Since the 1980s, new technologies and fundamental new insights have transformed the

biological sciences and most areas of medicine. The completion of the Human Genome
Project in 2002 provided a map of all of the genes of the human species. The soon-to-becompleted human haplotype map will provide a guide to individual variation of all of these
genes. Along with genomics, neuroscience has become one of the most exciting areas of
contemporary research. Recent discoveries have transformed the understanding of the brain,
demonstrating how neurogenesis continues throughout adulthood, mapping the dynamic
nature of cortical connectivity that can change in response to stimulation, and identifying
some of the categorical rules by which information is processed in the brain. By any measure,
recent decades have been revolutionary for the understanding of the human genome and how
the brain functions, two areas of science fundamental to psychiatry. Yet, during this same
period, clinical psychiatry has remained relatively unchanged.
Psychiatry today, as did psychiatry in the 1980s, lacks valid diagnostic tests, innovative
treatments, or an understanding of the basic pathophysiology of any of its major disorders.
Despite a century of neuropathological studies of schizophrenia, the location and the nature
of the lesion causing this illness are not yet known. Genomics and neuroimaging have
resulted in hundreds of findings, but none have yet changed how clinicians diagnose or treat
patients with mental disorders. Sadly, perhaps the biggest changes in psychiatry since the
1980s have been the decay and fragmentation of the delivery of care. The prevalence of
mental illness among those who are incarcerated has never been systematically determined,
but survey data taken among inmates indicate that the percentage is approximately 16
percent. As a consequence, current estimates suggest that at least five times as many
individuals with serious mental illness now reside in jails and prisons than in all hospitals in
the United States. Approximately 200,000 individuals with schizophrenia or bipolar disorder
are homeless, constituting one-third of the approximately 600,000 homeless population.
However, even for those who are neither incarcerated nor homeless, mental health care is
inadequate. Data from the last National Comorbidity Survey, a household survey of mental
disorder prevalence and treatment, estimate that 54 percent of individuals with serious mental
illness (broadly defined) received no treatment whatsoever in the previous 12 months.
The 2003 President's New Freedom Commission on Mental Health noted the catastrophic
state of mental health services in America and the lack of specialty care. Those who receive
care from a physician are most likely to receive medication from a primary care physician or
pediatrician, leaving psychiatrists to care for those who are either most difficult to treat or, in

the case of psychotherapy, wealthy enough to pay out of pocket. When medications are
prescribed mostly by nonpsychiatric physicians, psychotherapy delivered mostly by
nonphysicians, and the only procedure administered by psychiatrists is electroconvulsive
therapy (ECT), one can reasonably ask, What is the future of psychiatry as a medical
specialty? Will this branch of medicine be relevant in two decades? Of course, there are those
patients with severe and complex disorders who primary care physicians may not want to
manage. However, will those psychiatrists who make an admirable career caring for the
patients rejected by the rest of medicine have access to the resources needed to care for these
patients?
The answers to these questions are surprisingly hopeful, but they require fundamental
changes in how mental disorders are approached, how psychiatrists are trained, and how the
discipline is viewed. Although there is a tendency to consider psychiatry as the victim of a
society that stigmatizes mental illness, it is essential to recognize how psychiatrists have
contributed to this stigma in the past and how, by embracing ideology over evidence,
psychiatrists continue to contribute to psychiatry being seen as medicine's least respectable
branch. The answer for psychiatry, as for the rest of medicine, has to emerge from both
research and advocacy. Research needs to be informed by the public health burden,
recognizing that mental disorders are among the largest sources of medical disability in this
country and, like acquired immune deficiency syndrome (AIDS) and cancer, they are
problems that are both urgent and deadly. Few psychiatrists and fewer general physicians are
aware of the basic morbidity and mortality statistics of the major mental disorders (e.g., less
than 20 percent of people with schizophrenia are able to work full time and as many as 10
percent will die prematurely from suicide). Is it any wonder, then, that many physicians and
the nonmedical public often consider these disorders as character weaknesses rather than
brain illnesses with real treatments?
RESEARCH NEEDS
The research that will transform psychiatry has not yet been done. What is needed? The
answers come from other genetically complex disorders such as hypertension, Alzheimer's
disease, diabetes, and breast cancer, for which the identification of risk genes will be critical.
What is known from these illnesses is that elucidating the genes may be just the beginning,
but it is a critical entry point into the pathophysiology of each disorder. From this entry point
arises the possibility of identification of individuals at risk, early detection and diagnosis, and
specific evidence-based treatment. Scores of genes can be expected to be involved in
schizophrenia, autism, and bipolar disorder, but, as has been seen in hypertension, their

