR=normal 6 Chopra et al. 1975; Croxson and Ibbertson 1977; Komaki et al. 1992; Miyai et al. 1975;
Pirke et al. 1985a; Tamai et al. 1986
rT3 AN>normal 2 Kokei et al. 1986; Leslie et al. 1978
TSH AN=normal 5 R.C. Casper and Frohman 1982; Leslie et al. 1978; Lundberg et al. 1972; Miyai et al.
1975; Moshang et al. 1975
TSH AN<normal 1 Hurd et al. 1977
TRHDTSH Normal TSH response 5 Brown et al. 1977; Gwirtsman et al. 1983; Lundberg et al. 1972; Miyai et al. 1975;
Moshang et al. 1975
TRHDTSH Delayed TSH response 11 R.C. Casper and Frohman 1982; Croxson and Ibbertson 1977; Gold et al. 1980;
(66%–69% of patients) Gwirtsman et al. 1983; Leslie et al. 1978; Lundberg et al. 1972; Miyai et al. 1975; Tamai
et al. 1986; Vigersky and Loriaux 1977; Vigersky et al. 1976; Wakeling et al. 1979
TRHDTSH Blunted TSH response 14 Beumont et al. 1976; Brown et al. 1977; R.C. Casper and Frohman 1982; Croxson and
(12%–24% of Ibbertson 1977; Gold et al. 1980; Gwirtsman et al. 1983; Leslie et al. 1978; Lundberg
patients) et al. 1972; Macaron et al. 1978; Miyai et al. 1975; Moshang et al. 1975; Tamai et al.
1986; Travaglini et al. 1976; Vigersky et al. 1976
Note. AN=anorexia nervosa (underweight phase); ANWR=anorexia nervosa (recently weight recovered); FT3 =free triiodothyronine; FT4 =free thyroxine; rT3 =reverse
391
triiodothyronine; T3 =triiodothyronine; T4 =thyroxine; TBG=thyroxin-binding globulin; TSH=thyroid-stimulating hormone; TRHDTSH=Thyrotropin response to TRH.
Lobkov 1990; Jung et al. 1985), and in obese patients (Portnay et al. 1974;
Vagenakis et al. 1975). The pattern of low normal T4, diminished T3, and
normal TSH concentrations is known as the low T3 syndrome or the eu-
thyroid sick syndrome (Carter et al. 1974; Chopra et al. 1983). There is
evidence that the peripheral signs of hypothyroidism (i.e., bradycardia,
hypercholesterolemia) are related to the diminished T3 seen in anorexia
nervosa (Bannai et al. 1988). Both low thyroid indices and TBG abnor-
malities demonstrated in anorexia nervosa and in protein-calorie malnu-
trition are corrected after weight gain (Table 14–8). In anorexic patients,
T3 levels may even increase into the hyperthyroid range during the weight
gain phase of treatment (Moore and Mills 1979). This increase in T3 se-
cretion may be partially responsible for the diet-induced thermogenesis
and increased resting energy expenditure observed in anorexia nervosa
patients, which enhances their adaptive resistance to refeeding (Moukad-
dem et al. 1997).
Reverse T3, the metabolically inactive enantiomer of T3, has been
found to be increased in experimentally starved control subjects (Komaki
et al. 1986; Vagenakis et al. 1975), in patients with anorexia nervosa
(Table 14–8), and in obese individuals. It has also been found in protein-
calorie malnutrition and other disease states (Chopra et al. 1975; Kokei
et al. 1986). It is thought that the tissue conversion of T4 and T3 to rT3
represents a physiological adaptation to malnutrition and decreased ca-
loric intake, with the goal of preserving energy and preventing the (un-
necessary and potentially harmful) further burning of calories. There is
also evidence that the thyroid gland secretes less T3 in anorexia nervosa
and that this mechanism is another contributor of the low T3 reported in
this illness (Kiyohara et al. 1989).
Baseline levels of TSH in anorexia nervosa are in the normal range in
all studies but one, in which decreased TSH levels were found (Table 14–8).
In anorexia nervosa TSH secretion may be more predominantly regulated
by normal FT4 than by T3 levels (Bannai et al. 1988; Haraguchi et al.
1986), because high TSH levels have been reported in the presence of
low FT4 concentrations (Matsubayashi et al. 1988). TSH levels also do
not seem to be altered in acutely starved control subjects or overweight
patients (Portnay et al. 1974). TSH has a circadian rhythm in healthy in-
dividuals (Azukizawa et al. 1976; Vagenakis 1979), with a peak occur-
ring during or after the onset of sleep, and a nadir in the late afternoon.
Both indirect (Croxson and Ibbertson 1977) and direct (Gwirtsman et al.
1988) measurements of these circadian rhythms in anorexia nervosa in-
dicate a loss of the nighttime surge, with a general resetting of the curve
upward. Although these data are preliminary and require replication, it
is noteworthy that in experimental animals both hypothyroidism and
hypothalamic lesions can abolish TSH periodicity (Vagenakis 1979), im-

plying that such dysregulation in anorexia nervosa may reflect hypotha-
lamic dyscontrol.
A number of investigations have examined the TSH response to TRH
in small samples of anorexic patients; some show a normal curve, but
most (67%) demonstrate a delayed response. In clinical hypothyroidism,
the TSH response to TRH is exaggerated, and when this is due to disease
in the hypothalamus, the peak response of TSH after TRH is often de-
layed (Moshang et al. 1975; Vagenakis 1979). Although some studies
suggest that acute starvation of volunteers (Fichter et al. 1986; Jung et al.
1985; Vinik et al. 1975) and obese patients (Carlson et al. 1977) dimin-
ishes the TSH response to TRH, other studies have failed to find this
(Portnay et al. 1974; Vagenakis 1977). In approximately 12%–24% of
anorexic patients, the TSH response has been blunted (Table 14–8).
Delayed TSH responses to TRH are seen in both restricting-type and bu-
limic-type anorexia (Kiriike et al. 1987). After weight rehabilitation,
most anorexic patients develop a more rapid response to peak TSH after
TRH, and fewer blunted responses are reported (Leslie et al. 1978; Moore
and Mills 1979) but many continue to be abnormal (Kiyohara et al. 1987).
Although comorbid mood disturbances are common in patients with an-
orexia nervosa, the HPT axis aberrations in depression and anorexia are
divergent, in that approximately 30% of depressed patients demonstrate
blunted rather than delayed TSH responses to TRH (Loosen and Prange
1982) and reduced rather than elevated CSF TRH levels (Banki et al.
1988; Kirkegaard et al. 1979; Lesem et al. 1994).
Thyroid disease in patients with eating disorders is seen at twice the
rate of the healthy population (Hall et al. 1995), although classic thyroid
illness is rarely described together with anorexia nervosa. When these ill-
nesses co-occur, the hypermetabolic state of Graves’ disease can mask the
hypometabolism of anorexia nervosa (Kuboki et al. 1987). Patients with
eating disorders will occasionally abuse exogenous thyroid supplements
to control their weight (Kornhuber et al. 1996). In one case of severe thy-
rotoxicosis, the patient refused treatment for years until forced by symp-
toms of congestive heart failure and thyroid storm (Rolla et al. 1986).
Bulimia Nervosa
Several studies have examined thyroid function and RMR in bulimic pa-
tients, with equivocal results. Some investigators found RMR (Devlin et
al. 1990; Obarzanek et al. 1991) and serum T3 levels (Kiyohara et al.
1988; Obarzanek et al. 1991; Pirke et al. 1985b) to be significantly re-
duced in bulimic patients with normal weight, especially when patients
were studied during abstinence from binge eating, whereas other investi-
gators found thyroid indices, including basal TSH, to be normal (Devlin
et al. 1990; Gwirtsman et al. 1983; Mitchell and Bantle 1983). Two stud-
ies conducted at the National Institutes of Health reported that bulimic
patients studied shortly after admission had either normal thyroid indices
or slightly diminished T3 levels. However, after 3 weeks of abstinence
from binge eating and purging, T4 and T3 levels declined significantly,
whereas TSH levels increased modestly (Spalter et al. 1993). After 7 weeks
of abstinence, all thyroid indices, including FT4, FT3, rT3, and TBG levels
were reduced compared with the acute binge-eating phase and compared
with control subjects. The nocturnal TSH surge in the bulimic patients
was similar to that of control subjects and was unaffected by changes in
thyroid indices (Altemus et al. 1996). The authors concluded that this
represented a form of subclinical hypothyroidism during abstinence,
with an impaired feedback on the pituitary or the hypothalamus. In one
study (Spalter et al. 1993), levels of T3 were directly correlated with ca-
loric intake and were inversely correlated with body weight. RMR has
also been reported to decline significantly during abstinence from binge
eating and purging (Altemus et al. 1991; T. Leonard et al. 1996), com-
pared with the same patients during active binge eating. The data suggest
that binge-purge behavior may transiently increase thyroid indices and
RMR, whereas decreases in thyroid indices following abstinence from
binge eating and purging behaviors are probably related to either dimin-
ished caloric consumption or else may reflect hypothalamic-pituitary
dysregulation. Thus, normal-weight bulimic subjects who are abstinent
from binge-purge cycles may have a variant of the euthyroid sick syn-
drome (Spalter et al. 1993).
Binge-Eating Disorder
Binge-eating disorder is a newly described eating disorder in which in-
dividuals engage in binge eating episodes but do not purge their food,
leading inevitably to obesity (American Psychiatric Association 1994).
Recent epidemiological surveys indicate that this disorder is highly prev-
alent among the obese, perhaps exceeding 30% (Spitzer et al. 1992).
RMR or baseline thyroid indices do not differ in binge-eating and non-
binging obese patients (Wadden et al. 1993). However, a low RMR can
be a predictor of certain forms of obesity (Astrup et al. 1996; Ravussin
and Gautier 1999). Furthermore, the physiological role of leptin on energy
intake may be through a modulatory effect on the HPT axis—specifi-
cally, by regulating pro-TRH gene expression in the paraventricular nu-
cleus (Ahima et al. 1996; Legradi et al. 1997).
Summary: Thyroid Function in Eating Disorders

Thyroid abnormalities are common in anorexia nervosa. Acutely ill pa-
tients often demonstrate the low T3 or euthyroid sick syndrome, char-
acterized by normal concentrations of T4 and FT4, but low T3, FT3 and
TBG concentrations. Because the euthyroid sick syndrome usually re-
turns to normal after nutritional rehabilitation, it is thought to repre-
sent a physiological adaptation to the acute effects of starvation rather
than being causally linked to the illness. Delayed TSH responses to
TRH are also common in anorexia nervosa. Because delayed TSH re-
sponses may continue after weight gain (Kiyohara et al. 1987), it is pos-
sible that they are caused by other symptoms of abnormal eating, such
as vomiting (Kiyohara et al. 1987), or that they are the result of hy-
pothalamic dysfunction, perhaps involving a central TRH deficiency
(Croxson and Ibbertson 1977; Lesem et al. 1994; Lundberg et al.
1972).
Thyroid Function in Schizophrenia
Schizophrenia has attracted psychoendocrine investigation for more

than 100 years. Kraepelin (1896), Bleuler (1954), and Gjessing (1974)
observed certain endocrine disturbances and proposed related thera-
pies. For example, thyroid extract was widely used in schizophrenic pa-
tients (Bleuler 1954; Brauchitsch 1961), and T4 is still considered to be
of some use in periodic catatonia (Gjessing 1974). It was suggested that
an active or even hyperactive HPT axis may beneficially modify
the course of the illness (Brauchitsch 1961). Komori et al. (1997) con-
firmed the early work by Gjessing when they documented that periodic
catatonia could be abolished by a combination of thyroid hormone and
reserpine.

Early studies of thyroid function in schizophrenic patients have been ably
reviewed (Bleuler 1954; Michael and Gibbons 1963). The results of
more recent studies are equivocal in demonstrating normal thyroid func-
tion (Brambilla et al. 1976; Johnstone et al. 1987; Plunkett et al. 1964;
Rinieris et al. 1980; Simpson and Cooper 1966), decreases in serum T3
(Prange et al. 1979) or T4 (Rao et al. 1984), or increases in FT4I (Morley
and Shafer 1982; Prange et al. 1979; Spratt et al. 1982). Roca et al. (1990)
found that 22 of 45 (49%) acutely hospitalized psychiatric patients had

significant elevations of one or more thyroid hormone levels; these re-
searchers also observed significant positive correlations between psychi-
atric symptom severity and FT4I in schizophrenic patients. MacSweeney
et al. (1978) reported a significantly higher incidence of thyroid disease
in mothers of 104 schizophrenic patients than in a carefully matched
control group. DeLisi et al. (1991) noted that family histories of thyroid
disorders were significantly more common among schizophrenic patients
than among community control subjects.

Dewhurst et al. (1968) found increased baseline TSH levels in 5 of 20
(25%) schizophrenic patients. TSH elevations correlated significantly
with ratings of paranoid symptoms. Later studies found basal TSH con-
centrations to be decreased (Rao et al. 1984) or normal (Prange et al.
1979) in schizophrenic patients. Rao et al. (1995) reported a significantly
decreased TSH MESOR (i.e., the daily mean) in schizophrenic patients,
pointing to an abnormality in the circadian TSH secretion. In the only
study assessing thyroid antibodies in a schizophrenic population, Oth-
man et al. (1994) demonstrated that 51 of 249 patients (20%) with chronic
schizophrenia had thyroid antibodies.
Effects of Somatic Treatments on Thyroid Function

There is evidence that peripheral thyroid hormone concentrations can
decrease during neuroleptic therapy (Baumgartner et al. 1988; Rinieris et
al. 1980), although not all studies agree (Baptista et al. 1997; Konig et al.
1998; Naber et al. 1980). Baseline TSH concentrations have been re-
ported to be increased (Grunder et al. 1999), decreased (Grunder et al.
1995), or unchanged (Konig et al. 1998; Naber et al. 1980) during ther-
apy with various neuroleptics; the TRH-induced TSH response is usually
unchanged during such treatment (Grunder et al. 1995, 1999; Konig et
al. 1998; Markianos et al. 1994; Naber et al. 1980).
Summary: Thyroid Function in Schizophrenia

There is little evidence for abnormal thyroid function in schizophrenic
patients. However, the finding of an abnormally high prevalence rate of
thyroid disorders in the family history of schizophrenic patients (DeLisi
et al. 1991) and the intriguing behavioral effects of T4 in periodic catato-
nia, first described by Gjessing (1974), deserve further study.
Conclusion
The literature provides much support for the notion that there are many
associations between thyroid hormones and behavior, although the exact
nature of these associations remains unknown. The effects of thyroid hor-
mones (or the lack thereof) during early human development on brain
function, their use to supplement the treatment regimen of some pa-
tients who respond poorly to standard antidepressants, and their often
marked psychological effects in patients with thyroid disorders are be-
yond the scope of this review and have been discussed elsewhere (Ahmed
Smith and Loosen 1998; Bauer and Whybrow 1988; Loosen 1986).
The clinical studies of thyroid function in mental illness discussed
here have brought forward a plethora of findings; some are clinically rel-
evant. First, abnormal thyroid function is often observed in mood disor-
ders. In a similar way, mood disturbances are among the most prominent
psychological sequelae of overt thyroid disease. In both depression and
bipolar disorder, comorbid thyroid dysfunctions are not clinically innoc-
uous; they can negatively affect short-term and long-term outcome and
can complicate treatment. (Routine thyroid function tests are not indi-
cated in psychiatric patients, because only a very small percentage of
patients show even such mild thyroid abnormalities as subclinical hypo-
thyroidism. However, if thyroid dysfunction exists as a comorbid condi-
tion in mood disorders, early aggressive treatment is warranted.) Second,
the euthyroid sick syndrome and mild, transient hyperthyroxinemia are
common among acutely hospitalized psychiatric patients; both are dis-
ease nonspecific and usually normalize on recovery. Thyroid function
tests obtained at admission therefore need to be interpreted with caution.
Third, lithium and carbamazepine (but not valproic acid) decrease thy-
roid function; careful, repeated thyroid status assessments are therefore
necessary during the course of treatment. Fourth, abnormal thyroid func-
tion can be associated with a symptom of a disease rather than with the
disease itself. The effects of starvation on thyroid function are well known;
starvation and symptoms leading to starvation (e.g., loss of appetite,
weight loss) therefore need to be considered when interpreting results. In
a similar way, disease complications can lead to false-negative results. In al-
coholic patients without liver disease a blunted TSH response to TRH is
common. However, in those with liver disease TSH responses are nor-
mal, possibly due to decreased T3 concentrations (which, in turn, are
thought to be the direct result of alcohol-induced liver damage). Fifth,
there appears to be no direct causal relationship between thyroid func-
tion and various clinical states. Rather, changes in thyroid function can fa-
cilitate behavioral change in a positive direction (e.g., dynamic reductions

in serum T4 concentrations in depression during such diverse treatments
as various antidepressants, lithium, sleep deprivation, or ECT) or a nega-
tive direction (e.g., comorbid subclinical hypothyroidism facilitates a
rapid-cycling course in bipolar disorder and thus affects outcome and
complicates treatment). Sixth, acute manipulations of thyroid function
(by administering thyroid hormones directly or by interfering with their
metabolism) can be clinically useful in a variety of conditions: the addi-
tion of T3 has been shown to shorten the course of ECT and to attenuate
the cognitive side effects of ECT; a small dose of T3 can enhance the effect
of antidepressants in women and can convert treatment nonresponders
into responders in both sexes; substitution with T4 has proved useful in
some rapid-cycling bipolar patients, although high doses are often neces-
sary to induce clinical response; T4 can beneficially affect the course of
periodic catatonia; and pharmacologic inhibition of the conversion of T4
to T3 by propylthiouracil can be associated with increased survival in al-
coholic individuals with severe liver disease. The exact mechanism(s) by
which such manipulations exert their clinical effect are unknown.
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Chapter 15
Psychiatric and Behavioral

Manifestations of Hyperthyroidism
and Hypothyroidism
Michael Bauer, M.D., Ph.D.
Martin P. Szuba, M.D.
F or nearly 200 years, physicians have recognized that adequate

thyroid function is a prerequisite for normal brain development and mental
functioning. However, interest in the role that thyroid metabolism plays in
psychiatric disorders has burgeoned in the past 40 years, as scientific and
technological progress has illuminated the relationship between thyroid hor-
mones and behavior. With knowledge of the role of neurotransmitters and
their metabolism in controlling behavior and an awareness of the complexity
of neuronal interactions, the understanding of brain function has expanded
rapidly. As technology advanced, the chemical dissection of the thyroid
hormone system gained specificity—for example, by locating thyroid hor-
mones, nuclear thyroid hormone receptors, and thyroid-related peptides
such as thyrotropin-releasing hormone (TRH) in the brain (reviewed in
Bauer et al. 2002). At the clinical level, highly sensitive radioimmunoassays
for measuring hormones of the hypothalamic-pituitary-thyroid (HPT) sys-
tem, the use of thyroid hormones in the treatment of mood disorders (Bauer
and Whybrow 2001; Prange et al. 1969), and the finding of abnormal thy-
roid-stimulating hormone (TSH) responses to TRH in various psychiatric
disorders, particularly the mood disorders (Loosen and Prange 1982), have
all made their contributions in improving the understanding of the relation-
ships between thyroid, brain, and behavior (Bauer and Whybrow 2002).
The association between thyroid function and behavior was first noticed
early in the nineteenth century. Hyperfunction of the thyroid gland was
described by Parry (1825), who attributed the observed “various nervous af-
419
fectations” to an earlier frightening incident experienced by the patient.

Graves (1835) described the syndrome named after him and suggested a re-
lationship between the thyroid gland and the syndrome globus hystericus,
but it was not until the end of the nineteenth century that a thyrotoxic syn-
drome of endocrine origin was clearly distinguished from the group of neu-
roses. By the 1880s, behavioral changes in hypothyroid patients had been
noted, culminating in a report from the Clinical Society of London (1888)
describing a variety of mental disturbances. In the twentieth century, interest
in the relationship between thyroid function and mental disorders grew sig-
nificantly. A causative role of hypothyroidism in psychopathology was dem-
onstrated by Asher (1949) in a case series suggesting that thyroid hormone
deficiency may lead to depression and psychosis (“myxedematous mad-
ness”) and was reversible with administration of desiccated thyroid. During
the last four decades, systematic studies revealed that disorders of the thy-
roid gland are frequently associated with mental disturbances (Treadway et
al. 1967; Whybrow and Bauer 2000a, 2000b; Whybrow et al. 1969).
Thyroid disorders are common, occurring in up to 6% of the general
population. Rates of abnormal thyroid metabolism in psychiatric popula-
tions are higher than in the rest of the population (Whybrow 1995). In
part this may be iatrogenic; various psychotropic medications—including
lithium, neuroleptics, carbamazepine, and antidepressants—disturb HPT
axis function to varying degrees. Furthermore, given that the initial (and
sometimes the only) manifestations of hyperthyroid and hypothyroid states
are often neurobehavioral, the association of thyroid disease and behav-
ior, including psychiatric sequelae, is of substantial clinical importance to
the psychiatrist.
Most individuals who report clinical symptoms of thyroid dysfunc-
tion complain of a mental disturbance that remits on correction of their
thyroid illness. This observation is important, because it indicates the in-
volvement of the HPT system in the modulation of behavior (Whybrow
1995). Therefore, it is useful for the clinical psychiatrist to be familiar
with the behavioral syndromes of thyroid dysfunction. In this chapter we
review the psychiatric and behavioral manifestations of thyroid disorders
in patients with hyperthyroidism (thyrotoxicosis) and hypothyroidism.
Hyperthyroidism and Thyrotoxicosis
Hyperthyroidism is a condition that results from sustained increases in

thyroid hormone biosynthesis and secretion by the thyroid gland. Dis-
tinct from hyperthyroidism is thyrotoxicosis, the clinical syndrome of
Hyperthyroidism and Hypothyroidism 421
hypermetabolism that results from sustained increased serum concentra-

tions of free thyroxine (FT4), free triiodothyronine (FT3), or both (Braver-
man and Utiger 2000b). Subsequently, the secretion of TSH is suppressed,
resulting in decreased serum TSH concentrations. The distinction between
hyperthyroidism and thyrotoxicosis is important, because although most
patients with thyrotoxicosis have hyperthyroidism, this is not uniformly
the case (e.g., those in whom thyrotoxicosis is caused by exogenous thy-
roid hormone administration).
Epidemiology and Etiology

Thyrotoxicosis is a common thyroid disorder with multiple causes. Graves’
disease, which is associated with a diffuse toxic goiter and exophthalmos,
is the most frequent cause. It accounts for approximately 60%–90% of all
cases of thyrotoxicosis. Less frequent causes of thyrotoxicosis are toxic
multinodular goiter (multiple nodules that are benign but can produce
substantial amounts of thyroid hormones), autonomously functioning
thyroid adenomas (toxic adenomas), exogenous thyrotoxicosis (includ-
ing thyrotoxicosis factitia), excessive replenishment in hypothyroidism,
and TSH-secreting pituitary adenomas (Larsen et al. 1998).
Graves’ disease is an autoimmune thyroid disease that occurs most
frequently in women ages 20–40 years (Davies 2000). Patients with au-
toimmune thyroid disease show immune reactivity (both antibodies and
cell-mediated immunity) directed predominantly at three thyroid au-
toantigens: thyroglobulin, thyroid peroxidase, and the TSH receptor
(Marcocci and Chiovato 2000). Autoimmune thyroid disease clusters in
families, and the concordance rate for Graves’ disease is higher for mono-
zygotic (22%) than for dizygotic twins (0%) (Brix et al. 1998). Besides
genetic factors, several factors may play a role in the pathogenesis of Graves’
disease, including stress, cigarette smoking, and possibly infectious organ-
isms (Chiovato and Pinchera 1996; McLachlan and Rapoport 2000;
Whybrow and Bauer 2000b).
There has been much debate surrounding the role of psychosocial stress
and trauma in the precipitation of Graves’ disease. Anecdotal reports and
a considerable body of clinical opinion seem to support an association,
but objective evidence remains elusive. One of the major challenges is
determining a precise date of onset for thyrotoxicosis. The rapidity of on-
set is variable, and the disorder is probably subclinical for weeks or
months, so the thyrotoxicosis may have already begun by the time of the
putative precipitating event. Furthermore, the presence of a disturbance
in psychophysiology may affect the individual’s reaction to an event. Un-
fortunately, information distinguishing these relationships is difficult to
obtain retrospectively (Whybrow and Bauer 2000b).

Although prospective studies would be more effective in obtaining
this information, they are difficult to conduct. However, in one such study,
239 women from the general population who had “thyroid hot spots”—
areas of the thyroid gland found on screening to concentrate radioactive
iodine activity—were studied closely over time, with each subject’s thy-
roid and psychological status being evaluated independent of one an-
other. Through the 12-year follow-up period, the hot spots appeared to
wax and wane in direct relationship with life stress, with some women
developing clinical thyrotoxicosis during conditions of severe or pro-
longed life strain (Voth et al. 1970; Wallerstein et al. 1965).
Two retrospective controlled studies have been conducted that ex-
plore the onset of Graves’ disease. In a case-controlled study, patients de-
veloping Graves’ thyrotoxicosis reported more negative life events—such
as divorce, bereavement, and educational and occupational failure—than
did control subjects (Winsa et al. 1991). In another study, reports from a
sample of 70 age- and sex-matched patients attending an endocrine clinic
yielded similar results (Sonino et al. 1993). In this study the patients had
greater life change in the year preceding the diagnosis of Graves’ thyro-
toxicosis (both positive and negative) compared with control subjects.
Blinded raters judged rates of negative life events to be significantly greater
among study patients versus control subjects.
Environmental stress may also play a role in the course of thyrotoxicosis.
Support for this notion has been found in a longitudinal study of patients
receiving antithyroid drug therapy. In this study, the course of thyrotoxicosis
appeared to be related to the person’s ability to cope psychologically with
life stress, particularly when confronted with bereavement or loss (such as
financial difficulty) (Ferguson-Rayport 1956). If coping was successful, the
illness subsided; if not, the exacerbation progressed. Individual case reports
provide additional support for this finding (Cushman 1967). One patient
with Graves’ disease experienced a rapid increase in thyroid secretion after
a surgical biopsy for a benign breast tumor. Another patient, who had been
successfully treated for Graves’ thyrotoxicosis, had a recurrence of illness
within 2 months after the death of two young family members.
In conclusion, psychological stress may be associated with the onset
of thyrotoxicosis symptoms and may also influence its clinical course.
Clinical Manifestations
The clinical manifestations of an excessive availability of thyroid hor-
mones are numerous and are found in all systems of the body, including
the brain. Usually the manifestations of the illness are insidious, and fam-
ily members or friends may notice changes in the individual’s appearance

or behavior even before they are apparent to the patient. Physical symp-
toms include increased perspiration, weight loss, palpitations, heat intol-
erance, fatigue, weakness, and menstrual disturbances. In Graves’ disease,
the eyes may protrude (exophthalmos) and a palpable goiter is found. The
most common physical signs are tachycardia or atrial arrhythmia, warm
and moist skin, tremor, hyperreflexia, and muscle weakness (Braverman
and Utiger 2000b; Larsen et al. 1998). In severe cases, myopathies, pe-
ripheral neuropathies, and retinopathy may appear. Although they are
etiologically distinct, many of the effects of hyperthyroidism on physical
appearance, physical function, behavior, mood, and cognitive function
are similar regardless of the origin of the illness.
Neuropsychiatric Symptoms and Signs

Various neuropsychiatric symptoms may occur in thyrotoxicosis. How-
ever, the behavioral state in hyperthyroidism is best characterized as one
of intense dysphoria, usually with pronounced anxiety. In the early
stages, anxiety and tremor may occur alone with few physical manifesta-
tions. Other common complaints include nervousness, emotional labil-
ity, restlessness, and impaired concentration. Patients feel irritable and
jittery; they also have insomnia with fatigue and often feel too weak and
tired to carry through with their plans. Speech can also be rapid and dis-
jointed. An uncommon presentation of behavioral change with thyrotox-
icosis mimics a depressive disorder and usually occurs in elderly patients.
These patients feel apathy, lethargy, pseudodementia, and depressed
mood and often lack the standard physical findings associated with hyper-
thyroidism in young people (Peake 1981; Taylor 1975).
Studies estimating the prevalence of emotional and cognitive dys-
function in hyperthyroidism are subject to many limitations. Most reports
are based on collections of unselected patients with hyperthyroidism, but
from the studies summarized in Table 15–1, certain trends emerge. In-
vestigation of the neuropsychiatric status of thyrotoxic patients has cor-
roborated the clinical impressions of anxiety, mood, and cognitive dis-
turbances. Studies using modern diagnostic criteria have shown that in
patients with thyrotoxicosis, the prevalence of anxiety disorders was ap-
proximately 60%, and the prevalence of depressive disorders was
between 31% and 69% (Kathol and Delahunt 1986; Trzepacz et al.
1988b). Other studies using objective neuropsychiatric measurements
have confirmed these clinical impressions. Studies have shown increased
anxiety (Greer et al. 1973) on a standardized questionnaire, increased de-
pression on the Minnesota Multiphasic Personality Inventory (MMPI)
TABLE 15–1. Prevalence of psychiatric dysfunction in hyperthyroid

patients
Prevalence
Study N (%) Findings
Mandelbrote and 25 65 Neurosis

Wittkomer 1955
Kleinschmidt and 17 12 Psychosis
Waxenberg 1956
Bursten 1961 54 19 Psychosis
Wilson et al. 1962 26 54 Cognitive impairment
58 Depression
8 Elation
Hermann and Quarton 1965 24 4 Psychosis
Whybrow et al. 1969 10 100 Fatigue and/or irritability
20 Depression
40 Subjective confusion
MacCrimmon et al. 1979 19 10 Paranoia
Wallace et al. 1980 19 95 Fatigue
>50 Nervousness, irritability
Rockey and Griep 1980 14 71 Fatigue
79 Nervousness
64 Social withdrawal or
irritability
7 Major depression
Kathol et al. 1985 32 34 Organic mood disorder
Trzepacz et al. 1988a, 1988b 13 69 Major depression
62 Generalized anxiety
disorder
20 Panic disorder
23 Hypomania
scale (Artunkal and Togrol 1964), and increased depression and anxiety
on the MMPI (MacCrimmon et al. 1979). In addition, a study using the
Clyde Mood Scale also found an increased jittery score and reduced
score for clear thinking among thyrotoxic patients (Robbins and Vinson
1960).
Cognitive dysfunction, including decreased concentration and impaired
memory, are also correlated with the thyrotoxic state. Patients with thy-
rotoxicosis were found to resemble those with an organic brain syndrome
when assessed for neurotic and cognitive traits using standardized mea-
sures (Robbins and Vinson 1960). Performance on tasks requiring con-
centration and memory was also shown to decline in direct proportion to
the degree of increase in serum thyroxine (T4) (MacCrimmon et al.
1979). In addition, patients with thyrotoxicosis were shown to perform

poorly on the Porteus maze and the Trail Making Tests, another indica-
tion of cognitive impairment (Whybrow et al. 1969).
Psychosis, mania, and delirium have been reported and may accom-
pany a thyrotoxic storm (a relatively rare but life-threatening syndrome
characterized by exaggerated manifestations of thyrotoxicosis) (Greer
and Parsons 1968; Wartofsky 2000). Patients who typically develop a
true manic episode while thyrotoxic have either an underlying mood dis-
order or a family history (Checkley 1978; Hasan and Mooney 1981; Reus
et al. 1979). In the patients who do develop a psychotic illness, evidence
of delirium is often present (Beierwaltes and Ruff 1958; Whybrow et al.
1969).
Laboratory Diagnosis
A biochemical diagnosis of (overt) thyrotoxicosis is easily obtained by
measurement of levels of FT4, FT3, or both (increased) and of serum TSH
levels (decreased). Subclinical thyrotoxicosis is defined as a low serum
TSH concentration and normal serum FT4 and FT3 concentrations asso-
ciated with few or no symptoms or signs of thyrotoxicosis (Ross 2000).
Mild overt thyrotoxicosis is diagnosed when asymptomatic patients show
low TSH concentrations but have slightly high serum free thyroid hor-
mone concentrations. Ultrasensitive TSH assays now permit detection of
subnormal TSH values. In the absence of pituitary disease, if serum TSH
values are less than 0.2 mU/L, hyperthyroidism is the likely diagnosis. In
cases of ambiguity, a TRH challenge test can be of substantial value in
quantifying the hyperthyroid state. In the standard TRH test, 500 mg of
TRH is given intravenously and TSH values are drawn at baseline and
at 15, 30, 45, and 60 minutes. Peak values in normal women are usually
more than 6 mU/L above baseline values. In normal men, TSH levels
usually rise more than 6 mU/L before age 30 and by more than 2 mU/L
after age 40. Suppressed responses in the absence of pituitary disease are
virtually diagnostic of thyrotoxicosis, but if subjects show normal re-
sponses to TRH infusion, thyrotoxicosis can be ruled out.
Treatment of Neuropsychiatric Symptoms

After successful treatment of thyrotoxicosis the psychiatric symptoms
usually remit. Administration of an adrenergic antagonist agent such as
propranolol may be useful in controlling the anxiety associated with thy-
rotoxicosis. Among acutely psychotic patients, dopamine blockade may
be required to reduce excitement. Haloperidol or one of the newer atyp-
ical antipsychotic medications (e.g., risperidone or olanzapine) may

be used. There is a report of haloperidol precipitating thyrotoxic storm
(Hoffman et al. 1978). A combination of the b-adrenergic blocker pro-
pranolol and propylthiouracil, an antithyroid drug, has also been described
to be effective in controlling manic behavior secondary to thyrotoxicosis
(Lee et al. 1991).
Most studies conducted between 1956 and 2000 found substantial
improvement in neuropsychiatric symptoms that paralleled the resolu-
tion of the thyrotoxicosis (Table 15–2). After return to normal thyroid
status, patients had improvement in cognitive function (MacCrimmon et
al. 1979; Robbins and Vinson 1960), and in a study by Artunkal and Tog-
rol (1964) all 20 patients had improved MMPI profiles. Whybrow et al.
(1969) also found improvement in nervousness, anxiety, and motor ten-
sion. In some studies, however, patients showed incomplete neuropsychi-
atric recovery after reaching normal thyroid status. One study found 8 of
17 persons (47%) with various nonpsychotic and psychotic symptoms to
be improved on reestablishment of euthyroid status (Kleinschmidt and
Waxenberg 1956). In another study, of 45 patients who were hyperthy-
roid 10 years previously, only 25% were found to have markedly impaired
neuropsychological functioning (Bommer et al. 1990). Trzepacz et al.
(1988b) reported that patients’ mood and anxiety symptoms had im-
proved, but some attention deficit remained. A recent study investigating
the epidemiology of somatic and somatopsychic complaints in patients
with remitted hyperthyroidism confirmed the impression of residual
symptoms. In this study, one-third of patients had long-term mental se-
quelae and residual complaints such as lack of energy (Fahrenfort et al.
2000).
The incomplete remission of neuropsychiatric symptoms experi-
enced by some euthyroid patients is indicative of irreversible central ner-
vous system (CNS) damage. Although the underlying pathophysiological
mechanisms are unknown, it may be speculated that the autoimmune
processes associated with thyrotoxicosis play a role. In one study, a higher
number of previous hyperthyroid episodes was associated with more re-
sidual neuropsychiatric symptoms, indicating a relationship between dis-
ease severity and treatment outcome (Bommer et al. 1990).
In conclusion, most research has found that scores on various mood,
anxiety, and cognitive measures return to normal after a return to euthy-
roid status. The fact that most psychiatric symptoms are reversible after
treatment suggests that they are secondary to the hormonal abnormality.
Unfortunately, in some patients neuropsychiatric sequelae may persist
despite a return to normal thyroid status.
TABLE 15–2. Recovery of psychiatric function after treatment of hyperthyroidism
Study N Outcome
Kleinschmidt and Waxenberg 17 47% showed decreased mood and psychotic symptoms
1956
Robbins and Vinson 1960 10 Cognitive and neurosis scores improved
Artunkal and Togrol 1964 20 Minimal change
Hyperthyroidism and Hypothyroidism

Whybrow et al. 1969 10 Cognitive and psychopathological scores normalized
MacCrimmon et al. 1979, 19 Cognitive and psychopathological scores normalized
Wallace et al. 1980
Rockey and Griep 1980 14 Global measures improved in all, except 1 depressed subject
Trzepacz et al. 1988a 10 All mood and anxiety symptoms improved after 2 weeks of propranolol treatment; cognitive
symptoms improved only after 6 months of antithyroid treatment
Emanuele et al. 1989 4 Agoraphobia markedly better after treatment of hyperthyroidism in all subjects
Bommer et al. 1990 45 10 years after treatment, patients had persistent feelings of hostility and impaired cognitive
performance
Freedman et al. 1993 15 More relaxed, improved concentration and abstracting abilities after treatment
Fahrenfort et al. 2000 303 One-third showed residual neuropsychiatric symptoms years after treatment
427
Interactions Between the Hyperthyroid

State and Psychotropic Drugs
Particularly important is an awareness that if the patient’s thyrotoxicosis
was misdiagnosed and treated as psychosis or an affective state of other
origin, some psychotropic medications may be harmful. Both experimen-
tal (Coville and Telford 1970) and clinical (Prange et al. 1970) evidence
indicates that increasing levels of thyroid hormones potentiate catechol-
aminergic effects, perhaps by increasing b-adrenergic sensitivity. Augmented
thyroid function may therefore increase the toxicity of medications that
affect catecholamines. When the thyrotoxicosis is apathetic, mimicking
depression, administration of a tricyclic antidepressant drug can be haz-
ardous (Folks and Petrie 1982). The sensitivity to both the anticholin-
ergic and adrenergic effects of these drugs is increased in patients with
thyrotoxicosis, and serious cardiotoxic effects may occur, especially in
elderly patients. Although little has been written on the effects of mono-
amine oxidase inhibitors in hyperthyroidism, it has been demonstrated
that hyperthyroxinemia in animals increases the acute toxicity of these
drugs (Carrier and Buday 1961).
Treatment with lithium may interfere with thyroid physiology in the
periphery and in the brain (Lazarus 1998). The most prominent clinical
effects of lithium treatment are goiter (occurring in about 15%–20%
of patients) and hypothyroidism (in about 5% of patients). Although it
rarely occurs, lithium treatment can also confound thyrotoxicosis (Reus
et al. 1979). In a thyrotoxic patient who has psychiatric symptoms sim-
ulating mania, administration of lithium may result in masking of the thy-
rotoxic state (Wharton 1980). Lithium has antithyroid actions (Lazarus
1998; Rogers and Whybrow 1971), and its administration can result in
transient symptomatic improvement of thyrotoxicosis (Lazarus et al.
1974) but with exacerbation of thyrotoxicosis and also ophthalmopathy
when the lithium is discontinued (Reus et al. 1979; Rosser 1976; Segal
et al. 1973). Thompson and Baylis (1986) described a case of a 47-year-
old woman treated with lithium for bipolar disorder who developed ex-
ophthalmos and goiter; without biochemical evidence of thyroid disease,
she received no treatment. However, she returned to the endocrine clinic
6 months later with flagrant thyrotoxicosis. Notably, she had stopped tak-
ing lithium 7 weeks before this appointment, suggesting that her lithium
treatment had prevented the full-blown manifestations of Graves’ disease
by suppressing thyroid function; when the lithium was stopped, the hy-
perthyroidism manifested itself.
A series of case reports also suggest that hyperthyroid humans may be
at increased risk of toxicity from neuroleptics. Hyperthyroidism may
increase the risk for severe dystonic reactions (Witschy and Redmond
1981). There is also a case report of thyroid storm coinciding with halo-
peridol administration in a 13-year-old girl (Weiner 1979). Hyperthyroid
rats are more sensitive than euthyroid rats to side effects of neuroleptics
and are more likely to develop psychomotor activation from phenothi-
azines. Furthermore, administration of triiodothyronine (T3) to humans
increases sensitivity to chlorpromazine (Prange 1985). Taken together,
these clinical and animal findings suggest that the anticholinergic effects
of neuroleptics theoretically may worsen the tachycardia and cardiac dys-
rhythmias in hyperthyroid persons, demanding careful monitoring of
heart rate and electrocardiography in such cases.
Hypothyroidism
Hypothyroidism is defined as deficient thyroidal production of thyroid

hormone. The diminution in serum concentrations of thyroid hormone
causes an increased secretion of TSH, resulting in elevated serum TSH
levels (>4.7 mU/L). Hypothyroidism is a progressive and graded disor-
der, ranging from mild cases in which the only indication of disorder is an
abnormal laboratory value to severe cases with widespread symptoms that
can progress into life-threatening myxedema coma (Braverman and Uti-
ger 2000a; Larsen et al. 1998). Grade I is defined by a low serum free
thyroxine index (FTI) (serum T4 ´T3 resin uptake), an elevated TSH con-
centration, and multiple clinical findings, including physical and behav-
ioral signs. In grade II hypothyroidism there is a normal FTI but elevated
serum TSH levels and a few clinical signs of hypothyroidism, notably be-
havioral slowing and mild disturbances of mood and cognition. In grade
III hypothyroidism there are no changes in peripheral thyroid indices and
no clinical symptoms, but a slight increase in basal TSH levels and an exag-
gerated TSH response to TRH infusion are found. Grade IV hypothyroidism
(symptomless thyroiditis) is characterized by the presence of antithyroid
antibodies in the serum but with normal circulating thyroid hormone lev-
els, basal TSH, and a normal TRH stimulation test (Table 15–3) (Wenzel
et al. 1974).
Epidemiology and Etiology