function may aggregate around key intracellular pathways. The sequencing of the human
genome makes gene discovery a tractable problem, limited only by the ability to identify the
phenotype of the illnesses and to collect deoxyribonucleic acid (DNA) from enough patients
and their relatives.
The understanding and selection of biologically relevant phenotypes may emerge as the ratelimiting factor in defining the link between risk genes, behavior, and disease. Although the
current diagnostic system has done well in alleviating the Tower of Babel that characterized
medical communication in the preDiagnostic and Statistical Manual of Mental Disorders
(DSM) era, genetic, biological, and treatment-response studies clearly indicate that psychiatry
has not succeeded in carving nature at its joints. Across validators of psychiatric disease
articulated by Eli Robins and Samuel Guze over 30 years(1) clinical signs and symptoms, (2)
course, (3) family history/genetics, (4) biological markers, and (5) treatment responsethe
current diagnostic constructs are limiting. For example, psychosis is seen in conditions
ranging from postpartum depression to schizophrenia, and anxiety appears to be a core
feature of most forms of major depression, in addition to conditions currently classified as
anxiety disorders. Likewise, genetic studies indicate the shared familial aggregation of what
are now called schizophrenia, schizoaffective disorder, schizotypal personality, and psychotic
bipolar disorder.
Progress in defining new and more valid phenotypes for genetic studies requires the
dissection of the current DSM syndromes into pathophysiology-proximate symptom clusters.
Success in this effort depends critically on psychiatry's ability to secure the interest and active
collaboration of the best cognitive and behavioral scientists in addressing the problems of
mental illness.
DNA AND DESTINY
One will not find schizophrenia genes, bipolar genes, or autism genes. Genes code for
ribonucleic acid (RNA), which codes for protein, not for a disease. Although genes will not
code for an illness, one can expect to find a statistical association between genetic variation
and the endophenotype, an underlying physiological measure associated with a symptom
cluster or putative diagnostic entity. A common misconception is to assume that research on
genetics will yield a diagnostic test. Mendelian mutations, as in fragile X or cystic fibrosis,
can be used for diagnosis, but the complex genetics of schizophrenia, autism, and bipolar
disorder may not be any more helpful for diagnosis than apolipoprotein E4 (apoE4) and
BRCA are in the diagnosis of Alzheimer's disease and breast cancer, respectively.
Nonetheless, one can expect that variations in DNA sequence should yield an approach to

understanding risk. As with hypertension or breast cancer, identifying children at high risk for
autism or schizophrenia or bipolar disorder suggests who might benefit from aggressive
preventive interventions.
Preliminary evidence suggests that early detection and treatment may be associated with
better outcome in these illnesses. One might imagine that psychiatrists in the future will
spend more time with high-risk adolescents before a first psychotic break, just as
cardiologists today focus on managing cholesterol or inserting stents in high-risk patients
who have not yet had a myocardial infarction. Defining the genetics-based risk architecture of
major psychiatric illnesses will not, however, lead directly to a treatment. Many examples
from medicine, such as sickle-cell anemia and Huntington's disease, suggest that the ability to
identify the high-risk individual may emerge decades in advance of the ability to obviate,
reverse, or mitigate the disease. For this reason, it is critical that research efforts include a
substantive focus on health behavior broadly, ethical dimensions of genetic testing, and the
development of strategies for prevention in high-risk individuals.
Risk is not destiny, and the inherited sequence of nucleotides with which humans are
endowed is in no way the entire story. For example, it is becoming increasingly clear that
early environmental trauma interacts with genetic vulnerability in exerting a powerful impact
on the likelihood of depression in adulthood. In some ways, understanding the epigenetic
mechanisms by which trauma can have these long-term effects is not so different from
understanding how environmental toxins contribute to lung or skin cancer. Genomics in
psychiatry will need to grapple not only with classic genetics (i.e., finding sequence
variations associated with risk), but also with developmental changes in chromatin structure
conferring long-term effects on gene expression. On the other hand, measuring exposure to a
traumatic human experience may ultimately prove a far more vexing problem than measuring
exposure to carcinogens or ultraviolet radiation. How can one understand how and why
traumatic circumstances destroy hope and opportunity in some circumstances and build
character in others? Here again, one must depend on genomics to explain different levels of
individual susceptibility, as well as quantitative behavioral science, to define and measure
exposure to stress within the physical and interpersonal environment.
DISEASE BIOMARKERS
There are no valid quantitative traits, such as blood pressure or a glucose tolerance test, to
clarify the presence or absence of schizophrenia, depression, or bipolar disorder. The
discovery of the first reliable and valid biomarker for a psychiatric illness will be a defining
event for the future of psychiatric medicine. Diagnostic tests will require, as they do in most