Hypothyroidism is the most common clinical disorder of thyroid function
(Braverman and Utiger 2000a). Inadequate thyroid hormone production
from the thyroid gland accounts for 95% of all cases of hypothyroidism
TABLE 15–3. Grades of hypothyroidism

Serum TSH
Basal response to Signs and
Grade Hypothyroidism FTI TSH TRH symptoms
I Overt Decreased Increased Increased Multiple

II Mild Normal Increased Increased One or more
III Subclinical Normal Slightly Increased None
increased
IV Symptomless Normal Normal Normal Serum antithyroid
thyroiditis antibodies
Note. FTI=free thyroxine index (serum thyroxine´triiodothyronine resin uptake); TRH=
thyrotropin-releasing hormone; TSH=thyroid-stimulating hormone.
and is referred to as primary hypothyroidism. Primary hypothyroidism is

a prevalent disease worldwide. It is endemic in iodine-deficient regions,
but it is also a common disease in iodine-replete areas, as demonstrated
by a number of population-based studies. The most extensive data has
been obtained from the Whickham Survey, a study of 2,779 adults ran-
domly selected from the general population who were evaluated between
1972 and 1974 and again 20 years later (Tunbridge et al. 1977; Vander-
pump et al. 1995). In these studies, most striking is the high prevalence
of thyroid microsomal antibodies (10.3% in women, 2.7% in men), overt
hypothyroidism (1.8% in women, 1% in men), and subclinical hypothy-
roidism (7.5% in women, 2.8% in men). These data from the Whickham
Survey also demonstrate the marked female preponderance.
Hypothyroidism is usually brought about through either iodine defi-
ciency or iatrogenic, idiopathic, or autoimmune processes. Iodine defi-
ciency persists in many parts of the world and is the most common cause
of primary hypothyroidism worldwide (Braverman and Utiger 2000a). In
the industrialized countries, where iodine supplementation is common-
place, thyroid hormone deficiency is most frequently caused by inade-
quate production and secretion of thyroid hormones due to destruction
of the thyroid gland as a consequence of disease or therapies to control
thyrotoxicosis (Larsen et al. 1998). In the United States, the most frequent
cause of hypothyroidism is iatrogenic, resulting from surgical or radiation
ablation of the thyroid gland to treat Graves’ disease. In adults, idiopathic
hypothyroidism usually occurs between ages 40 to 60. Up to 80% of
these patients have antithyroid antibodies, and many have additional au-
toimmune illnesses (Weetman 2000). The elevated TSH levels found in
Hashimoto’s thyroiditis (thought to be immunologically mediated) can re-
sult in enlargement of the thyroid.
Decreased thyroidal secretion of thyroid hormone can also be caused

by insufficient stimulation of the thyroid gland by TSH, due to factors di-
rectly interfering with pituitary TSH release (secondary hypothyroidism)
or indirectly diminishing hypothalamic TRH release (tertiary hypothy-
roidism). In clinical practice it is not always possible to discriminate be-
tween secondary and tertiary hypothyroidism, which are consequently
often referred to as “central” hypothyroidism. Diminished TSH release
due to pituitary failure is a rare cause of hypothyroidism. In this manifes-
tation, the thyroid gland is normal, but because of inadequate stimulation
from the pituitary, secretion of thyroid hormone is low. The most com-
mon causes of pituitary hypothyroidism are postpartum necrosis and pi-
tuitary tumors damaging pituitary thyrotrophs. Laboratory tests reveal
diminished TSH levels and diminished TSH released in response to a TRH
challenge. In very rare cases, symptoms and signs of thyroid hormone de-
ficiency are caused by mutations in the nuclear thyroid hormone receptor
TRb with the consequence that tissues do not respond normally to the
presence of thyroid hormone. This condition, known as resistance to thy-
roid hormone, is typically associated with deficits in attention. It is char-
acterized by an increased thyroidal secretion of thyroid hormones and
increased thyroid hormone concentrations in serum, secondary to the
compensatory effects of the body to overcome the resistance to thyroid
hormone (Hauser et al. 1993).
Clinical Manifestations
In adults, the onset of hypothyroidism is usually insidious. Symptoms
may be present for a period of years before dramatic events occur. Phys-
ical symptoms include enlarged thyroid, constipation, cold intolerance,
weight increase with decreased appetite, fatigue, dry and rough skin, hair
loss, puffiness of the face, lethargy, and slowed motor activity (Braver-
man and Utiger 2000a). The behavioral presentation of thyroid hormone
deficiency varies considerably depending on the cause, duration, and se-
verity of the hypothyroid state. Characteristically there is a slowing of
mental and physical activity and a slowing of many organ functions.
Neuropsychiatric Symptoms and Signs

Cognitive dysfunction and depression are the most common psychiatric
syndromes associated with hypothyroidism. In severe forms of hypo-
thyroidism, psychotic and delusional symptoms may occur (“myxedema
madness”), and the syndrome may mimic melancholic depression and de-
mentia (Treadway et al. 1967). The reversible nature of most psychiatric
symptoms after treatment with thyroxine indicates that they are second-
ary to the hormonal abnormality. A wide variety of neuropsychiatric
symptoms are associated with hypothyroidism, including impaired cogni-
tion, mood changes, anxiety, irritability, and psychotic symptoms. Vague
symptoms of inattentiveness, slowing of thought, weakness, fatigue, and
poor memory are prevalent in mild hypothyroidism. Depressive mood is
the most common mood change, but it may be accompanied by anxiety
and insomnia. Progressively, the patients’ ability to carry out daily activ-
ities or to interact with others deteriorates. In addition, impaired percep-
tion with paranoia and visual hallucinations may develop (Whybrow and
Bauer 2000a; Whybrow et al. 1969). The few studies examining behav-
ioral changes have confirmed these clinical impressions (Table 15–4). In
one study, 5 of 7 consecutive patients with hypothyroidism were de-
pressed and one was anxious (Whybrow et al. 1969). Of 30 consecutive
patients with hypothyroidism, 22 had some psychopathology; however,
the severity of the hypothyroidism and the psychiatric symptoms were
unrelated (Jain 1972). In this study, 33% had anxiety and 43% had de-
pression. In a study by Haggerty et al. (1993), of 31 persons at risk for
hypothyroidism with no manifestations of the disease, 16 were found to
have subclinical hypothyroidism; these patients were considerably more
likely to have a lifetime history of depression than a matched control
group of 15 euthyroid subjects.
TABLE 15–4. Prevalence of psychiatric dysfunction in hypothyroid

patients
Prevalence
Study N (%) Findings
Clinical Society of 109 50 Psychosis

London 1888 65 Impaired memory
98 Psychomotor slowing
Whybrow et al. 1969 7 86 Subjective disorientation
100 Mood symptoms
14 Psychosis
Jain 1972 30 43 Depressed mood
33 Anxiety
27 Confusion
7 Psychosis
Drinka and Voeks 16 0 No higher incidence of
1987 nonvegetative, depressive
symptoms vs. control subjects
Haggerty et al. 1993 16 56 Lifetime episode of major depression
Significant cognitive impairment can be caused by hypothyroidism,

including short-term memory loss; disorientation; and impaired percep-
tion, attention, and problem solving (Dugbartey 1998). The Clinical
Society of London (1888) conducted a classic study of untreated myx-
edema and found intellectual slowness in almost all cases. In a study in
which the intellectual function of 15 patients with hypothyroidism was
compared with age- and sex-matched control subjects diagnosed with
brain damage or neurosis, “a generalized suppression of intellectual func-
tions which would become statistically significant if the groups were
larger” was found (Reitan 1953). In another study, disorientation was
found in 6 of 7 consecutive patients with hypothyroidism (Whybrow et
al. 1969).
Overt Psychiatric Manifestations

Approximately 5% of all patients with hypothyroidism have psychosis.
Gross mental changes may include disorientation, distractibility, halluci-
nations, and paranoia. Visual and auditory distortions may result in bi-
zarre behavior and paranoid ideas (Whybrow and Bauer 2000a). The
study of untreated myxedema conducted by the Clinical Society of Lon-
don in 1888 found delusions and hallucinations in almost half of the 109
patients studied. Today, however, as a result of early diagnosis and effec-
tive treatment, psychotic features have become rare manifestations of
hypothyroidism.
In recent years, investigators have become increasingly aware of an as-
sociation between grade II and III hypothyroidism and mood disorders.
Grade II or III hypothyroidism was found in 20 of 250 consecutive per-
sons with major depression admitted to an inpatient unit (Gold et al.
1981). Among women with postpartum depression, about 5% also have
postpartum thyroiditis. An investigation of 145 women with high serum
thyroid antibody concentrations 6 weeks postpartum (thyroglobulin and
microsomal antibodies) found that 47% had significant symptoms of de-
pression compared with 32% of women with normal serum antibody
concentrations (Harris et al. 1992).
Laboratory Diagnosis
In most cases of florid hypothyroidism, T4 level and FTI are below nor-
mal and TSH level is elevated (>4.7 mU/L). Frequently, patients with
primary hypothyroidism may also manifest hypercholesterolemia. How-
ever, as noted earlier, subtle cases of hypothyroidism that may not produce
physical abnormalities but are associated with psychiatric disturbance oc-
cur when T4 and T3 serum levels are in the normal range. The TSH level
may be solely elevated or the pituitary thyrotrophs may be abnormally
sensitive to TRH stimulation in individuals with these psychiatric manifes-
tations. This suggests that the CNS may be more sensitive to the alteration
of the thyroid economy than are other organs. Therefore, in psychiatric
practice, it is important to measure TSH levels, after TRH challenge if
necessary.
Treatment of Neuropsychiatric Symptoms

In the majority of cases, the behavioral changes associated with hypothy-
roidism remit after treatment with thyroid hormone and the return to eu-
thyroid status (Table 15–5). Of the available thyroid hormone replacement
preparations, T4 is currently recommended as the drug of choice in view
of its long half-life, ready quantitation in the blood, ease of absorption,
and availability of multiple tablet strengths (Brent and Larsen 2000). Re-
plenishment of thyroid hormone must be undertaken gradually, however.
Rapid increases of thyroid hormones can compromise cardiac function,
especially in elderly patients or patients with cardiac disease, and can ini-
tially worsen the behavioral disturbance. Residual symptoms may some-
times persist, particularly after severe and prolonged hypothyroidism
(Whybrow et al. 1969).
TABLE 15–5. Recovery of psychiatric function after treatment of

hypothyroidism
Study N Outcome
Asher 1949 14 9 recovered, 2 died, 3 were unchanged after

12 weeks of treatment; all patients were initially
severely psychotic
Schon et al. 1961 24 Cognitively improved at 5 months
Tonks 1964 18 Only 8 of the severely psychiatrically ill patients
improved
Whybrow et al. 4 Mood scales improved in 3; psychosis resolved in 1;
1969 no cognitive improvement in any
Nyström et al. 20 20% of patients with subclinical hypothyroidism
1988 showed memory improvement after 6 months of
thyroid replacement
Russ and 11 Major depression did not respond to standard
Ackerman (1989) antidepressants until thyroid supplementation was
used
After T4 treatment is initiated, exacerbation of psychosis may occur,

particularly if supplementation is conducted too rapidly (Browning et
al. 1954); therefore, severely disturbed patients should ideally be hos-
pitalized. Therapy with a major tranquilizing drug may be necessary in
some patients, but the drug should be given with caution and in con-
junction with T4 therapy to avoid precipitating myxedema coma. Halo-
peridol and the phenothiazines are the drugs most often used. When
the hypothyroidism is mild and complicating a predominantly depres-
sive syndrome, the therapeutic goal is to provide sufficient T4 to reduce
the serum TSH concentration to normal; however, the amount may not
be sufficient to reverse the melancholia (Treadway et al. 1967). In such
cases, antidepressant drugs or even electroconvulsive therapy may be
necessary. If the patient has a family history of affective disorder, par-
ticularly bipolar, initiation of treatment to correct hypothyroidism may
lead to mania. In such cases, addition of a mood-stabilizing drug may be
required. A review article revealed 18 hypothyroid cases of significant
psychiatric sequelae, predominantly mania, during replacement therapy
for hypothyroidism (Josephson and Mackenzie 1980). All but one of
these patients had psychiatric symptoms before the initiation of treat-
ment. These results suggest the need to proceed cautiously when cor-
recting hypothyroid status in patients who have experienced significant
behavioral changes. Although subclinical hypothyroidism is associated
with lesser mood syndromes, it has not yet been established if correct-
ing the thyroid deficit will reverse such symptoms (Haggerty et al.
1990).
Recently, Bunevicius and colleagues (1999) compared the effects of
T4 alone (at the usual replacement dosage) with those of T4 (50 mg/day
less than the usual dosage) plus T3 (12.5 mg/day) in 33 patients with hy-
pothyroidism in a randomized, double-blind, 2´5 week crossover study.
Partial substitution of T3 for T4 improved neuropsychological function
significantly in 6 of 17 tests and mood in 10 of 15 visual self-rating scales.
Therefore, a combination of T4 plus T3 may be beneficial in patients
who do not respond sufficiently to an adequate trial of monotherapy
with T4.
In summary, the majority of patients who undergo mood, cognitive,
and psychotic changes due to hypothyroidism will return to normal
with treatment. Nonetheless, response is not uniform, and differences
may be due to other psychiatric illnesses or the duration or severity of
the hypothyroidism (Whybrow and Bauer 2000a). There is some indi-
cation that a combination of T4 plus T3 is superior to T4 alone.
Interactions Between the Hypothyroid

State and Psychotropic Drugs
Adjuvant psychotropic medication may be necessary in some hypothyroid
persons either because the symptoms do not fully remit with normaliza-
tion of thyroid status or because the exigencies of the clinical situation so
dictate. Systematic studies to determine the proper therapeutic regimen
of psychotropic agents for patients with hypothyroid-induced psychiatric
disorders are needed. However, certain caveats worthy of note have accu-
mulated in the literature regarding such treatment of hypothyroid indi-
viduals with psychotropic medications.
As noted above under “Interactions Between the Hyperthyroid State
and Psychotropic Drugs,” treatment with lithium can cause hypothyroid-
ism. This must be considered when using this medication in those with a
history of thyroid dysfunction. Although it is associated with a slight low-
ering of serum levels of T4 and T3, carbamazepine has not been found to
cause hypothyroidism (Strandjord et al. 1980). The antipsychotic agents
have been the subject of a few case reports of untoward effects in hypo-
thyroidism, for example, hypothermia and coma. Gomez and Scott (1980)
further suggested that hypothyroidism can predispose to neuroleptic-
induced cardiac dysrhythmias. However, in the case they reported, a di-
minutive woman received some 270 mg of haloperidol, 400 mg of thio-
ridazine, and 40 mg of trifluoperazine in the 4 days before her cardiac
arrest. The use of sedative-hypnotics of the benzodiazepine and barbitu-
rate classes has not been associated with untoward effects, although there
is some evidence that hypothyroidism may slow drug metabolism by liver
microsomal enzyme (Kato et al. 1969).
Antidepressant therapy may not be efficacious until thyroid status is
corrected, as may be expected on theoretical grounds (Whybrow and
Prange 1981). Rapid-cycling mood illness in clinical or subclinical hypo-
thyroidism may be induced by tricyclic (Extein et al. 1982) or occasion-
ally by monoamine oxidase inhibitor (Mattson and Seltzer 1981) anti-
depressants, although there are few data suggestive of increased toxicity
otherwise in using these drugs in hypothyroid persons.
Brain Imaging to Study the Thyroid

System and Brain Activity In Vivo
Despite the evidence of a close relationship between thyroid status and

behavioral disturbances, the actions of thyroid hormones in CNS func-
tion in the mature mammalian brain have rarely been investigated in

vivo. This lack of interest seems to have originated in the 1950s and 1960s,
when early physiological studies suggested that oxygen consumption in
the mature human brain did not change with changing thyroid status
(Sokoloff et al. 1953; reviewed in Bauer and Whybrow 2002). Currently,
no methods for direct in vivo measurements of brain thyroid metabolism
exist. However, studies using brain imaging techniques to evaluate the
relationships between the brain, thyroid hormones, and behavior have
recently been initiated and may provide such assessment. Studies using
magnetic resonance spectroscopy and positron emission tomography have
indicated that the adult human brain, particularly the frontal lobe, is re-
sponsive to thyroid hormone (Bauer et al. 2002b; Silverman et al. 2002;
Smith and Ain 1995). These studies provide a neuroanatomical basis for
the prevalent neurological and psychiatric signs found in hypothyroidism
(Dugbartey 1998). The study by Smith and Ain (1995) indicated that
hypothyroid patients exhibit decreased cerebral metabolism in the fron-
tal lobes (as measured by 31P magnetic resonance spectroscopy) that re-
turned to normal after T4 replacement therapy. Animal studies in adult
hypothyroid rats found a significant decline in 14C-2-deoxyglucose up-
take throughout the brain, except for the brainstem and pons, indicating
a general decline in metabolic and functional activity during thyroid hor-
mone deficiency (Calza et al. 1997). Therefore, by further elucidating
the relationship among thyroid status, brain, and mood disorders, func-
tional brain imaging techniques may provide new insights into the patho-
physiology and treatment of these disorders.
Summary and Conclusion
Disorders of the thyroid gland are frequently associated with mental dis-
turbances. Hyperthyroidism and hypothyroidism can induce distur-
bances of mood and intellectual function, and in severe states there may
be a profound disturbance of behavior that can mimic melancholic de-
pression and dementia. The mental changes accompanying thyroid gland
dysfunction are usually reversed with return to euthyroid status.
The cellular and molecular mechanisms that can uniformly explain
the many psychiatric symptoms associated with thyroid illness are not yet
understood. The manifestations of both hypothyroidism and hyperthy-
roidism are manifold, from very mild cognitive deficits and dysphoria to
psychosis and delirium. Thyroid hormones are widely distributed in the
brain and have a multitude of effects on the CNS, and many of the limbic
system structures where thyroid hormones are prevalent have been im-
plicated in the pathogenesis of mental disorders. The specific neuro-
chemical basis and functional pathways for the therapeutic effects of
thyroid hormones on mental functions are also unknown. The influence
of the thyroid system on neurotransmitters that putatively play a major
role in the regulation of mood and behavior, particularly serotonin and
norepinephrine, may contribute to the mechanisms of action (Bauer et
al. 2002a; Whybrow and Prange 1981). However, it is not clear whether
these are the seminal disturbances accounting for behavioral change. Fur-
thermore, within the CNS, the regulatory cascade through which the
thyroid hormones, particularly T3, exert their effects is not well under-
stood: deiodinase activity, nuclear binding to genetic loci, and ultimately
protein synthesis may all be involved. What is clear, however, is that
without optimal thyroid function, psychiatric and mood symptoms often
emerge. Therefore, despite the lack of understanding of fundamental
mechanisms, the evaluation of thyroid status is of vital concern to the
physician and especially to the psychiatrist. In addition to what has been
learned about the association of thyroid dysfunction with behavior and
mood, the adjunctive treatment of mood disorders with thyroid hormones
has become a valuable strategy (Bauer and Whybrow 2001). These issues
are addressed in detail in other chapters of this volume.
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Chapter 16
Thyroid Hormone Treatment of

Stephen Sokolov, M.D., F.R.C.P.C.

Russell Joffe, M.D.
T here has been a long-standing interest in thyroid hormones

as treatments for psychiatric disorders, largely arising from observed asso-
ciations between psychiatric symptomatology and thyroid disease states.
Clinical case studies, in particular, have documented the occurrence of
psychiatric symptoms in both hyperthyroid and hypothyroid illness. Sev-
eral general observations have emerged. In hyperthyroidism, anxiety and
emotional lability are most commonly observed (Bauer and Whybrow
1988; MacCrimmon et al. 1979), with symptoms of mania, psychosis,
and marked cognitive impairment in more severe forms, including thyro-
toxicosis (Fava et al. 1987). Hypothyroidism, on the other hand, is most
commonly associated with symptoms of depression (Bauer and Whybrow
1988; Hall 1983; Jain 1972; Whybrow et al. 1969). When psychiatric and
cognitive symptoms are present in thyroid illness, successful treatment of
the thyroid illness is usually associated with resolution of these symptoms
(Hall 1983; MacCrimmon et al. 1979; Whybrow et al. 1969), especially
in patients with hypothyroidism (Hall 1983; Whybrow et al. 1969).
The rationales for the proposed use of thyroid hormones as treat-
ments for psychiatric illnesses are derived from several observations.
First, it has been noted that psychiatric symptoms are present in thyroid
disease and that these symptoms improve with treatment of the under-
lying thyroid illness (Hall 1983; Jain 1972; MacCrimmon et al. 1979;
Prange et al. 1978). Second, there have been observations in animal ex-
periments that thyroid hormones enhance antidepressant toxicity, and it
445
has been speculated that similar use in humans may enhance the thera-
peutic effect of antidepressants (Breese et al. 1974). Finally, data from
animal studies suggest that thyroid hormones may interact with biogenic
amines, in some instances potentiating the effects of the amines (Breese
et al. 1974).
Approaches undertaken in the use of thyroid hormones in psychiatric
illnesses include their use as monotherapy and in combination with other
psychotropic agents. Thyrotropin-releasing hormone (TRH), thyroid-
stimulating hormone (TSH), and the peripheral thyroid hormones thy-
roxine (T4) and triiodothyronine (T3) have been used and investigated in
various psychiatric illnesses, including major depression, bipolar disorder,
and anxiety disorders.
Major Depression
Thyroid hormone medications have been employed using several ap-

proaches. These include monotherapy as antidepressant medication, com-
bination therapy to accelerate the effect of antidepressants, and combi-
nation therapy to augment (potentiate) the effects of antidepressant
medication in patients who do not respond to antidepressants. In addi-
tion, there is some evidence to suggest that thyroid hormones may be
useful in ameliorating cognitive side effects associated with administra-
tion of electroconvulsive therapy (ECT).
Thyrotropin-Releasing Hormone
TRH is a tripeptide released from the hypothalamus whose principal en-
docrine role is to regulate synthesis and secretion of TSH, which in turn
regulates thyroid hormone synthesis and release. TRH may also affect
brain function in a manner separate from its role within the thyroid axis
by acting as a neurotransmitter (Griffiths 1985). Effects of the adminis-
tration of exogenous TRH include reversal of drug-induced sedation or
anesthesia; stimulation of motor activity; and other effects on cardiac,
respiratory, gastrointestinal, and neurological function (Griffiths 1985;
Prange et al. 1978).
Use of TRH in antidepressant therapy was suggested by its apparently
widespread role in the central nervous system and by its potential for
stimulating the thyroid axis. The use of this hormone in combination
with ECT has been suggested on the basis of its beneficial effect on neu-
rological and cognitive function.
Thyroid Hormone Treatment of Psychiatric Disorders 447
Monotherapy
Thirteen double-blind studies have evaluated the effect of TRH on symp-
toms of major depression by intravenous, oral, or intrathecal admin-
istration (Coppen et al. 1974; Ehrensing et al. 1974; Furlong et al. 1976;
Hollister et al. 1974; Karlberg et al. 1978; Kastin et al. 1972; Kiely et al.
1976; Marangell et al. 1997; Mountjoy et al. 1974; Prange et al. 1972; Van
Den Burg et al. 1975, 1976; Vogle et al. 1977). The equivocal results of
the oral and intravenous TRH studies may be explained by the relatively
short half-life of TRH in serum (5.3±0.5 minutes after intravenous ad-
ministration) and by the impermeability of the blood-brain barrier to pe-
ripherally administered TRH (Marangell et al. 1997). To overcome these
limitations, Marangell and co-workers (1997) used a double-blind, pla-
cebo-controlled crossover design and administered TRH intrathecally in
a group of patients with highly refractory depression. Although robust
improvement was seen in the majority of subjects, the improvement was
short-lived.
Therefore, the fact that the majority of studies of TRH do not dem-
onstrate a significant antidepressant effect is likely accounted for by the
peripheral route of administration. When effects were demonstrated,
they were mostly either minimal or transient (Furlong et al. 1976; Kastin
et al. 1972; Prange et al. 1972; Van Den Burg et al. 1975, 1976). Although
robust effects were demonstrated in the one study using a central route
of administration, response was short-lived, and in clinical practice ad-
ministration of TRH intrathecally is impractical (Marangell et al. 1997).
On the basis of investigations to date, it cannot be concluded that TRH
monotherapy has a significant role in the treatment of depression.
Combination With ECT

Khan et al. (1994) administered 500 mg of TRH in a randomized, dou-
ble-blind, placebo-controlled crossover design to eight depressed pa-
tients undergoing ECT. Infusion of TRH (but not placebo) before ECT
treatments resulted in greater levels of arousal and better cognitive func-
tioning after treatment, as assessed by a neuropsychiatric battery. TRH
infusion did not result in alteration of ECT variables such as energy re-
quired to induce the seizure or seizure duration. The study design did
not allow distinction between whether TRH administration reversed
anesthetic effects or ECT-specific effects on cognition. More recently,
Zervas et al. (1998), in a placebo-controlled crossover design, admin-
istered 400 mg of TRH intravenously before two treatments of ECT.
Administration of ECT was associated with improvement in 24-hour re-
call but not in immediate cognitive measures. In summary, there is lim-
ited evidence that TRH has some efficacy in preventing cognitive side
effects of ECT. Further replication using larger numbers of subjects is
required.
Thyroid-Stimulating Hormone
On the basis of the known physiological role of TSH in stimulation of
thyroid hormone synthesis and release, it was postulated that TSH ad-
ministration might have antidepressant effects. In the only study to ex-
amine antidepressant effects of TSH, Prange et al. (1969) administered
10 IU of TSH intravenously to 20 depressed women 24 hours before ini-
tiating imipramine therapy. The researchers observed that TSH-treated
women experienced a more rapid response than did patients who received
a saline injection. The precise mechanism of this effect is not clear, and
although these results are intriguing, replication of these data is required
before it can be concluded that TSH administration has substantial clin-
ical utility.
Thyroxine
The original studies evaluating thyroid hormone treatment of depression
used T3, on the basis of the observation that T3 is several times more bi-
ologically active than T4. However, it was assumed that in the treatment
of psychiatric illness, T4 would function similarly to T3 and that because
it had a considerably longer half-life than T3, its psychotropic effects
would be more enduring.
A number of studies, however, have attempted to evaluate T4 aug-
mentation (Bauer et al. 1998; Rudas et al. 1999; Targum et al. 1984). In
the earliest study, Targum et al. (1984) administered T4 as an augmenta-
tion agent in 21 patients who had not responded to treatment with a tri-
cyclic antidepressant. Although 7 patients responded, 5 of these had
evidence of subclinical hypothyroidism, as determined by a maximum
TSH response to TRH greater than 25 mIU/mL at baseline before thy-
roid hormone augmentation. Therefore, in this study, it appeared that T4
may have played a role as replacement therapy for subclinical hypothy-
roidism—a role presumably distinct from the use of T3 in augmentation
therapy of euthyroid depressed patients (see “Augmentation” under “Tri-
iodothyronine” below). Bauer et al. (1998) openly added supraphysiolog-
ical doses of T4 (mean, 482±72 mg/day) to antidepressant medication in
12 bipolar and 5 unipolar patients with highly refractory depression.
High-dosage T4 was generally well tolerated, with 10 patients responding
robustly and 7 of the 10 maintaining excellent response over the follow-
up period. Rudas et al. (1999), also in an open trial, added 150–300 mg

of T4 to the treatment regimens of 9 patients with chronic or recurrent
depression that was refractory to the current antidepressant treatment.
Five patients responded fully over the course of the 8-week trial, and 1
patient had a partial response. Two patients had to withdraw from the
study due to restlessness and tremor at 100 mg/day. Conclusions that can
be made on the basis of these studies are limited in that all were open tri-
als and one trial (Bauer et al. 1998) studied a heterogeneous group of ill-
nesses. In addition, the use of high-dosage T4 is potentially hazardous, as
it can be associated with increased risk of osteoporosis (Greenspan and
Greenspan 1999).
In the only study to directly compare T3 and T4, Joffe and Singer
(1990) (using a double-blind, randomized, controlled design) found T3
to be superior to T4. However, the findings are limited by the failure to
include a placebo control group; the findings also require replication be-
fore it can be definitively concluded that T4 is less effective than T3 in the
treatment of depression.
At present there is little evidence for the efficacy of T4 administration
at nearly physiological doses in treatment-resistant depression, and ben-
eficial effects may be limited to patients with depression associated with
subclinical hypothyroidism. Although the more recent studies using su-
praphysiological doses are intriguing, replication using controlled meth-
odology is required, and the treatment may be associated with certain
medical risks. Finally, although there is preliminary evidence to suggest
that T4 is an inferior augmentation agent to T3 when the two agents are
directly compared, further replication is required.
Triiodothyronine
T3 has been used in the treatment of depression in four distinct ways: as
monotherapy; in combination with ECT; in conjunction with antidepres-
sants to produce a more rapid response (acceleration); and in conjunction
with antidepressants to potentiate response in patients who have not re-
sponded to adequate antidepressant treatment (augmentation).
Monotherapy
Two early anecdotal reports suggested that T3 might be effective in in-
creasing spontaneous motor activity and improvement in depression
symptoms in a mixed cohort of psychiatric patients (Feldmesser-Reiss
1958; Flach et al. 1958). Unfortunately, these data have not been repli-
cated using current methodological and diagnostic paradigms. Monother-
apy with T3 for depression is therefore not considered to be clinically

useful at this time.
Combination With ECT

Prange et al. (1990) reported retrospective data on thyroid hormone mea-
sures in psychiatric inpatients before ECT. Patients with higher pre-ECT
free T4 index values had less post-ECT cognitive disturbance. In a double-
blind study, Stern et al. (1991) randomly assigned 20 male patients with
major depression, schizoaffective disorder depressed type, or bipolar dis-
order depressed phase to receive either 50 mg of T3 or placebo before each
ECT treatment. The T3-treated group required fewer treatments and
showed less cognitive impairment after ECT. However, the study design
did not allow differentiation between whether T3 improved anesthetic-
related or ECT-related cognitive effects. To address this, Stern et al.
(1995) attempted to investigate the effects of T3 on electroconvulsive
shock (ECS)–related memory effects using ECS and ECS-sham treatments
in rats. T3 was found to decrease ECS-related retrograde and anterograde
amnesia but not ECS-sham–related cognitive effects, suggesting that T3
may specifically improve the ECS-related cognitive effects.
There is preliminary evidence to suggest significant benefits may be
associated with use of T3 in combination with ECT. In particular, T3-ECT
combination may be associated with improved antidepressant effect and
in diminishing cognitive side effects (Prange et al. 1990; Stern et al.
1991). Although the cognitive improvement appears similar to that noted
in the use of TRH with ECT (see “Combination with ECT” under “Thy-
rotropin-Releasing Hormone” above), the effects may not be mediated
through the same mechanism, because the evidence is that TRH (and not
T3) acts as a neurotransmitter (Griffiths 1985). Further replication of
these data is needed.
Acceleration
There is some evidence to suggest that when used in combination with
antidepressant medication T3 is effective in accelerating the onset of an-
tidepressant response. Several studies undertaken more than 30 years ago
(Prange et al. 1969; Wheatley 1972; Wilson et al. 1970) examined the
use of 25–50 mg/day of T3 started simultaneously with tricyclic antide-
pressant treatment. In these studies, patients receiving T3 responded
more quickly to antidepressants than patients who did not receive T3. For
reasons that are not clear, this effect appeared to be more prominent in
women. Other reports (Feighner et al. 1972) suggest that the accelera-
tion effect of T3 may not be consistently observed.
Although these results are of potential importance both theoretically

and clinically, further replication would be required using current diag-
nostic criteria and careful assessment of early response to treatment be-
fore T3 can be regarded as a therapeutic tool to reduce the lag in onset of
antidepressant response.
Augmentation
In addition to reports of the T3 acceleration effect, 11 studies (Banki
1975, 1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe
and Singer 1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al.
1984; Thase et al. 1989; Tsutsui et al. 1979) examined the addition of
small amounts of T3 to augment response in patients who did not re-
spond to a trial of tricyclic antidepressants. These studies are reviewed in
Table 16–1.
The six open studies (Banki 1975; Earle 1970; Ogura et al. 1974;
Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979) demon-
strated that of subjects who did not respond to tricyclic antidepressants,
approximately 25%–91% (weighted mean, 63.1%) had a response within
2–4 weeks after the addition of 5–50 mg of T3 to their antidepressant. The
one negative open trial (Thase et al. 1989) consisted of a study sample of
severely ill patients with highly recurrent major depressive illness, possi-
bly explaining the lack of response to T3.
The five controlled studies (Banki 1977; Gitlin et al. 1987; Goodwin
et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b) are generally sup-
portive of the results from the open studies, with rates of response ap-
proximating 50%. The one negative study (Gitlin et al. 1987) is difficult
to evaluate owing to several methodological issues (for example, it used
a 2-week crossover design, which may not be the most appropriate pro-
tocol for evaluating the efficacy of antidepressant treatment with a de-
layed onset and cessation of action of unknown duration). Across the six
studies, response to antidepressant augmentation with T 3 was not
affected by sex, bipolar/unipolar diagnosis, type of heterocyclic antide-
pressant used, or baseline thyroid status of the patients. A recent meta-
analysis of 292 patients treated in six studies suggests that T3 augmentation
is twice as likely to produce a response as control treatments (Aronson et
al. 1996).
Two of the controlled T3 augmentation studies warrant special note.
First, Joffe and Singer (1990) conducted the only study to directly com-
pare T3 augmentation to T4 augmentation. Using a double-blind design,
the researchers found that 9 of 17 patients responded significantly bet-
ter to T3 (P=0.026, Fisher exact test) than to T4 (4 of 21 patients). All
452
TABLE 16–1. Augmentation of tricyclic antidepressants with triiodothyronine (T3)
Dosage
Study N (mg/day) Tricyclic Design Response (%)
Earle 1970 25 25 AMI, IMI Open 14 (56.0)

Ogura et al. 1974 44 20–30 Various Open 29 (65.9)
Banki 1975 52 20–40 Various Open 39 (75.0)
Banki 1977 33 20 AMI Partially controlled 23 (69.7)
Tsutsui et al. 1979 11 5–25 Various Open 10 (90.9)
Goodwin et al. 1982 12 25–50 Various Double-blind 8 (66.7)
Schwarcz et al. 1984 8 25–50 DMI Open 4 (50.0)
Gitlin et al. 1987 16 25 IMI Double-blind, placebo T3 =placebo
Thase et al. 1989 20 25 IMI Open 5 (25.0)
Joffe and Singer 1990 38 37.5 DMI, IMI Double-blind vs. T4 9 of 17 (52.9) for T3, superior to T4
Joffe et al. 1993b 51 37.5 DMI, IMI Double-blind, placebo and lithium 10 of 17 (58.8) for T3, T3 >placebo, T3 =lithium
Note. AMI=amitriptyline; DMI=desipramine; IMI=imipramine; T4 =thyroxine.
patients were euthyroid. Potential shortcomings of this study are the lack
of a placebo group and the possibility that there was a delayed (undetec-
ted) onset of effect of T4 owing to the short duration of the trial period
and the considerably longer half-life of T4 compared with T3. Second,
in a randomized, double-blind, placebo-controlled design, Joffe et al.
(1993b) directly compared T3 and lithium augmentation in 51 patients
who did not respond to adequate treatment with desipramine or imipra-
mine. Subjects received 2 weeks’ treatment with either 37.5 mg/day of
T3, 900–1,200 mg/day of lithium, or placebo in addition to their antide-
pressant. Lithium doses were adjusted by a nonblind overseer at the end
of the first week of treatment to standardize serum levels to 0.58 mmol/
L or above. Ten of 17 patients (58.8%) responded to T3, 9 of 17 (52.9%)
responded to lithium, and 3 of 16 (18.8%) responded to placebo. Both
T3 and lithium were significantly better than placebo (T3 versus placebo,
P=0.018; lithium versus placebo, P=0.038, Fisher exact test) and did not
differ from each other. These findings are interesting in light of clinical
lore suggesting that lithium is the “gold standard” for antidepressant aug-
mentation, and as such, the efficacy of T3 augmentation has been met
with skepticism (reviewed in Joffe et al. 1993b; Nemeroff 1991).
The open and controlled studies of T3 augmentation (Banki 1975,
1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer
1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al. 1984; Thase
et al. 1989; Tsutsui et al. 1979) suggest that the use of T3 augmentation
is effective in patients who do not respond to tricyclic antidepressants. In
general, rates of response in these studies are comparable to those re-
ported with lithium augmentation (reviewed in Joffe et al. 1993b). Fur-
thermore, when lithium augmentation and T3 augmentation are directly
compared (Joffe et al. 1993b), T3 may be at least comparable in efficacy.
However, although T3 and lithium augmentation may have comparable
response rates, they may not necessarily be effective in the same individ-
uals; several case series suggest that nonresponse to one does not predict
nonresponse to the other (Garbutt et al. 1986; Joffe 1988a).
Side effects and tolerability. T3 administration is generally considered a
well-tolerated treatment with few side effects. The likely low incidence of
side effects associated with T3 augmentation probably relates to the small
doses being used (25–50 mg), which are below what would be considered
physiological replacement doses. However, the studies to date have com-
mented only generally on side effects and have not systematically logged
adverse reactions (Banki 1975, 1977; Earle 1970; Gitlin et al. 1987; Good-
win et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b; Ogura et al.
1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979).
Several case reports of more severe adverse effects have appeared.