of medicine, identification of a lesion. Of course, the problem for mental disorders is that the
brain is not accessible in the way that blood or urine is. Two current approaches are likely to
reveal biomarkers that could be used for diagnosis of mental disorders. First, neuroimaging
gets past the black box approach to brain disorders. This research is still in its early stages,
but one can imagine that functional magnetic resonance imaging (fMRI) will reveal patterns
of brain activation after stimulation that may be diagnostic, just as a nuclear stress test is now
used widely by cardiologists to diagnose coronary artery disease. Similarly, imaging of
receptors may reveal regional abnormalities, as recently reported for the 5-hydroxytryptamine
type 1A (5-HT1A) receptor in the cingulate cortex of patients with panic disorder. A second
approach that is even more exploratory uses proteomics to identify potential biomarkers
associated with major mental disorders. More than 50 percent of the genome is expressed in
the brainthat is more than 15,000 RNAs and perhaps five to ten times that number of protein
products, because each gene may code for many different proteins. Thus far, research has
been limited to a handful of monoamines, amino acids, peptides, and proteins. In the future,
this period may be looked back on as the dark age of neurochemistry, when many of the most
important neurotransmitters and intracellular effectors had not yet been discovered. It seems
likely that, among this vast sea of RNAs or proteins, some will be associated with specific
mental disorders, providing either a trait or state marker that will permit a finer grain of
diagnosis than has been possible with clinical interviews. These may come from
cerebrospinal fluid (CSF), from central nervous system (CNS) cells, or from peripheral cells
grown in culture.
THERAPEUTICS
In spite of increases in both federal and industry research and development investment
throughout the 1990s, the number of new molecular entities submitted for approval for
treatment of human disease has fallen precipitously. Psychiatric medications have been
discovered almost exclusively by serendipity rather than by a rational approach to the
pathophysiology of mental disorders. The field has been both blessed and cursed by
medications that control many of the symptoms of these illnessesblessed because these drugs
have provided treatment for many gravely ill people, cursed because they have allowed those
in the field to stop short of finding cures. Indeed, all currently used antidepressants and
antipsychotic agents are variations on drugs developed before the 1960s, yet there are no
current medications for the core symptoms of autism, the cognitive deficits of schizophrenia,
or rapid antidepressant action. Nonmedication therapies, such as cognitive-behavioral therapy
for depression, have been shown to be effective but are used infrequently. Experimental

treatments, such as deep brain stimulation for obsessive-compulsive disorder (OCD), are just
emerging and are far from routine clinical practice in psychiatry, although these approaches
are now widely used in neurology.
The development of a new generation of breakthrough psychiatric medications rests on the
identification