Gitlin (1986) reported a case of a 59-year-old man with a history of an-
gina who responded to 25 mg/day of T3 augmentation but experienced
an exacerbation of his angina. Cole et al. (1993) reported on a case of a
68-year-old woman augmented with 50 mg of T3 who developed parox-
ysmal atrial fibrillation 2–3 days after an orthopedic procedure. She re-
turned to sinus rhythm after discontinuation of the T3. Although the
exact incidence of significant T3-related adverse effects is unknown, these
case reports suggest caution in the use of T3 augmentation in elderly pa-
tients or patients with preexisting cardiac conditions.
The adverse effects possibly associated with long-term T3 treatment
are unknown. This is relevant because T3 augmentation treatment is re-
served for patients with refractory illness. Patients with refractory illness
are at greater risk of relapse and recurrence and are therefore more likely
to be candidates for long-term maintenance therapy with the agents to
which they acutely respond. Are patients receiving long-term mainte-
nance therapy with T3 then at increased risk of osteoporosis (mediated
through effects of thyroid hormone on accelerated bone turnover and
shortening of the bone remodeling cycle)? Although there are no long-
term studies on the use of T3, some inferences can be drawn from the lit-
erature on T4 replacement.
A recent meta-analysis of the data (Greenspan and Greenspan 1999)
suggested that an increased risk of osteoporosis was most associated with
dosages of T4 resulting in full suppression of TSH (i.e., to less than 0.1
mU/mL) as measured by ultrasensitive assay. Dosages of T4 resulting in
partial suppression of TSH (to between 0.2 and 0.5 mU/mL) were equiv-
ocal in effect. The authors recommended that premenopausal and post-
menopausal women who are taking fully suppressive doses of T4 and are
not receiving hormone replacement therapy should have cortical bone
mineral density assessed every 1–2 years (Greenspan and Greenspan 1999).
It is possible that this should also apply to women with depression who
are not receiving hormone replacement therapy and are taking mainte-
nance doses of T3 resulting in full suppression of TSH.
Antidepressant class. All clinical trials of T3 augmentation used T3 in
combination with tricyclic antidepressants. Therefore, the evidence for
efficacy of T3 augmentation of other antidepressant classes is limited to
several case reports that suggest efficacy of T3 augmentation with mono-
amine oxidase inhibitors (Hullett and Bidder 1983; Joffe 1988b) and se-
lective serotonin reuptake inhibitors (Joffe 1992). On the basis of these
case reports and our own clinical experience, it appears that T3 can be
helpful when combined with nontricyclic antidepressants, although the
precise rate of response is not clear. To confirm this impression, con-

trolled trials of T3 augmentation in alternate classes of antidepressants are
required.
Mechanism of action. There is evidence to suggest that the effects of T3
augmentation are not mediated through the enhancement of plasma lev-
els of tricyclic antidepressants (Goodwin et al. 1982). Furthermore, it is
unlikely that T3 acts as hormone replacement therapy, because the ma-
jority of depressed patients are euthyroid and baseline thyroid function
does not appear to predict response to T3 (Joffe et al. 1993a).
There are several competing hypotheses regarding the mechanism of
action of T3 augmentation. First, Whybrow and Prange (1981) suggested
that the therapeutic effects of T3 may occur through potentiation of cat-
echolamine effects at central adrenergic receptor sites mediated through
an increase in b-adrenergic receptor activity. This is an attractive and
potentially unifying hypothesis, because catecholamine deficiency is pos-
tulated to be of etiologic importance in depression. However, further
systematic investigation is warranted. Second, Bauer and Whybrow
(1988) suggested that depression may be associated with a state of relative
thyroid hypofunction and that increases in thyroid hormone levels are
required to promote antidepressant response. Third, Joffe et al. (1984)
speculated that T3 may possibly act by lowering brain thyroid hormone
levels through negative feedback mechanisms within the thyroid axis.
That is, exogenously administered T3 increases serum levels of circulating
T3. This is detected by the hypothalamus and pituitary, which downregu-
late endogenous production and release of T4 and T3. Levels of brain T3
and T4 would be reduced because brain T3 and T4 derive almost exclu-
sively from T4 circulating in the blood. This potentially explains the lack
of efficacy for T4 augmentation because exogenous T4 would presumably
result in an increase in both brain T3 and T4, whereas T3 circulating in the
blood does not cross the blood-brain barrier appreciably (Joffe et al. 1992).
To attempt to clarify whether it was “prothyroid” or “antithyroid”
mechanisms that were associated with response to T3 augmentation,
Joffe et al. (1992) openly treated seven euthyroid patients with highly
treatment-refractory illness for 4 weeks with 20 mg/day of methima-
zole—an antithyroid compound used in the treatment of clinical hyper-
thyroidism. Of the six patients who tolerated methimazole, three were
considered responders, as defined by a decrease in scores on the Hamilton
Rating Scale for Depression by 50% to a final score less than 10. Al-
though these data are interesting, they are nonetheless preliminary.
Conclusion. T3 augmentation therapy in patients who do not respond
to treatment with antidepressants remains to date the best-evaluated use
of thyroid hormones in psychiatric illness. There is evidence that T3 aug-

mentation results in rates of response comparable to lithium augmenta-
tion. On the basis of the controlled studies, T3 can be recommended as a
viable treatment strategy in refractory depression. Unresolved issues,
however, include the following: What is the most appropriate dose?
What is an adequate duration of a T3 trial? What is the appropriate length
of time that T3 should be continued? What are the risks of long-term
treatment with T3, and what monitoring should be performed? (Joffe
1998). Clinical recommendations regarding the use of T3 augmentation
are summarized in Table 16–2.
TABLE 16–2. Triiodothyronine (T3) augmentation: clinical

recommendations
Indication Refractory depression
Evidence Double-blind, placebo-controlled data only with
tricyclic antidepressants
Case reports of effectiveness with SSRIs and MAOIs
Usual dosage 25–50 mg/day
Usual duration of trial 2–4 weeks?
Duration of treatment Unknown
Adverse effects Gastrointestinal discomfort, headaches, and anxiety—
usually short-lived. Possible angina or arrhythmia in
vulnerable patients
Theoretically may increase risk of osteoporosis in
women if T3 results in full suppression of TSH (<0.1
mU/mL)
Monitoring ? Cortical bone densitometry every 1–2 years in women
with full suppression of TSH
Note. MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibi-
tor; TSH=thyroid-stimulating hormone.
Bipolar Disorder
A number of studies have investigated whether a higher prevalence of

clinical and subclinical thyroid illness exists in patients with rapid-cycling
bipolar illness (Bartalena et al. 1990; Bauer et al. 1990; Cho et al. 1979;
Cowdry et al. 1983; Joffe et al. 1988; Wehr et al. 1988). The three positive
studies (Cho et al. 1979; Cowdry et al. 1983; Bauer et al. 1990) suggest a
higher prevalence of subclinical and clinical hypothyroidism associated
with rapid cycling. Cho et al. (1979) reported that 31.7% of rapid-cycling
versus 2.1% of non–rapid-cycling women had evidence of grade I clinical
hypothyroidism. Cowdry et al. (1983) reported 92% of rapid-cycling ver-

sus 32% of non–rapid-cycling patients had evidence of either grade I or II
hypothyroidism. Bauer et al. (1990) found higher prevalence of a variety
of grades of hypothyroidism in their sample of rapid cyclers compared to
published prevalence in non–rapid-cycling bipolar illness (grade I, 23%;
grade II, 27%; grade III, 10%). As a result of these findings the use of thy-
roid hormone has been suggested in rapid-cycling bipolar patients.
On the other hand, Wehr et al. (1988) observed a high prevalence of
hypothyroidism in both rapid-cycling and non–rapid-cycling patients
(47% vs. 39%). Joffe et al. (1988) evaluated 43 bipolar outpatients who
had received at least 3 months of treatment with lithium carbonate. Thy-
roid function tests were obtained on all patients, and detailed life charting
was obtained on 39 patients. Seventeen patients were classified as rapid
cyclers and 25 as non–rapid cyclers. None of the thyroid indices corre-
lated with course-of-illness variables, but patients who developed clinical
hypothyroidism had a significantly longer mean duration of lithium treat-
ment. Bartalena et al. (1990) compared 11 rapid-cycling and 11 non–
rapid-cycling women matched for age and mode of treatment. A high
prevalence of subclinical hypothyroidism was found in both groups.
Therefore, the three negative studies (Bartalena et al. 1990; Joffe et al.
1988; Wehr et al. 1988) found a higher-than-expected prevalence of
hypothyroidism in both rapid-cycling and non–rapid-cycling groups
compared with rates in the healthy population. However, no significant
difference was found between the rapid-cycling and non–rapid-cycling
groups. Furthermore, in one study (Joffe et al. 1988), it was suggested
that hypothyroidism in bipolar illness may be more closely correlated
with duration of lithium treatment than with rapid-cycling status.
More recently, Zarate et al. (1997) retrospectively evaluated a sample
of 72 medication-free subjects presenting in first-episode mania or mixed
state. Elevations in TSH concentration but not in other thyroid measures
differentiated between mixed-episode and manic patients. This is inter-
esting, because bipolar patients who experience mixed episodes may be
more prone to rapid cycling (Keller et al. 1986). Finally, Frye et al. (1999)
reported that in a cohort of 52 patients, lower measures of T4 were asso-
ciated with greater mood instability and severity in patients receiving
lithium or carbamazepine.
Non–Rapid Cycling
Baumgartner et al. (1994) reported on the use of high-dosage T4 in non–
rapid-cycling patients with treatment-refractory bipolar disorder. Six
patients were treated with 250–500 mg/day of T4. Four of the six patients
obtained a significant response as measured by mean number of relapses
and mean length of hospitalizations during the follow-up period (12–46
months). However, four of the patients in the study had evidence of
subclinical hypothyroidism. Therefore, it is unclear whether the benefi-
cial effect of T4 was due to its being employed as thyroid replacement
therapy.
Rapid Cycling
Although the specificity of hypothyroidism in rapid-cycling bipolar dis-
order is not known, T4 has been used by several investigators in an at-
tempt to treat rapid-cycling bipolar illness. Reports to date have used
dosages of T4 up to 500 mg/day in combination with mood stabilizers—
high enough to induce a hypermetabolic state (Bauer and Whybrow 1990;
Leibow 1983; Stancer and Persad 1982). First, Stancer and Persad (1982)
openly treated 10 rapid-cycling patients whose illness had been refrac-
tory to conventional treatments (lithium, ECT, neuroleptics) with sup-
raphysiological thyroid hormone. Five of 7 women treated with 300–500
mg/day of T4 obtained complete remission of their illness (follow-up pe-
riod, 1.5–9 years), 2 women treated with 240–400 mg/day of T3 had tem-
porary or slight responses, and 2 men treated with T4 also responded
minimally. Subsequently, Leibow (1983) reported a single case of rapid
cycling that responded to 400 mg/day of T4. More recently, Bauer and
Whybrow (1990) openly treated 11 rapid-cycling patients with 150–400
mg/day of T4. Depressive symptoms improved in 10 of 11 patients, and
manic symptoms improved in 5 of the 7 patients who exhibited these
symptoms at baseline. Three of 4 patients who were randomized in ei-
ther a single- or double-blind manner to discontinuation of T4 subse-
quently relapsed.
In the reports to date, supraphysiological T4 has been reported to be
generally well tolerated because the treatment algorithms have called for
slow dose titration, with the upper limit of dosing usually determined by
the appearance of side effects. There is nevertheless a risk of iatrogeni-
cally induced hyperthyroidism, and as such this treatment technique
needs to be used with caution. With respect to other risks of treatment,
there is a theoretical risk of osteoporosis owing to the observation of a
higher prevalence of this condition in untreated hyperthyroidism (Green-
span and Greenspan 1999). To address this concern, Gyulai et al. (1997)
followed up on 10 of the 11 patients previously treated by Bauer and
Whybrow (1990). Serial bone densitometry was performed, and no dif-
ference was observed in bone density in patients treated with high-dosage
T4 compared with age- and sex-matched control subjects.

With respect to thyroid hormone therapy in bipolar illness, there is
limited controlled evidence for the efficacy of supraphysiological T4 in
the treatment of rapid cyclers. Unfortunately, the available data arise
from a total of 22 cases reported in the literature, and all the studies to
date have used uncontrolled designs. Furthermore, the hypothesis under-
lying the use of high dosages of T4—the greater prevalence of hypothyroid-
ism in rapid-cycling bipolar illness—is brought into question by several
surveys (Bartalena et al. 1990; Joffe et al. 1988; Wehr et al. 1988) and by
the observation that response to T4 is not related to baseline thyroid func-
tion tests (Bauer and Whybrow 1990).
Nevertheless, the dramatic nature of the responses obtained in the
open trials (Bauer and Whybrow 1990; Leibow 1983; Stancer and Persad
1982) suggests that supraphysiological T4 may be an important treat-
ment for the highly refractory illness of this patient group. However, fur-
ther replication using larger numbers of patients and more rigorous study
designs are required.
Anxiety Disorders
Anxiety is a well-recognized symptom associated with thyroid disease,

especially hyperthyroidism (Kathol and Delahunt 1986). Kathol et al.
(1986) observed depression and anxiety disorders to occur frequently in
patients with hyperthyroidism in an endocrinology clinic. Twenty-three
of 29 patients met the criteria for either generalized anxiety disorder or
panic disorder. In most patients, the symptoms resolved with antithyroid
therapy.
Stein and Uhde (1990) administered 20–30 mg/day of T3 in a single-
blind manner to 8 euthyroid panic disorder patients who had not responded
to treatment with tricyclic antidepressants alone. The duration of the
trial was from 2 to 5 weeks. The results were that 3 patients experienced
no change in their anxiety, 4 experienced an exacerbation in their symp-
toms, and only 1 responded.
Although the literature of the thyroid and anxiety disorders is limited,
the available data suggest that patients with anxiety disorder may differ
biologically from depressed patients with respect to the thyroid axis. This
appears to be preliminarily confirmed by the single available clinical trial
of T3 augmentation in panic disorder, suggesting that although a history
of depression may predict response to T3 augmentation, pure panic dis-
order is not associated with a positive response to this treatment.
Conclusion
Thyroid hormone treatments have been used in a variety of psychiatric

illnesses suggested by observations of a variety of psychiatric symptoms
in frank thyroid disease. With respect to anxiety disorders, the limited ev-
idence currently available suggests that T3 augmentation is not useful in
pure panic disorder and in fact may worsen symptoms. In bipolar illness,
there are several studies, albeit uncontrolled ones, suggesting that hyper-
metabolic doses of T4 (and possibly T3) may result in dramatic improve-
ment in rapid-cycling patients who are unresponsive to conventional
mood-stabilizing therapy. Recently reported follow-up data on some of
the original patients treated with supraphysiological T4 suggest that these
patients may not be at risk of decreased bone density. With regard to
both panic disorder and bipolar illness, replication of the available data
using controlled designs is needed before definitive conclusions regarding
the utility of thyroid treatments in these conditions can be drawn. Fur-
thermore, as a consequence of the potential risks, the unavailability of
controlled data, and the availability of safer alternatives (atypical antipsy-
chotics, novel anticonvulsants) we cannot recommend the use of high-
dosage T4 as a treatment for rapid-cycling bipolar disorder, but its use
may be better justified once further data are available.
Several types of thyroid hormone treatment have been investigated in
major depression. The use of T3 to augment antidepressants in patients
who do not respond to treatment is the best-evaluated treatment. Al-
though T3 acceleration may be more prominently effective in women,
there does not appear to be any sex difference with respect to response
in T3 augmentation. Recent evidence suggests that in augmentation, the
type of thyroid hormone used may be important and that T3 may be a
superior agent to T4. Further evidence obtained through the largest clin-
ical trial to date with reasonable clinical power suggests that T3 augmen-
tation is comparable to lithium augmentation. A notable caveat is that all
studies to date have evaluated T3 augmentation in patients did not respond
to tricyclic antidepressants. However, there are reports in the literature
of positive response to T3 augmentation of other classes of antidepres-
sants. Nevertheless, there has been a significant shift in treatment prac-
tices to the first-line use of selective serotonin reuptake inhibitors. To
confirm a comparable degree of response as is seen with tricyclics, ran-
domized trials of T3 augmentation of this class of antidepressants are
required. In conclusion, we can recommend that T3 augmentation be
considered as a primary augmentation strategy (comparable to lithium)
in the augmentation of tricyclic antidepressants. In the case of selective
serotonin reuptake inhibitors, lithium augmentation should precede con-

sideration of T3 augmentation, given the presence of controlled data that
lithium is an effective augmenter of response to selective serotonin re-
uptake inhibitors.
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Part VI
Laboratory Testing
Chapter 17
Laboratory Evaluation of
Neuroendocrine
Systems
David Michelson, M.D.

Philip W. Gold, M.D.
O ver the past two decades there has been a rapid increase in
the understanding of neuroendocrine physiology and how it relates to nor-
mal and pathological brain activities. Neuroendocrine function—the ac-
tions of hormones produced and active in the nervous system—has come to
be understood as being critical to the workings of the brain, and particularly
to the integrative processes that characterize much of human behavior.
This information has come from several sources, including extrapolations
from animal models, clinical research in human subjects, and observations
of abnormalities in people with psychiatric and neurological illnesses. An
important part of this work has been the development of a variety of tests
to characterize human neuroendocrine systems. In this chapter we focus on
some of the tests of human neuroendocrine function that are important in
psychiatric illness, on the proper uses and interpretation of these tests, and
on their relevance to clinical practice. This survey is by no means complete,
and it excludes from consideration a number of neuroendocrine hormones.
In particular we focus on the hypothalamic-pituitary-adrenal (HPA) axis
and the hypothalamic-pituitary-thyroid (HPT) axis, with briefer overviews
of the hypothalamic-pituitary-gonadal (HPG) axis and of growth hormone.
The guidelines presented in this chapter can stand alone but can also use-
fully complement the guidelines presented in other chapters of this book
dedicated to the individual endocrine axes.
469
Basic Principles in the Evaluation of

Neuroendocrine Systems
In humans, neuroendocrine function is generally tested under two differ-

ent conditions. The first is the basal or nonstimulated state. Typically
such studies examine a particular hormone and its metabolites and, if it
is an effector outside the brain, its products. Because the system is not
being manipulated, substances measured presumably reflect basal activ-
ity. An example of such a test is quantitation of 24-hour excretion of uri-
nary free cortisol (UFC), an end product of HPA axis activation. In most
studies, about half of the people with depression have elevated 24-hour
UFC compared with control populations (Gold et al. 1988) (see Chapter 6
in this volume). Integrated 24-hour UFC reflects adrenal production of
cortisol, which in turn is related to levels of hypothalamic and pituitary
activity. Its elevation suggests increased activity at some level of the HPA
axis—hence the observation that HPA axis activity in about half of de-
pressed patients is increased.
Basal studies can provide several kinds of information. When they are
integrative (i.e., they reflect the sum of activity over a given period), such
as 24-hour UFC, they provide a quantifiable picture of the general level of
activity of a system, but not the character of that activity. To obtain a pic-
ture of the pattern of activity of the HPA axis in depression, one might turn
to repeated blood sampling at specific time points. Such a strategy can pro-
vide information about whether release follows normal patterns, whether
there are disturbances in circadian rhythms, and whether elevations in
overall activity result from brief bursts of increased activity in a setting of
otherwise normal tone, or from more modest but sustained hyperactivity.
This points to an important consideration in designing and using tests of
basal neuroendocrine function: the need to consider what kind of informa-
tion is being sought and whether the proposed methodology can provide it.
The second condition under which neuroendocrine systems are com-
monly studied is using provocative stimuli. In these paradigms, an exoge-
nous agent that is known to affect one or another component of a system
of interest is administered or an environmental condition is altered, thus
“provoking” a change in the system’s activity. The widely used dexa-
methasone suppression test is an example of this kind of intervention.
Under normal conditions, increasing the level of glucocorticoid negative
feedback has powerful suppressive effects on the activity of the HPA axis
(i.e., this provocation decreases activity). The failure to suppress HPA
axis activity after administration of dexamethasone in some depressed
patients suggests an alteration in normal function, further evidence of a
Laboratory Evaluation of Neuroendocrine Systems 471
change in its regulation. Provocative tests can also be used to activate a

system, allowing comparison of different populations under nonbasal
conditions. The rationale for such tests rests on the observation that cer-
tain body systems that appear to function adequately under unstressed
conditions become pathological in the setting of increased demand. Thus,
for example, a person with coronary disease who is asymptomatic at rest
or while walking slowly may show signs of cardiac compromise while ex-
ercising vigorously on a treadmill.
In addition to providing an opportunity to change the conditions un-
der which a system is studied, provocative tests can be aimed at specific
elements of a system. Most neuroendocrine systems have multiple compo-
nents as well as feedback loops that can compensate for changes at different
levels of the system. A subtle defect at one level with potential patho-
physiological implications may be relatively compensated elsewhere and
may not be detectable except by targeted manipulations. In a situation in
which basal testing can show an alteration in overall axis function but not
its locus, provocative tests can often tease out the function of the parts of
the axis and provide clues to pathophysiological mechanisms.
As with basal tests, different provocative tests provide different kinds
of information. Using different doses of an agent may yield very different
results. There may be insensitivity at low doses that can be overridden at
high doses, or preservation of basal function but loss of reserves needed for
stimulation. The response to a bolus may be different than to a constant
infusion. The internal milieu may affect response (e.g., circadian rhythms).
Using physiological and pharmacologic doses may provide different infor-
mation. Thus again the information sought and the conditions under
which it is obtained are critical in planning studies and interpreting results.
Appropriate Use of Neuroendocrine Tests
Neuroendocrine testing is broadly useful in two kinds of situations: deter-

mining abnormalities in individuals that are of clinical relevance, and char-
acterizing differences among populations of subjects with and without a
particular condition. In the enthusiasm for developing biological grounding
for psychiatry, one problem that sometimes arises is confusion between
these aims. A number of medical conditions can present with psychiatric
symptoms, or indeed may appear to be primary psychiatric illnesses. For
such illnesses (e.g., thyroid disease or Cushing’s syndrome), neuroendo-
crine tests can clarify the differential diagnosis and help determine the ap-
propriate treatment. The important issue in using tests in this setting is
ensuring that the test chosen will provide the information required and
then using it in a manner consistent with good clinical decision making.

The second situation—characterizing neuroendocrine abnormalities present
in a particular psychiatric syndrome—is primarily appropriate for research
settings, for several reasons. First, the demonstration of a neuroendocrine
abnormality in the setting of an illness is, initially at least, an association
that may or may not have treatment implications. Second, the response
to many neuroendocrine tests is often widely variable among individuals,
and demonstrating an abnormality is typically a statement that, as a group,
people with a particular illness have a different neuroendocrine profile
than people without the illness. Within groups, however, there may be
wide variation and thus much overlap between healthy and ill popula-
tions (this is the case in, for example, HPA axis activation in depression).
Data from these sorts of tests about a particular individual are not useful
unless they have some diagnostic or treatment implications, and they
should not be routinely obtained outside the context of a research study.
Keeping these basic principles in mind, let us now consider some of the
neuroendocrine tests used in psychiatry.
Hypothalamic-Pituitary-Adrenal Axis
The HPA axis regulates glucocorticoid production and release. In addi-

tion to the hypothalamus and the pituitary and adrenal glands, its activity
involves a complex set of interrelated feedback loops, including elements
of the immune system, the limbic areas of the brain, and the locus coe-
ruleus. Stress responses are mediated through the HPA axis initially by
the release of corticotropin-releasing hormone (CRH), a 41–amino acid
peptide, synthesized in the parvocellular cells of the paraventricular nu-
cleus of the hypothalamus. It is released into the hypophyseal portal
blood of the median eminence and is transported to the anterior lobe of
the pituitary. Although relatively little is known about the determinants
of extrahypothalamic CRH secretion, the regulation of CRH secretion by
the hypothalamus is becoming increasingly well understood. Preclinical
studies in rats have shown that the neurotransmitters norepinephrine,
acetylcholine, and serotonin stimulate the release of CRH (Calogero et al.
1988a, 1988b, 1989), as do the cytokines interleukin-1 and interleukin-6
(Naitoh et al. 1988; Sapolsky et al. 1987).
CRH is not the only neuropeptide that stimulates pituitary adrenal
activation. The hypothalamus also produces and secretes a second im-
portant stimulant of glucocorticoid secretion, the 9–amino acid peptide
arginine vasopressin (AVP). Most hypothalamic AVP is produced in the
magnocellular region and is transported to the posterior pituitary to be

released as an element active in maintaining fluid and volume balance by
conserving free water. However, AVP is also produced in smaller amounts
in the parvocellular region of the hypothalamus, and, like CRH, it acts at
the anterior pituitary to induce the release of adrenocorticotropic hor-
mone (ACTH) (Salata et al. 1988). Compared with CRH, AVP is a rela-
tively weak secretagogue of ACTH; however in the presence of CRH
AVP has a powerful synergistic effect that causes greater ACTH release
than either AVP or CRH alone can induce (DeBold et al. 1984). AVP-
induced ACTH secretion may not be glucocorticoid suppressible (Bilez-
ikjian et al. 1987), and this may permit AVP to play an important role in
the maintenance of chronic stress responses.
Exposure to CRH, AVP, or the two together leads to pituitary activa-
tion, and this in turn results in the release of ACTH, a 39–amino acid
peptide that acts at the adrenal cortex to release cortisol, the primary pe-
ripheral stress hormone. ACTH interacts with adrenal cell membrane re-
ceptors, ultimately causing activation of adenylate cyclase, increase in
cyclic adenosine monophosphate concentrations, and protein phosphory-
lation. (The biochemistry and relevance to psychoneuroendocrinology
of CRH, AVP, and ACTH are further discussed in Chapter 3 of this
volume.)
The major effect of ACTH on steroidogenesis is to stimulate the rate-
limiting step (conversion of cholesterol to pregnenolone). Cortisol is de-
rived from cholesterol, which is both synthesized in the adrenal gland
and also taken up by the gland in low-density lipoprotein or high-density
lipoprotein particles synthesized in the liver. In the adrenal cortex, choles-
terol is converted first to pregnenolone, then to 17a-OH-pregnenolone,
17a-OH-progesterone, 11-deoxycortisol, and finally cortisol. ACTH is
the primary circulating cortisol releasing factor, and it stimulates both the
release of cortisol and cortisol synthesis.
Cortisol has an exceptionally wide range of actions. Although a com-
plete review of these would exceed the scope of this chapter (for a detailed
discussion see Chapter 19 in this volume), two very general categories are
critical. These are 1) counterregulatory effects, particularly with respect to
the immune system, on which cortisol acts to decrease activity and pre-
vent unrestrained and potentially self-injurious activity in response to an
immune trigger, and 2) the mobilization and optimization of energy use in
the setting of acute stress (providing a metabolic substrate for the fight-or-
flight response) (Chrousos and Gold 1992; Munck et al. 1984).
To test HPA axis function, it is necessary to be familiar not only with
the elements of the axis, but also with the ways in which they are typi-
cally secreted and metabolized. The major secretory products of the HPA
axis are released into the circulation with a circadian rhythm, with diur-
nal peaks and nadirs. Cortisol and ACTH secretion are highest in the
morning and lowest in the evening. All three of these hormones are se-
creted in a pulsatile fashion, with pulses of CRH leading to ACTH re-
lease, which then leads to cortisol release. CRH has a very short half-life
(several minutes) in the peripheral circulation; ACTH has a slightly
longer half-life (10–20 minutes), and the half-life of cortisol is approxi-
mately 45–60 minutes.
The characteristics described above suggest some of the issues that
arise in testing the HPA axis. First is the problem of hierarchy—the most
accessible and stable product of the axis, cortisol, is also the farthest re-
moved from the brain. Direct measurement of CRH is extremely diffi-
cult because of its short half-life and the relative inaccessibility of the
brain to direct measurement. Basal sampling measures must be taken
with care, because secretory pulses that occur between measurements
spaced too far apart may be undetected. The phenomenon of negative
feedback coupled with circadian variation means that time of day will
usually affect the result of a test.
Basal HPA Axis Activity

To examine the nonstimulated activity of the HPA axis, two measures
are commonly used. These are plasma measurements of ACTH and
cortisol, and quantitation of 24-hour UFC (see Table 17–1 for normal
values). Hyperactivity of the HPA axis can often be detected by measure-
ment of plasma ACTH and cortisol. Concentrations of the hormones
over brief intervals (minutes to hours) are quite variable, both because of
diurnal variation in the activity of the axis and because of the pulsatile
nature of the activity and relatively short-half-lives of these substances.
In individuals or in small groups, therefore, single samples of cortisol and
especially of ACTH rarely provide meaningful information. Plasma sam-
pling should usually be serial, and sampling time points should be at or
within the plasma half-life of cortisol (30–60 minutes) or ACTH (10–20
minutes) to allow detection of pulses. We have shown that sampling at
15-minute intervals over 2 hours between 6:00 P.M. and 8:00 P.M. dem-
onstrates modest hypercortisolism in both depressed patients and pa-
tients with multiple sclerosis (Gold et al. 1986; Michelson et al. 1994).
Other studies have shown that sampling at 20-minute intervals between
1:00 P.M. and 4:00 P.M. discriminates cortisol hypersecretors (Halbreich
et al. 1982). Consideration should be given to whether morning (i.e.,
peak) or evening (nadir) concentrations are of interest; typically subtle
hyperactivity will be more visible during periods of relative quiescence.
TABLE 17–1. Normal values of pituitary-adrenal hormones at the

National Institutes of Health Clinical Pathology
Laboratory
Hormone Normal values Comments
Adrenocorticotropin <60 pg/mL Diurnal rhythm, lowest in the
evening; large variations and
short half-life
Cortisol 7–25 mg/dL (A.M.) Diurnal rhythm, lowest in evening
2–14 mg/dL (P.M.)
Urinary free 20–90 mg/24 hours Increased with stress or exercise
cortisol
Absent overt pituitary or adrenal failure, hypoactivity is difficult to de-

tect using this technique, but conditions such as depression and multiple
sclerosis have been shown to be associated with elevations in evening
plasma cortisol levels using serial sampling (Gold et al. 1988; Michelson
et al. 1994). Care should be taken to avoid artifactual increases or de-
creases in ACTH and cortisol levels; common reasons for false elevation
of ACTH and cortisol level include sampling in the context of a stressful
situation (e.g., a patient in pain), sampling in the context of stress (e.g.,
vigorous exercise, novelty, illness), and obtaining an insufficient number
of samples so that a single pulse of activity skews the results. Experience
in our laboratory has also shown that the needle stick required to insert
an intravenous catheter can be associated with a rise in ACTH and corti-
sol (M. A. Altemus, unpublished data), either because of the pain or
because of apprehension, and we therefore wait an hour after catheter in-
sertion before any sampling is done. Artifactually low ACTH values can
be the result of failure to chill samples immediately after they are drawn,
allowing protease degradation of ACTH, and failure to spin and freeze
samples within 2 hours of collection (after which point significant degra-
dation of ACTH occurs even in chilled samples).
To obtain an integrated measure of cortisol production through the
day, quantitation of 24-hour urinary excretion of free cortisol is the most
commonly used measure. Among patients with depression, most studies
have shown significant elevations of 24-hour UFC excretion in up to half
of subjects (Gold et al. 1988). Patients with multiple sclerosis have been
found to have similar elevations. Studies of 24-hour UFC excretion in de-
pressed patients that follow daily UFC excretion over a period of weeks
show a pattern of alternation between elevated and normal values, sug-
gesting that even at the higher levels of activity typical of many depressed
patients, HPA axis negative feedback mechanisms are not entirely abol-
ished (M.A. Kling, unpublished data). From a practical perspective, this

also means that measuring 24-hour UFC excretion only once or twice
may underestimate the number of patients with HPA axis activation,
because some collections are likely to occur during periods of relative
quiescence. Cortisol in the urine is highly stable and so collection is tech-
nically easy, with many assay techniques not requiring refrigeration or
preservatives. However, careful instructions to patients on how to collect
the sample are important, because the rate of cortisol excretion varies
and incomplete collections may yield inaccurate results. We generally ask
patients to begin the collection at a specified hour of the morning
by having them empty their bladder and discarding that void. All subse-
quent voids are collected, and at the same time the following day the pa-
tient is instructed to void one last time and include it in the collection (a
detailed sample set of instructions for patients can be found in the Orth
et al. 1992 reference). Averaging results from collections from multiple
days provides more accurate measures than single-day collections, be-
cause levels of activity and stress can cause variation in cortisol produc-
tion, and also because patients will often have difficulty collecting all the
urine produced during a 24-hour period. Production can be artifactually
increased by exposure to any significant stress during the collection pe-
riod, and subjects must be instructed not to perform unusual activities or
to exercise strenuously during periods of collection. In addition to corti-
sol, it is useful to quantitate 24-hour urine creatinine excretion to assess
the adequacy of the collection. People of average weight and build nor-
mally excrete creatinine at the rate of about 1.0 g/24 hours, and values
significantly below this level suggest an incomplete collection.
Free cortisol is secreted into saliva and can be quantitated using assays
described below. Levels have been shown to accurately reflect serum lev-
els of free cortisol (Evans et al. 1984; Orth et al. 1992), and reference
ranges have been published (Aardal and Holm 1995). This procedure is
particularly useful in situations in which plasma and urine collections are
impractical or problematic, such as screening children for Cushing’s syn-
drome or other conditions (Gispen-de Wied et al. 1998; Martinelli et al.
1999), in ambulatory outpatient settings, and in settings in which infor-
mation about ACTH is not required.
Clinically, basal measurements of HPA axis function are most impor-
tant in several situations. Hypercortisolism is a defining feature of Cush-
ing’s syndrome, which is part of the differential diagnosis of major
depression. Particularly in early Cushing’s syndrome it can be difficult to
distinguish the two clinically; the absence of elevations of 24-hour UFC
would point one away from Cushing’s syndrome, whereas elevations might
lead to further workup (described below) (see Chapter 8 in this volume).
A second situation in which it may be useful to have a picture of unstim-

ulated HPA axis activity is in refractory depression, because an emerging
literature suggests that steroid inhibition may have some therapeutic ben-
efit in such patients. We note, however, that these data are highly prelim-
inary, and the role of antiglucocorticoids in the treatment of depression has
yet to be demonstrated in adequately designed and controlled trials. (This
topic is discussed further in Chapter 6 of this volume.)
Provocative Tests of HPA Axis Function

Because the HPA axis contains three distinct components, tests that ex-
amine its stimulated activity can be aimed at different levels and provide
different information. Most research to date has examined pituitary and
adrenal function and has inferred information about hypothalamic func-
tion for the simple reason that satisfactory stimulatory agents of the hypo-
thalamic CRH neuron are quite limited. There is, however, an evolving
body of work describing central stimulation of hypothalamic CRH re-
lease, which is reviewed here.
Administration of naloxone moderately stimulates both ACTH and
cortisol release; the mechanism of action is thought to be blockade of tonic
opiate inhibitory effects on the hypothalamic CRH neuron. In our labora-
tory, however, the variability in response among healthy subjects has been
high, and we have been unable to show significant differences in either
ACTH or cortisol response to naloxone between healthy volunteers and
patients with depression (Michelson et al. 1996a). Insulin-induced hypo-
glycemia has also been used as a central stimulus of hypothalamic CRH
release, and it does induce a significant response in most subjects (Fish et
al. 1986). It has the disadvantages, however, of being a rather severe and
nonspecific stress as well as being both cumbersome and risky to adminis-
ter, because the actual provocative effect, hypoglycemia, can be life
threatening. More recently, we and others have shown that graded tread-
mill exercise is a potent, safe, and reliable stressor that leads to hypotha-
lamic CRH release and consequent pituitary-adrenal activation (Deuster
et al. 2000; Luger et al. 1987; Singh et al. 1999). Exercise has the advan-
tage of being dose dependent (i.e., the degree of activation of the HPA axis
is a function of the amount of lactate produced by the body, and this can
be controlled by the percentage of maximal aerobic capacity to which sub-
jects exercise). Because the HPA axis response correlates with the percent-
age of maximal aerobic capacity achieved rather than with the degree of
aerobic conditioning of individual subjects, subjects with different levels
of physical fitness can still be meaningfully compared in terms of HPA axis
response to exercise. Exercise-induced HPA axis activation, therefore,
holds out the promise of providing more direct assessment of hypotha-

lamic CRH neuron function than has generally been possible. Importantly
it may also provide a means to investigate putative states of centrally in-
duced HPA axis hypoactivity, which, because of dynamic compensatory
mechanisms, are notoriously difficult to document by conventional stim-
uli of pituitary and adrenal activity. In addition to the paradigms described
above, several other potential stimuli of hypothalamic CRH release have
been proposed and are in varying stages of development.
CRH Stimulation Test

At the level of the anterior pituitary, there now exists a large body of
work using CRH-induced stimulation of corticotroph ACTH release.
CRH stimulation has been performed in a variety of pathological states
and has been shown to have characteristic patterns of abnormal response
in major depression. Clinically it has been used to diagnose Cushing’s
syndrome and to distinguish it from depression. Because these studies are
reviewed elsewhere in this volume, the emphasis in this chapter is on the
methodology and utility of the test.
The CRH test is generally performed using natural or synthetic ovine
CRH (oCRH). Compared with human CRH, oCRH has the advantage
of a relatively long half-life (approximately 30–60 minutes) and of induc-
ing a more potent ACTH response. Although some researchers adminis-
ter it in a single 100-mg or 250-mg dose, more commonly it is administered
on a weight-adjusted basis of 1 mg/kg body weight. CRH can be given as
a bolus through a peripheral intravenous catheter, and it elicits a peak
ACTH response in 15–30 minutes and a peak cortisol response in 45–90
minutes. The expected responses are a cortisol rise of at least 10 mg/dL
above baseline; ACTH responses are more variable (Nieman and Loriaux
1989). Most researchers report that the ACTH and cortisol responses
correlate inversely with basal plasma cortisol levels (i.e., that the response
is subject to glucocorticoid negative feedback), and probably for this rea-
son the response to oCRH administration is greatest in the evening when
plasma cortisol levels are at a nadir. Response to oCRH is generally mea-
sured as the peak response over baseline of ACTH and cortisol or as the
net integrated area under the response curve after subtracting the base-
line. Because oCRH is a peptide, it is not thought to cross the blood-brain
barrier. Administration of oCRH has few significant side effects other
than a transient metallic taste and flushing in 15%–20% of subjects.
As a research tool, the response to oCRH is most helpful when the
patterns of ACTH and cortisol response can be used to determine the
locus of hyperactivity of the HPA axis. Although some suggestive data are
now beginning to emerge, attempts to document putative subtle (i.e.,

nonaddisonian) states of hypoactivity of the CRH neuron in the setting
of an intact pituitary (e.g., chronic fatigue syndrome) have generally been
less successful than characterization of HPA axis hyperactivity (e.g., mel-
ancholic depression, Cushing’s syndrome). Clinically, the CRH test is
most useful in the diagnosis of Cushing’s syndrome. In the early stages of
Cushing’s syndrome, before the stigmata of florid, sustained hypercorti-
solism set in, depressed mood may be the only sign of the illness, and 50%
of patients may show no evidence of increased plasma ACTH (Tyrrel et
al. 1978). Under these conditions, it can be extremely difficult to distin-
guish Cushing’s syndrome from pseudo-Cushing’s states such as primary
depressive illness. The CRH test has been used to differentiate these. In
depression, the intact pituitary is hyporesponsive because of persistent
hyperstimulation from the CRH neuron, and it has an extremely attenu-
ated response to exogenous CRH administration. Among patients with
Cushing’s disease, a pituitary adenoma secreting ACTH exhibits a robust
response to oCRH so that the blunted response expected in the setting
of hypercortisolism (due to glucocorticoid negative feedback) is not seen.
Unfortunately, however, there is considerable variation in individual re-
sponse, and so the CRH test alone is not sufficiently sensitive or specific
to be used generally, and diagnostic workups using modifications of the
CRH test have been proposed. One suggested algorithm for differentiat-
ing Cushing’s syndrome and pseudo-Cushing’s syndrome involves the
initial collection of two or three 24-hour urine samples for determination
of UFC excretion. If the UFC is increased, a dexamethasone suppression
test is performed. A negative result in either of these tests rules out Cush-
ing’s syndrome but not depression. If both are positive, a CRH test is per-
formed shortly after dexamethasone administration (0.5 mg every
6 hours for 8 doses); depressed patients are more responsive to negative
feedback, and their characteristic ACTH blunting is exaggerated, provid-
ing better differentiation of the two groups (Orth 1995; Yanovski et al.
1993).
The following are guidelines for the CRH stimulation test, which
tests the ability of the pituitary to release ACTH:
Dose: 1 mg/kg ovine CRH as an intravenous injection