of

new

disease-related

molecular

targets

and

their

associated

pathophysiological states and clinical correlates. Just as today's treatments target a limited
number of well-defined molecular targets (monoamine receptors and transporter proteins),
they rely on a well-worn but limited set of clinical targets, such as the positive symptoms of
psychosis or Hamilton Rating Scale for Depression (HAM-D)defined depression. Like
progress in genetics, innovation in therapeutics also requires the dissection of the DSM
entities into pathophysiology-proximate symptom clusters (such as cognition in
schizophrenia, anhedonia in depression, or delayed extinction in posttraumatic stress disorder
[PTSD]) that can become new clinical end points in treatment trials of therapeutics based on
new molecular mechanisms. As is true in the current treatment of human immunodeficiency
virus (HIV), cancer, and congestive heart failure, the psychopharmacology of the future will
likely be based on individualized co-therapies that are prescribed to target the specific
constellation of measurable pathophysiological perturbations unique to each patient.
Creating a new generation of therapeutics will require new approaches to government,
industry, and academic collaboration. The next generation of treatments will need to begin
with an understanding of the pathophysiology of these illnesses based on identification of the
genes, the proteins, neural systems, and clinical targets involved. From the development of
statins for atherosclerosis to deep brain stimulation for Parkinson's disease, this has been the
path to novel therapeutics in modern medicine.
The identification of biomarkers can provide a powerful catalyst for accelerated treatment
development. Before identification of the CD4 count as a marker of disease progression in
HIV, for example, evaluating a new treatment designed to prolong the period between HIV
infection and clinical AIDS might take a decade. With a valid biomarker, the same study can
be conducted in months, vastly increasing the efficiency of the treatment development
process. One might imagine how biomarkers in psychiatry could allow accurate prediction of
treatment response before or immediately after the first dose of medication.
PSYCHIATRY AND PUBLIC HEALTH
Psychiatry in the future will need to become more clearly focused on public health needs for
inescapable reasons. Mental disorders are among the greatest source of burden of
diseasebased on years lost to disability and premature mortalityamong individuals between

the ages of 15 and 44 (Table 55.3-1). Suicide, which 90 percent of the time involves mental
illness, accounts for 30,000 deaths each year in the United States alone, more deaths than
from homicide, AIDS, or prostate cancer. Increasingly, mental disorders have been
recognized as the chronic diseases of the young. The economic costs are enormous and
continuing to grow. More than 50 percent of atypical antipsychotics are purchased via
Medicaid, costing the nation more than $3 billion per year, increasing at a rate of roughly 25
percent for the past 3 years.
The U.S. Surgeon General's report of 1999 stated unequivocally that symptoms related to
behavior or our mental lives clearly reflect variations or abnormalities in brain functioning
and recognized that there are effective treatments for these illnesses. However, this same
report documented the growing gap between what is known and what is done. Many practice
guidelines and metaanalyses indicate that a range of inexpensive, low-tech, evidence-based
practices available today can make a difference for people with mental disorders, but these
are rarely used in the community (Table 55.3-2). Improving care for people with mental
disorders in the near term need not require finding the genes or the proteins, so much as
providing many of the common-sense practices that reduce relapse after a psychotic break or
facilitate remaining in treatment.
PSYCHIATRIST OF THE FUTURE
Psychiatry is the medical specialty entrusted with primary responsibility for overseeing and
directing the diagnosis, care, and treatment of individuals with mental illness. Reducing the
burden of suffering associated with mental illness, as well as organizing efforts to apply
science to improve on the effectiveness and efficacy of the best current methods of
prevention, diagnosis, care, and treatment will remain the core mission of psychiatry for the
foreseeable future. Given the dizzying pace and multiple directions in which neuroscience is
expanding basic knowledge of brain functioning, however, perhaps the most difficult
question is what (in a concrete sense) will the psychiatrist of 2020 do, and what will he or she
need to know to do it well?
As the domains of knowledge potentially relevant to the treatment of mental illness expand
exponentially, the tension between achieving an appropriate balance between breadth and
depth of knowledge related to understanding disease and optimizing patient care will become
acute. Is it reasonable to expect the future practitioner to maintain competence in a dozen
forms of cognitive-behavioral therapy, competence in weaving together the patchwork of
funding sources needed to operate a treatment center, and competence to interpret the results

of a gene arrayderived expression profile to predict treatment response and rationally

sequence a pharmacological treatment plan?
The clinical epidemiology of mental illness indicates that, as is the case at present, in the
future, the majority of care for mental illness will be delivered by primary care physicians
and nonmedical mental health practitioners. Psychiatry as a profession should be vitally
engaged in defining evidence-based standards of mental health treatment for patient care
across the full range of settings in which it will be delivered. Within the de facto mental
health system, the unique value provided by psychiatry will likely derive from two sources:
(1) the direct provision of care to the most complex patients and (2) the ability to integrate
and coordinate treatment plans that achieve synergies by inclusion of both biological and
psychosocial treatment modalities.
Clinical neuroscience will define the knowledge base required to care for patients with
complex brain dysfunction that does not readily respond to first-line or standardized
treatments. Relevant areas of substantive knowledge will include clinical phenomenology,
functional neuroanatomy, neuropharmacology, and the ability to interpret tests based on
genomic, proteomic, neurophysiological, or imaging-based biomarkers. As science yields a
deeper understanding of pathophysiology, disease-based specialization may become more
common when psychiatrists are used as consultants in tertiary care settings for particularly
complex patients. Indeed, the need for generalists notwithstanding, the value of the
psychiatrist in both the medical and intellectual marketplace may increasingly derive from
deep competency in disorder-based (psychosis, affective illness), age-based (child, geriatrics),
and setting-based (public psychiatry) areas of specialization. Given the catastrophic nature of
acute psychiatric illness, the inpatient setting (albeit with a short length of stay) will remain a
critical component of the continuum of services required for comprehensive care. Similarly,
until cures for mental illness are achieved, the need for long-term protective asylum, both in
institutions and community settings, can be anticipated in the foreseeable future for some
portion of those with mental disorders. These considerations suggest that psychiatric
residency training be reformed and refocused to allow earlier specialization and more indepth training experiences while ensuring the achievement of clinical competency in
evidence-based diagnostic and treatment modalities.
Some have argued that 21st century neuroscience will ultimately lead to a convergence
between the narrative psychodynamic and neurobiological traditions such that the biology
and phenomenology of processes such as unconscious motivation, ambivalence, and
attachment will inform progress in understanding mental life in health and disease. Whether

or not these promises are achieved, as in other areas of medicine, the doctorpatient
relationship will remain a central concern of psychiatry. The best diagnostic tests are of no
value if patients do not seek them, and therapeutics are useless if not taken. To paraphrase
Harry Stack Sullivan, a psychiatrist's competence and value is enhanced to the extent that he
or she is an expert in interpersonal relations. The psychiatrist's understanding of human
behavior and human experience, derived both from didactic study and supervised clinical
work, should place him or her in the unique position of being able to create and monitor
treatment plans that integrate both biological and psychosocial perspectives. Evidence-based
reviews of treatment effectiveness increasingly suggest that, for the most severe disorders,
such as schizophrenia, integrated psychosocial and biological treatments yield superior
outcomes. A complex treatment plan that introduces psychosocial interventions of graded
complexity as a patient's functional capacities are restored by pharmacological interventions
requires coordination and oversight best provided by a psychiatrist who understands both the
disease and the person experiencing it. Similarly, the psychiatrist's expertise in understanding
the subjective and psychological world of the individual patient will facilitate a doctorpatient
relationship characterized by shared decision making that supports the achievement of illness
self-management as a treatment goal relevant for many long-term psychiatric conditions.
FUTURE DIRECTIONS
Sitting at the intersection of an age of discovery in the neurosciences, the complexity of
behavior, and the mysteries of human mental life, psychiatry may reemerge in the 21st
century as, once again, among the most compelling and intellectually challenging medical
specialties. This promise of the future depends vitally on psychiatry's integration into the
mainstream of medicine by adoption of a culture of evidence-based practice; by the
psychiatric physician's assumption of leadership in setting standards of science-based
diagnosis, care, and treatment; and by retaining among the medical specialties a unique focus
on human experience and behavior in health and disease.
It is cruelly ironic that, at the beginning of a new century in which scientific advances are
poised to deliver profound insights into humankind's most vexing and disabling illnesses,
health care systems stand at a moral crossroads at which willingness to apply what has been
learned to alleviate suffering is being severely tested. Science will undoubtedly alter what is
possible in the early detection, prevention, and alleviation of mental illness. However, science
is ultimately financed by the public, and, without access to the tangible benefits of this
investment, the public's trust and, with it, the public's support of the scientific enterprise will
flounder. For these reasons, the future of medicine and psychiatry in the 21st century cannot

be disentangled from this democratic society's commitment to public health. In psychiatry,

this means not only a focus on those who are in greatest need, but a commitment to ensure
that all Americans have access to affordable and effective health care.