Timing: Insert intravenous catheter at 6:00 P.M.
Starting at 7:00 P.M., sample for ACTH and cortisol at 15-minute intervals
Inject ovine CRH at 8:00 P.M.
Test ends at 10:00 P.M.
ACTH release is often blunted in depression, but cortisol release is of-

ten normal or increased; in Cushing’s disease ACTH release is normal or
exaggerated and cortisol release is normal or increased.
AVP Infusion
As noted above, AVP is also a stimulus to pituitary ACTH release. Com-
pared with CRH, relatively fewer studies have examined its role in states
of HPA axis dysfunction, perhaps because it is a less potent stimulus than
CRH. However, when it is presented to the pituitary in the presence of
CRH, a synergism between the two peptides leads to greater ACTH re-
lease than either one alone can achieve. In addition, there is evidence in an-
imal models that AVP-induced HPA axis activation is not glucocorticoid
suppressible. These two facts have led some researchers to suggest that
AVP serves as an important modulator of stress responses, and AVP may
also play an important role in chronic HPA axis activation. Studies of AVP
effects on the human HPA axis are much more limited than studies of
CRH, and no single means of administration has become the standard.
Nonetheless, AVP infusion may be helpful in determining the pathophys-
iological mechanisms that maintain hypercortisolism in different states.
We have developed a paradigm in which we administer AVP in a 60-minute
infusion of 1 mIU/kg per minute for 60 minutes. We are currently at-
tempting to determine whether this test can be used to demonstrate hypo-
secretion of CRH in various fatigue states (the response to AVP in the
absence or relative paucity of CRH should be blunted). We have also used
AVP infusion together with oCRH stimulation to provide evidence that
HPA axis hyperactivity in states of immune activation may be physiologi-
cally distinct from that of depression (Michelson et al. 1994). Studies with
AVP are generally well tolerated by subjects. The most important side ef-
fects in our experience, occurring in 5%–10% of subjects, are abdominal or
bladder cramping, and women who undergo the test at the end of the men-
strual cycle may experience painful, exaggerated uterine cramping. These
effects typically resolve within minutes of discontinuing the infusion.
ACTH Stimulation Test

The best direct test of adrenal function is ACTH stimulation. Clinically
this is most important in cases of suspected adrenal failure (Addison’s
disease). Failure of the adrenal gland to significantly increase cortisol se-
cretion (to at least 20 mg/dL) in response to a bolus of ACTH indicates
inadequate adrenal responsivity. As a research tool, ACTH stimulation
has been used in a variety of ways. The adrenal gland is quite sensitive to
changes in the stimulatory environment, and it hypertrophies both ana-
tomically and functionally in the setting of persistent increased ACTH

secretion (Dallman 1984–1985; Payet et al. 1980). Thus, ACTH stimu-
lation is used to test not only for primary changes in adrenal function, but
also for changes in its activity that reflect alterations in HPA axis tone.
The ACTH dose-response curve of adrenal cortisol secretion has been
well characterized, and by using different doses, it has been possible to
demonstrate changes in the regulatory environment of the adrenal gland
in different diseases. At supramaximal doses (e.g., 250 mg), the integrity
of the adrenal gland is tested (i.e., Addison’s disease can be ruled out),
but subtle changes in function may not be detectable. In subjects with
depression, the response to supramaximal stimulation has been shown to
be increased (Amsterdam et al. 1993), whereas submaximal and maxi-
mal doses (0.05 mg/kg and 0.2 mg/kg respectively) may differentiate de-
pressed subgroups (Amsterdam et al. 1989). Using the lowest effective
stimulatory dose (0.003 mg/kg), Demitrack and colleagues (1991) have
been able to demonstrate alterations in adrenal function consistent with hy-
poactivity of the HPA axis in a state of putative HPA axis hypofunction
(chronic fatigue syndrome).
The following are guidelines for the ACTH stimulation test, which
tests the ability of the adrenal gland to release cortisol:
Dose: 250 mg ACTH as an intravenous injection

Timing: Insert intravenous catheter at 5:00 P.M.
Starting at 6:00 P.M., sample for cortisol at 15-minute intervals for 1 hour.
Inject ACTH at 6:00 P.M.
Test ends at 7:00 P.M.
In settings of primary adrenal failure, cortisol release is impaired.
Dexamethasone Suppression Test

One of the earliest neuroendocrine tests to become widely used in psychi-
atry was the dexamethasone suppression test. In this procedure, the syn-
thetic steroid dexamethasone is administered to subjects, and over the
ensuing 24 hours plasma cortisol is measured. The expected effect is inhi-
bition of pituitary-adrenal activity due to negative feedback induced by
dexamethasone occupancy of type II glucocorticoid receptors. Increased
activity of the HPA axis is associated with dexamethasone nonsuppres-
sion. Several different methodologies for dexamethasone administration
and sampling of cortisol and ACTH have been proposed. However, the
usual procedure is 1 mg of dexamethasone administered at 11:00 P.M.,
with blood sampled at 8:00 A.M., 4:00 P.M., and 11:00 P.M. the following
day (in outpatients the test may be performed with a single sample taken
at 4:00 P.M., though some sensitivity may be lost). Although the dexa-
methasone suppression test has been widely studied and provides an inter-
esting research tool, it is of little clinical value because it is neither highly
sensitive (i.e., it produces many false negatives) nor specific (it produces
many false positives). Most studies suggest that its sensitivity is about 50%
and its specificity is 90% or less (Arana and Baldessarini 1987), although
in some subpopulations such as the psychotically depressed it may be more
meaningful (Nelson and Davis 1997). Although there is evidence that
dexamethasone nonsuppression following successful treatment of depres-
sion is a predictor of poorer outcome (i.e., earlier relapse) (Ribeiro et al.
1993; Zobel et al. 1999), these findings are, in our judgment, neither sen-
sitive nor specific enough to usefully guide clinical practice.
The following are guidelines for the dexamethasone suppression test,
which tests the negative feedback response of the HPA axis to glucocor-
ticoids:
Dose: 1 mg dexamethasone orally

Timing: Administer at 11:00 P.M.
Draw blood for cortisol determination at 8:00 A.M., 4:00 P.M., and 11:00 P.M.
(in outpatients may draw blood at 4:00 P.M. only).
Approximately half of patients with depression do not appropriately

suppress cortisol secretion.
Factors reported to cause nonsuppression in the absence of depression:
• Cushing’s disease
• Severe stress
• Increased metabolism of dexamethasone
• Recent hospitalization
• Pregnancy or increased estrogen
• Recent weight loss
• Medications (e.g., carbamazepine, phenytoin, barbiturates)
• Alcohol withdrawal
• Serious medical illness
Factors reported to cause suppression despite the presence of depression:
• Addison’s disease
• Exogenous glucocorticoid administration
• Medication
Methods and Problems in Measurements

The study of the HPA axis requires plasma and urine measurements of rel-
evant substances, particularly cortisol and ACTH, and obtaining useful test
results requires proper handling and assaying of specimens. Normal values
for ACTH and cortisol vary through the day, with higher levels occurring
in the morning and lower levels at night. Furthermore, because of its short
half-life, variations in ACTH concentrations are large, even over brief pe-
riods of time. In our laboratory, normal reference values for plasma ACTH
are less than 60 pg/mL, whereas normal reference values for cortisol are 7–
25 mg/dL in the morning and 2–14 mg/dL in the evening. Normal reference
values for 24-hour excretion of UFC are 20–90 mg/24 hours.
The majority of circulating cortisol (90% or more) at any time is bound
to proteins, primarily cortisol-binding globulin (CBG). Plasma cortisol is
thus in two pools—bound and free. In most circumstances this is of little
concern, because as long as there are free binding sites, the relationship
between bound and free cortisol remains relatively constant and measure-
ments of total cortisol correlate well with free cortisol and hence biological
availability. In the setting of high total cortisol concentrations, however,
carrier proteins become saturated, leading to more rapid, nonlinear in-
creases in the free cortisol pool. Under conditions in which the concen-
tration of CBG changes, the equilibrium between bound and free cortisol
also changes. Estrogen, for example, increases CBG, so that conditions of
increased estrogen are associated with higher levels of CBG (e.g., preg-
nancy, use of oral contraceptives). When protein synthesis decreases (e.g.,
during chronic illness or in liver disease), CBG concentrations also tend
to decrease (Rosner 1991). Under these conditions assay of free cortisol
is needed to obtain an accurate picture of cortisol bioavailability.
The assay of cortisol can be performed by several different methods,
but radioimmunoassay (RIA) is most commonly used because it is rapid,
reliable, and inexpensive. Assay of ACTH is methodologically more prob-
lematic. Because ACTH is a peptide and is cleaved in the plasma by pepti-
dases, there are a number of different cleavage products in the circula-
tion, some biologically active and some not. ACTH is most commonly
measured by RIA and by immunoradiometric assay. Different RIAs mea-
sure different fragments, and therefore results of different assays cannot
always be reliably compared, and they may also yield information that is
biologically different. From a practical perspective, the clinician or clini-
cal researcher measuring ACTH needs to be aware of several potential
pitfalls when measuring ACTH. First, as noted above, values can be spu-
riously elevated by samples drawn after a painful stimulus. Conversely,
improperly handled specimens (i.e., delayed handling, failure to chill
specimens) will be spuriously low. Specimens to be compared should ide-

ally be assayed together to reduce problems of interassay variability; if
this is not possible there is at least an absolute requirement to use a single
assay methodology to make reliable comparisons. Finally, because secre-
tion is pulsatile and the half-life short, single time-point ACTH values are
rarely meaningful.
Hypothalamic-Pituitary-Thyroid Axis
Although disorders of the HPT axis are among the most common prob-
lems seen by internists, they are highly relevant for the practicing psychi-
atrist as well. Thyroid dysfunction can manifest itself in psychiatric
symptoms, and psychiatric illness has been associated with abnormalities
of the HPT axis (Jackson 1998; Rosner 1991). A complete description of
the physiology and pathophysiology of the HPT axis is beyond the scope
of this chapter; however, we briefly review the organization and function
of the axis to provide a background against which its laboratory exami-
nation can be considered.
Like glucocorticoid secretion, thyroid hormone secretion involves
hypothalamic, pituitary, and end-organ elements. Thyrotropin-releasing
hormone (TRH), a three–amino acid peptide, is secreted from the paraven-
tricular nucleus of the hypothalamus and is carried in the portal circulation
to the anterior pituitary. There it stimulates the release of thyroid-
stimulating hormone (TSH), a glycoprotein, from thyrotroph cells. TSH is
carried in the peripheral blood to the thyroid gland, where it in turn stim-
ulates secretion of the thyroid hormones tetraiodothyronine (T4) (thyrox-
ine) and triiodothyronine (T3). T4 and some T3 are produced by the
thyroid, but the predominant circulating hormone is T4, and most T3 is
produced from peripheral conversion of T4 at the tissues by deiodination
of the T4 outer ring. T4 can also be metabolized by deiodination of its inner
ring, which results in the production of metabolically inactive reverse T3
(rT3). Regulation of the axis is dynamic, with circulating T4 levels feeding
back at the pituitary to control TSH secretion (increased T4 levels inhibit
TSH secretion, whereas decreased levels stimulate TSH secretion). Also
like the HPA axis, the activity of the HPT axis is pulsatile and has a circa-
dian rhythm. TSH secretion decreases in the afternoon and early evening
and increases late at night and in the early hours of the morning. Thyroid
function can become disordered at either extreme of function (hypoactiv-
ity and hyperactivity), and as with the HPA axis, pathology can occur at the
level of the end-target gland (the thyroid) or the pituitary. Central (i.e., hy-
pothalamic) hypothyroidism, though it does occur, is rare.
Basal Measurement
The appropriate evaluation of thyroid function in patients depends on
their clinical presentation. With the advent of the sensitive assay for TSH
(see “Assays” below), the following algorithm has been recommended (Klee
and Hay 1987; Surks et al. 1990; Utiger 1995). In apparently euthyroid
people in whom thyroid screening is indicated, the first step and the single
best screening test of thyroid function is measurement of TSH. If TSH lev-
els are within the normal range, no further testing need be done. If TSH
levels are abnormally high (associated with hypothyroidism) or low (asso-
ciated with hyperthyroidism), a further test to evaluate free T4 (FT4) con-
centration is indicated. Because T4 is largely bound to proteins in the plasma,
the total plasma T4 concentration is not always an accurate reflection of
the FT4 that is biologically active at the cellular level. Biologically mean-
ingful measurement of T4 therefore requires either direct measurement
of the FT4 concentration or measurement of total T4 and some measure
of protein binding of T4 to allow calculation of the free thyroxine index
(FTI). Therefore, in patients with illnesses in which thyroid dysfunction
should be ruled out (including many psychiatric patients), a sensitive TSH
test and either direct or estimated determination of FT4 is appropriate. In
patients who present with clinical pictures suggestive of either hypothy-
roidism or hyperthyroidism, both TSH and either direct or estimated FT4
should be evaluated initially. T3 is not a good general measure of thyroid
function because levels fluctuate rapidly and may reflect nonthyroidal fac-
tors. In particular, nonthyroidal illness is often associated with decreases
in concentrations of T3 that result from decreased conversion of T4. Non-
thyroidal illness is associated with a number of other abnormalities of thy-
roid hormones as well, which can include increased rT3, decreases in both
T3 and T4 (the euthyroid sick syndrome), and, paradoxically, increases in
T4 (Gow et al. 1986; Wartofsky and Burman 1982). These changes are
thought to result from several different factors, which include alterations
in protein binding due to changes in protein production as well as meta-
bolic changes associated with the state of illness. Distinguishing true hy-
pothyroidism from the euthyroid sick syndrome can be difficult; the most
useful tools are probably determinations of TSH and FT4, but in severely
ill patients even these may not provide definitive answers (Surks et al.
1990). Normal values for thyroid hormones are listed in Table 17–2.
Thyroid Antibodies
The most common cause of hypothyroidism (outside of areas of endemic
iodine deficiency) is autoimmune thyroiditis (Utiger 1995). Although a
TABLE 17–2. Normal values of pituitary-thyroid hormones at the

Laboratory
Hormone Normal values Comments
Thyroxine 5–10 mg/dL Includes protein-bound hormone
Free thyroxine 0.9–1.9 ng/dL
Thyroid-stimulating hormone 0.4–4.6 mU/mL Diurnal rhythm, lowest in
evening
Triiodothyronine 88–162 ng/dL Includes protein-bound hormone
Free triiodothyronine 250–550 pg/dL
variety of antibodies have been described, only two are commonly assayed
in patients suspected of having autoimmune thyroiditis: antimicrosomal
antibodies (also called antithyroid peroxidase antibodies) and antithyro-
globulin antibodies. It is important to be aware that although these tests
can provide confirmation of a presumptive diagnosis of autoimmune thy-
roiditis, they are not highly specific, and many healthy people, patients
with nonthyroidal illnesses, and those with subclinical thyroid disease
will also test positively for these antibodies.
Provocative Tests of Thyroid Function

In contrast to the HPA axis, provocative tests of the HPT axis are not
widely used. The TRH stimulation test, in which exogenous TRH is ad-
ministered to subjects and response is measured by determining the in-
crease in TSH secretion, has limited clinical value owing to the wide
variability of response among individuals (Utiger 1995). It has been used
as a psychiatric research tool, and it has been reported that 25%–30% of
depressed patients have blunted responses to TRH (Joffe and Levitt 1993).
However, these findings have also been reported in other psychiatric ill-
nesses, and there are no generally accepted clinical psychiatric applica-
tions for the TRH stimulation test at this time.
Assays
TSH
Radioimmunoassays of TSH have been available for some years and have
become the most widely available method for determining serum TSH
levels. Early assays were not sensitive enough to distinguish between low
normal TSH levels and those typical of hyperthyroidism. Second-generation
assays extended the lower limits of detection to 0.1–0.2 mU/L, permit-
ting identification of patients with mildly low TSH, whereas third-gener-

ation assays can reliably detect TSH levels as low as 0.01–0.02 mU/L and
thus can be used to screen for both hyperthyroidism and hypothyroidism
(Gow et al. 1986). TSH is quite stable, so special handling of samples is
not required. When interpreting a low normal or borderline low value, it
is therefore important to be aware of the assay being used. Clinicians
should be aware that TSH is secreted with a circadian rhythm, reaching
a nadir in the early evening and a peak in the early hours of the morning.
Some commonly prescribed drugs can affect its concentration in the
plasma, including levodopa and glucocorticoids, which inhibit its pro-
duction, and perhaps most importantly thyroid hormone replacement,
which inhibits TSH release by means of negative feedback.
T4
As noted above, T4 can be measured as total T4 or as FT4. When total T4
is measured, it is important to assess what portion is not bound to protein
and hence is biologically available. A number of methodologies for mea-
suring total T4 exist, including competitive protein binding assays, immu-
noassays, and enzyme assays. The most commonly used methodology,
however, is probably RIA. Although RIAs vary in sensitivity, typical as-
says have lower limits of detection around 0.4 mg/dL (however, more sen-
sitive assays are available) (Whitley et al. 1994b). As noted above, serum
T4 levels should be measured together with an estimate of how much hor-
mone is bound by proteins to estimate the percentage of FT4. This is com-
monly done using the T3 resin uptake test. In this procedure, radiolabeled
T3 is added to serum, and then a resin that binds T3 is also added to the
serum. Finally, the resin is separated out and the amount of T3 that has
been bound to it is measured (T3 is used because it does not displace T4
already bound to protein and thus measures only open binding sites). This
result is expressed as a percentage of the total T3 added. The difference
between the total added T3 and the amount bound to the resin represents
T3 bound to available protein binding sites in the serum. Often this result
is expressed as a ratio of the percentage uptake in patient serum to the
percentage uptake in a reference serum and is called the thyroid hormone
binding ratio (THBR). The normal value for this ratio is an interval around
1.0; the width of the interval varies somewhat from one laboratory to an-
other. The FTI, an estimate of FT4, is calculated from the T4 and THBR.
As an example, consider the situation of an elevated T3 resin uptake
(and hence an elevated THBR). This implies decreased available protein
binding sites for thyroid hormone (more T3 than expected is binding to the
resin because fewer protein sites are available to bind it). It can occur when
protein production (primarily thyroxine-binding globulin) is low (fewer

binding sites available), when thyroid hormone concentrations are increased
(normal number of binding sites but fewer available because of increased
T4 occupying them), or when another substance (e.g., a drug) competes for
binding sites (normal number of binding sites but fewer available). In these
situations, however, the serum T4 values will differ—in hyperthyroidism
there is more T4 produced and circulating, and hence both THBR and se-
rum T4 levels are higher and the FTI is high, whereas in the other two sit-
uations T4 is lower (production is adjusted to maintain homeostasis) while
THBR is elevated and the FTI is normal. Some common conditions and the
expected associated T4 values are shown in Table 17–3.
TABLE 17–3. Common conditions that alter observed thyroxine (T4)

and free thyroxine (FT4) concentrations
Observed
Condition effect Cause
Pregnancy, liver disease, drugs T4 increased, Increased thyroxine-binding

(estrogens, oral FT4 normal globulin (TBG) production
contraceptives, opiates)
Genetic TBG deficiency, T4 decreased, Decreased TBG
chronic illness,a drugs FT4 normal concentration or binding
(salicylates, phenytoin,
steroids)
Exogenous T4 administration T4 normal, FT4 Endogenous T4 replaced
normal
Exogenous T3 administration T4 decreased, Endogenous T4 suppressed
FT4 decreased
a
Chronic illness may also lead to other changes in thyroid function.
Direct measurement of FT4 can be done by equilibrium dialysis (se-

rum and a buffer are separated by a membrane that allows passage of FT4
but not protein, and after an incubation period equilibrium is reached
and T4 in the protein-free dialysate is measured) or by RIA. For most pur-
poses, the choice of measuring FT4 or T4 and a calculated FTI will depend
on cost and convenience. T4 is stable, and no special handling of speci-
mens is required.
Many factors can influence measurement of thyroid hormones, in-
cluding psychiatric illnesses. Physiologically, pregnancy is associated with
increases in T4 levels due primarily to increased serum thyroxine-binding
globulin (Glinoer et al. 1990). Illness, as noted earlier, can alter hormone
metabolism, catabolic demands, and protein production, leading to both
apparent and real abnormalities. Drugs that compete for protein binding
sites (e.g., salicylates, phenytoin) or alter protein production (e.g., ste-
roids, including glucocorticoids and estrogens) alter measured T4 levels
(note, however, that changes in binding proteins do not affect the actual
“metabolic state”). Exogenous administration of T4 or T3 suppresses thy-
roid production and release of hormone.
Gonadotropins and Sex Steroids
Hypogonadotropic hypogonadism can accompany a number of condi-

tions commonly encountered by psychiatrists, including drug abuse, liver
disease associated with alcoholism, and obesity. It can also occur in ill-
nesses such as anorexia nervosa and depression, perhaps related to HPA
axis activation and CRH-induced suppression of gonadotropin release. In
some women, phases of the menstrual cycle are associated with mood
changes, and these changes appear to be linked to alterations in HPG
regulation (Schmidt et al. 1998). Similarly, the menopause, with its at-
tendant alterations in gonadal steroids, is associated with mood changes
(Schmidt et al. 1997). A comprehensive evaluation of gonadotropins and
sex steroids is outside the scope of usual psychiatric practice; however,
questions related to gonadotropins and sex steroids arise commonly, and
many patients receive psychiatric care in the setting of medical workup
or treatment of problems involving the HPG axis (e.g., fertility or sexual
problems, replacement estrogens). We restrict our focus to several basic
elements and measurements likely to be encountered in the course of
psychiatric practice, and again we note that it is important to keep in mind
the distinction between research applications and those intended to
guide clinical practice, which are more limited. Normal values for gona-
dotropins and sex steroids are listed in Table 17–4.
The HPG axis consists of the hypothalamus, the pituitary, and the
ovaries (in women) or the testes (in men). The hypothalamus secretes
gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. This sin-
gle releasing factor acts at the anterior pituitary to induce the release of
both follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
In women, the relative amounts of FSH and LH secreted in response to
GnRH are modulated by feedback from circulating estrogen and proges-
terone and follow a cyclic pattern, whereas in men modulation also ap-
pears to be negative-feedback dependent but without a cyclic pattern. In
men, FSH stimulates spermatogenesis and LH controls Leydig cell pro-
duction of testosterone; in women FSH stimulates ovarian follicular
TABLE 17–4. Normal values of pituitary-gonadal hormones at the

Laboratory
Hormone Normal values
Luteinizing hormone
Male 6–17 mIU/mL
Female Follicular: 3–20 mIU/mL
Ovulatory: >35 mIU/mL
Luteal: 3–22 mIU/mL
Postmenopausal: >25 mIU/mL
Follicle-stimulating hormone
Male 7–20 mIU/mL
Female Follicular: 6–23 mIU/mL
Ovulatory: 18–46 mIU/mL
Luteal: 2–19 mIU/mL
Postmenopausal: >25 mIU/mL
Estradiol
Male <50 pg/mL
Female Follicular: 10–200 pg/mL
Midcycle: 100–400 pg/mL
Luteal: 15–260 pg/mL
Postmenopausal: <50 pg/mL
Progesterone
Male <0.4 ng/mL
Female Follicular: 0.1–1.5 ng/mL
Luteal: 2.5–28 ng/mL
Postmenopausal: <0.2 ng/mL
Testosterone (total)
Male 300–1,200 ng/dL
Female 20–80 ng/dL
Testosterone (free)
Male 9–30 ng/dL
Female 0.3–1.9 ng/dL
growth and LH stimulates ovulation, luteinization of the ovarian follicle,

and (together with FSH) sex steroid production.
Follicle-Stimulating Hormone and Luteinizing Hormone

In men, LH and FSH levels are not associated with the cyclic variation
characteristic of the menstrual cycle in women. Nonetheless, because the
hormones are secreted in a pulsatile fashion, levels can vary significantly
from one measurement to another. In women, both LH and FSH are se-
creted at various levels throughout the menstrual cycle. LH has a marked
rise just before ovulation in midcycle, whereas FSH is highest at the be-
ginning of the follicular phase, declines as the follicular phase progresses,
and has another peak just before ovulation. During the onset of meno-
pause, there is much variation as ovarian function becomes irregular and
the pituitary is exposed to varying levels of negative feedback from ova-
rian sex steroids. In postmenopausal women (and in men and women
with primary gonadal failure) levels of both LH and FSH are persistently
elevated due to the lack of negative feedback from gonadal production of
sex steroids. By contrast, in pituitary or hypothalamic hypogonadism, LH
and FSH are hyposecreted. Thus, under different circumstances, similar
LH and FSH levels in different patients may reflect healthy normal phys-
iology or a pathophysiological process; interpretation requires knowledge
of the clinical context. LH and FSH are stable in serum, and no special
handling is required.
Testosterone
Testosterone, the most important male sex steroid, is secreted with a di-
urnal rhythm, peaking early in the morning and declining in the evening.
Like other steroids, the majority of testosterone is bound to proteins in
the plasma. These include a specific binding protein called sex hormone–
binding globulin (SHBG) (sometimes referred to as testosterone/estra-
diol–binding globulin), and albumin, which binds testosterone more
weakly. Bound testosterone equilibrates with a smaller pool of free test-
osterone. As with other protein-bound hormones, the total plasma pool
of testosterone is altered by conditions that affect protein levels and by
substances that compete for protein binding sites. The best measure of
bioavailable testosterone is probably the pool of free testosterone and al-
bumin-bound testosterone, because the latter is relatively weakly bound
(Whitley et al. 1994a). Total testosterone, free testosterone, and bioavail-
able testosterone (i.e., free and albumin-bound testosterone) can all be
measured.
Estrogen and Progesterone

Although there are a number of circulating estrogens, the most important
are estradiol, estriol, and estrone. The major portion of circulating estro-
gens in women is made up of estradiol, which is secreted by the ovary.
Other estrogens present in significant quantities include estrone, which
is a metabolite of estradiol, and estriol. In pregnant women, the placenta
secretes estriol; in nonpregnant women circulating estriol is derived from

metabolism of estradiol. For most purposes in nonpregnant women as-
sessment of estrogens can be accomplished by measurement of estradiol.
Although estradiol is bound to SHBG and albumin, its affinity for SHBG
is lower than that of testosterone, and for clinical purposes it is not gen-
erally necessary to measure plasma free estradiol (Winters 1994). Estra-
diol varies with menstrual cycle, rising through the follicular phase to
a peak just before ovulation, and falling sharply toward the end of the
luteal phase. Estrogen is stable but has a tendency to adsorb to plastic
tubes and so should be collected in glass (Wartofsky and Burman 1982).
Unlike estrogen, progesterone is present in significant amounts in
nonpregnant women only during the luteal phase. Circulating progester-
one is bound by proteins, primarily CBG (Whitley et al. 1994a), but free
progesterone is not routinely assayed. Progesterone is stable and does not
require special collection procedures.
Growth Hormone
Growth hormone is an anterior pituitary hormone that promotes linear
growth as well as other metabolic functions, some immediate and some
delayed (e.g., decrease in blood glucose levels acutely, reduction in body
fat, increase in nitrogen balance). Its secretion is controlled by two hypo-
thalamic factors: growth hormone–releasing hormone, which induces pi-
tuitary growth hormone release, and somatostatin, which inhibits
pituitary growth hormone release. Many of its actions are mediated
through a second hormone, insulin-like growth factor I (IGF-I). Although
psychiatrists will not generally be the primary physicians treating or inves-
tigating disorders of growth hormone, some children with severe psycho-
social stressors experience suppression of growth hormone secretion and
delayed growth and may initially come to psychiatric attention or require
psychiatric care as part of overall treatment. Growth hormone may also be
of importance in depressive disorders, because emerging data suggest that
bone mineral density, the normal regulation of which is linked to growth
hormone, is decreased in depressed patients (Michelson et al. 1996b).
Evaluation of growth hormone usually requires both basal and stim-
ulated measurement. Single samples of growth hormone do not provide
an accurate picture of pituitary growth hormone secretory activity, be-
cause secretion is pulsatile and values can vary widely. Basal function is
therefore best assessed by frequent, multiple samples, overnight if possi-
ble. Plasma IGF-I has not been shown to be well correlated with tissue
activity, and therefore is not a widely used measure (however, in patients
with growth hormone receptor abnormalities resulting in Laron dwarf-
ism, plasma growth hormone levels are high and IGF-I levels are low, and
in patients with acromegaly IGF-I values are high). Typically patients
with suspected growth hormone abnormalities undergo provocative test-
ing to assess pituitary growth hormone release. Many agents—including
arginine, clonidine, levodopa, and insulin—induce growth hormone re-
lease and are used to assess the functional capacity of the pituitary soma-
totroph. Normal responses are generally defined as pituitary secretion
increasing plasma growth hormone concentrations to some minimum
threshold whose specific value depends on the particular provocative
agent and the growth hormone assay used.
Prolactin
Prolactin is a 199–amino acid peptide hormone secreted by the anterior
pituitary. Its best-characterized physiological action is the stimulation and
maintenance of lactation at the breast. Prolactin secretion is tonically in-
hibited by dopamine from tuberoinfundibular neurons; consequently,
conditions that interfere with dopamine secretion can lead to increases in
prolactin secretion and potentially galactorrhea. This can be particularly
important in psychiatric patients who take drugs that interfere with dopa-
mine secretion. Although many drugs have been associated with galactor-
rhea, antipsychotic agents, many of which have specific effects blocking
dopamine receptors, are particularly relevant to psychiatric practice (for
some newer agents, particularly clozapine and olanzapine, changes in pro-
lactin have been demonstrated to be minimal [Breier et al. 1999; Tollefson
and Kuntz 1999]). One case report showed a strong correlation between
plasma prolactin levels and severity of galactorrhea (Gioia and Asnis 1988),
and the authors suggested obtaining weekly plasma prolactin levels as a
way of adjusting medication dosage. However, serum prolactin levels vary
widely in patients with galactorrhea (Frantz and Wilson 1992), and the
usefulness of plasma prolactin levels in neuroleptic-induced galactorrhea
remains uncertain. Although they were at one time proposed for diagnos-
tic use, prolactin stimulation and suppression tests are not generally fa-
vored by endocrinologists in current practice because the results are too
variable to be generally useful (Frantz and Wilson 1992).
Summary
Over the past several decades, rapid growth in the knowledge of neu-
roendocrinology and the involvement of neuroendocrine factors in
normal brain functioning as well as psychiatric illness has opened many
exciting new lines of inquiry. One of these has been the effort to develop
laboratory measures that can inform diagnosis and guide clinical decision
making. As discussed in this chapter, much progress has been made, and
for some illnesses such as depression it seems likely that it will soon be
possible to match different neuroendocrine patterns with specific patho-
physiologies. As yet, however, the primary role of neuroendocrine testing
in the clinical practice of psychiatry remains largely in distinguishing pri-
mary psychiatric illness from other conditions that can cause psychiatric
symptoms. The challenge that lies ahead is to further expand and refine
the knowledge of the neurobiology of psychiatric illnesses and the thera-
peutic armamentarium. In so doing it will be possible to develop tests
that can reliably differentiate the underlying pathology of similar pheno-
types and that can inform clinical interventions.
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Chapter 18
Endocrine Imaging in Depression
Kishore M. Gadde, M.D.

K. Ranga R. Krishnan, M.D.
O ver the years, researchers have made use of various

approaches—such as genetic linking studies; measurement of concentra-
tions of various neurochemicals such as neurotransmitters, neuro-
peptides, and their metabolites; neuroendocrine challenge paradigms;
and correlates of responses to pharmacotherapy—in pursuit of furthering
their knowledge of the neurobiological basis of psychiatric disorders. Ad-
vances in imaging techniques in the past decade have provided additional
tools that facilitated better and dependable visualization of anatomical
structures suspected to be involved in the etiopathology of various men-
tal disorders. In this chapter, we focus on anatomical correlates of affec-
tive disorders and attempt to tie these findings to the available data from
psychoneuroendocrinologic investigations.
Hypothalamic-Pituitary-Adrenal Axis
One of the most well-studied biological systems in major depression is

the hypothalamic-pituitary-adrenal (HPA) axis (Gold et al. 1984). Hy-
peractivity of the HPA axis has been recognized in depressed patients
through findings of increased cortisol levels in plasma (Sachar et al.
1970) and cerebrospinal fluid and in 24-hour urine samples (Carroll et
al. 1976); resistance to suppression of cortisol, adrenocorticotropic hor-
mone (ACTH), and b-endorphin by dexamethasone (Carroll et al. 1981;
Krishnan et al. 1990b; Reus et al. 1982; Sherman et al. 1984); increased
499
concentrations of corticotropin-releasing hormone (CRH) in cerebrospi-

nal fluid (Nemeroff and Evans 1984); and blunted ACTH response to
ovine CRH (Gold et al. 1984). Exogenous administration of corticoster-
oids has been demonstrated to induce profound mood changes in healthy
persons without psychiatric histories (Su et al. 1993; Wolkowitz 1994).
Conversely, drugs that lower cortisol levels, such as ketoconazole and
metyrapone, have been found to produce varying degrees of mood-
enhancing effects in patients with Cushing’s syndrome and in individuals
with major depression (reviewed by Wolkowitz and Reus 1999).
ACTH, released by the anterior pituitary, stimulates cortisol secretion
from the adrenal cortex, and ACTH itself is regulated by the hypotha-
lamic peptide CRH. In addition, it is known that the hippocampus,
which has an abundance of glucocorticoid receptors (De Kloet and Reul
1987), exerts a significant feedback inhibition of the HPA axis (Jacobson
and Sapolsky 1991). Therefore, if one were to investigate anatomical cor-
relates of endocrine dysregulation, the organs and areas of interest would
be the adrenal, pituitary, hypothalamus, and hippocampus. To our
knowledge, there are no specific imaging studies of the hypothalamus
that examined differences between depressed and nondepressed human
subjects.
Adrenal Pathology in Depression
Each adrenal gland lies bilaterally in the perirenal space. The weight of
the normal adrenal, from autopsy reports, varies considerably (Quinian
and Berger 1933). On the computed tomographic scan, the adrenal
glands show an inverted Y configuration. Computed tomography is an
excellent technique—and is probably the single best and most cost-effective
technique—for imaging the adrenals (Dunnick 1988). Routine radio-
graphic examinations use 1-cm sections through the whole gland, and
slices of 5 mm thickness provide even better detail of pathology when
smaller-size pathology is suspected to be present.
Neuroendocrine challenge studies have noted that a high dose of ACTH
results in a greater-than-normal cortisol response in depressed patients
(Kalin et al. 1987); however, this was not the case when a low dose of
ACTH was administered (Krishnan et al. 1990b), suggesting that sensi-
tivity of the adrenal cortex to the pituitary hormone is not altered in de-
pression. In animals, hypertrophy of all layers of the adrenal cortex, but
not the adrenal medulla, occurs after long-term stimulation with ACTH
(Malendowicz 1986). These observations, when taken together with the
Endocrine Imaging in Depression 501
finding of increased weight of adrenals in suicide victims compared with

those of subjects that died of causes such as automobile accidents and
cardiovascular events (Zis and Zis 1987), raised the possibility of finding
hyperplasia or hypertrophy of adrenal glands in depressed individuals.
Amsterdam and colleagues (1987), in a pilot study, found a significant
enlargement of the adrenal gland, as measured by computed tomography,
in 8 of 16 patients with depression. In this study, no relationship was
found between 9:00 A.M. serum cortisol levels and adrenal volume. Our
group took this a step further and conducted a computed tomographic
imaging study of adrenals, using a high-resolution GE 9800 scanner
(Nemeroff et al. 1992). The sample size in this study was 38 depressed
patients and 11 nondepressed control subjects. Contiguous sections of
5 mm thickness were obtained through the adrenal glands without using
contrast material. Assessments consisted of 1) global ratings by two ex-
perienced radiologists who were blind to the diagnosis and 2) calculation
of adrenal volume. The radiologists globally rated the adrenal glands as
normal or enlarged. Calculation of the adrenal volume was done by means
of a systematic sampling method (Gundersen and Jensen 1987), which
had been previously applied to the measurement of various brain struc-
tures (Krishnan et al. 1990a). The radiologists judged the adrenals of 12
of the 38 depressed patients as being enlarged, whereas none of the con-
trol subjects were considered to have adrenal enlargement (P<0.046,
Fisher exact test). The adrenal volumes of depressed patients (14±5.9
mL) were significantly larger than those of the control subjects (8.9±2.5
mL; t test, P<0.0076; Wilcoxon mean rank test, P<0.034). The adrenal
enlargement in this study was thought to be most likely due to hypertro-
phy or hyperplasia of the adrenal cortex rather than enlargement of the
medulla; because the medulla constitutes a very small portion of the
gland, it would have to increase enormously in size to account for the
overall enlargement of the gland, seen in this study. Also, adrenocortical
cells are known to be capable of enlargement as well as proliferation,
whereas the adrenal medullary cells are not known to increase in size or
multiply except when there is a neoplastic change. Adrenal gland size in
this study was not correlated with dexamethasone suppression test (DST)
results or depression severity.
Hypercortisolemia is one of the most consistent findings in depres-
sion. In recent years, investigators have grappled with the question of
whether hypercortisolemia has a role in the etiology of mood disturbance
or whether it is a secondary response such as a compensatory mecha-
nism—and if it is a compensatory mechanism, whether it is state depen-
dent or a trait phenomenon. It has been observed (Nemeroff and Evans
1984) that persistent DST nonsuppression after a patient’s clinical recov-
ery from an acute depressive episode is associated with increased risk of

relapse. Taken together with the finding of persistent elevation of 24-hour
urinary free cortisol in depressed patients after clinical recovery (Kathol
and Gehris 1985), it appeared that patients with major depression might
not have normalization of some of their neurohormonal regulatory mech-
anisms even after clinical improvement.
Rubin and associates (1995) measured adrenal volumes using mag-
netic resonance imaging (MRI) in 11 depressed patients and 11 control
subjects; both groups included 2 adolescents each. Images were obtained
in the axial plane with 5 mm thickness. The depressed patients’ adrenals
were scanned during their illness and during full remission. The patients
had a mean Hamilton Rating Scale for Depression score of 25.4±4.6 at
the time of first imaging, and 2.5±2.5 when the second set of images was
obtained. When clinically depressed, the patients had significantly larger
adrenal volumes (median, 5.7 mL) compared with the control group
(median, 3.4 mL; P<0.02). The log-transformed data of adrenal volumes
were presented as median and first and third quartiles. The patient group
was found to have a significantly larger adrenal volume when depressed
(median, 5.7 mL) than while in remission (median, 2.9 mL; P<0.008).
There was no difference between the adrenal volumes of the patients in
remission and the control subjects. There were no differences in the basal
plasma cortisol levels among the three groups. There were no meaningful
relationships between adrenal gland volume and basal cortisol and
ACTH levels; neither was there a close correlation between adrenal vol-
ume, and cortisol and ACTH responses to ovine CRH. Although it may
be rather puzzling that no relationship could be established between
functional hyperactivity of the adrenal gland in depression and the gland’s
enlargement in such a state, in the studies discussed here, some investi-
gators have argued that the adrenal size reflects the adrenal capacity
rather than plasma cortisol concentration at that particular time (Nem-
eroff et al. 1993).
Although there may not be compelling reasons for routine adrenal
imaging in psychiatric clinical practice, a clinician should not quickly con-
clude that an incidental finding of adrenal enlargement in a depressed pa-
tient is representative of Cushing’s syndrome in the absence of classic
clinical symptoms and signs of this endocrine disorder; enlargement of
the adrenals is seen in primary depression as well. Clinicians should also
be aware that major depression is extremely common in patients with
Cushing’s syndrome (Loosen et al. 1992), and as many as 80% of Cush-
ing’s syndrome patients acknowledge suicidal ideation. Although hyper-
cortisolemia is a common finding in Cushing’s syndrome as well as in
primary depression, serum cortisol levels are not generally as high in pri-
mary depression as in Cushing’s syndrome (Gadde and Krishnan 1994).

In addition, adrenal enlargement appears to be of a greater magnitude in
patients with Cushing’s syndrome compared with those presenting with
primary depression. However, there have been no direct comparisons,
and some depressed patients have been found to have adrenal enlarge-
ment of similar magnitude to that observed in patients with Cushing’s
syndrome.
Pituitary Pathology in Depression
The pituitary is a small gland that lies in the sella turcica at the base of the
brain, connected to the hypothalamus by the pituitary stalk. The gland is
about 1 cm in diameter and weighs 0.5–1 g. The volume of the pituitary
gland in a living individual can be estimated with MRI technology using
sagittal and coronal sections through the gland.
Numerous neuroendocrine investigators have reported that ACTH
secretion is increased in depressed patients, and this appears to be in re-
sponse to hypersecretion of CRH (Gold et al. 1984). Metyrapone, a drug
that inhibits 11b-hydroxylase and leads to decreased serum cortisol level,
has been given orally or intravenously in clinical neuroendocrine experi-
ments to assess the ability of the pituitary to enhance its secretion of
ACTH when cortisol synthesis is inhibited. In depressed patients, after
metyrapone administration, ACTH response to CRH was found to be
greater than in nondepressed control subjects (Lisansky et al. 1989). Sim-
ilarly, exaggerated ACTH response to CRH was observed in depressed
patients after administration of dexamethasone (Holsboer et al. 1987). In
animal experiments, it has been demonstrated that with short-term ad-
ministration of CRH (Westlund et al. 1985), there is enlargement of pi-
tuitary corticotrophs, whereas long-term administration of this peptide
results in an increase in numbers of these adenohypophyseal cells that se-
crete ACTH (Gertz et al. 1987).
When taken together, the findings described above raised a strong sus-
picion that an enlargement of the pituitary might be found in depressed
patients. This prompted Krishnan et al. (1991) to conduct an imaging
study of pituitary size in depression. This study included 19 patients and
19 control subjects. Sixteen patients had unipolar depression and 3 had
bipolar depression, and 14 of the 19 patients had recurrent depression.
In this MRI study, the midsagittal T1 image centered around the pituitary
stalk was used to measure the central height, maximum length, and cross-
sectional area of the pituitary, a method previously applied by Lemort et
al. (1988). The coronal T1 image through the pituitary stalk was used to
measure the maximum width of the gland. Estimates of the volume of
the pituitary were made by applying the same method used by Gonza-
lvez et al. (1988). Depressed patients had significantly greater pituitary
cross-sectional area (43±10 mm2) than did control subjects (32±9 mm2;
P<0.0009). Depressed patients also had a significantly larger pituitary
volume (577.5±167 mm3) compared with nondepressed control sub-
jects (408.4±172 mm3; P<0.0007) in this study (Krishnan et al. 1991).
The increased volume most likely reflected increase in the size of the an-
terior pituitary, because the posterior pituitary is a neural tissue com-
posed mainly of glial-like cells called pituicytes, and the only conditions
that are expected to enlarge the size of this tissue would be extremely
rare neuroendocrine tumors. A difference in pituitary length was also ob-
served, with depressed patients having a greater length of the pituitary
(P<0.04).
The next step was to study whether there was a relationship between
the observed pituitary anatomical changes and DST findings. Hence, an-
other experiment was conducted in our laboratory in which 24 patients
(17 females and 7 males) with depression underwent the standard DST;
their pituitary volumes were estimated using 3-mm sagittal slices (Axelson
et al. 1992). In this study, pituitary volume was measured directly from
high-quality hard copies of magnetic resonance images instead of estimat-
ing it using linear parameters. After determination of point counts for each
sagittal image of the pituitary, the volume was calculated using Cavalieri’s
(1966) systematic sampling theorem, with the following formula:
Volume=(scan plane thickness)´(number of points)´(area of square on

lattice grid)´(magnification factor)2
This study showed a significant positive correlation, after adjusting

for age and sex, between pituitary size and 11:00 P.M. postdexametha-
sone plasma cortisol concentration. A consistent observation in the mag-
netic resonance studies of the pituitary is that the gland’s volume tends
to get smaller with age (Axelson et al. 1992; Lurie et al. 1990), and there-
fore it is important that an adjustment be made in this regard when com-
paring pituitary volumes between any diagnostic groups.
Pituitary Pathology in Eating Disorders
In addition to affective disorders, the other group of psychiatric condi-

tions in which hypothalamic-pituitary dysfunction has been frequently
observed is eating disorders (Newman and Halmi 1988). In a preliminary

MRI study in our laboratory, Doraiswamy and associates (1990) reported
smaller cross-sectional area and height of the pituitary in patients with
eating disorders (8 with anorexia and 10 with bulimia). These findings
were confirmed in a subsequent study (Doraiswamy et al. 1991) with a
larger sample size of 26 patients (all but one were female) with eating
disorders (12 with bulimia and 14 with anorexia) and 14 control subjects.
Patients with eating disorders were noted to have smaller pituitary cross-
sectional area (those with anorexia, 36.6±8 mm2; those with bulimia,
37.6±6 mm2; control subjects, 48±11 mm2; P<0.0015) and smaller pi-
tuitary height (those with anorexia, 5.1 ± 1 mm; those with bulimia,
5.3±1 mm; control subjects, 6.5±1 mm). There was an inverse relation-
ship between the duration of eating disorder and pituitary size, suggesting
that with a prolonged course of anorexia or bulimia, structural changes in
the pituitary are likely. However, more studies are needed to confirm
these data and to address further questions, such as whether such changes
are reversible.
Hippocampal Changes in Depression
Glucocorticoid receptors are densely distributed in the hippocampus

(Jacobson and Sapolsky 1991; Stumpf and Sar 1975), and the type II glu-
cocorticoid receptor has been implicated in the mediation of responses to
stress (De Kloet and Reul 1987). Sapolsky and McEwen (1988) showed
that there is a gradual deterioration of hippocampal feedback inhibition
of the HPA axis due to downregulation of glucocorticoid receptors from
repeated stress. Landfield and Eldridge (1991) suggested that the normal
downregulatory process of glucocorticoid receptors in the hippocampus
is impaired with aging, due to a hypercortisol state. This failure of adap-
tation may explain the increased vulnerability of elderly persons to de-
pression. In Cushing’s syndrome, which is manifested by a very high
incidence of depression, it was noted that hippocampal volume corre-
lated negatively with plasma cortisol levels (Starkman et al. 1992).
To determine if there are anatomical changes in the hippocampus,
Axelson and associates (1993) in our laboratory compared hippocampal
volumes in 19 depressed patients and 30 nondepressed control subjects
using MRI. Contiguous 5-mm-thick, T1-weighted coronal images were
obtained and the volume of the amygdala-hippocampal complex (AHC)
was measured, applying a systematic sampling method, which was previ-
ously used. No attempt was made to separate the hippocampus from the
amygdala. The uncus, cornu ammonis, dentate gyrus, fimbria, and subic-
ulum were included in the measurement. The two investigators who
rated AHC volumes were blind to the diagnoses and to endocrine data.
No differences were found in hippocampal volume between depressed
patients and nondepressed control subjects. In this study, the patients
were also given the standard DST. There was no difference between DST
suppressors and DST nonsuppressors in their left or right hippocampal
volumes. Also, there were no relationships between the peak postdexa-
methasone cortisol level at 3:00 P.M. or 11:00 P.M. and either left or right
hippocampal volume. Age was negatively correlated with both left and
right AHC volumes. A relationship was observed between left hippo-
campal volume and postdexamethasone cortisol concentration at 11:00
P.M., after covarying for age and sex. In general, the results of this study
provided limited support for the hypothesis of Sapolsky and McEwen
(1988) regarding a key role for the hippocampus in the hypersecretory
state of glucocorticoids in major depression.
The finding of reduced hippocampal volumes was noted even after
resolution of a depressive episode. Sheline et al. (1999) studied 24 women
with a history of depression and found a significant inverse correlation
between hippocampal volume and total lifetime duration of depression.
There was no significant correlation between age and hippocampal vol-
ume in either the patients or the matched control subjects in this study.
Interestingly, decreased hippocampal volume and increased pituitary
volume have been noted in patients with alcohol dependence also (Beres-
ford et al. 1999).
In light of the knowledge that elevated cortisol levels are associated
with depressive symptoms as well as cognitive impairments (Sapolsky
and McEwen 1988), O’Brien et al. (1996) examined this issue further
and found an inverse relationship between hippocampal volume and
postdexamethasone cortisol levels in patients with Alzheimer’s disease
and suggested that hippocampal damage might explain high rates of ab-
normal DST results in Alzheimer’s disease.
Summary
Adrenal enlargement as a finding in major depression has been replicated,

and the changes appear to be state dependent.
Pituitary enlargement has been observed in patients with major depres-
sion. The pituitary enlargement may be secondary to altered secretion or
responsiveness of one or more of the following: corticotropin (ACTH),
thyrotropin (thyroid-stimulating hormone), and growth hormone. Fur-

ther studies on pituitary size and psychoneuroendocrine correlates are
needed to help understand these aspects more precisely. It is not known
whether pituitary size returns to normal after resolution of the acute psy-
chiatric illness.
It might be interesting to examine whether endocrine anatomical ab-
normalities exist in family members of patients with depression.
Unlike the increased adrenal volume, which seems to resolve after re-
mission from depression, hippocampal volume loss seems to persist. Ex-
planation for the observed hippocampal volume loss with prolonged
history of depression may include repeated stress-induced hypercorti-
solemia, reduction in neurogenesis, and increased vulnerability to glutamate
neurotoxicity (Sheline 2000).
The pineal gland and the thyroid are two other structures that have
been implicated in depression, and it would be worthwhile to investigate
if these structures undergo anatomical changes in depression.
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Part VII
Stress
Chapter 19
Stress and Neuroendocrine Function

Individual Differences and Mechanisms
Leading to Disease
Stress is frequently seen as a significant contributor to disease,

including psychiatric illness. Clinical and experimental evidence is accumu-
lating for specific effects of stress on the immune and cardiovascular systems
as well as on the central nervous system. However, aspects of stress that pre-
cipitate disease have been obscure. Because it fails to account for dynamic
aspects of adaptation, the concept of homeostasis has not been able to help
us understand the hidden toll of chronic stress on the body or to appreciate
the significance of individual differences in the response to stress. Rather
than maintaining constancy, systems within the body fluctuate to meet an-
ticipated demands from external forces, a state termed allostasis (Sterling
and Eyer 1988). An important component of allostasis is anticipation of real
or imagined events, and anxiety is a highly potent stressor that varies among
individuals (Schulkin et al. 1994; Sterling and Eyer 1988). Chronic stress,
including chronic anxiety and psychosocial stressors, generates a condition
called allostatic load, in which there is a hidden toll on the body through the
persistent activation of the same physiological systems that normally cope
with stressors (McEwen 1998; McEwen and Stellar 1993).
Research in my laboratory related to this article is supported by NIH Grant MH

41256. I also wish to acknowledge intellectual and collegial support from mem-
bers of the MacArthur Foundation Health and Behavior Network and from sci-
entific colleagues who have participated in activities supported by the MacArthur
Foundation.
513
The secretion of glucocorticoid stress hormones is a universally ac-

knowledged physiological response to stressful events, and Mason (1959)
emphasized the association of the release of these hormones with negative
responses to an event. In this chapter I consider the role of glucocorti-
coids as mediators of allostatic load, after first considering their impor-
tant role in containment of the body’s primary response to stressful events.
A primary focus is on the brain, because this organ interprets and directs
the physiological response to stress and is itself a target of stress hor-
mones. Finally, I discuss the differences between the protective and dam-
aging effects of adrenal steroids; this discussion also requires considering
the role of other mediators in the response to stress.
Connections Between Stress and Disease
Stress is a highly individualized experience, and what is stressful for one

person may not be stressful for another. Moreover, genetic factors, influ-
ences in early development, and prior experiences play a powerful role in
determining whether something is truly stressful to any one person. In
Figure 19–1 the factors that contribute to an experience being inter-
preted as stressful by some individuals and not by others are diagrammed.
The figure also illustrates that biological mediators are activated by stress-
ful events and that they alter the brain as well as the immune system, car-
diovascular system, metabolic control systems, and adipose tissue.
It is difficult to assess whether stress actually causes a disease. Dis-
cussed below are examples in which stressful life experiences appear to
exacerbate the progression of disease. Of course, ascertaining when dis-
ease actually begins is very much dependent on methods of detection.
Because of the steady evolution of sensitive methods to pick up early
warning signs of disease, the concept of allostatic load offers the possibil-
ity that markers of heightened physiological reactivity, such as blood pres-
sure and production of catecholamines and adrenal steroids, may actually
predict the onset of outright disease. Among the most consistent and per-
vasive risk factors for predicting later pathology related to stressful life
events are the adrenal steroids.
Paradoxical Role of Glucocorticoids
The work of Selye (1956) revealed the delicate balance between the pro-
tective effects of adrenal steroids secreted in response to stressful experi-
Stress and Neuroendocrine Function 515
ences and the negative consequences that these same hormones may have
for many processes. Indeed, the body depends on adequate levels of ad-
renal steroids to prevent extremes of responses to challenge, and yet too
much adrenal steroid is also deleterious.
On the positive side, acute elevations of adrenal steroids promote
adaptive processes, such as increased appetite (McEwen et al. 1993), mem-
ory for emotionally charged events (deQuervain et al. 1998; Roozendaal
et al. 1996), and enhanced immunological function (Dhabhar and McEwen
1999) On the negative side, chronic elevations of adrenal steroid levels
promote abdominal obesity and insulin resistance (Bjorntorp 1990; Brind-
ley and Rolland 1989; Jayo et al. 1993), suppress immune function (Dhab-
har and McEwen 1997; McEwen et al. 1997), and impair memory (see
“Importance of the Brain as Controller of and Target for Stress” below as
well as Newcomer et al. 1999; Wolkowitz et al. 1990).
However, whereas chronic exposure to adrenal steroids suppresses
immune defense mechanisms and causes negative consequences such as
neural damage, muscular atrophy, and calcium loss from bone (Sapolsky
1992; Sapolsky et al. 1986), an insufficiency of adrenal steroids makes
the organism much more vulnerable to inflammatory disturbances and
autoimmune responses, fever, and damage from catecholamine metabo-
lites and alcohol (Leonard et al. 1991; Morrow et al. 1993; Ramey and
Goldstein 1957; Spencer and McEwen 1990; Sternberg et al. 1989), and
it also increases fear response and anxiety (Weiss et al. 1970). Therefore,
the adrenocortical system is vital for survival, and there is a generalized
inverted U–shaped dose-time response curve to describe its actions that
range from protection in the low to intermediate range to exacerbation
of pathology at the extreme end of dose and duration of exposure.
Importance of the Brain as Controller of and

Target for Stress
Fear and anxiety are neural events, and the brain governs the endocrine
and autonomic nervous systems and their numerous effects on the im-
mune system and metabolic processes. Moreover, circulating stress hor-
mones feed back on the brain and regulate its structure and function.
Therefore, it is imperative to consider the impact of stress on the nervous
system.
The brain is involved directly in the response to stressors and to diur-
nal changes in the secretion of adrenal steroids; this was shown after it
became possible to detect intracellular steroid hormone receptors. In

1968, we reported that in the rat the adrenal glucocorticoid corticoster-
one was taken up and retained in high levels by the hippocampal for-
mation after rats had been adrenalectomized to remove endogenous
hormone from receptor sites (McEwen et al. 1968). The hippocampal
localization of corticosterone was a surprise, particularly because the
hippocampus was not known to be directly associated with neuroen-
docrine function, whereas the hypothalamus and preoptic area were
known as the hypophysiotropic area and were the sites of uptake and
FIGURE 19–1. (Opposite page) Conceptual model of biology and behav-

ior in which responses that are stressful result from the interpretation of,
and behavioral and physiological responses to, environmental challenges
that may be stressful to some individuals and less stressful or not stressful
to others.
A. (1) Physical and psychological challenges operate within a social context that includes
individual social status. (2) The processing of this information by the nervous systems is bi-
ased by factors such as genetic predisposition that are operated on by developmental his-
tory, learning, and socioeconomic status; developmental age and gender are also important
factors. (3) Interpretation of a stimulus as threatening results in behavioral responses that
vary in degree and cost to the individual and that are therefore stressful to varying degrees.
Nonthreatening situations and low-cost responses are not considered stressful because they
do not elevate physiological responses; stress refers to responses that are costly in terms of
arousal of physiological systems and elicitation of behaviors that are harmful. Thwarted re-
sponses may lead to aggression or result in helplessness, which is similar to a response being
unavailable. High-cost responses, which may include aggression, are ones that consume en-
ergy and that further increase risk to additional challenge. All of these responses, including
vigilance and helplessness, have biological counterparts (see below), and they feed back to
influence further stimulation and processing of that stimulation. B. Behavioral responses are
accompanied by neural, immune, and neuroendocrine responses that act on effectors, such
as the brain and cardiovascular systems and adipose tissue and muscle. Chronic or repeated
stimulation of these effectors may be due to thwarted or high-cost responses or to anxiety
associated with vigilance or helplessness and may lead to allostatic load which, over time,
increases risk for pathology and disease. Acute stress more readily precipitates acute disease
when chronic stress has laid a pathophysiological foundation.
Source. Reprinted from McEwen BS, Stellar E: “Stress and the Individual: Mechanisms
Leading to Disease.” Archives of Internal Medicine 153:2093–2101, 1993. Copyright 1993,
American Medical Association. Used with permission.
retention of sex steroid hormones. The hippocampus plays a major role

in spatial and episodic learning and memory and is also involved in the
matching of expectations to actual events in situations where there may
be punishment or reward (Eichenbaum and Otto 1992; Gray 1982).
Both noradrenergic and serotonergic input play a major role in modulat-
ing hippocampal responsiveness. Noradrenergic innervation, acting via
a and b receptors, increases excitability of neurons and produces disin-
hibition, a process that also results in facilitation of neural activity, in the
hippocampus (Doze et al. 1991; Dunwiddie et al. 1992). Serotonergic
neurotransmission in the hippocampus, acting through postsynaptic
5-hydroxytryptamine type 1A (5-HT1A) receptors, has suppressive ef-
fects on long-term potentiation (Sakai and Tanaka 1993) and facilitates
extinction or inhibits learning of aversive associations (Deakin and Graeff
1991; Graeff 1993). Thus, disruption of hippocampal neuronal circuitry
or alterations in noradrenergic or serotonergic activity of the hippocam-
pus are likely to have profound effects on the role that the hippocampus
plays in learning and memory and in the response to novel aversive events
(Gray 1982).
The circuitry, electrophysiology, and neurochemistry of the hippoc-

ampus is uniquely sensitive to circulating adrenal steroids. These hor-
mones have an important role in maintaining hippocampal function
during the diurnal cycle, and one mechanism for this is the ability of ad-
renal steroids to biphasically modulate excitability in the form of long-
term potentiation in the hippocampus (Diamond et al. 1992; Pavlides et
al. 1993, 1994, 1995a, 1995b). In this capacity, adrenal steroids appear
to have a role in the phenomenon of jet lag (McEwen et al. 1992, 1993).
Adrenal steroids also stabilize the neuronal population of the dentate gy-
rus, whereas reductions in adrenal steroid levels enhance neuronal turn-
over by increasing both neuronal death and neurogenesis; in this capacity,
it is speculated that the adrenal secretions may participate in seasonal ad-
justments to hippocampal function (Gould and McEwen 1993).
Finally, adrenal steroids play a vital role in containing the response of
the body and brain to stressful events, and as long as adrenal secretion is
itself contained, adaptation occurs (McEwen et al. 1992, 1993). How-
ever, when adrenocortical secretion is no longer self-regulated and be-
comes persistently augmented, there are several negative consequences:
for example, normal hippocampal neuronal circuitry is disrupted and
serotonin receptor levels are altered. Both of these consequences may
reduce effective cognitive processing of and coping with threatening
events.
Adaptation and Maladaptation in the

Face of Stressful Events
Homeostasis and Allostasis
What is stressful? To begin to understand the differences between adap-
tive and maladaptive responses to stressors, it is necessary to first define
what is stressful. Stress is often defined as a perceived threat to homeo-
stasis and as an event or stimulus that causes an often abrupt but always
large change in autonomic activity and hormone secretion—particularly
hormones such as cortisol and prolactin (see Figure 19–1). The term per-
ceived stress emphasizes the extremely important point that each in-
dividual may react differently to an event or situation depending on
physical status and prior experiences. Thus, trained athletes and seden-
tary individuals will react differently to physical exertion, and prior ex-
periences will cause some individuals to be more or less anxious in the
face of psychological challenges, such as examinations or events in the
workplace.
Stress represents a physiological response to a large deviation from

what is expected, and such a response perturbs the homeostatic balance.
The term homeostasis captures the idea of a body set point that is rees-
tablished after stress, but homeostasis fails to consider the dynamic as-
pect of anticipation of expected events (McEwen 1998; McEwen and
Stellar 1993; Sterling and Eyer 1988). Normally, anticipation is a short-
lived process, but in psychopathology, expectancies or fears can become
self-sustaining and detached from reality in individuals with anxiety dis-
orders and depression.
An adjunct to homeostasis is allostasis, and the term was introduced
(Sterling and Eyer 1988) because the body is a dynamic system that re-
sponds and adapts to new situations. Allostasis refers to the systems of the
body (neural, endocrine) that are activated by a stressful challenge and
that participate in adaptation—in other words, allostasis, or achieving sta-
bility through change, helps to maintain or restore homeostasis (Sterling
and Eyer 1988).
Containment by Glucocorticoids
Glucocorticoid secretion is one of the most frequent responses to stress-
ful events. Adrenal steroid secretion as a result of stress has multiple ac-
tions on the brain and body that have been characterized as containing or
counterregulating other responses to stress and trauma such as inflamma-
tions, fever, edema, and immune responses (Munck et al. 1984). The
term containment implies that glucocorticoids prevent responses from be-
ing excessive (Figure 19–2). In the brain, glucocorticoids contain the syn-
thesis of corticotropin-releasing hormone (CRH) and vasopressin, two
neuropeptide-releasing hormones that stimulate production of adreno-
corticotropic hormone (ACTH); in doing this they prevent hypothalamic
CRH—which has anxiogenic, arousing, immunosuppressive, and anorex-
igenic effects—from becoming hyperactive (McEwen et al. 1992). Other
examples of containment are discussed below in conjunction with the
noradrenergic and serotonergic systems.
Stress and Noradrenaline

Stressors of many kinds activate the release and turnover of noradrena-
line, along with the release of catecholamines from the autonomic ner-
vous system. Uncontrollable stressors tend to have more prolonged effects
on noradrenaline turnover (Tsuda and Tanaka 1985; Weiss et al. 1981).
One of the consequences of repeated stress is the induction of tyrosine
hydroxylase, the rate-limiting enzyme for noradrenaline and epinephrine
FIGURE 19–2. Counterregulation of stress effects by adrenal steroids.

A. CRH system and hypothalamic-pituitary-adrenal axis. B. Containment of noradrenergic
activity by glucocorticoids. C. Positive and negative effects of adrenal steroids on serotoner-
gic activity and receptor sensitivity.
cAMP=cyclic adenosine monophosphate; CRH=corticotropin-releasing hormone; 5-HT=
5-hydroxytryptamine; NA=noradrenaline.
formation, in both the locus coeruleus and the adrenal medulla (see Nisen-
baum et al. 1991). Stress-induced activation of catecholamine biosynthe-
sis also increases the catalytic efficiency of tyrosine hydroxylase and leads
to increased catecholamine formation (see Nisenbaum et al. 1991).
Thus, in the face of increased amount and activity of tyrosine hydroxyl-
ase, there is a need for various forms of containment (see Figure 19–2).
Glucocorticoids fill this role in several ways, reducing the formation of
cyclic adenosine monophosphate in the cerebral cortex in response to
noradrenaline (see McEwen et al. 1992), and decreasing catecholamine
biosynthesis and release (Pacak et al. 1992, 1993).
In view of the importance of noradrenaline in promoting excitability
and disinhibition of hippocampal neurons (Doze et al. 1991; Dunwiddie
et al. 1992), it is interesting that after repeated stress, noradrenergic ter-

minals in the hippocampus retain the potential to release larger amounts
of noradrenaline in response to a novel stressor (Nisenbaum et al. 1991).
Yet this release is contained to a large extent by presynaptic a-adrenergic
mechanisms (Nisenbaum and Abercrombie 1993) that may also be aided
by circulating glucocorticoids (Pacak et al. 1992, 1993). A similar situa-
tion exists with respect to ACTH and glucocorticoid secretion in re-
sponse to novel stressors in animals that have been repeatedly stressed, as
discussed below under “Neurobiology of Stress and Glucocorticoid Ef-
fects on Dendritic Branching.”
Stress and Serotonin

Stressors also activate serotonin turnover and thereby activate a system
that has both anxiogenic and anxiolytic pathways within the forebrain
(Deakin and Graeff 1991; Graeff 1993). Serotonin has a powerful role in
the learning and retention of fear (Archer 1982). A primary distinction
in the qualitative nature of the actions of serotonin is between the dorsal
raphe and median raphe nuclei: dorsal raphe innervation of the amygdala
and hippocampus is believed to have anxiogenic effects, very likely via
5-HT2 receptors; conversely, median raphe innervation of the hippo-
campus reaches 5-HT1A receptors, stimulation of which facilitates the
disconnection of previously learned associations with aversive events or
suppresses formation of new associations, thus providing a resilience to
aversive events (Deakin and Graeff 1991; Graeff 1993).
Glucocorticoids have a complex role in regulating the 5-HT system
(see Figure 19–2). Circulating glucocorticoids acutely facilitate 5-HT
turnover provoked by a wide variety of stressors (Azmitia and McEwen
1974; Neckers and Sze 1975; Singh et al. 1990), and repeated treatment
with ACTH or glucocorticoids (or chronic stress) increases 5-HT2 recep-
tors in the cerebral cortex (Kuroda et al. 1992, 1993; McKittrick et al.
1995) while reducing 5-HT1A receptors in the hippocampus (Burnet et
al. 1992; Chalmers et al. 1993; Martire et al. 1989; McKittrick et al.
1995; Mendelson and McEwen 1991, 1992). Therefore, although in the
short term glucocorticoids facilitate the activity of the whole 5-HT sys-
tem during stress, in the long term glucocorticoids tip the balance in favor
of 5-HT2-mediated actions of 5-HT (at least in the cerebral cortex) and
suppress 5-HT1A-mediated responses in the hippocampus.
These changes have implications for the pathophysiology of depres-
sion (Deakin and Graeff 1991; Graeff 1993). Moreover, the inadequate
operation of the serotonergic system has been linked to the pathophysiol-
ogy of anger and hostility, and suicide and myocardial infarcts are among
the consequences of the hypoactivity of reduced serotonergic activity

(Williams and Chesney 1993; Williams and Williams 1993). There is also
a reported link between low fat and cholesterol levels and violent death,
and there are indications that reduced serotonergic function may be in-
volved (Muldoon et al. 1990, 1992).
Containment of the Hypothalamic-Pituitary-Adrenal Axis

A key to successful adaptation as opposed to maladaptive effects of stress
is the self-containment of the hypothalamic-pituitary-adrenal (HPA)
axis; that is, the ability of the HPA axis to shut itself down as well as to
contain other neurochemical responses to stress such as release of CRH
and noradrenaline (see “Stress and Noradrenaline” above).
The paraventricular nuclei, which produce the CRH and vasopressin
that stimulate ACTH release, are innervated by catecholaminergic and
serotonergic inputs. Catecholaminergic input acts via a-adrenergic re-
ceptors to facilitate HPA activity and via b-adrenergic receptors to inhibit
it (Al-Damluji and White 1992; Saphier 1992). In contrast, serotonergic
input to the paraventricular nuclei via 5-HT1A receptors is reported to in-
hibit HPA activity (Welch et al. 1993).
In response to repeated stressors, HPA axis activity tends to become
habituated if the stressor is the same, but it tends to become hypersensi-
tive to novel stressors (Akana and Dallman 1992; McEwen 1992). Partial
inhibition of glucocorticoid secretion in response to stress unmasks a
strong facilitation, indicating that containment by glucocorticoids plays
an important role (Akana and Dallman 1992) (see Figure 19–2). As
noted, glucocorticoids contain the stress-induced release of catechola-
mines in the paraventricular nuclei (Pacak et al. 1993). Moreover, the role
of glucocorticoids in enhancing 5-HT release in stress (see “Stress and Se-
rotonin” above) may have a role in maintaining inhibition via 5-HT1A re-
ceptors (Welch et al. 1993). It therefore appears likely that the relative
strengths of catecholaminergic and serotonergic input as a result of the
same or different stressors may determine whether or not the HPA axis
will become habituated or be enhanced by repeated application of the
same stressor. Moreover, the relative densities of the various adrenergic
and serotonergic receptor types will play an important role in the net HPA
response—that is, to what degree it remains contained. Finally, the effi-
cacy of glucocorticoid feedback on the containment mechanisms will be
an important factor in the containment response. In this connection, it is
interesting that depressed patients show a larger elevation of ACTH level
in response to administration of mifepristone (RU 486) compared with
control subjects (Bailey 1991). RU 486 is an antagonist of the type 2 adre-
nal steroid receptors, and its effect in depressed subjects indicates that
there is an increased drive to release ACTH that is held partially in check
by glucocorticoid feedback acting via type II receptors (Bailey 1991).
Stress and Progression of Disease:

Examples of Allostatic Load
Definitions of Allostasis and Allostatic Load
When referring to repeated or chronic stress, the body is thought of as
maintaining function despite an external load. As noted above, allostasis
is a term that means stability through change, and allostatic load refers to
the hidden price that is paid when an individual is under continuing stress
and is affected by the repeated activation of allostatic systems and by
their failure to shut off properly after the stressful event has passed (see
Figure 19–3). Although it has been shown that glucocorticoids are bene-
ficial in the body’s and the brain’s response to stressful situations, it has
also been noted that it is imperative that the HPA axis shut down again
after the end of stress; if it does not, or if the stress persists without re-
spite, then a vicious cycle may ensue in which elevated glucocorticoid
levels cause a variety of consequences that can be seen as the exacerba-
tion of a disease or a pathophysiological process that leads to disease.
Heightened Sympathetic Reactivity, Glucocorticoid

Increase, Insulin Hypersecretion, and Insulin Resistance
Heightened sympathetic activity is one form of allostatic load, and in-
creased heart rate and peripheral resistance in the circulatory system are
two outcomes of this activity that result in increased blood pressure and
eventually lead to formation of atherosclerotic plaque (J.R. Kaplan et al.
1991a). The combination of elevated insulin and glucocorticoid levels,
which can also result in increased sympathetic activity (Troisi et al. 1991),
is well known to promote obesity and to be a risk factor for formation of
atherosclerotic plaque (Brindley and Rolland 1989). Allostatic load in
the form of sympathetic hyperactivity and heightened HPA axis activity
are likely contributors to increased formation of atherosclerotic plaque in
dominant male cynomolgus monkeys on a normal diet in an unstable so-
cial situation (J.R. Kaplan et al. 1991b). Female cynomolgus monkeys
that are subordinate show increased atherogenesis that may be due, at
least in part, to suppression of ovarian function and its protective effect
on the cardiovascular system (Shively and Clarkson 1994). Thus, gender
FIGURE 19–3. Introducing the concept of allostatic load.

The term allostatic load reflects the dynamic nature of physiological response to environ-
mental challenges more completely than the term homeostasis, and it emphasizes the con-
cept that continued responses to external or internal challenges can cause wear and tear on
the body, either by the repeated fluctuations of physiological responses or through the in-
creased activity of systems over long periods of time that may have deleterious conse-
quences, for example, obesity and atherosclerosis; atrophy and loss of hippocampal
neurons.
differences in the effects of social interactions on allostatic load and the

mechanisms leading to pathophysiological changes are very important to
keep in mind.
Stress and Immune Function

The immune system is sensitive to behavioral influences and to stressful
experiences. There are both positive and negative effects. Acute stress
enhances immune function (Dhabhar and McEwen 1999), as measured
by the trafficking of immune cells to targets where they are needed and by
the enhancement of delayed-type hypersensitivity (Dhabhar and McEwen
1999; Dhabhar et al. 1996). Also on the positive side is the effect of sup-
portive group therapy to double the survival time for breast cancer pa-
tients after the end of intervention (Spiegel et al. 1989). On the negative
side are reports that psychological stress increases the susceptibility to
the common cold (Cohen et al. 1991) and increases the incidence of
mononucleosis in medical students with examination stress (Kiecolt-Glaser
and Glaser 1991).
More prolonged effects of stress on diseases related to the immune
system are not so easy to document. Nevertheless, a recent study of type
1 diabetes in children found that stressful life events stemming from ac-
tual or threatened losses within the family and occurring during ages 5–9
years increased the relative risk for the disease, even after normalization
for confounding factors such as age, gender, and family socioeconomic
status (Hagglof et al. 1991). An increased frequency of negative life
events is also associated with newly diagnosed Graves’ disease in adults,
which suggests a possible interaction between hereditary factors and
stress (Winsa et al. 1991). Moreover, psychosocial influences on another
autoimmune disease, rheumatoid arthritis, are strongly suggestive but are
confounded by the heterogeneity of the disease (Weiner 1992), as is also
the case for asthma (Mrazek and Klinnert 1991). Personality features,
such as the ability to express anger and irritation, as well as stressful life
events, were implicated as risk factors in women with rheumatoid arthritis
in whom there was not a family history of this disease (Yehuda et al. 1991).
Adrenal steroids have multiple effects on the immune system, acting
along with autonomic nervous system innervation (and virtually every
hormone in the body) to biphasically modulate immune function (Mad-
den and Felten 1995; McEwen and Sapolsky 1995). These modulatory
actions can best be appreciated in states of disease. Although many of the
actions of adrenal steroids on the immune system are adaptive and pro-
mote the body’s ability to fight an infection, tumor, or inflammatory or
autoimmune disorder, continuing high levels of HPA activity and sympa-
thetic neural activity (allostatic load) are deleterious to immune function.
Stress and Depression

Insulin resistance and elevated cortisol level are features of endogenous
depressive illness (Winokur et al. 1988), and depressed individuals have
an increased risk for cardiovascular disease as well as shorter life spans
(Anda et al. 1993). Whether or not metabolic disturbances are frequent
features of depressive illness, stressful life events are often implicated as
precipitating factors in depressive illness (Anisman and Merali 1997),
and the model of learned helplessness provides a plausible model for hu-
man depression, involving a loss of self-confidence in the ability to cope
with life events (Seligman 1975). It has been reported that adrenal ste-
roid insufficiency exacerbates learned helplessness in an animal model
(Edwards et al. 1990). As noted above (see “Stress and Serotonin”), ad-
renal steroids potentiate serotonergic activity, and the risk for anger and
hostility is linked in some cases to suicidal depression in individuals with
low levels of serotonergic activity (Williams and Chesney 1993; Williams
and Williams 1993).
Recurrent depression is a model of brain and systemic allostatic load.
Not only is there an increased incidence of cardiovascular disease in de-
pressive illness (Musselman et al. 1998), there is also exaggerated platelet
reactivity and hence increased risk for stroke and myocardial infarction
(Musselman et al. 1996), as well as increased abdominal fat deposition
(Thakore et al. 1997) and decreased heart rate variability (Krittayaphong
et al. 1997). Recurrent depression is also associated with decreased bone
mineral density in association with elevated glucocorticoid levels (Mich-
elson et al. 1996). In the brain, recurrent depression has been linked to
atrophy of the hippocampus and amygdala (Sheline et al. 1996, 1999) as
well as the prefrontal cortex (Drevets et al. 1997). The cellular basis for
these changes is not known; reduced glial cell volume is a possibility,
along with reduced branching of dendrites, reduced numbers of dentate
gyrus granule neurons, and outright loss of pyramidal neurons. This is dis-
cussed further under “Neurobiology of Stress and Glucocorticoid Effects
on Dendritic Branching” below.
It is noteworthy that hippocampal atrophy is also reported in post-
traumatic stress disorder, which occurs along with depressive illness in
many subjects (Bremner et al. 1995, 1997; Gurvits et al. 1996). It is not
clear when the reduced hippocampal volume develops in relation to the
traumatic event, although existing evidence suggests that it may be a
gradual and delayed event over years, as also appears to be the case for
depressive illness.
Stress and Individual Differences in

Aging and Risk for Dementia
The first clue to an effect of adrenal steroids in the hippocampus was the
finding that treatment of guinea pigs with ACTH or cortisone causes ne-
crosis of pyramidal neurons of the hippocampus (aus der Muhlen and
Ockenfels 1969). Landfield and co-workers (see Landfield 1987) later
found that aging in the rat results in some loss of pyramidal neurons in
the hippocampus, which can be retarded by adrenalectomy in midlife.
Sapolsky and his colleagues (1985) subsequently demonstrated that in-
jecting corticosterone into young adult rats daily for 12 weeks produced
a mimicking of the pyramidal neuron loss seen in aging. Sapolsky went

on to demonstrate that excitatory amino acids play an important role in
the cell loss by showing, first, that corticosterone exacerbates kainic acid–
induced damage to the hippocampus as well as ischemic damage, and
second, that glucocorticoids potentiate excitatory amino acid killing of
hippocampal neurons in culture (Sapolsky 1992) (Figure 19–4). How-
ever, the story has turned out to be more complicated and interesting. In
addition to permanent damage caused by stress, glucocorticoids, and ex-
citatory amino acids, there are a number of types of structural plasticity
exhibited by nerve cells in the hippocampus. They are regulated by stress
and by stress hormones, acting in concert with neurotransmitters in the
hippocampal formation.
Neurobiology of Stress and Glucocorticoid

Effects on Dendritic Branching
To examine the response of hippocampal neurons to high levels of glu-
cocorticoids, researchers in my laboratory used the Golgi technique to
examine neuronal morphology after both corticosterone exposure and
repeated stress. We found that after 21 days of daily corticosterone
exposure, apical dendrites of CA3 pyramidal neurons had atrophied
(Woolley et al. 1990); moreover, this atrophy is prevented by adminis-
tering phenytoin, a blocker of excitatory amino acid release and action,
before corticosterone each day (Watanabe et al. 1992a) (Figure 19–5).
The effect of corticosterone on dendritic length and branching is not
found on basal dendrites of CA3 pyramidal neurons, nor is it found on
CA1 pyramidal neurons or dentate gyrus granule neurons (Watanabe et
al. 1992a; Woolley et al. 1990). The sensitivity of the CA3 pyramidal
neurons is reminiscent of the specific damage to CA3 neurons as a result
of kainic acid infusion or as a consequence of seizure-inducing stimula-
tion of the perforant pathway into the hippocampus; both of these ef-
fects are attributable to the mossy fiber input to CA3 from the dentate
gyrus (see Watanabe et al. 1992a).
To investigate whether the corticosteroid effect occurs physiologi-
cally, we subjected rats to repeated daily restraint stress, which is known
to induce glucocorticoid secretion. Restraint stress for 21 days produced
atrophy of apical dendrites of CA3 pyramidal neurons without affecting
basal dendritic length or branching (Watanabe et al. 1992c); the pattern
and specificity of changes were identical to those produced by corticos-
terone treatment (Woolley et al. 1990). Like corticosterone-induced
atrophy, stress-induced atrophy was blocked by phenytoin, which pre-
vents the release and actions of excitatory amino acids (Watanabe et al.
FIGURE 19–4. Schematic diagram of neuronal endangerment.

The synaptic accumulation of glutamate that typically accompanies a necrotic insult, such
as ischemia or seizure, is worsened by glucocorticoids (GCs). (a) This is likely to arise from
GCs’ inhibiting the removal of glutamate from the synaptic cleft. Such inhibition has been
demonstrated to occur at glia and is speculated to occur at neurons as well. (b) However,
GCs do not appear to enhance the initial release of glutamate. (c) As a result of these ac-
tions of GCs, there is enhanced mobilization of free cytosolic calcium in the postsynaptic
neuron. (d) In addition, this accumulation of calcium is augmented by GCs’ inhibiting the
efflux of calcium, via both the Ca2+ ATPase and the Ca2+/Na+ exchanger. (e) At present,
however, there is no evidence that GCs directly enhance the influx of calcium, either by
opening voltage-gated calcium channels or by acting at N-methyl-D-aspartate (NMDA) re-
ceptor–gated channels. As a result of the excessive cytosolic calcium, GCs exacerbate cal-
cium-dependent degenerative events. To date, these have been shown to include worsening
of the proteolysis of the cytoskeletal protein spectrin, the accumulation of the abnormally
phosphorylated tau protein, and the production of oxygen radicals during necrotic insults.
Source. Reprinted from McEwen BS, Sapolsky RM: “Stress and Cognitive Function.” Cur-
rent Opinion in Neurobiology 5:205–216, 1995. Copyright 1995, Current Biology Ltd. Used
with permission.
FIGURE 19–5. Schematic summary of actions of adrenal steroids that af-

fect hippocampal function and alter cognitive performance.
(a) Adrenal steroids biphasically modulate long-term potentiation (LTP), facilitating it via
type I receptors and inhibiting it via type II receptors; type I and type II receptors coexist
in hippocampal neurons. (b) The biphasic modulation of excitability is also seen for
primed-burst potentiation (PBP) as a function of increasing levels of circulating cortico-
sterone, and this may be relevant to diurnal changes in hippocampal function, to the phe-
nomenon of jet lag, and to the effects of acute stress- or disease-induced elevation of
glucocorticoid levels that impair PBP and episodic or verbal memory. (c) Hippocampal cir-
cuitry is diagrammed, showing some of the main connections between entorhinal cortex
(ENT), Ammon’s horn (H), and the dentate gyrus (DG). f=fornix; pp=perforant pathway.
(d), Moderate-duration stress, acting through both glucocorticoids and excitatory amino
acids (especially glutamate), causes reversible atrophy of apical dendrites of CA3 pyramidal
neurons; severe and prolonged stress causes pyramidal cell loss that is especially apparent
in CA3 but spreads to CA1 as well. The mechanistic relationship between reversible atro-
phy and permanent neuron loss is not currently known, although both glucocorticoids and
excitatory amino acids are involved.
Source. Reprinted from McEwen BS, Sapolsky RM: “Stress and Cognitive Function.” Cur-
rent Opinion in Neurobiology 5:205–216, 1995. Copyright 1995, Current Biology Ltd. Used
with permission.
1992a). Moreover, a blocker of N-methyl-D-aspartate (NMDA) recep-

tors also prevents stress-induced dendritic atrophy (Magarinos and McEwen
1995). At the same time, a role for inhibitory neurotransmission was shown
by the fact that a benzodiazepine, adinazolam, blocks stress-induced den-
dritic atrophy (Magarinos et al. 1999).
In addition, stress-induced atrophy of apical dendrites of CA3 pyra-
midal neurons was prevented by administration of cyanoketone, a drug
that virtually eliminates the stress-induced surge of corticosterone
(Magarinos and McEwen 1995). Thus, stress-induced release of cortico-
sterone synergizes with excitatory amino acid release to produce the at-
rophy, and there is evidence (see Magarinos and McEwen 1995) that
corticosterone actually facilitates the release of glutamate from nerve ter-
minals in the hippocampus.
Serotonin also plays a role in the stress- and corticosterone-induced
atrophy of dendrites of CA3 pyramidal neurons. This was shown by the
finding that tianeptine, a tricyclic antidepressant that facilitates serotonin
reuptake, attenuates the atrophy of apical CA3 dendrites caused by re-
peated restraint stress (Watanabe et al. 1992b). The fact that tianeptine
also blocks the atrophy caused by corticosterone treatment rules out the
possibility of any type of inhibition by tianeptine of corticosterone secre-
tion having a direct effect on dendritic atrophy. Rather, it appears that se-
rotonin released during stress (or as a result of injecting corticosterone)
may synergize with excitatory amino acid release in causing the atrophy.
In fact, some evidence for a serotonin-glutamate interaction has been
found, and 5-HT2 receptor antagonists are known to attenuate ischemic
damage to the hippocampus, a process that also involves glutamate release
and that is exacerbated by glucocorticoids (see Watanabe et al. 1992b).
It is very important to note that severe and prolonged stress (e.g., re-
peated cold swim stress or social stress [i.e., dominance-subordinance
hierarchies]) has been reported to produce actual loss of hippocampal
neurons (Fuchs et al. 1995; Mizouguchi et al. 1992; Uno et al. 1989). We
have found that social stress in rats and tree shrews causes the same type
of atrophy of apical dendrites of hippocampal CA3 pyramidal neurons as
that caused by corticosterone and by repeated restraint stress (Magarinos
et al. 1996). Although dendritic atrophy precedes cell loss after cortico-
sterone treatment and repeated restraint stress, the causal relationship of
the dendritic atrophy to neuronal loss is not yet known: that is, although
it is attractive to suppose that atrophy may represent the first stage of cell
damage, the fact that this atrophy occurs on apical but not on basal den-
drites argues that it may be an adaptive process by viable neurons. We
have determined that the atrophy caused by repeated restraint stress for
21 days is reversible (Conrad et al. 1999); therefore, it may represent a
mechanism whereby synaptic connectivity is reduced temporarily, per-

haps to spare the CA3 pyramidal neurons from excessive bombardment
by excitatory input.
Reversible and adaptive as it may be, the stress effect on hippocampal
CA3 pyramidal neurons is accompanied by transient impairment of learn-
ing of a radial maze task (Luine et al. 1994); this impairment can be
blocked by the same agents—phenytoin and tianeptine—that prevent
the stress-induced atrophy of CA3 apical dendrites (Luine et al. 1994).
Neurogenesis in the Adult Dentate Gyrus

Another part of the hippocampus that shows structural plasticity is the
dentate gyrus, which develops later than Ammon’s horn and continues
to replace neurons during adult life. This finding, first in rodents and then
in primates, has recently been extended to the human brain, as described
below.
Neurogenesis in the dentate gyrus of adult rodents has been reported
(M.S. Kaplan and Bell 1984; M.S. Kaplan and Hinds 1977) but never
fully appreciated until recently, and the reactivation of interest in this
topic occurred in an unusual manner. First, bilateral adrenalectomy of an
adult rat was shown to increase granule neuron death by apoptosis (Gould
et al. 1990; Sloviter et al. 1989). Subsequently, neurogenesis was also
found to increase after adrenalectomy in adult rats (Cameron and Gould
1994) as well as in the developing dentate gyrus (Cameron and Gould
1996a). In adult rats, very low levels of adrenal steroids, sufficient to oc-
cupy type I adrenal steroid receptors, completely block dentate gyrus
neuronal loss (Woolley et al. 1991); however, in newborn rats, type II re-
ceptor agonists protect against neuronal apoptosis (Gould et al. 1997c).
This is consistent with the fact that dentate gyrus neuronal loss in the de-
veloping rat occurs at much higher circulating steroid levels than in the
adult, and it represents another example of the different ways that the
two adrenal steroid receptor types are involved in hippocampal function
(Lupien and McEwen 1997).
In adult rats, newly born neurons arise in the hilus, very close to the
granule cell layer, and then migrate into the granule cell layer, presumably
along a vimentin-staining radial glial network that is also enhanced by
adrenalectomy (Cameron et al. 1993). Most neuroblasts labeled with
[3H]thymidine lack both type I and type II adrenal steroid receptors
(Cameron et al. 1993), indicating that steroidal regulation occurs via
messengers from an unidentified steroid-sensitive cell. Recent data sug-
gest an important signaling role for transforming growth factor a and the
epidermal growth factor receptor system (Tanapat and Gould 1997).
The question of whether dentate gyrus neurogenesis is a widespread

phenomenon among mammals was addressed by studies showing that
neurogenesis occurs in the marmoset (Gould et al. 1998), a New World
primate, as well as in an Old World primate species, the rhesus monkey
(Gould et al. 1999a), and in the adult human dentate gyrus (Eriksson et
al. 1998). Thus changes in size of the human hippocampus, described un-
der “Changes in Hippocampal Volume and Cognitive Function in Human
Subjects” below, may include changes in neuron number in the dentate
gyrus.
Granule neuron birth is accelerated by seizure-like activity (Parent et
al. 1997), and the stimulus for this neurogenesis is likely to be apoptotic
cell death, because seizures kill granule neurons (Bengzon et al. 1997),
and local increases in apoptosis simulate local neurogenesis (Cameron
and Gould 1996b). Granule neuron birth is also accelerated by blocking
NMDA receptors or lesioning the excitatory perforant pathway input
from the entorhinal cortex (Cameron et al. 1995). Unlike adrenalectomy,
these treatments do not increase granule neuron apoptosis, and a single
dose of an NMDA blocking drug results in a 20% increase in neuron
number in the dentate gyrus several weeks later (Cameron et al. 1995).
Therefore, although increased apoptosis leads to increased neurogenesis
(Gould and Tanapat 1997), the two processes occur in different regions
of the granule cell layer and can be uncoupled from each other. Never-
theless, the adrenal steroid suppression of neurogenesis is through an
NMDA receptor mechanism (Gould et al. 1997b; Noguchi et al. 1990).
It was recently reported that serotonin may be a positive signal for
neurogenesis in the adult dentate gyrus. Treatment with the serotonin-
releasing drug d-fenfluramine increased neurogenesis (Jacobs et al.
1998). Likewise, the 5-HT1A agonist 8-hydroxydipropylaminotetralin
stimulated neurogenesis, whereas blockade of 5-HT1A receptors had the op-
posite effect and prevented the effect of d-fenfluramine treatment (Jacobs
et al. 1998), as well as preventing increased neurogenesis caused by pilo-
carpine-induced seizures (Radley et al. 1998).
It has been reported that neurogenesis declines in the aging dentate
gyrus in rodents (Kempermann et al. 1998) and rhesus monkeys (Gould
et al. 1999a). Recent studies of aging rats showed that adrenalectomy
could reverse the decline in dentate gyrus neurogenesis (Cameron and
McKay 1999), suggesting that it is the result of age-related increases in
HPA activity and glucocorticoid levels that have been reported (Landfield
and Eldridge 1994; McEwen 1992; Sapolsky 1992; Sapolsky et al. 1986).
One reason for turnover of dentate gyrus granule neurons in adult life
is to adjust needs for hippocampal function in spatial learning and mem-
ory to environmental demands (Sherry et al. 1992). Birds that use space
around them to hide and locate food, and voles and deer mice that
traverse large distances to find mates, have larger hippocampal volumes
than closely related species that do not have these behaviors; moreover,
there are indications that hippocampal volume may change during the
breeding season (Galea et al. 1994; Sherry et al. 1992). Indeed, the rate
of neurogenesis in the male and female prairie vole varies according to
the breeding season (Galea and McEwen 1999). In contrast, an enriched
environment has been found to increase dentate gyrus volume in mice by
increasing neuronal survival without altering the rate of neurogenesis
(Kempermann et al. 1997). Thus there are several ways to maintain the
balance between neuronal apoptosis and neurogenesis.
Learning that involves the hippocampus also appears to affect the
survival of newly formed dentate granule neurons. When rats were
trained in a task involving the hippocampus, the survival of previously la-
beled granule neurons was prolonged (Gould et al. 1999b).
Another important effect is that of acute and chronic stress. Acute
stress involving the odor of a natural predator, the fox, inhibits neurogen-
esis in the adult rat (Galea et al. 1996). Acute psychosocial stress in the
adult tree shrew, involving largely visual cues, inhibits neurogenesis
(Gould et al. 1997a). Inhibition of neurogenesis is also seen in the den-
tate gyrus of the marmoset after acute psychosocial stress (Gould et al.
1997a). Chronic psychosocial stress in the tree shrew results in a more
substantial inhibition of neurogenesis than after a single acute stressful
encounter (Gould et al. 1997a). This finding suggests that there may be
other changes such as atrophy of dendritic branching to account for the
decrease in dentate gyrus volume.
Changes in dentate gyrus volume appear to have consequences for cog-
nitive functions subserved by the hippocampus. In enriched-environment
studies (Kempermann et al. 1997), increased dentate gyrus volume was
accompanied by better performance on spatial learning tasks. In contrast,
decreased dentate gyrus volume in chronically stressed tree shrews is par-
alleled by impaired spatial learning and memory (Czeh et al. 2001), al-
though this might be as much due to atrophy of dendrites of CA3
pyramidal neurons and dentate granule neurons (see “Neurobiology of
Stress and Glucocorticoid Effects on Dendritic Branching” above) as to
reduced dentate gyrus neurogenesis.
Changes in Hippocampal Volume and

Cognitive Function in Human Subjects
A key question is whether there are any parallels to the findings in the rat
hippocampus from studies on human disorders. Besides the studies on
recurrent depressive illness noted above (see “Stress and Depression”), a

report on patients with Cushing’s disease indicates that some who show
impairment of verbal memory also have decreased hippocampal volume,
as determined by magnetic resonance imaging (Starkman et al. 1992). A
similar study reported individual differences in hippocampal volume in
aging human subjects that correlate negatively with cortisol levels and
positively with measures of memory impairment (Convit et al. 1995;
Golomb et al. 1994). Another series of longitudinal studies of human
brain aging revealed individual differences in HPA activity that parallel
declines in hippocampus-specific forms of memory (Lupien et al. 1994,
1998). In the more recent of these studies, deficits in spatial and verbal
memory were associated with a 14% smaller hippocampal volume, as
well as with elevated cortisol levels (Lupien et al. 1998). What is inter-
esting about hippocampal atrophy in the aging human brain in mild cog-
nitive impairment is that it predicts later onset of Alzheimer’s disease (de
Leon et al. 1993). However, the mechanisms by which this progression
occurs are not clear, and more remains to be learned about the reversibil-
ity and structural basis of the changes in hippocampal volume, not only
in mild cognitive impairment with aging but also in recurrent depressive
illness, Cushing’s disease, and posttraumatic stress disorder. Any of the
mechanisms described above may be involved—ranging from reduced
glial cell number to atrophy of dendrites to reduced number of dentate
gyrus granule neurons to permanent loss of pyramidal neurons. Some of
these events may be reversible, whereas others will be permanent.
However, structural changes in the hippocampus, whether reversible
or permanent, are not the only way to bring about impairment of mem-
ory in aging, depressive illness, and Cushing’s disease. Memory associated
with the hippocampus and temporal lobe is acutely inhibited by gluco-
corticoids through a reversible mechanism involving neuronal excitabil-
ity (see DeKloet et al. 1998; McEwen and Sapolsky 1995 for reviews; see
also Kirschbaum et al. 1996; Lupien et al. 1997; Newcomer et al. 1999;
Wolkowitz et al. 1990).
Conclusion
I argue in this chapter that containment of a variety of physiological re-

sponses to stress is a key feature of successful adaptation. This includes
the HPA axis, because when glucocorticoid secretion is augmented for
prolonged periods, then (besides the containment effects) other actions
of glucocorticoids that are not beneficial begin to accumulate. It has been
suggested that repeated stress may impair successful behavioral adapta-

tion and may do so via glucocorticoid secretion. Evidence in support of
this hypothesis has come from use of the adrenal steroid synthesis inhib-
itor metyrapone to increase behavioral adaptation to restraint stress (Kennet
et al. 1985).
One of the adverse events promoted by glucocorticoids is altering the
balance between 5-HT2 and 5-HT1A transmission in the forebrain; an-
other deleterious result of repeated, unremitting stress is the atrophy of
apical dendrites of hippocampal CA3 pyramidal neurons. These events
are associated with some cognitive impairment on a radial maze task.
Whereas elevated 5-HT2 transmission in cerebral cortex would enhance
the anxiogenic side of stress, the reduced 5-HT1A transmission due to glu-
cocorticoid actions in the hippocampus would impair adaptation to stress
by reducing the ability of the hippocampus to suppress negative associa-
tions (Deakin and Graeff 1991; Graeff 1993) and by impairing hippocam-
pal function in interpreting the context in which to make appropriate
responses (Phillips and LeDoux 1992). At the same time, synaptic con-
nections through CA3 pyramidal neurons that are presumably disrupted
by glucocorticoid-induced atrophy of dendrites would reduce the effi-
cacy of the hippocampus in its role in determining the context for appro-
priate responses and in matching expected outcomes with reality (Gray
1982; Phillips and LeDoux 1992). Such impairment might further in-
crease the likelihood that fears and anxieties would become self-sustain-
ing and less subject to matching with real events. This is a situation in
which the concept of allostatic load, with its emphasis on anticipation, is
of particular relevance to psychiatric disorders.
How might this sequence of events start in the first place? The control
of ACTH secretion through the paraventricular nuclei involves both fa-
cilitative and inhibitory influences via catecholamines and serotonin. It
may be that the balance between these opposing influences breaks down
in some individuals under stress, giving rise to persistently elevated corti-
sol levels. Depressed individuals show a high degree of stress and consid-
erable containment of the ACTH response, as shown by challenge with
RU 486 (Krishnan et al. 1992). Nevertheless, if containment breaks
down sufficiently that the elevation in cortisol concentration above base-
line begins to alter neurochemical features of the brain by increasing
5-HT2 receptors in the cortex and suppressing 5-HT1A receptors in the
hippocampus, as well as causing atrophy of dendrites in the hippocam-
pus, then some of the negative features of glucocorticoid action on be-
havioral adaptation may occur.
Stressful life events are acknowledged as an important risk factor for
major depressive illness (Anisman and Merali 1997) and posttraumatic
stress disorder (Green et al. 1992), and possibly also for schizophrenia
(Norman and Malla 1993). It is interesting to note that both posttrau-
matic stress disorder and schizophrenia appear to involve neuroanatom-
ical disturbances in hippocampal volume and structure (Arnold et al.
1991; Barbeau et al. 1995; Bogerts et al. 1993; Bremner et al. 1995; Luchins
1990; Shenton et al. 1992), whereas there are some suggestions that ma-
jor depressive illness may be linked through glucocorticoid excess to re-
duced hippocampal volume and cognitive impairment (Axelson et al.
1993; McEwen and Sapolsky 1995; Sheline et al. 1996, 1999). However,
we are at a very early stage of understanding the etiology of these disor-
ders and the role of neurological disturbances, and much remains to be
learned about the pathways from perceived stress to the neurochemical
and neuroanatomical features of these disorders. Therefore, the discus-
sion of the roles of the hippocampus, glucocorticoids, CRH, the HPA
axis, serotonin, and noradrenaline will have to be broadened to include
other brain structures and neurochemical mediators. Nevertheless, the
principles outlined in this chapter concerning anticipation and anxiety
leading to allostatic load and the normal role of adrenal steroids in con-
taining various aspects of the primary stress response should be useful in
understanding the roles of other mediators and brain regions in coping
with potentially stressful events.
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Index
Page numbers in boldface type refer to tables or figures.
AASs. See Anabolic-androgenic treatment of, 169–170

steroids dehydroepiandrosterone, 218
Abel, John Jacob, 15 Adenylate cyclase, 473
Acetylcholine, 17, 29, 30 Adiposogenital syndrome, 18–19
corticosteroid effects on, 197 Adrenal glands
prolactin regulation by, 108 computed tomographic scanning
stimulation of corticotropin- of, 500, 501
releasing hormone release by, enlargement of, 501–503
472 in Cushing’s syndrome, 502–503
Acromegaly, 111–112, 493 in depression, 35, 501–503, 506
ACTH. See Adrenocorticotropic in suicide victims, 501
hormone magnetic resonance imaging of,
ADAS (Alzheimer’s Disease 502
Assessment Scale), 221 normal weight of, 500
Addison, Thomas, 12–13 Adrenal hyperfunction, 170, 171. See
Addisonian crisis, 168 also Cushing’s disease and
Addison’s disease, 5, 13, 15, 29, 126, Cushing’s syndrome
166–170 Adrenal insufficiency, 167. See also
clinical course of, 168 Addison’s disease
diagnosis of, 169, 480–481 differentiation from steroid
differential diagnosis of, 168–169 withdrawal syndrome, 194
etiology of, 167 Adrenal tumors, 170–171, 178, 180
gender distribution of, 167 Adrenalectomy, 13, 16
neuropsychiatric symptoms of, Adrenaline, 15, 17
168–169 Adrenocorticotropic hormone
psychotropic medications for (ACTH), 31, 32, 473
patients with, 170 in Addison’s disease, 169
somatic effects of insufficient behavioral effects of, 139, 182
adrenal hormones in, 167–168 circadian fluctuations in plasma
stress and, 168, 170 level of, 167, 474
547
Adrenocorticotropic hormone Agitation, in hypercalcemia, 123

(ACTH) (continued) AHC (amygdala-hippocampal com-
in Cushing’s disease, 170–171, 173 plex), in depression, 505–506
relationship between hormone Alcmaeon of Croton, 10–11
levels and depression, 179 Alcoholism
in depression, 179, 502, 503 arginine vasopressin in, 44
ectopic tumor production of, 170 hypothalamic-pituitary-adrenal
functions of, 473 axis activity in, 37, 38
half-life of, 474 decreased hippocampal volume
measuring plasma level of, and increased pituitary
474–475, 475 volume, 506
causes of falsely elevated or thyroid function in, 376, 383–387
decreased levels, 475 in abstinent patients with liver
timing and frequency of, disease, 385–386
474–475 in abstinent patients without
neuropsychiatric effects in liver disease, 384
multiple sclerosis patients during acute alcohol
with family history of withdrawal, 383–384
depression, 192 cerebrospinal fluid studies of,
response to corticotropin-releasing 386–387
hormone stimulation test, 34, effects of ethanol
478–480 administration on, 383
secretion of, 166, 473 in subjects at risk for developing
excessive, 170 alcoholism, 386
Adrenocorticotropic hormone Aldosterone deficiency, 167–168
(ACTH) stimulation test, 169, Allopregnanolone, 288, 319
480–481 premenstrual syndrome and, 252
Aggression/violence Allostasis, 513, 516, 518–518, 523,
dehydroepiandrosterone effects in 524
animals, 209 Allostatic load, 513, 514, 516, 523
induced by anabolic-androgenic Alzheimer’s disease
steroids, 335, 337–339, arginine vasopressin in, 45–46
344–345, 349 effects of dehydroepiandrosterone
insulin responses and, 121–122 and dehydroepiandrosterone
Aging, 3. See also Elderly persons sulfate on cognitive
decline in dehydroepiandrosterone performance in, 215, 220–221
with, 208 estrogen in, 307–308
decline in pituitary volume with, growth hormone in, 115
504 hippocampal volume and
effect on dexamethasone dexamethasone suppression
suppression test, 143–144 test in, 506
hippocampal changes with, 505, hypothalamic-pituitary-adrenal
526–527, 533–534 axis activity in, 37, 38–39
stress and individual differences in, neurotensin in, 54
526–527 somatostatin in, 50, 59
Index 549
Alzheimer’s Disease Assessment Scale dosage and, 339–340, 347

(ADAS), 221 high-dose laboratory studies of,
g-Aminobutyric acid (GABA) 340–342
corticosteroid effects on, 197 mania or hypomania, 336, 338,
estrogen-induced increased activity 341, 347
of, 305 modest-dose laboratory studies
g-Aminobutyric acid (GABA) type A of, 335–336
receptors naturalistic studies of, 336–340
allopregnanolone binding to, 288, withdrawal depression, 336,
319 339, 343, 348
3¢-5¢-a-tetrahydrodeoxycortico- syndromes associated with use of,
sterone modulation of, 289 342–345
Aminoglutethimide dependence, 343
for depression, 152 muscle dysmorphia, 343
for obsessive-compulsive disorder, progression to opioid abuse or
153 dependence, 345
Amitriptyline violence, 344–345
effect on cerebrospinal fluid treatment for users of, 348–349
corticotropin-releasing use by athletes, 332, 335–338
hormone concentration, 33 adolescents, 338
triiodothyronine augmentation of, “stacking,” 336
452 use by women, 345–346
Amygdala-hippocampal complex Anabolic Steroids Control Act of
(AHC), in depression, 505–506 1990 (P.L. 101-647), 332
Anabolic-androgenic steroids (AASs), Ancient concepts of
6, 331–349. See also Testosterone psychoneuroendocrinology,
for anemia, 333 10–11
antidepressant effects of, 333 Androgens, 6, 12. See also Anabolic-
classification as schedule III androgenic steroids; Testosterone
substances, 332 decrease with aging, 247
definition of, 331 deficiency of, 167
detecting use of, 347–348 effect on visuospatial tasks, 334
for female-to-male transsexuals, in pregnancy and puerperium, 288
334 postpartum depression and,
for human immunodeficiency 291
virus–infected men, 334 premenstrual syndrome and, 252
for hypogonadal men, 334 Androstenedione, 308
for muscular dystrophy, 333 Anemia, anabolic-androgenic steroids
physiological effects of, 331–332 for, 333
for postmenopausal women, 334 Anger/hostility
prevalence of use of, 332 hyperprolactinemia and, 286
psychiatric effects of, 332–342 induced by anabolic-androgenic
clinical implications of, steroids, 335–337
347–349 serotonergic hypoactivity and, 521,
clinical studies of, 332–334 526
Anisomysin, 209 triiodothyronine augmentation of,

Anorexia nervosa, 31 451–456, 452, 460–461
arginine vasopressin in, 45 to accelerate antidepressant
dehydroepiandrosterone and response, 450–451
dehydroepiandrosterone antidepressant class and,
sulfate in, 213 454–455, 460–461
effects of treatment with, 219 mechanism of action of, 455
hypothalamic-pituitary-adrenal precautions for use in elderly
axis activity in, 37, 39 cardiac patients, 454
pituitary pathology, 504–505 recommendations for, 456, 456
neuropeptide Y in, 55 side effects and tolerability of,
thyroid function in, 390–393, 391 453–454
abnormal circadian thyrotropin use in Addison’s disease, 170
rhythm, 368 use in Cushing’s syndrome, 179
Antiandrogens, for male-to-female use in pregnancy, 293
transsexuals, 321 Antidepressants, tricyclic (TCAs)
Antidepressants. See also specific drugs effects on glucose regulation, 118
and classes effects on thyroid function, 378–379
anabolic-androgenic steroids as, rapid-cycling bipolar disorder
333 and hypothyroidism, 374
dehydroepiandrosterone effects in estrogen augmentation of, 306
animals, 209 neuroendocrine pathophysiology
dexamethasone suppression test and actions of, 31
and response of dysthymic for steroid-induced psychopathol-
patients to, 147 ogy, 195, 198
effect on cerebrospinal fluid triiodothyronine augmentation of,
corticotropin-releasing 451–456, 452, 456, 460
hormone concentration, 33 use in hyperthyroidism, 378–379,
effects on thyroid function, 366, 428
378–379 Antidiuretic hormone. See Arginine
in hyperthyroidism, 378–379, vasopressin
428 Antiestrogens, 317–318
in hypothyroidism, 435, 436 Antiglucocorticoid medications,
estrogen augmentation of, 306 152–153
glucocorticoids as, 190 in bipolar depression, 153
impact on glucose regulation, in depression, 152–153
118–119 in obsessive-compulsive disorder,
neuroendocrine pathophysiology 153
and actions of, 30–31 in schizophrenia and schizoaffec-
for perimenopause-related tive disorder, 153
depression, 272 Antipsychotics
for postpartum depression, 293 effect on dexamethasone
for premenstrual syndrome, 315 suppression test, 148
for steroid-induced effect on neurotensin level, 53
psychopathology, 195, 198 effect on thyroid function, 396
Index 551
galactorrhea induced by, 493 Anxiolytics

neuroendocrine pathophysiology cholecystokinin receptor
and actions of, 30 antagonists as, 52
for postpartum psychosis, 295 dehydroepiandrosterone effects in
for steroid-induced animals, 209
psychopathology, 195 neuroendocrine pathophysiology
use in Addison’s disease, 170 and actions of, 30
use in hyperthyroidism, 426, progesterone metabolites as, 319
428–429 thyroid hormones as, 446, 459,
use in hypothyroidism, 435, 436 460
Antisocial personality disorder, insulin Appetite. See also Eating disorders
responses in, 122 in Cushing’s syndrome, 176
Antithyroid antibodies, 367–368, dehydroepiandrosterone and
485–486 dehydroepiandrosterone
in anxiety disorders, 389 sulfate levels and, 213
in bipolar disorder, 372, 373 glucocorticoid effects on, 515
in depression, 372, 373 neuropeptide Y in, 55
postpartum, 433 postpartum, 282
in hypothyroidism, 429, 430 during premenstrual phase, 262
lithium-induced increase in, 377 Arginine vasopressin (AVP), 43–47,
prevalence in general population, 472–473
372 disorders associated with
in schizophrenia, 372, 396 alterations of, 44–45
Anxiety disorders. See also specific Alzheimer’s disease, 45–46
anxiety disorders anorexia nervosa, 45
cholecystokinin and, 51–52 bipolar disorder, 45
Cushing’s syndrome and, 176 depression, 44–45
diazepam-binding inhibitor and, neurodegenerative disorders,
57 45
growth hormone and, 114 schizophrenia, 46–47
hyperprolactinemia and, 111, 286 functions of, 44, 473
hypothalamic-pituitary-adrenal corticotropin-releasing
axis activity and, 37, 38 hormone and, 44, 45, 473
thyroid function and, 376, 388–389 plasma osmolality, 44
cerebrospinal fluid studies of, infusion of, 480
389 modulation of stress response by,
in hyperthyroidism, 423–424, 480
424 synthesis and secretion of, 43–44,
in hypothyroidism, 432, 432, 473
445 Aristotle, 12
in panic disorder, 388, 389 Arthritis, rheumatoid, 525
peripheral thyroid hormones, Asthmatic children, cognitive effects
388–389 of prednisone in, 193
thyrotropin and antithyroid Autism, opioid antagonists for self-
antibodies, 389 injurious behavior in, 42
Autoimmune thyroid disease thyroid hormone treatment for,

Graves’ disease, 421–423 374–375, 446, 456–460
Hashimoto’s thyroiditis, 367–368, in non–rapid-cycling disease,
430, 485–486 457–458
AVP. See Arginine vasopressin in rapid-cycling disease,
458–459
Bailey, Percival, 18 Blues, postpartum, 282, 290–291
Barbiturates, use in hypothyroidism, consequences of, 291
436 endocrine factors in etiology of,
Battery, Robert, 16 290
Bayliss, William, 15 natural history of, 282
BDHI (Buss-Durkee Hostility nonendocrine factors in etiology of,
Inventory), 336–339 290
Beck Depression Inventory, 333 prevalence of, 282
Benzodiazepines, use in symptoms of, 282
hypothyroidism, 436 treatment of, 290–291
Bernard, Claude, 12, 17, 19 Bone mineral density
Berthold, Arnold Adolph, 12 hormone replacement therapy
Binge-eating disorder, thyroid effects on, 305
function in, 394 after menopause, 305
Bipolar disorder recurrent depression and, 526
arginine vasopressin in, 45 tamoxifen effects on, 317
cholecystokinin in, 51 Borderline personality disorder
dexamethasone suppression test in dexamethasone suppression test in,
manic phase of, 145–146 146–147
diabetes and, 117 opioid antagonists for self-injurious
growth hormone in, 114 behavior in, 43
ketoconazole for depression in, BPRS (Brief Psychiatric Rating Scale),
153 149
postpartum psychosis and, Brain. See also specific brain structures
283–284, 295 cholecystokinin in, 50–51
prevalence of, 117 as controller of and target for stress,
prolactin in, 111 515–518
rapid cycling, 372–375, 383, gonadal hormones, behavior and,
456–459 304–305
gender distribution of, 374 imaging of, 7
predisposing factors for, 374 in depression
prevalence of, 372 hippocampal changes,
thyroid function in, 366–367, 505–507
372–375, 383 pituitary pathology,
antithyroid antibodies, 372, 373 503–504, 506–507
cerebrospinal fluid studies of, thyroid system, 436–437
376 lithium blockage of corticosterone-
rapid cycling and, 374–375, induced increases in dopamine
383, 456–459 activity in, 196
Index 553
neurotensin in, 52–53 Cardiovascular disease

progesterone receptors in, 319 depression and, 525, 526
somatostatin in, 47 precautions for triiodothyronine
substance P in, 56 augmentation of
thyroid function, behavior and, antidepressants in elderly
419–438, 484 patients with, 454
early studies of, 419–420 serotonergic hypoactivity and
hyperthyroidism and myocardial infarction, 521
thyrotoxicosis, 420–429 Catechol O-methyltransferase,
hypothyroidism, 429–436 estrogen inhibition of, 305
in vivo brain imaging of, Cavalieri’s systematic sampling
436–437 theorem, 504
thyrotropin-releasing hormone, CCK. See Cholecystokinin
419 Cerebrospinal fluid concentration
triiodothyronine, 362 of arginine vasopressin, 44
“windows into,” 3, 5 in Alzheimer’s disease, 45–46
Brain-derived neurotrophic factor, in anorexia nervosa, 45
corticosteroid effects on, 197 in bipolar disorder, 45
Breast cancer, tamoxifen for, 317–318 in depression, 44–45
Breastfeeding in schizophrenia, 46–47
pharmacotherapy during, 294 of cholecystokinin
lithium, 294 in bipolar disorder, 51
prolactin levels during, 286 in panic disorder, 52
Bremer, Frédéric, 18 in schizophrenia, 51
Brief Psychiatric Rating Scale (BPRS), of corticotropin-releasing hormone
149 in Cushing’s syndrome, 182
Bright light exposure, for circadian in depression, 32–33
rhythm disorders, 84 dexamethasone
Bromocriptine, for nonsuppression and, 36
hyperprolactinemia, 109 treatment effects on, 33
Brown-Séquard, Charles-Edouard, in other psychiatric disorders,
13–14 37, 37–39
Bulimia nervosa anorexia nervosa, 39
insulin responses in, 121 anxiety disorders, 38
pituitary pathology in, 504–505 neurodegenerative disorders,
during premenstrual phase, 262 38–39
thyroid function in, 393–394 schizophrenia, 38
Buserelin, to suppress ovulation, Tourette’s syndrome, 39
313 of dehydroepiandrosterone and
Buss-Durkee Hostility Inventory dehydroepiandrosterone
(BDHI), 336–339 sulfate, age effects on, 208
of delta sleep–inducing peptide
Cannon, Walter Bradford, 19–20 in depression, 57
Carbamazepine, effects on thyroid lithium effects on, 58
function, 379 in schizophrenia, 58
Cerebrospinal fluid concentration in panic disorder, 51–52

(continued) receptors for, 51
of diazepam-binding inhibitor in in schizophrenia, 51
depression, 57 Cholecystokinin (CCK) receptor
of endogenous opioid peptides, 41 antagonists, 52
in self-injurious autistic Cholesterol
children, 43 hypothyroidism and
of 5-hydroxyindoleacetic acid, hypercholesterolemia, 433
methyltestosterone effects on, violent death and low levels of, 522
342 Chronic fatigue syndrome (CFS),
of neuropeptide Y dehydroepiandrosterone and
in anorexia nervosa, 55 dehydroepiandrosterone sulfate
in depression, 55 levels in, 214
of neurotensin, in schizophrenia, Chronobiotic disorders, 5, 83–84, 84
53–54 Chronobiotics, 83, 100
antipsychotic effects on, 53 for circadian rhythm disorders,
of neurotransmitters and 83–84
neuropeptides, corticosteroid compared with hypnotics, 83–84
effects on, 197 CI-988, 52
of somatostatin, 49–50 CIBIC-Plus (Clinician’s Interview-
in Alzheimer’s disease, 50 Based Impression of Change with
in depression, 49 Caregiver Input), 221
of substance P, 56 Circadian rhythm disorders, 83–84,
of thyroid hormones 84
in alcoholism, 386–387 bright light exposure for, 84
in anorexia nervosa, 393 chronobiotics for, 83–84
in anxiety disorders, 389 melatonin for, 98–100, 99
in mood disorders, 375, 376 Circadian rhythms, 85–87
Cerulein, 51 entrainment and, 86
Ceruletide, 51 light-dark cycle and, 85, 86
CFS (chronic fatigue syndrome), suprachiasmatic nucleus and,
dehydroepiandrosterone and 85–87, 86
dehydroepiandrosterone sulfate Cirrhosis, thyroid function in patients
levels in, 214 with, 385–386
Chlorimipramine, effects on thyroid Clinical Global Inventory, 333
function, 366 Clinician’s Interview-Based
m-Chlorophenylpiperazine (mCPP), Impression of Change with
111 Caregiver Input (CIBIC-Plus),
Chlorpromazine 221
effect on neurotensin level, 53 Clomiphene, 318
use in hyperthyroidism, 429 Clonidine, growth hormone responses
Cholecystokinin (CCK), 30, 50–52 to, 47
brain distribution of, 50–51 in depression, 114
dopamine and, 51 Clozapine, effect on neurotensin
gastrointestinal, 50 level, 53
Index 555
Clyde Mood Scale, 424 Corticosteroids, 5. See also specific

Cognitive-behavioral therapy, for corticosteroids
postpartum depression, 293 abuse potential for, 192–193
Cognitive disturbances for Addison’s disease, 169–170
in Addison’s disease, 168 effects on immune system, 515,
calcium imbalance and, 123 525
corticosteroid-induced, 193–194 hippocampal effects of, 152, 197
in Cushing’s syndrome, 174, dendritic branching, 527–531,
176–177 529
posttreatment improvement in, neuropsychiatric effects of, 139,
178–179 173–174, 189–198
dehydroepiandrosterone and cognitive disturbances,
dehydroepiandrosterone 193–194, 515
sulfate levels and, 208, 215 dosage and, 191–192
treatment effects of, 220– duration of, 192
222 frequency and character of,
in diabetes, 119 189–194
electroconvulsive therapy–induced, gender and, 191
effect of thyrotropin-releasing informing patient of risk of,
hormone on, 447–448 198
glucocorticoid excess, hippo- potential etiologic mechanisms
campal atrophy and, for, 196–198
533–534, 536 predictors of risk for, 191–192
in hyperthyroidism, 423–425, 424 related to steroid compound,
effect of treatment on, 426 196
in hypoparathyroidism, 124 steroid withdrawal syndrome,
in hypothyroidism, 431–433, 432 194–195
progesterone metabolite–induced, differentiation from adrenal
319 insufficiency, 194
Cognitive effects of estrogen, duration of, 194–195
307–308 etiology of, 194
Computed tomography of adrenal management of, 195
glands, 500, 501 symptoms of, 194
in depression, 35, 501–503, 506 timing of onset of, 192
Conduct disorder, dehydroepiandro- treatment of, 195–196, 198
sterone sulfate and, 212 paradoxical role of glucocorticoids,
Conflict Tactics Scale, 344 514–515
Contraceptive hormones, 6, 303–304, in pregnancy and puerperium, 289
315–317 roles in central nervous system
modes of administration for, 315 function, 196–197
mood and behavioral effects of, steroid psychosis, 5
315–317 in stress response, 514, 519 (See
pyridoxine deficiency and, 311 also Stress)
for women with history of containment, 519, 520,
depression, 311 522–523
Corticotropin-releasing hormone excess of, 165–166, 170, 171, 173

(CRH), 19, 31–40, 32, 166, 472 (See also Cushing’s disease and
arginine vasopressin and, 44 Cushing’s syndrome)
behavioral effects of, 182 antiglucocorticoid strategies for,
biosynthesis and secretion of, 166, 152–153
472 differential diagnosis of, 183,
circadian fluctuations in plasma 502–503
level of, 474 outcome and, 150–152
in Cushing’s syndrome, 182 specific symptoms associated
in depression, 32–36 with, 150
functions of, 31–32 functions of, 473
half-life of, 474 half-life of, 474
neuropeptide Y and, 55 in mania, 145–146
in other psychiatric disorders, 37, measuring plasma level of, 142,
37–39 474–475, 475
anorexia nervosa, 39 causes of falsely elevated or
anxiety disorders, 38 decreased levels, 475
neurodegenerative disorders, commentary on, 143
38–39 timing and frequency of,
schizophrenia, 38 474–475
Tourette’s syndrome, 39 in posttraumatic stress disorder,
Corticotropin-releasing hormone 147–148
(CRH) receptor antagonists, in pregnancy and puerperium, 289
39–40, 60 postpartum blues and, 290
Corticotropin-releasing hormone postpartum depression and,
(CRH) receptors, CRH1 and 291
CRH2 subtypes of, 40 psychiatric effects of abnormalities
Corticotropin-releasing hormone of, 139
(CRH) stimulation test, 34, ratio of dehydroepiandrosterone
478–480 to, 208, 210–212
in Cushing’s syndrome, 173, 184, response to corticotropin-releasing
478–480 hormone stimulation test, 34,
in depression, 34, 479, 480, 502, 478
503 response to dexamethasone
methodology for, 478–479 suppression test, 33–34,
Cortisol, 20, 32, 165–184, 473 139–144
behavioral effects of, 181–182 salivary, 141–143, 476
circadian fluctuations in plasma in schizophrenia, 148–150
level of, 167, 474 synthesis and secretion of, 166, 473
lithium blunting of, 196 urinary free, 142, 143, 151, 470,
deficiency of, 167, 169 (See also 475, 475–476
Addison’s disease) Cortisol synthesis inhibitors, 152
in depression, 35, 144–145, Cortisone, behavioral effects of, 139,
500–502 189
in dysthymic disorder, 146–147 Crawford, Albert, 15
Index 557
Cretinism, 13 somatic effects of excess

CRH. See Corticotropin-releasing glucocorticoids in, 172
hormone stress and, 171
Criminality, anabolic-androgenic testosterone in, 182
steroids and, 344–345, 349 treatment of, 178
Cushing, Harvey, 19, 139, 165 Cyclic adenosine monophosphate, 520
Cushing’s disease and Cushing’s Cyproheptadine, 47
syndrome, 5, 29, 139, 165–166 Cyproterone acetate, for male-to-
adrenal gland enlargement in, female transsexuals, 321
502–503
adrenocorticotropic hormone– 5¢D-I (5¢-deiodinase type I), 361, 362
dependent, 170 5¢D-II (5¢-deiodinase type II), 362
adrenocorticotropic hormone– Dale, Henry, 17, 18
independent, 170–171 Danazol, to suppress ovulation, 313
clinical features of, 165 Danocrine. See Danazol
dexamethasone suppression test in, DBI (diazepam-binding inhibitor),
173 57, 59
diagnosis of, 172–173 de Bordeu, Théophile, 11–12
differential diagnosis of, 182–184 De Medicis Sajous, Charles E., 17
basal hypothalamic-pituitary- Dehydroepiandrosterone (DHEA),
adrenal axis testing for, 4–6, 205–227
476–477 in Addison’s disease, 169
corticotropin-releasing behavioral effects in animals,
hormone stimulation test 209–210
for, 173, 184, 478, 479 anti-anxiety effects, 209
b-endorphin in, 182 anti-aggressive effects, 209
etiology of, 171 antidepressant effects, 209
gender distribution of, 167 eating behavior, 210
hippocampus in, 177, 505 memory enhancement, 209
b-lipotropin in, 182 biosynthetic pathway of, 206
neuropsychiatric symptoms of, concerns about unregulated use of,
173–182 207, 224–225, 227
behavioral effects of adrenocor- contraindications to, 225
ticotropic hormone and cotreatment with prednisone, 196
cortisol, 181–182 decreasing levels with aging, stress,
biological drives, 176 and illness, 208, 212, 247
cognition, 174, 176–177 discontinuation of, 226
mood and affect, 165–166, dosage of, 226
174–176, 502 effects on mood, memory, and
pathogenesis of, 177 functional abilities in humans,
posttreatment improvement of, 211–215
178–179 chronic fatigue syndrome, 214
relationship between hormone cognitive performance,
levels and depression, 214–215
179–181 depression, 211–213
Dehydroepiandrosterone (DHEA) cognitive effects of treatment with,

(continued) 221
effects on mood, memory, and decreasing levels with aging, stress,
functional abilities in humans and illness, 208, 212
(continued) effects on mood, memory, and
eating behavior and anorexia functional abilities in humans,
nervosa, 213 211–215
elderly persons, 214 chronic fatigue syndrome, 214
perimenopause-related cognitive performance,
depression, 272 214–215
pregnancy and postpartum depression, 211, 213
period, 212 eating behavior and anorexia
schizophrenia, 213–214 nervosa, 213
guidelines for clinical use of, elderly persons, 214
225–227 panic disorder, 213
mass marketing of, 207 postmenopausal women,
as a neurosteroid, 207–208 212–213
neurotrophic potential of, 210 schizophrenia, 213
patient monitoring during as a neurosteroid, 207–208
treatment with, 225–226 neurotrophic potential of, 210
possible mechanisms of neuropsy- obtaining baseline serum level of,
chiatric effects of, 222–224, 226
223 in pregnancy and puerperium, 286,
in pregnancy and puerperium, 288 288
ratio to cortisol, 208, 210–212 5¢-Deiodinase type I (5¢D-I), 361, 362
side effects of, 224–225 5¢-Deiodinase type II (5¢D-II), 362
treatment effects on well-being, Delirium, in thyrotoxicosis, 425
mood, and memory in Delta sleep–inducing peptide (DSIP),
humans, 216–222 57–58
Addison’s disease, 218 in depression, 57–58
anorexia nervosa, 219 lithium effects on level of, 58
cognition-enhancing effects, in schizophrenia, 58
220–222 in sleep disorders, 57
depression, 218–219 Delusions
dysthymia, 219 in hypothyroidism, 431, 433
elderly persons, 217–218 induced by anabolic-androgenic
Dehydroepiandrosterone sulfate steroids, 333, 336
(DHEA-S) postpartum, 283
behavioral effects in animals, Dementia. See also Alzheimer’s
209–210 disease; Cognitive disturbances
anti-anxiety effects, 209 corticosteroid-induced, 194
antidepressant effects, 209 effects of dehydroepiandrosterone
eating behavior, 209–210 and dehydroepiandrosterone
memory enhancement, 209 sulfate on cognitive
biosynthetic pathway of, 206 performance in, 215, 220–221
Index 559
Dementia praecox, 17 hypothalamic-pituitary-adrenal

Dendritic branching of hippocampal axis activity in, 20–21, 31–36,
neurons, glucocorticoid effects 33, 144–145, 499–500
on, 527–531, 529 adrenocorticotropic hormone,
Dentate gyrus neurogenesis, 531–533 503
11-Deoxycortisol, 473 antiglucocorticoid medications,
Depo-Provera. See Medroxyprogest- 152–153
erone acetate, depot basal tests of, 476–477
Depression. See also Antidepressants corticotropin-releasing hor-
arginine vasopressin in, 44–45 mone, 32–34, 479, 480,
cardiovascular disease and, 525, 502
526 cortisol hypersecretion, 35,
corticosteroid-induced, 190, 191 144–145, 500–502
treatment of, 195 dexamethasone suppression
corticosteroid-withdrawal, 193, test, 35–36, 140, 141,
194 144–145, 150, 184
Cushing’s syndrome and, 165–166, dexamethasone–corticotropin-
174–175, 502 releasing hormone test, 36
differential diagnosis of, effects of antiglucocorticoid
183–184, 476, 479 strategies, 152–153
posttreatment improvement in, imaging of, 499–507
178, 179 adrenal pathology, 35,
relationship with hormone 500–503, 506
levels, 179–181 hippocampal changes,
dehydroepiandrosterone and 505–507, 526
dehydroepiandrosterone pituitary pathology, 35,
sulfate in, 211–213 503–504, 506–507
effects of treatment with, pituitary gland enlargement, 34
218–219 principles for evaluation of, 470
delta sleep–inducing peptide in, relationship between hypercor-
57–58 tisolemia and outcome,
diabetes and, 117–118 150–151
diazepam-binding inhibitor in, 57, urinary free cortisol, 470, 475
59 insulin responses in, 121, 525
due to anabolic-androgenic steroid MK-869 for, 56, 60
withdrawal, 336, 339, 343, neuropeptide Y in, 55
348 obsessive-compulsive disorder and,
b-endorphin in, 41–42 114
growth hormone in, 48, 49, 50, perimenopause-related, 265–269
112–114, 492 causal relationship for, 269–271
hyperparathyroidism and, 123 symptoms of, 267, 268
hyperprolactinemia and, 109, 110, treatment of, 271–272
286 postmenopausal, 305, 306
hypoparathyroidism and, 125 postpartum, 267, 282–283,
hypopituitarism and, 126 291–294
Depression (continued) peripheral thyroid hormones,

postpartum (continued) 365–366
consequences of, 294 thyrotropin sources of variance,
duration of, 283 372
endocrine factors in etiology of, thyroid hormone treatment for,
291–292 372, 446–456, 460–461
premenstrual syndrome and, approaches to, 446
262 thyroid-stimulating hormone,
prevalence of, 282 448
psychotic vs. nonpsychotic, 282 thyrotropin-releasing hormone,
recurrence of, 294 446–448
risk factors for, 282–283, 283, combined with electrocon-
292 vulsive therapy,
severity of, 282 447–448
symptoms of, 282 monotherapy, 447
thyroiditis and, 433 thyroxine, 448–449
treatment of, 292–294 triiodothyronine, 449–456
poststroke, 110 to accelerate antidepressant
during pregnancy, 282–283 response, 450–451
premenstrual, 250, 251, 259 for antidepressant augmen-
prolactin in, 109, 110 tation, 451–456, 452,
psychotic, 21, 33 456, 460–461
antiglucocorticoid strategies for, combined with electrocon-
152–153 vulsive therapy, 450
dexamethasone suppression monotherapy, 449–450
test in, 141, 144–145 side effects and tolerability
postpartum, 282, 283 of, 453–454
recurrent, physiological effects of, winter, 83 (See also Seasonal
526 affective disorder)
schizophrenia and, 148–149 Desipramine
serotonergic hypoactivity and, effect on cerebrospinal fluid
521 corticotropin-releasing
somatostatin in, 49, 50 hormone concentration,
substance P in, 56 33
thyroid function and, 363, 364, effect on thyroid function, 366,
365–366, 368–372, 381–382 378
abnormal circadian thyrotropin triiodothyronine augmentation of,
rhythm, 368, 369 452
antithyroid antibodies, 372, 373 Dexamethasone
hyperthyroidism, 423–424, 424 “amphetamine-like” reaction to,
hypothyroidism, 431–433, 432, 192
445 cognitive disturbances induced by,
subclinical, 368–372, 193
370–371 effects on dopamine and
treatment of, 435 homovanillic acid levels, 197
Index 561
Dexamethasone suppression test impact of antidepressants on

(DST), 5, 21, 139–144, glucose regulation in,
153–154, 470–471, 481–482 118–119
in Alzheimer’s disease, influence of psychosocial factors
hippocampal volume and, 506 in, 116–117
clinical use of, 141–144, 154, 482 prevalence of, 115–116
age effects, 143–144 psychiatric effects of, 115–119
salivary cortisol, 141–143 bipolar disorder, 117
urinary free cortisol, 142, 143 depression, 117–118
in Cushing’s syndrome, 173 related to early age at onset, 116
definition of nonsuppression on, sexual dysfunction and, 116
140 stress and, 116, 525
in depression, 35–36, 140, vascular complications of, 118, 119
144–145, 184 Diagnostic Interview Schedule, 339
correlation with pituitary Diazepam-binding inhibitor (DBI),
volume, 504 57, 59
psychotic depression, 141, Dietary Supplement Health and
144–145 Education Act of 1994 (P.L. 103-
vs. schizophrenia, 141, 145 417), 207
in dysthymic disorder, 146–147 5a-Dihydroprogesterone (5a-DHT),
hypercortisolemia and specific 320
symptoms, 150 Dihydrotestosterone, 331
in mania, 145–146 Disinhibition, 517
plasma dexamethasone Distractibility, corticosteroid-
concentrations and, 140–141 induced, 191
in posttraumatic stress disorder, 38, Dizocilpine, 210
148 Dopamine, 30
protocol for, 33–34, 140, 481–482 cholecystokinin and, 51
relationship of hypercortisolemia corticosteroid effects on, 197
to outcome, 150–152 estrogen effects on, 287, 305
sampling times for, 140 lithium blockage of corticosterone-
in schizophrenia, 141, 145, induced increases in brain
148–150 activity of, 196
Dexamethasone–corticotropin- prolactin regulation by, 108, 286,
releasing hormone test, 36, 143 493
DHEA. See Dehydroepiandrosterone Dreams, in Cushing’s syndrome,
5a-DHT (5a-dihydroprogesterone), 176
320 DSIP. See Delta sleep–inducing
Diabetes mellitus, 5 peptide
adaptation to, 116 DST. See Dexamethasone suppression
cognitive symptoms in, 119 test
comorbidity with psychiatric Dyadic Adjustment Scale, 344
illness, 116 Dynorphins, 40–41
Cushing’s syndrome and, 172 Dyslipidemia, induced by anabolic-
fatigue and, 116 androgenic steroids, 332
Dysthymic disorder thyroid function and, 366, 380,

dexamethasone suppression test in, 398
146–147 thyroid hormone therapy
effects of dehydroepiandrosterone combined with, 446
treatment in, 219 thyrotropin-releasing hormone,
447–448
Eating behaviors. See also Appetite triiodothyronine, 450
dehydroepiandrosterone and use in hypothyroidism, 435
dehydroepiandrosterone Electroencephalography, in Cushing’s
sulfate effects on, 213 syndrome, 177
in animals, 209–210 Elliott, Thomas Renton, 17
neuropeptide Y and, 55 Emotional lability, corticosteroid-
Eating disorders induced, 191
diabetes and, 117 Endocrine therapy, history of, 13
insulin responses in, 121 b-Endorphin(s), 31, 34, 40–41
pituitary pathology in, 504–505 corticosteroid effects on
ECT. See Electroconvulsive therapy cerebrospinal fluid levels of,
Elderly persons 197
dexamethasone suppression test in, in Cushing’s syndrome, 182
143–144 in depression, 41–42
effects of dehydroepiandrosterone luteal-phase decreases in
on mood, memory, and premenstrual syndrome, 253
functional abilities in, 214, in pregnancy and puerperium, 286
217–218 postpartum blues and, 290
hippocampal glucocorticoid secretion of, 167
receptors in, 505 Enkephalins, 40–41
hyperthyroidism mimicking Entrainment, 86
depression in, 423 melatonin and, 88
pituitary volume in, 504 in blind persons, 89, 90
precautions for use of Epinephrine, 15, 17
triiodothyronine for ERPs (event-related potentials),
antidepressant augmentation during dehydroepiandrosterone
in cardiac patients, 454 treatment, 220
Electroconvulsive therapy (ECT) Estraderm. See Estradiol, transdermal
dehydroepiandrosterone sulfate patch
levels and response to, Estradiol, 247, 491–492
213 crystalline subcutaneous implants,
effect on cerebrospinal fluid for premenstrual syndrome,
corticotropin-releasing 314
hormone concentration, 33 effect on serotonergic receptors,
for postpartum psychosis, 295 287
for steroid-induced effects of dehydroepiandrosterone
psychopathology, 195 treatment on, 225, 226
for steroid withdrawal syndrome, levels during perimenopause, 271
195 measurement of, 492
Index 563
after menopause, 246, 305 in oral contraceptives, 315

metabolism of testosterone to, 331 for postmenopausal depression,
in normal menstrual cycle, 246, 305, 306
492 in pregnancy and puerperium,
normal values of, 490 286–288
placental production of, 286 postpartum blues and, 290
in pregnancy and puerperium, postpartum depression and,
286–287 291, 293
postpartum blues and, 290 for premenstrual syndrome, 314
postpartum depression and, prolactin regulation by, 108
291 role in mood, behavior, and anxiety
in premenopausal women, 308 disorders, 287–288, 303
premenstrual syndrome and, 252, Estrone, 491
254, 256 in hormone replacement therapy,
protein binding of, 492 308–309
secretion of, 491 in postmenopausal women, 308
transdermal patch in pregnancy and puerperium,
for postmenopausal women, 286–287
309 17a-Ethinyl testosterone, 313
for premenstrual syndrome, Euthyroid sick syndrome, 363–365,
314 364, 485
Estriol, 491–492 anorexia nervosa and, 392, 395
Estrogen(s), 491–492 Event-related potentials (ERPs),
effect on neurotransmitters, during dehydroepiandrosterone
287 treatment, 220
effect on thyroid function, 386 Exercise-induced hypothalamic-
for hormone replacement therapy, pituitary-adrenal axis activation,
305–312 (See also Hormone 477–478
replacement therapy)
adverse effects of, 311–312, Fatigue
312 in Cushing’s syndrome, 176
Alzheimer’s disease and, dehydroepiandrosterone and
307–308 dehydroepiandrosterone
antidepressant properties of, sulfate levels in chronic
305–306 fatigue syndrome, 214
cognitive effects of, 307–308 in diabetes mellitus, 116
contraindications to, 311, 312 postpartum, 282
preparations and dosages of, Female-to-male transsexuals, anabolic-
308–310 androgenic steroids for, 334
pros and cons of regimens of, Fight-or-flight response, 19
310–311 Fluoxetine
for male-to-female transsexuals, effect on cerebrospinal fluid
321 corticotropin-releasing
measurement of, 492 hormone concentration, 33
in normal menstrual cycle, 246 effect on thyroid function, 366
Fluoxetine (continued) GHRH (growth hormone–releasing

for postpartum depression, 293 hormone), 47, 48, 492
use in diabetic patients, 118 Gigantism, 111–112
Fluvoxamine, effect on thyroid Globus hystericus, 420
function, 366, 378 Glucagon, 122
Follicle-stimulating hormone (FSH), insufficiency of, 119, 122
246, 247, 247, 489–491 metabolic effects of, 122
measurement of, 490–491 Glucagonoma, 122
in men vs. women, 489–490 Glucocorticoids. See also Antigluco-
after menopause, 305, 491 corticoid medications; Cortico-
normal values of, 490 steroids; specific hormones
during perimenopause and antidepressant action of, 190
menopause, 271 effects on dendritic branching,
in pregnancy and puerperium, 527–531, 529
285–286 effects on immune system, 515,
premenstrual syndrome and, 252, 525
255 excess of, 172 (See also Cushing’s
secretion of, 304, 489–491 disease and Cushing’s
Four bodily humors, 10–11 syndrome)
Freud, Sigmund, 17 hippocampal receptors for, 505
Frölich, Alfred, 18 paradoxical role of, 514–515
FSH. See Follicle-stimulating in stress response, 514, 519
hormone containment, 519, 520,
522–523
GABA (g-aminobutyric acid) Glycogen storage diseases, 119
corticosteroid effects on, 197 GnRH (gonadotropin-releasing
estrogen-induced increased activity hormone), 246, 489
of, 305 in pregnancy and puerperium, 285
GABA (g-aminobutyric acid) type A secretion of, 304, 489
receptors Goiter, 13
allopregnanolone binding to, 288, in Graves’ disease, 421
319 lithium-induced, 428
3a-5a-tetrahydrodeoxycortico- toxic multinodular, 421
sterone modulation of, 289 Gonadal hormones, 6. See also specific
Galactorrhea, 493 hormones
Galen, 11, 12 clinical psychotropic effects of
“General adaptation syndrome,” 20 gonadal hormone medications
Generalized anxiety disorder in women, 303–322
cholecystokinin in, 52 effects of female hormones on
hypothalamic-pituitary-adrenal male-to-female
axis activity in, 38 transsexuals, 320–321
thyroid function in, 388, 389 gonadotropin-releasing
thyroid hormone treatment for, hormone analogs and
459 estrogen for premenstrual
Gerard, Ralph, 22 syndrome, 312–315
Index 565
hormone replacement therapy, in depression, 48, 49, 50, 112–114,

305–312 492
oral contraceptives, 315–317 measurement of, 492–493
progesterone and progestins, psychiatric effects of deficiency of,
318–320 112–113, 119
tamoxifen and other estrogen psychiatric effects of
antagonists, 317–318 overproduction of, 111–112
evaluation of, 489–492, 490 (See regulation of plasma levels of, 111
also Neuroendocrine testing) releasing and inhibiting factors for,
interaction between brain, 47, 48, 492
behavior and, 304–305 response to exogenous growth
in menstrual cycle–related and hormone–releasing hormone,
perimenopause-related 48
affective disorders, 245–272 in schizophrenia, 114–115
in postpartum psychiatric secretion of, 47, 111, 492
disorders, 281–296 treatment with, 112, 113
psychiatric effects of exogenous Growth hormone–releasing hormone
anabolic-androgenic steroids, (GHRH), 47, 48, 492
331–349 Gynecomastia, induced by anabolic-
regulation of secretion of, 304 androgenic steroids, 331, 332
role in mood and anxiety disorders,
287–288 Hallucinations
Gonadotropin-releasing hormone in hypothyroidism, 432, 433
(GnRH), 246, 489 induced by anabolic-androgenic
in pregnancy and puerperium, 285 steroids, 336
secretion of, 304, 489 postpartum, 283
Gonadotropin-releasing hormone Haloperidol
(GnRH) analogs, 313–315 effect on neurotensin level, 53
for premenstrual syndrome, for psychiatric symptoms of
313–315 hypothyroidism, 435, 436
Graves’ disease, 420. See also for psychiatric symptoms of
Thyrotoxicosis thyrotoxicosis, 426
clinical features of, 423 thyroid storm induced by, 426, 429
epidemiology of, 421 Hamilton Rating Scale for Depression
onset of, 421, 422 (Ham-D), 149, 179, 180, 219,
pathogenesis of, 421 333, 366, 502
psychological coping and course of, Harris, Geoffrey, W., 19
422 Hashimoto’s (autoimmune) thyroidi-
stress and, 421, 422, 525 tis, 367–368, 430, 485–486
thyrotoxicosis due to, 421 hCG (human chorionic gonadotro-
in twins, 421 pin), 253
Growth hormone, 47–48, 111–115, in pregnancy and puerperium,
492–493 285
in Alzheimer’s disease, 115 5-HIAA (5-hydroxyindoleacetic
in anxiety disorders, 114 acid), 342
Hippocampus homeostasis and stress, 19–20

in alcoholism, 506 HPA axis activity and depression,
in Alzheimer’s disease, 506 20–21
cognitive function of human present and future, 21–22
subjects and changes in Histrionic personality disorder, insulin
volume of, 533–534 responses in, 122
corticosteroid effects on, 152, 197 HIV (human immunodeficiency
serotonin receptor modulation, virus) infection, anabolic-
197 androgenic steroids for men with,
in Cushing’s syndrome, 177, 505 334
in depression, 505–507, 526 Homeostasis, allostasis, and stress,
effects of adrenal steroids on, 518, 19–20, 513, 518–519, 523, 524
526 Homovanillic acid, dexamethasone
effects of aging on, 505, 526–527, effect on plasma level of, 197
533–534 Hormone replacement therapy
glucocorticoid effects on dendritic (HRT), 6, 271–272, 303–312
branching in, 527–531, 529 adverse effects of, 311–312, 312
glucocorticoid receptors in, 505 cognitive effects of, 307–308
neurogenesis in adult dentate gyrus contraindications to, 311, 312
of, 531–533 estrogen preparations and dosages
neuroprotective effects of dehy- for, 308–310
droepiandrosterone on, 210 oral conjugated estrogens,
in posttraumatic stress disorder, 308–309
526 oral esterified estrogen and
role in learning and memory, 517 methyltestosterone,
serotonergic and noradrenergic 309–310
modulation of responsiveness transdermal patch, 309
of, 517 indications for, 305
Hippocrates of Cos, 11 antidepressant augmentation,
Historical roots of 306
neuroendocrinology, 4, 9–22, 10 osteoporosis prevention, 305
ancient concepts, 10–11 postmenopausal depression,
birth of modern endocrinology, 305, 306
14–15 mood and behavioral effects of,
development of 306–307
neuroendocrinology, 18–19 prevalence of use of, 305
early modern endocrinology, progesterone for, 303–304,
11–13 310–311
era of organotherapy, 13–14 pros and cons of regimens for,
growth of appreciation for 310–311
psychiatric aspects of Hormones. See also specific hormones
endocrinologic disorders, early definition of, 15
15–17 laboratory evaluation of, 469–494
growth of modern neurochemistry, (See also Neuroendocrine
17–18 testing)
Index 567
in pregnancy and puerperium, 3a-Hydroxy-5a-dihydroxyprogester-

284–289 one, 288
Hostility/anger 5-Hydroxyindoleacetic acid
hyperprolactinemia and, 286 (5-HIAA), 342
induced by anabolic-androgenic 3a-Hydroxy-5a-pregnan-20-one, 319,
steroids, 335–337 320
serotonergic hypoactivity and, 521, 3a-Hydroxy-5a-pregnan-20-one, 319
526 17-Hydroxyprogesterone, 318
Hot flushes, 268, 271 5-Hydroxytryptamine (5-HT). See
HPA axis. See Hypothalamic- Serotonin
pituitary-adrenal axis 5-Hydroxytryptophan (5-HTP), 47
HPG (hypothalamic-pituitary- Hypercalcemia, 123–124
gonadal) axis, 304, 489–490 in Addison’s disease, 169
assessment of, 489–492 (See also Hypercholesterolemia,
Neuroendocrine testing) hypothyroidism and, 433
hPL (human placental lactogen), 285 Hypercortisolemia. See also Cortisol
HPT (hypothalamic-pituitary- antiglucocorticoid strategies for,
thyroid) axis, 361–362 152–153
assessment of, 362–363, 419, in Cushing’s syndrome, 165–166,
484–489 (See also 170, 171, 173
Neuroendocrine testing) differential diagnosis of, 183
homeostatic control within, 362, outcome and, 150–151
484 plasma sampling for diagnosis of,
HRT. See Hormone replacement 474–475
therapy specific symptoms associated with,
5-HT (5-hydroxytryptamine). See 150
Serotonin Hyperglucagonemia, 122
5-HTP (5-hydroxytryptophan), 47 Hyperglycemia. See also Diabetes
Human chorionic gonadotropin mellitus
(hCG), 253 antidepressant-induced, 118
in pregnancy and puerperium, 285 comorbidity with psychiatric
Human immunodeficiency virus illness, 115
(HIV) infection, anabolic- glucagonoma and, 122
androgenic steroids for men with, psychiatric effects of, 115–119
334 Hyperkalemia, in Addison’s disease,
Human placental lactogen (hPL), 285 168, 169
Hunter, John, 12 Hyperparathyroidism, 123–124
Huntington’s disease causes of, 123
hypothalamic-pituitary-adrenal hypercalcemia and, 123–124
axis activity in, 37, 38 psychiatric effects of, 123–124
neurotensin in, 54 prevalence of, 123
Hydrocortisone, cognitive effects of, symptoms of, 123, 124
193 Hyperprolactinemia, 108–109. See
17-Hydroxycorticosteroid, 21 also Prolactin
in pregnancy and puerperium, 289 anxiety and, 111, 286
Hyperprolactinemia (continued) Hypogonadotropic hypogonadism,

depression and, 109, 110, 286 489
“functional,” 108 Hypokalemia, in Cushing’s syndrome,
gender-related effects of, 109 172
hostility and, 286 Hypomania
in pregnancy and lactation, 286 corticosteroid-induced, 191
psychotic disorders and, 109 in multiple sclerosis patients
schizophrenia, 110–111 with family history of
Hyperthyroidism, 420–429. See also depression, 192
Graves’ disease; Thyrotoxicosis induced by anabolic-androgenic
cause of, 420 steroids, 338, 341
clinical features of, 423 Hyponatremia, in Addison’s disease,
differentiation from thyrotoxicosis, 168, 169
421 Hypoparathyroidism, 124–125
early studies of behavioral changes causes of, 124
in, 419–420 clinical symptoms of, 124
interactions between psychotropic hypocalcemia and, 124
drugs and, 428–429 psychiatric effects of, 124–125
antidepressants, 378–379, 428 Hypopituitarism, 125–126
antipsychotics, 428–429 causes of, 125–126
lithium, 428 clinical features of, 126
laboratory diagnosis of, 425 diagnosis of, 126
neuropsychiatric symptoms and psychiatric effects of, 126
signs of, 423–425, 445 Hypothalamic-pituitary-adrenal
in elderly persons, 423 (HPA) axis, 4, 5, 9, 31, 32,
prevalence of, 423, 424 139–154, 472–474
panic disorder and, 388 in Addison’s disease, 166–170
Hyperthyroxinemia, transient, 363–365 assessment of, 33–34, 139–144,
Hypocalcemia, 124 472–484 (See also Neuro-
Hypoglycemia, 119–120 endocrine testing)
antidepressant-induced, 118 in Cushing’s syndrome/Cushing’s
causes of, 119 disease, 165–166, 170–184
cognitive symptoms and, 119 dehydroepiandrosterone and
comorbidity with psychiatric dehydroepiandrosterone
illness, 115 sulfate effects on, 222–223
fasting, in Addison’s disease, 168 in depression, 20–21, 31, 33,
idiopathic postprandial, 119–120 144–145, 150, 499–500
insulin-induced, to stimulate adrenal gland enlargement, 35
hypothalamic corticotropin- corticotropin-releasing
releasing hormone release, hormone, 32–34
477 cortisol hypersecretion, 35
psychiatric effects of, 119–120 dexamethasone suppression
relationship between panic test nonsuppression, 35–36
disorder and, 120 dexamethasone–corticotropin-
symptoms of, 120 releasing hormone test, 36
Index 569
imaging of, 499–507 homeostatic control within, 362,

adrenal pathology, 500–503 484
hippocampal changes, Hypothalamic releasing factors, 4, 29,
505–506 30
pituitary pathology, 503–504 clinical implications of alterations
pituitary gland enlargement, 34 of, 58–60, 59
psychotic depression, 144–145 corticotropin-releasing hormone,
urinary free cortisol, 470 19, 31–40, 32
hypercortisolemia and specific Hypothalamo-hypophyseal portal
symptoms, 150 system, 43, 44
major secretory products of, Hypothalamus, 18–19
472–474 corticotropin-releasing hormone–
circadian fluctuations in plasma containing neurons in, 31
levels of, 167, 474 production of arginine vasopressin
mediation of stress responses by, in, 473
32, 32, 472, 514 regulation of corticotropin-
containment of, 519, 520, releasing hormone secretion
522–523 by, 472
habituation vs. enhancement of, Hypothyroidism, 429–436
522 abnormal circadian thyrotropin
in other psychiatric disorders, 37, rhythm in, 368
37–39, 147–150 anorexia nervosa and, 390, 392
anorexia nervosa, 39 bipolar disorder and, 374–375,
anxiety disorders, 38 383, 456–459
neurodegenerative disorders, thyroid hormone treatment for,
38–39 457–459
posttraumatic stress disorder, causes of, 429–431
38, 147–148 central, 431, 484
schizophrenia, 38, 148–150 clinical features of, 431
Tourette’s syndrome, 39 definition of, 429
physiology of, 166–167, 472–473 depression and, 368–372,
regulatory mechanisms of, 166, 370–371, 382
472 due to iodine deficiency, 430
relationship of hypercortisolemia due to resistance to thyroid
to outcome, 150–152 hormone, 431
Hypothalamic-pituitary-gonadal early studies of behavioral changes
(HPG) axis, 304, 489–490 in, 420
assessment of, 489–492 (See also epidemiology of, 429–430
Neuroendocrine testing) grades of, 367, 367, 429, 430
Hypothalamic-pituitary-thyroid hypercholesterolemia and, 433
(HPT) axis, 361–362. See also iatrogenic, 430
Thyroid function idiopathic, 430
assessment of, 362–363, 419, interaction between psychotropic
484–489 (See also Neuro- drugs and, 436
endocrine testing) lithium, 377, 428, 436
Hypothyroidism (continued) Insomnia. See also Sleep disturbances

laboratory diagnosis of, 433–434 in Cushing’s syndrome, 174, 176
neuropsychiatric symptoms and delta sleep–inducing peptide in, 57
signs of, 431–433, 445 Insulin, 115–122
overt psychiatric antidepressant effects on, 118
manifestations, 433 in Cushing’s disease, 172
prevalence of, 432, 432 in depression, 121, 525
treatment of, 434–435 in eating disorders, 121
primary, 429–430 glucocorticoid elevation and
recovery of psychiatric function resistance to, 515, 523–524
after treatment of, 434, in personality disorders and
434–435 aggression, 121–122
seasonal affective disorder and, 375 psychiatric effects of
secondary, 431 hyperglycemia and diabetes,
subclinical, 367, 367–368, 429, 115–119
430, 430, 435 psychiatric effects of hypoglycemia
causes of, 367 or overproduction of, 119–120
indications for treatment of, Insulin-induced hypoglycemia, to
368 stimulate hypothalamic
progression to overt corticotropin-releasing hormone
hypothyroidism, 368 release, 477
tertiary, 431 Insulin-like growth factor I (IGF-I),
111, 223, 492–493
IGF-I (insulin-like growth factor I), Insulin tolerance test (ITT), 107–108,
111, 223, 492–493 120
Imaging studies, 7. See also specific Insulinoma, 119, 120
imaging modalities Interleukin-1, 223
of hypothalamic-pituitary-adrenal Interleukin-6, 223
axis activity in depression, Interpersonal therapy, for postpartum
499–507 depression, 293
adrenal pathology, 500–503, Involutional melancholia, 267, 269
506 Iodine deficiency, 430
hippocampal changes, 505–507 Irritability
pituitary pathology, 503–504, in Cushing’s syndrome, 174, 183
506–507 in hyperthyroidism, 423
in vivo brain imaging to study induced by anabolic-androgenic
thyroid system and brain steroids, 335, 338
activity, 436–437 postpartum, 282
Imipramine Isocarboxazid, effect on glucose
effect on thyroid function, 366, 378 regulation, 118
triiodothyronine augmentation of, ITT (insulin tolerance test), 107–108,
452 120
Immune function
glucocorticoid effects on, 515, 525 Jet lag, 83, 84, 518
stress and, 524–525 melatonin for, 98–99, 99
Index 571
Ketoconazole monitoring recommendations,

antidepressant effects of, 152–153 377
in bipolar illness, 153 rapid-cycling bipolar disorder,
in schizophrenia and 374
schizoaffective disorder, use in hyperthyroidism, 428
153 when combined with
for Cushing’s syndrome, 178 carbamazepine, 380
Kraepelin, Emil, 17 hyperparathyroidism induced by,
123
L-365,260, 52 for steroid-induced psychopathol-
Laboratory evaluation of ogy, 195–196, 198
neuroendocrine systems, 7, Liver disease, thyroid function in
469–494. See also alcoholic patients with, 385–386
Neuroendocrine testing Loewi, Otto, 18
Lamotrigine, to prevent steroid Lupron. See Leuprolide acetate
psychosis, 196 Luteal phase of menstrual cycle, 246.
Laron dwarfism, 492–493 See also Premenstrual syndrome
Learned helplessness, 525–526 mood disorders in, 248–259
Leptin, 394 Luteinizing hormone (LH), 246, 247,
Leucine-enkephalin (leu-enkephalin), 489–491
40, 41 measurement of, 490–491
Leuprolide acetate, for premenstrual in men vs. women, 489–490
syndrome, 256, 260–261, 314 after menopause, 305, 491
Levonorgestrel, 316–317 normal values of, 490
LH. See Luteinizing hormone in pregnancy and puerperium,
Light-dark cycles 285–286
circadian rhythms and, 85, 86 premenstrual syndrome and, 252,
melatonin secretion and, 87 255
b-Lipoprotein, corticosteroid effects secretion of, 304, 489–491
on cerebrospinal fluid levels of,
197 Magnetic resonance imaging
b-Lipotropin, 41 in Cushing’s syndrome, 177
in Cushing’s syndrome, 182 in depression
Lithium adrenal gland enlargement, 35,
for augmentation of selective 502
serotonin reuptake inhibitors, hippocampal changes, 505
460–461 pituitary gland enlargement,
contraindicated during 35, 503–504
breastfeeding, 294 in eating disorders, 505
effect on delta sleep–inducing Magnetic resonance spectroscopy,
peptide, 58 studies of thyroid system and
effects on thyroid function, 366, brain activity, 437
377 Male-to-female transsexuals, effects
lithium-induced hypothyroid- of female hormones in, 304,
ism, 377, 428, 436 320–321
Mania. See also Bipolar disorder Melatonin, 4–5, 83–85, 87–102

corticosteroid-induced, 190 biology of, 87
dosage and, 192 dosage of, 96, 101
in multiple sclerosis patients effect on reproductive biology,
with family history of 87
depression, 192 entraining effects of, 88
Cushing’s syndrome and, 176 fad use of, 85
dexamethasone suppression test in, for jet lag, 98–99
145–146 light-dark cycles and secretion of,
in hypercalcemia, 123 87
induced by anabolic-androgenic for night-shift workers, 92–96, 94,
steroids, 336, 338, 341, 347 95
postpartum psychosis and, 284 pharmacokinetics of, 101
during premenstrual phase, 262 phase resetting in humans by,
in thyrotoxicosis, 425 88–92, 90–92
treatment of, 426 in blind persons, 88–89
MAOIs. See Monoamine oxidase dim light melatonin onset, 89
inhibitors phase response curves for, 87–88
Maprotiline, effect on thyroid safety of, 101–102
function, 366, 378 sleep-promoting (hypnotic) effects
Maternity blues, 282, 290–291 of, 84, 96–98, 98
consequences of, 291 interaction with chronobiotic
endocrine factors in etiology of, effects, 98–100
290 species differences in phase-
natural history of, 282 shifting effects of, 88
nonendocrine factors in etiology of, Melatonin analogs, 100
290 Memory
prevalence of, 282 enhancement of
symptoms of, 282 by dehydroepiandrosterone,
treatment of, 290–291 209, 220
mCPP (m-chlorophenylpiperazine), by estrogen, 307
111 impairment of
MDAI (Multidimensional Anger corticosteroid-induced, 191,
Inventory), 337 193–194, 515
Medroxyprogesterone acetate in Cushing’s syndrome, 174,
depot, for contraception, 316–317 176–177
for hormone replacement therapy, hypothyroidism and, 432, 432,
310, 311 433
for male-to-female transsexuals, progesterone
321 metabolite–induced, 319
Melancholia, involutional, 267, 269 in thyrotoxicosis, 424
Melanocyte-stimulating hormone role of hippocampus in learning
(MSH), 32 and, 517
in Addison’s disease, 168 MEN (multiple endocrine neoplasia)
in Cushing’s disease, 170 syndromes, 122, 123, 125
Index 573
Menopause, 246–247, 305, 489. See Methyltestosterone

also Postmenopausal women with estrogen for hormone
average age at onset, 265 replacement therapy,
gonadal hormone levels after, 305, 309–310
491 psychiatric effects of, 333
Menstrual cycle, 6, 245–246 high-dose laboratory studies of,
behavioral effects of hormone 341
changes during, 245 Methysergide, 47
modulation of preexisting Metyrapone, for depression, 152
psychopathology by, Mifepristone (RU 486), 253, 257–258
259–262, 263 depression and adrenocortico-
normal, 246 tropic hormone response to,
recrudescence of previously 522–523
experienced psychiatric illness for psychotic depression, 153
triggered by, 262 Minnesota Multiphasic Personality
Menstrual cycle–related mood Inventory (MMPI), 335, 424,
disorders (MRMD), 248–259, 426
489. See also Premenstrual Mitotane, for Cushing’s syndrome,
syndrome 178, 180
association with abnormal MK-869, 56, 60
physiological events, MMPI (Minnesota Multiphasic
252–253, 254–255 Personality Inventory), 335, 424,
case example of, 248 426
definition of, 248 Monoamine oxidase, estrogen
luteal phase–specific mood inhibition of, 305, 306
disturbances, 250, 251 Monoamine oxidase inhibitors
necessity of luteal phase for occur- (MAOIs)
rence of, 253–259, 257, 258 effect on glucose regulation, 118
research diagnostic criteria for effect on thyroid function,
premenstrual dysphoric 377–378
disorder, 249 neuroendocrine pathophysiology
thyroid function in premenstrual and actions of, 31
dysphoric disorder, 389–390 use in hyperthyroidism, 378, 428
Mental retardation, opioid antagonists Mood stabilizers. See also specific drugs
for self-injurious behavior in, 42 for postpartum psychosis, 295
Mesterolone, antidepressant effect of, for steroid-induced
333 psychopathology, 195–196,
Metabolic alkalosis, in Cushing’s 198
syndrome, 172 MRMD. See Menstrual cycle–related
Methimazole, 366 mood disorders
Methionine-enkephalin (met- MSH (melanocyte-stimulating
enkephalin), 40, 41 hormone), 32
3-Methoxy-4-hydroxyphenylglycol, in Addison’s disease, 168
corticosteroid effects on in Cushing’s disease, 170
cerebrospinal fluid levels of, 197 Mueller, Johannes, 12
Multidimensional Anger Inventory of gonadotropins and sex steroids,

(MDAI), 337 489–493, 490
Multidimensional Personality estrogen and progesterone,
Questionnaire, 337 491–492
Multiple endocrine neoplasia (MEN) follicle-stimulating hormone
syndromes, 122, 123, 125 and luteinizing hormone,
Multiple sclerosis 490–491
effects of dehydroepiandrosterone growth hormone, 492–493
treatment in, 216 prolactin, 493
neuropsychiatric effects of adreno- testosterone, 491
corticotropic hormone for, of hypothalamic-pituitary-adrenal
192 axis activity, 33–34, 139–144,
lithium prophylaxis for, 195–196 472–484
Murray, George, 13 basal activity, 474–477
Muscle dysmorphia, induced by to differentiate depression
anabolic-androgenic steroids, 343 from Cushing’s
Muscular dystrophy, anabolic- syndrome, 476–477
androgenic steroids for, 333 plasma adrenocorticotropic
Myocardial infarction, serotonergic hormone and cortisol,
hypoactivity and, 521 142, 474–475, 475
Myxedema, 13, 16. See also in refractory depression, 477
Hypothyroidism salivary cortisol, 141–143,
Myxedema coma, 429, 435 476
“Myxedematous madness,” 420, 431 urinary free cortisol, 142,
143, 475, 475–476
Nalmefene, in schizophrenia, 42 methods and problems in,
Naloxone, 42 482–484
provocative test for adrenocortico- provocative tests, 477–482
tropic hormone and cortisol adrenocorticotropic
response, 477 hormone stimulation
in schizophrenia, 42 test, 169, 480–481
for self-injurious behavior, 42 arginine vasopressin
Naltrexone, for self-injurious infusion, 480
behavior, 42–43 corticotropin-releasing
Nandrolone decanoate, 335 hormone stimulation
Narcolepsy, delta sleep–inducing test, 34, 478–480
peptide in, 57 dexamethasone suppression
Neodynorphin, 41 test, 33–34, 139–144,
Neurodegenerative disorders 153–154, 481–482
arginine vasopressin in, 45 dexamethasone–cortico-
hypothalamic-pituitary-adrenal tropin-releasing
axis activity in, 37, 38–39 hormone test, 36, 143
Neuroendocrine testing, 7, 469–494 exercise, 477–478
appropriate use of, 471–472 insulin-induced hypoglyce-
in basal (nonstimulated) state, 470 mia, 477
Index 575
naloxone administration, neuropeptide Y, 54–56

477 neurotensin, 52–54
of hypothalamic-pituitary-thyroid somatostatin, 47, 49–50
axis activity, 362–363, 419, substance P, 56
484–489 Neurotensin, 52–54
antithyroid antibodies, in Alzheimer’s disease, 54
485–486 brain distribution of, 52–53
assays for thyroid-stimulating effects of antipsychotics on level of,
hormone, 486–487 53
assays for thyroxine, 487–489, as endogenous neuroleptic, 53
488 in Huntington’s disease, 54
basal hormone measurements, in schizophrenia, 53–54
485, 486 antipsychotic effects on, 53
during lithium treatment, 377 postmortem studies of, 53–54
provocative tests, 486 Neurotensin receptor agonists, 54
principles of, 470–471 Neurotensin receptor antagonists, 54
provocative tests, 470–471 Neurotransmitters, 17–18, 29–30, 30
Neuroendocrine window strategy, 29, corticosteroid effects on, 181, 197
31, 59 effects on glucose regulation, 118
Neurokinin A, 56 endogenous opioid peptides as, 40
Neurokinin B, 56 estrogen effects on, 287
Neuroleptics. See Antipsychotics prolactin regulation by, 108
Neuronal atrophy, corticosteroid- stimulation of corticotropin-
induced, 197–198 releasing hormone release by,
Neuropeptide Y, 50, 54–56 472
anatomical distribution of, 55 stress and, 519–522, 520
in appetitive behaviors and norepinephrine, 519–521
anorexia, 55 serotonin, 521–522
corticotropin-releasing hormone thyroid hormone effects on, 438
and, 55 Night-shift work maladaptation, 83, 84
in depression and suicide victims, melatonin for, 92–96, 94, 95
55 Norepinephrine, 18, 29, 30
receptors for, 55 corticosteroid effects on
Neuropeptide Y receptor agonists, 56 cerebrospinal fluid levels of,
Neuropeptide Y receptor antagonists, 197
56 estrogen effects on receptors for,
Neuropeptides, 4, 29. See also specific 287
neuropeptides modulation of hippocampal
cholecystokinin, 50–52 responsiveness by, 517
clinical implications of alterations stimulation of corticotropin-
of, 58–60, 59 releasing hormone release by,
delta sleep–inducing peptide, 472
57–58 stimulation of growth hormone
diazepam-binding inhibitor, 57 release by, 47
endogenous opioids, 40–43 stress and, 519–521, 520
Norethindrone acetate, 311 pyridoxine deficiency and, 311

Norplant. See Levonorgestrel for women with history of
depression, 311
Obesity Organotherapy, 13–14
arginine vasopressin in, 44 Osmolality, plasma, 44
in binge-eating disorder, 394 Osteoporosis, postmenopausal, 305
in Cushing’s syndrome, 172 Ovariectomy, 16
glucocorticoid elevation and, 515 Ovulation, 246, 247
Obsessive-compulsive disorder (OCD) clomiphene for induction of, 318
depression and, 114 premenstrual syndrome and, 313
aminoglutethimide for, 153 suppression of, 265, 313–314
growth hormone in, 114 Oxytocin, 44
hypothalamic-pituitary-adrenal
axis activity in, 37, 38 Panhypopituitarism, 125–126
prolactin in, 111 causes of, 125–126
thyroid function in, 388, 389 clinical features of, 126
17a-OH-pregnenolone, 473 diagnosis of, 126
17a-OH-progesterone, 473 psychiatric effects of, 126
Olanzapine Panic disorder
for psychiatric symptoms of cholecystokinin in, 51–52
thyrotoxicosis, 426 Cushing’s syndrome and, 176
for steroid psychosis, 195 dehydroepiandrosterone sulfate in,
Oliver, George, 14–15, 17 213
Opioid abuse/dependence, anabolic- growth hormone in, 114
androgenic steroid use and, 345 hypothalamic-pituitary-adrenal
Opioid agonists, 42 axis activity in, 37, 38
Opioid antagonists, 42 during premenstrual phase, 262
in schizophrenia, 42 prolactin in, 111
for self-injurious behavior, 42–43 relationship between
Opioid peptides, endogenous, 40–43 hypoglycemia and, 120
classes of, 41 thyroid function in, 388, 389
effect on thyrotropin secretion, thyroid hormone treatment for,
368 459, 460
as neurotransmitters, 40 Paranoia, hypothyroidism and, 432,
precursors of, 40–41 433
prolactin regulation by, 108 Parathyroid adenoma, 123
role in psychiatric disorders, 41 Parathyroid hormone, 123–125
depression, 41–42 factors affecting secretion of, 123
self-injurious behaviors, 42–43, psychiatric effects of
59 hyperparathyroidism,
Oral contraceptives, 6, 303, 304, 123–124
315–317 psychiatric effects of
modes of administration for, 315 hypoparathyroidism, 124–125
mood and behavioral effects of, Parkinson’s disease
315–316 arginine vasopressin in, 45
Index 577
hypothalamic-pituitary-adrenal enlargement of, in depression, 34,

axis activity in, 37, 38 503–504, 506–507
PD. See Psychotic depression magnetic resonance imaging of,
Pentagastrin, 52 503–504
Perimenopause, 6, 246–247, 265–272 normal size and weight of, 503
age window for, 265–266 Pituitary hormones, 18–19, 30
behavioral effects of hormone arginine vasopressin, 43–47,
changes during, 245 472–473
definition and characterization of, growth hormone, 47–48, 111–115,
265–266 492–493
occurrence of mood disturbances oxytocin, 44
during, 266–267 panhypopituitarism, 125–126
relationships between mood prolactin, 108–111, 493
disturbances and, 267–269 PMS. See Premenstrual syndrome
causal relationship, 269–271 POMC (pro-opiomelanocortin),
symptoms of depression during, 40–41, 167
267, 268 in Addison’s disease, 168
treatment of mood and behavioral POMS (Profile of Mood States),
disturbances during, 271–272 336–339
Personality disorders, insulin Porteus maze, 425
responses in, 121–122 Positron emission tomography,
Phencyclidine, 30 60
Phenelzine, effect on glucose studies of thyroid system and brain
regulation, 118 activity, 437
Phenothiazines. See also Postmenopausal women
Antipsychotics anabolic-androgenic steroids for,
for psychiatric symptoms of 334
hypothyroidism, 435 dehydroepiandrosterone sulfate
for steroid-induced levels in, 212–213
psychopathology, 195 depression in, 305, 306
use in hyperthyroidism, 429 hormone replacement therapy for,
Phentolamine, inhibition of growth 6, 271–272, 303–312 (See also
hormone release by, 47 Hormone replacement
Pheochromocytoma, 123, 125, therapy)
169 osteoporosis in, 305
Phototherapy, effect on thyroid Postpartum psychiatric disorders, 6,
function, 381 281–296
Pigmentation changes blues, 282, 290–291
in Addison’s disease, 168 consequences of, 291
in Cushing’s disease, 170 endocrine factors in etiology of,
Pituitary adenoma, thyrotropin- 290
secreting, 421 nonendocrine factors in
Pituitary gland etiology of, 290
in alcoholism, 506 treatment of, 290–291
in eating disorders, 504–505 classification of, 281
Postpartum psychiatric disorders gonadotropin-releasing

(continued) hormone, 285
dehydroepiandrosterone human chorionic gonadotropin,
supplementation and, 212 285
depression, 267, 282–283, 291–294 human placental lactogen, 285
consequences of, 294 postpartum blues, 290
duration of, 283 postpartum depression,
endocrine factors in etiology of, 291–292
291–292 postpartum psychosis, 294–295
premenstrual syndrome and, progesterone, 288
262 prolactin, 286
prevalence of, 282 thyroid hormones, 288–289
psychotic vs. nonpsychotic, 282 Posttraumatic stress disorder (PTSD),
recurrence of, 294 535–536
risk factors for, 282–283, 283, dexamethasone suppression test in,
292 38, 148
severity of, 282 hippocampal atrophy in, 526,
symptoms of, 282 536
thyroiditis and, 433 hypothalamic-pituitary-adrenal
treatment of, 292–294 axis activity in, 37, 38,
historical perspectives on, 281 147–148
menstrual cycle and, 262 stress, 38, 148
psychosis, 262, 283–284, 294–296 thyroid function in, 388–389
bipolar disorder and, 283–284, Prednisone
295 abuse potential for, 193
consequences of, 295–296 dehydroepiandrosterone
endocrine factors in etiology of, cotreatment with, 196
294–295 neuropsychiatric effects of, 173,
incidence of, 283 190
nonendocrine factors in in asthmatic children, 193
etiology of, 295 cognitive disturbances, 193
onset of, 283 dosage and, 191
recurrence of, 295–296 in multiple sclerosis patients
symptoms of, 283 with family history of
treatment of, 295 depression, 192
role of endocrine changes in sensory flooding, 191
pregnancy and puerperium in Pregnancy. See also Postpartum
etiology of, 281, 284–289 psychiatric disorders
androgens, 288 dehydroepiandrosterone in, 212
corticosteroids, 289 depression during, 282–283
b-endorphin, 286 endocrine changes in, 284–289
estrogen, 286–288 androgens, 288
follicle-stimulating hormone corticosteroids, 289
and luteinizing hormone, b-endorphin, 286
285–286 estrogen, 286–288
Index 579
follicle-stimulating hormone prevalence of, 250, 312–313

and luteinizing hormone, role of ovulation in
285–286 pathophysiology of, 313
gonadotropin-releasing treatment of, 264–265
hormone, 285 antidepressants, 315
human chorionic gonadotropin, estrogen, 314
285 gonadotropin-releasing
human placental lactogen, 285 hormone analogs and
progesterone, 288 estrogen, 313–314
prolactin, 286 leuprolide, 256, 260–261, 314
thyroid hormones, 288–289, progesterone, 264, 320
488 symptomatic, 315
use of antidepressants in, 293 Pro-opiomelanocortin (POMC),
5a-Pregnane-3,20-dione, 320 40–41, 167
Pregnanolone, 319 in Addison’s disease, 168
premenstrual syndrome and, 252 Prodynorphin, 41
Pregnenolone, 320, 473 Proenkephalin, 41
Pregnenolone sulfate, 319–320 Profile of Mood States (POMS),
Premarin. See Hormone replacement 336–339
therapy Progesterone, 247, 492
Premenstrual dysphoric disorder, 248 brain receptors for, 319
prevalence of, 313 in hormone replacement therapy,
research diagnostic criteria for, 303–304, 310–311 (See also
249, 250 Hormone replacement
thyroid function in, 389–390 therapy)
Premenstrual syndrome (PMS), measurement of, 492
248–259. See also Menstrual after menopause, 246, 305
cycle–related mood disorders metabolites of, 288, 319
Daily Rating Form for, 264 mood and behavior effects of
depression self-ratings in, 250, 251 progestins and, 318–320
etiology of, 313 in normal menstrual cycle, 246,
evaluation of patient with, 264 318, 320, 492
menstrual cycle–related hormone normal values of, 490
changes and, 252–253, in oral contraceptives, 310,
254–255 315–316
mood side effects of hormone in pregnancy and puerperium, 288
replacement therapy in postpartum blues and, 290
women with history of, postpartum depression and,
310–311 291
mood side effects of oral for premenstrual syndrome, 264,
contraceptives in women with 320
history of, 316 premenstrual syndrome and, 252,
operational definition of, 250 254, 256
postpartum behavioral changes protein binding of, 492
and, 262, 290 Proglumide, 51
Prolactin, 108–111, 493. See also corticosteroid-induced, 139, 173,

Hyperprolactinemia 190, 191
in anxiety, 111, 286 dosage and, 192
in bipolar disorder, 111 treatment of, 195
deficiency of, 109 hyperparathyroidism and, 123
in depression, 109, 110, 286 hypoparathyroidism and, 125
dopamine regulation of, 108, 286, hypopituitarism and, 126
493 hypothyroidism and, 431–433,
fenfluramine-induced increase in, 432
110 treatment of, 435
galactorrhea and plasma levels of, induced by anabolic-androgenic
493 steroids, 336
measurement of, 493 postpartum, 262, 283–284,
in pregnancy and puerperium, 294–296
286 bipolar disorder and, 283–284,
role in inducing psychiatric 295
symptoms, 108–109 consequences of, 295–296
role in lactation, 286, 493 endocrine factors in etiology of,
in schizophrenia, 110–111 294–295
secretion of, 108, 362, 493 incidence of, 283
Prolactinoma, 108, 109 menstrual cycle and, 262
Propranolol, for psychiatric symptoms nonendocrine factors in
of thyrotoxicosis, 425 etiology of, 295
combined with propylthiouracil, onset of, 283
426 recurrence of, 295–296
Propylthiouracil symptoms of, 283
combined with propranolol for treatment of, 295
mania in thyrotoxicosis, 426 in thyrotoxicosis, 424, 425
effects in alcoholic patients with Psychostimulants, 30
liver disease, 385 Psychotherapy, for postpartum
Provera. See Medroxyprogesterone depression, 293
acetate Psychotic depression (PD), 21, 33
Provocative tests, 470–471. See also antiglucocorticoid strategies for,
Neuroendocrine testing 152–153
of growth hormone release, 493 dexamethasone suppression test in,
of hypothalamic-pituitary-adrenal 141, 144–145
axis activity, 477–482 postpartum, 282, 283
of thyroid function, 486 PTSD. See Posttraumatic stress
Psychoneuroendocrinology disorder
clinical importance of, 3 Public Law 101-647 (Anabolic Ste-
history of, 4, 9–22, 10 roids Control Act of 1990), 332
paths of investigation in, 4 Public Law 103-417 (Dietary
Psychopharmacologic bridge Supplement Health and
technique, 31, 59 Education Act of 1994), 207
Psychosis. See also Schizophrenia Pyridoxine deficiency, 311
Index 581
Raloxifene, 318 relationship between

Reserpine, 30 hypercortisolemia and
Reverse triiodothyronine (rT3), 362, outcome, 151
484 negative symptoms of, 149
in anorexia nervosa, 393 neurotensin in, 53–54
in depression, 365 opioid antagonists in, 42
Rheumatoid arthritis, 525 prolactin in, 110–111
Risperidone, for psychiatric suicidality and, 148–149
symptoms of thyrotoxicosis, 426 thyroid function in, 363, 364,
Rosenzweig Picture-Frustration 395–396
Study, 336 antithyroid antibodies, 372
rT3 (reverse triiodothyronine), 362, 484 cerebrospinal fluid studies, 376
in anorexia nervosa, 393 early studies, 395
in depression, 365 effects of somatic treatments,
RU 486 (mifepristone), 253, 257–258 396
depression and peripheral thyroid hormones,
adrenocorticotropic hormone 395–396
response to, 522–523 thyrotropin and antithyroid
for psychotic depression, 153 antibodies, 396
Rush, Benjamin, 16 SCID (Structured Clinical Interview
for DSM-III), 336, 338, 339
S20098, 100 SCL-90 (Symptom Checklist–90),
SAD. See Seasonal affective disorder 337, 339
Salivary cortisol test, 141–143, 476 SCN (suprachiasmatic nucleus),
Scale for Assessment of Negative circadian rhythms and, 85–87,
Symptoms (SANS), 149 86, 166
Schäfer, Edward A., 15, 17 melatonin effects on, 88
Schedule for Affective Disorders and Scopolamine, 209
Schizophrenia, 267 Seasonal affective disorder (SAD), 83
Schizoaffective disorder, insulin responses in, 121
ketoconazole for, 153 thyroid function in, 367, 375
Schizophrenia. See also Psychosis effects of phototherapy, 381
arginine vasopressin in, 46–47 Secretin, 15
cholecystokinin in, 51 Sedative-hypnotics, use in
dehydroepiandrosterone and hypothyroidism, 436
dehydroepiandrosterone Seizures, in hypoparathyroidism, 124
sulfate levels in, 213–214 Selective serotonin reuptake
depression and, 148–149 inhibitors (SSRIs)
ketoconazole for, 153 effects on glucose regulation, 118
endogenous opioid peptides in, 41 estrogen augmentation of, 306
growth hormone in, 114–115 lithium augmentation of, 461
hypothalamic-pituitary-adrenal for premenstrual syndrome, 265,
axis activity in, 38, 148–150 315
dexamethasone suppression for steroid-induced
test, 141, 145, 148–150 psychopathology, 198
Selective serotonin reuptake Sheehan’s syndrome, 125–126, 293

inhibitors (SSRIs) (continued) Simmonds’ disease, 125
use in Addison’s disease, 170 Simple phobia, prolactin in, 111
use in hyperthyroidism, 379 Sleep deprivation, effect on thyroid
use in with Cushing’s syndrome, function, 366, 381
179 Sleep disturbances
Self-injurious behavior, opioid circadian rhythm disorders, 83–84,
antagonists for, 42–43 84
Selye, Hans, 7–8, 20 melatonin for, 98–100, 99
Semon, Felix, 13 in Cushing’s syndrome, 174, 176
“Sensory flooding,” corticosteroid- delta sleep–inducing peptide in, 57
induced, 191 postpartum, 282
Serotonin (5-HT), 29, 30 Social phobia
effect on glucose regulation, 118 growth hormone and, 112, 114
glucocorticoid regulation of, 521 prolactin and, 111
glucose metabolism in low Social withdrawal, in Cushing’s
serotonin syndrome, 122 syndrome, 175
modulation of hippocampal Somatostatin, 47, 49–50, 492
responsiveness by, 517 in Alzheimer’s disease, 50, 59
premenstrual syndrome and luteal brain distribution of, 47
phase decreases in platelet corticosteroid effects on cere-
uptake of, 253 brospinal fluid levels of, 197
prolactin regulation by, 108 in depression, 49, 50
psychiatric effects of serotonergic functions of, 49
hypoactivity, 521–522 secretion of, 47
receptors for Spinocerebellar degeneration,
estrogen effects on, 287 hypothalamic-pituitary-adrenal
hippocampal, corticosteroid axis activity in, 39
effects on, 197 SSRIs. See Selective serotonin
stimulation of corticotropin- reuptake inhibitors
releasing hormone release by, Starling, Ernst, 15
472 Stress, 7–8, 513–536. See also
stress and, 520, 521–522, 535 Posttraumatic stress disorder
Sertraline Addison’s disease and, 168, 170
effect on thyroid function, 366, allostasis and, 513, 516, 518–519,
379 523, 524
for postpartum depression, 293 allostatic load, 513, 514, 516,
use in diabetic patients, 118 523
Sex hormone–binding globulin vs. homeostasis, 19–20, 513,
(SHBG), 491, 492 518–519
Sexual dysfunction anxiety and, 513
Cushing’s syndrome and, 176 arginine vasopressin modulation of
diabetes mellitus and, 116 response to, 480
SHBG (sex hormone–binding brain as controller of and target for,
globulin), 491, 492 515–518
Index 583
chronic, 513 rheumatoid arthritis and, 525

connections between disease and, serotonin and, 520, 521–522, 535
513, 514 Structured Clinical Interview for
contributors to experience being DSM-III (SCID), 336, 338, 339
interpreted as stressful, 514, Substance P, 56
516 brain distribution of, 56
Cushing’s disease and, 171 in depression, 56
definition of, 518 functions of, 56
dehydroepiandrosterone and Substance P antagonists, 56
dehydroepiandrosterone Suicidality
sulfate levels and, 208, 212 adrenal gland enlargement and, 35,
depression and, 525–526, 535 501
diabetes and, 116, 525 corticosteroid-induced, 190
“general adaptation syndrome” to, corticosteroid-withdrawal, 194
20 corticotropin-releasing hormone
glucocorticoid effects on dendritic receptor density and, 34
branching and neurobiology cortisol level and, 181
of, 527–532, 529 Cushing’s syndrome and, 174, 502
Graves’ disease and, 421, 422, 525 neuropeptide Y and, 55
heightened sympathetic reactivity, postpartum, 282
glucocorticoid increase, premenstrual, 259
insulin hypersecretion, insulin among schizophrenic patients,
resistance and, 523–524 148–149
human studies of changes in serotonergic hypoactivity and, 521
hippocampal volume, Suprachiasmatic nucleus (SCN),
cognitive function and, circadian rhythms and, 85–87,
533–534 86, 166
hypothalamic-pituitary-adrenal melatonin effects on, 88
axis response to, 32, 32, 472 “Sympathico-adrenal medullary
adrenal steroids and adaptation system,” 19
to stress, 518 Symptom Checklist–90 (SCL-90),
containment of, 519, 520, 337, 339
522–523 Systemic lupus erythematosus
glucocorticoid secretion, 514, effects of dehydroepiandrosterone
519, 535 treatment in, 216
immune function and, 524–525 neuropsychiatric effects of steroids
individual differences in aging and for, 190
risk for dementia and, differentiation from lupus
526–527, 528 cerebritis, 190–191
as individualized response, 514, Systen. See Estradiol, transdermal
518 patch
neurogenesis in adult dentate gyrus
and, 531–533 T3. See Triiodothyronine
noradrenaline and, 519–521, 520 T4. See Thyroxine
perceived, 518 Tachykinins, 56
Takamine, Jokichi, 15 3a,5a-Tetrahydroprogesterone

Tamoxifen, 304, 317–318 (3a,5a-THP), 320
for breast cancer, 317–318 Tetraiodothyronine. See Thyroxine
depression related to, 317–318 THBR (thyroid hormone binding
effect on bone mineral density, 317 ratio), 487–488
mood and behavior effects of, 3a,5a-THP (3a,5a-tetrahydro-
317–318 progesterone), 320
TBG. See Thyroxin-binding globulin Thyroid adenoma, 421
TBPA (thyroxine-binding Thyroid carcinoma, 123, 125
prealbumin), 361 Thyroid function, 6–7, 361–398, 484.
TCAs. See Antidepressants, tricyclic See also Hyperthyroidism;
Testosterone, 331, 491 Hypothyroidism; Thyrotoxicosis
androgen receptor binding of, 331 in alcoholism, 376, 383–387
androgenic effects of, 331 abstinent patients with liver
antidepressant effects of, 333 disease, 385–386
chemical structure of, 331 abstinent patients without liver
clinical studies of psychiatric disease, 384
effects of, 332–333 during acute alcohol
in Cushing’s syndrome, 182 withdrawal, 383–384
effects of dehydroepiandrosterone cerebrospinal fluid studies,
treatment on, 225, 226 386–387
with estrogen for hormone effects of ethanol
replacement therapy, administration, 383
309–310, 334 subjects at risk for developing
measurement of, 491 alcoholism, 386
metabolism to estradiol, 331 in anxiety disorders, 376, 388–389
normal values of, 490 cerebrospinal fluid studies, 389
ovarian failure and deficiency of, panic disorder, 388, 389
309 peripheral thyroid hormones,
for perimenopause-related 388–389
depression, 272 thyrotropin and antithyroid
in pregnancy and puerperium, 288 antibodies, 389
postpartum depression and, 291 in bipolar disorder, 366–367,
protein binding of, 491 372–375, 383
secretion of, 491 antithyroid antibodies, 372,
synthetic analogs of, 331 (See also 373
Anabolic-androgenic steroids) cerebrospinal fluid studies, 376
Testosterone cypionate, 341 rapid cycling and, 374–375
Testosterone decanoate, 335 brain, behavior and, 419–438, 484
Testosterone enanthate, 335 early studies of, 419–420
Testosterone/estradiol–binding in hyperthyroidism and
globulin, 491 thyrotoxicosis, 420–429
Tetany, in hypoparathyroidism, 124 in hypothyroidism, 429–436
3a-5a-Tetrahydrodeoxycorticoster- in vivo brain imaging of,
one, 289 436–437
Index 585
in depression, 363, 364, 365–366, thyrotropin and antithyroid

368–372, 381–382 antibodies, 396
abnormal circadian thyrotropin in seasonal affective disorder, 367,
rhythm, 368, 369 375
antithyroid antibodies, 372, 373 Thyroid function tests, 362–363,
cerebrospinal fluid studies, 375, 484–489
376 antithyroid antibodies, 485–486
peripheral thyroid hormones, assays for thyroid-stimulating
363, 364, 365–366 hormone, 486–487
subclinical hypothyroidism, assays for thyroxine, 487–489, 488
368–372, 370–371 basal hormone measurements,
thyrotropin sources of variance, 485, 486
372 during lithium treatment, 377
in eating disorders, 390–395 provocative tests, 486
anorexia nervosa, 390–393, 391 Thyroid hormone binding ratio
binge-eating disorder, 394 (THBR), 487–488
bulimia nervosa, 393–394 Thyroid hormone treatment, 398,
effects of somatic treatments on, 445–461. See also specific thyroid
377–381 hormones
carbamazepine and valproic for anxiety disorders, 446, 459,
acid, 379–380 460
electroconvulsive therapy, 380 for bipolar disorder, 374–375, 446,
lithium, 377 456–460
monoamine oxidase inhibitors, for depression, 372, 446–456,
377–378 460–461
neuroleptics, 396 approaches to, 446
phototherapy, 381 thyroid-stimulating hormone,
sleep deprivation, 381 448
tricyclic antidepressants, thyrotropin-releasing hormone,
378–379 446–448
in general psychiatric population, combined with electrocon-
363–365, 364, 420 vulsive therapy, 447–448
physiology of, 361–362 monotherapy, 447
in pregnancy and puerperium, thyroxine, 448–449
288–289, 488 triiodothyronine, 449–456
postpartum depression, 291–292 to accelerate antidepressant
in premenstrual dysphoric response, 450–451
disorder, 389–390 for antidepressant augmen-
prevalence of disorders of, 420 tation, 451–456, 452,
in schizophrenia, 395–396 456, 460–461
early studies, 395 combined with electrocon-
effects of somatic treatments, vulsive therapy, 450
396 monotherapy, 449–450
peripheral thyroid hormones, side effects and tolerability
395–396 of, 453–454
Thyroid hormone treatment in premenstrual dysphoric

(continued) disorder, 390
history of, 13, 14, 16 in rapid-cycling bipolar disorder,
for hypothyroidism, 434–435 374
rationale for use in psychiatric in schizophrenia, 396
disorders, 445–446 in seasonal affective disorder, 375
thyrotoxicosis induced by, 421 in thyrotoxicosis, 421, 425
Thyroid hormones, 361–398, 484. See in treatment of psychiatric
also specific hormones disorders, 446
neuroregulatory role of, 362, 363 depression, 448
normal values for, 486 Thyroidectomy, 362
Thyroid-stimulating hormone (TSH), Thyrotoxicosis. See also Graves’
361, 484 disease; Hyperthyroidism
abnormal circadian rhythm of, causes of, 421
368, 369 definition of, 421
abnormal responses to thyrotropin- differentiation from
releasing hormone in hyperthyroidism, 421
psychiatric disorders, 419 due to exogenous thyroid hormone
in alcoholism, 387 administration, 421
abstinent patients with liver factitia, 421
disease, 385–386 interactions between psychotropic
abstinent patients without liver drugs and, 428–429
disease, 384 antidepressants, 378–379,
during acute alcohol 428
withdrawal, 384 antipsychotics, 428–429
subjects at risk for developing lithium, 428
alcoholism, 386 laboratory diagnosis of, 425
in anorexia nervosa, 368, 391, lithium-induced, 377
392–393 neuropsychiatric symptoms and
in anxiety disorders, 389 signs of, 423–425
assays of, 362, 367, 425, 485–487, treatment of, 425–426
486 onset of, 421, 422
biosynthesis and release of, 361, psychological coping and course of,
484 422
hypothyroidism due to recovery of psychiatric function
diminished release, 431 after treatment of, 425–426,
in bulimia nervosa, 394 427
in depression, 365, 382 subclinical, 421, 425
abnormal circadian rhythm, Thyrotropin. See Thyroid-stimulating
368, 369 hormone
sources of variance, 372 Thyrotropin-releasing hormone
in hypothyroidism, 367, 367, 429, (TRH), 361–362, 484
433–434 in brain, 419
normal values for, 486 cerebrospinal fluid concentrations
in pregnancy and puerperium, 289 in alcoholic patients, 386–387
Index 587
effects of exogenous in pregnancy and puerperium,

administration of, 446 288–289
functions of, 446, 484 postpartum depression and,
hypothyroidism due to diminished 292
release of, 431 in premenstrual dysphoric
prolactin regulation by, 108, 362 disorder, 390
in treatment of depression, protein binding of, 361, 485
446–448 in schizophrenia, 395–396
combined with electroconvul- in thyrotoxicosis, 421, 425
sive therapy, 447–448 transient hyperthyroxinemia,
monotherapy, 447 363–365
in treatment of psychiatric in treatment of psychiatric
disorders, 446 disorders, 446
Thyroxin-binding globulin (TBG), bipolar disorder, 457–459
361 non–rapid cycling, 457–458
in anorexia nervosa, 390–392, 391 rapid cycling, 458–459
in bulimia nervosa, 394 depression, 448–449
in pregnancy and puerperium, 289 Thyroxine-binding prealbumin
Thyroxine (T4), 361–362, 484 (TBPA), 361
in alcoholism, 384–385 Tourette’s syndrome, hypothalamic-
abstinent patients with liver pituitary-adrenal axis activity in,
disease, 385 39
abstinent patients without liver Trail Making Tests, 425
disease, 384 Transsexuals
during acute alcohol female-to-male, anabolic-
withdrawal, 384 androgenic steroids for, 334
in anorexia nervosa, 390–392, 391 male-to-female, effects of female
in anxiety disorders, 388–389 hormones on, 304, 320–321
assays for total or free thyroxine, Tranylcypromine, effect on glucose
362, 485, 486, 487–489 regulation, 118
conditions causing alterations TRH. See Thyrotropin-releasing
in, 488, 488–489 hormone
biosynthesis and release of, 361, Tricyclic antidepressants. See
484 Antidepressants, tricyclic
in bipolar disorder, 366–367 Triiodothyronine (T3), 361–362, 484
in bulimia nervosa, 394 in alcoholism, 387
in depression, 365–366, 381–382 abstinent patients with liver
evidence for neuroregulatory role disease, 385, 386
of, 362, 363 abstinent patients without liver
in general psychiatric population, disease, 384
364 in anorexia nervosa, 390–392, 391,
for hypothyroidism, 434–435 395
in hypothyroidism, 367, 367, in anxiety disorders, 388–389
433–434 assays for free triiodothyronine,
normal values for, 486 361, 486
Triiodothyronine (T3) (continued) side effects and tolerability

biosynthesis and release of, 361, of, 453–454
484 combined with electroconvul-
in bulimia nervosa, 393–394 sive therapy, 450
circulating, 361 monotherapy, 449–450
evidence for neuroregulatory role in treatment of psychiatric
of, 362, 363 disorders, 446
in general psychiatric population, Triiodothyronine (T3) resin uptake
364 test, 487
for hypothyroidism, 435 L-Tryptophan, 47
in hypothyroidism, 367, 367 TSH. See Thyroid-stimulating
normal values for, 486 hormone
in pregnancy and puerperium, 289 Tumor necrosis factor a, 223
postpartum depression and, Tyrosine hydroxylase, 519–520
292
in premenstrual dysphoric Urinary free cortisol (UFC), 142, 143,
disorder, 390 151
protein binding of, 361 in Cushing’s syndrome, 476, 479
regulation of brain levels of, 362 in depression, 502
reverse (rT3), 362, 484 measurement of, 470, 475,
in anorexia nervosa, 393 475–476
in depression, 365
in schizophrenia, 395–396 Valproic acid
in thyrotoxicosis, 421, 425 effect on thyroid function, 380
in treatment of anxiety disorders, to prevent steroid psychosis, 196
459 Vasopressin. See Arginine vasopressin
in treatment of depression, Venlafaxine, for postpartum
449–456 depression, 293
to accelerate antidepressant Violence/aggression
response, 450–451 dehydroepiandrosterone effects in
for antidepressant animals, 209
augmentation, 451–456, induced by anabolic-androgenic
452, 460–461 steroids, 335, 337–339,
antidepressant class and, 344–345, 349
454–455, 460–461 insulin responses and, 121–122
mechanism of action of, 455 von Euler, Ulf, 18
precautions for use in elderly von Haller, Albert, 12
cardiac patients, 454
recommendations for, 456, “Windows into the brain,” 3, 5
456
Zeitgebers, 85

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PSYCHONEURO-

Owen M. Wolkowitz, M.D.

To Judy, Rachel, and Amanda;

This book is also dedicated to our dear colleague and con-

Jay D. Amsterdam, M.D.

Michael Bauer, M.D., Ph.D.

Lee S. Cohen, M.D.

Kishore M. Gadde, M.D.

Philip W. Gold, M.D.

Harry Gwirtsman, M.D.

Uriel Halbreich, M.D.

Mady Hornig, M.D.

Rod J. Hughes, Ph.D.

Russell Joffe, M.D.

Linda S. Kahn, Ph.D.

David L. Katz, M.D., J.D.

K. Ranga R. Krishnan, M.D.

Alfred J. Lewy, M.D., Ph.D.

Steven E. Lindley, M.D., Ph.D.

Peter T. Loosen, M.D., Ph.D.

Bruce S. McEwen, Ph.D.

David Michelson, M.D.

Dominique L. Musselman, M.D., M.S.

Charles B. Nemeroff, M.D., Ph.D.

David O’Connor, M.D.

Harrison G. Pope Jr., M.D.

Victor I. Reus, M.D.

Magda Rittenbaum, M.D.

Anthony J. Rothschild, M.D.

David R. Rubinow, M.D.

Robert L. Sack, M.D.

Alan F. Schatzberg, M.D.

Peter J. Schmidt, M.D.

Stephen Sokolov, M.D., F.R.C.P.C.

Monica N. Starkman, M.D., M.S.

Martin P. Szuba, M.D.†

Steven J. Wamback, B.S.

Lisa S. Weinstock, M.D.

Peter C. Whybrow, M.D.

Owen M. Wolkowitz, M.D.

Introduction and Overview

Owen M. Wolkowitz, M.D.

T he importance of endocrinology for psychiatric practice has

atrists, neurologists, endocrinologists, obstetrician-gynecologists, internists,

analogs as chronobiotic drugs (i.e., they reset circadian rhythms) in con-

the importance of hormonal homeostasis for proper central nervous sys-

Steven E. Lindley, M.D., Ph.D.

C linical psychoneuroendocrinology is a relatively young area

TABLE 2–1. Early conceptual advances in the

The beginnings of psychoneuroendocrinology can be traced to black bile

maeon of Croton (a pupil of Pythagoras, around 500 B.C.), Hippocrates

Early Modern Endocrinology

During the Renaissance period, scientists described the anatomy of most of

of a syndrome in patients with gross adrenal disease (Addison’s disease).

The Era of Organotherapy

The enthusiasm generated by the advances described above was soon

Birth of Modern Endocrinology

Despite its negative impact, organotherapy did generate advances in en-

tee today. Dr. Oliver approached Edward A. Schäfer, a professor of phys-

Growth of an Appreciation for Psychiatric

With the expansion of knowledge in hormones came a greater apprecia-

Such successes with hormonal therapy generated curiosity as to whether

in general. Emil Kraepelin theorized about endocrine etiologies for de-