Académique Documents
Professionnel Documents
Culture Documents
JAMES L. LEVENSON,
MD
CONSTANTINE G. LYKETSOS,
MD
PAULA T. TRZEPACZ,
MD
Guest Editors
PREFACE
This issue is devoted to psychiatric care of the medically ill. The major US
organization dedicated to this care is the Academy of Psychosomatic Medicine.
The articles in this issue represent authors and topics selected from among the
best papers and presentations at the annual meeting of the academy in November 2000, expanded and updated for this special issue of Psychiatric Clinics of
North America.
Psychiatric disorders occur very frequently in the medically ill, with about
30% to 50% of patients with serious medical illnesses suffering from a comorbid
psychiatric disorder. Mood disorders, anxiety disorders, delirium, dementia, and
substance abuse are most common. Psychopathology is especially frequent in
patients with complex medical illnesses such as HIV, end-stage renal disease,
organ transplantation, cancer, and traumatic brain injury. Consequently, patients
in general hospitals have the highest rate of psychiatric disorders, compared
with community samples or primary care patients. Compared with community
residents, hospitalized patients have major depression and substance abuse two
to three times as often and somatization disorder 10 times as often. Medically ill
patients with psychopathology also may present to primary care and specialists
ofces, nursing homes, home health care, and other health care environments.
Extensive research has documented the frequency and nature of the specic
psychiatric morbidities found in specic medical disease patient populations,
the serious consequences of the psychiatric morbidity, and the benets to patients and the health care system of having psychiatric care provided to these
patients by expert psychiatrists.
Why are psychiatric disorders so frequent in medical settings? Some represent reactions to the stresses of illness and treatment, while others are a direct
xi
physiologic consequence of the illness (e.g., delirium) or complications of treatment (e.g., steroid psychosis). Psychiatric disorders may be coincident with
but etiologically unrelated to a medical disorder. Still, each complicates the
management of the other. Schizophrenia may make it very hard for a patient to
follow a diabetic regimen, while the diabetics glucose intolerance and hyperlipidemia complicate the choice of a neuroleptic. There are also frequent psychophysiological (psychosomatic) inter-relationships between disorders. For example, depression and coronary disease commonly occur together, and each
appears to be a risk factor for the development of, or aggravation of, the
other. Explanatory pathophysiologic mechanisms are being worked out. Another
reason for common medical-psychiatric comorbidity is that there are a number
of commonly shared risk factors for the development of a variety of psychiatric
and medical disorders (e.g., smoking or low socioeconomic status). Finally,
patients who have comorbid medical and mental disorders are high utilizers
of medical services compared with patients with only medical disorders, and
thus the former present disproportionately for diagnosis and treatment in medical settings.
The higher concentration of patients with psychiatric disorders in medical
settings provides a critical opportunity to intervene in patients who might
otherwise go undiagnosed and untreated. Failure to identify, evaluate, diagnose,
treat, or achieve palliation results in signicant adverse outcomes, including an
increase in psychological and medical morbidity, mortality, and higher health
care utilization and costs. Yet failure to treat occurs all too frequently.
The presence of signicant medical illness complicates the diagnosis of psychopathology. It is often difcult to determine if the vegetative symptoms of
depression or the somatic symptoms of anxiety are evidence of a psychiatric
disorder or symptoms of medical illness (or both). Physical illness can mimic
psychiatric disorders, and some psychopathology presents as a semblance of
medical illness (the somatoform disorders). In this issue, Drs. Schneider, Robinson,
and Levenson review three infectious diseases with prominent neuropsychiatric
manifestations that present diagnostic challenges: neurocysticercosis, Lyme disease,
and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Drs. Bostwick and Philbrick review the electroencephalogram, which
can be helpful in discriminating between etiologies of neuropsychiatric symptoms.
As noted, psychopathology is especially common in patients with complex
medical illnesses, and this can have important effects on diagnosis, disease
course, management, treatment, prognosis, and outcome. In this issue, contributors focus on psychiatric care of patients recovering from car accidents (Dr.
Mayou), traumatic brain injury (Drs. Rao and Lyketsos), refractory chronic
pain (Drs. Clark and Cox), pulmonary disease (Dr. Coffman), and burns (Dr.
Ilechukwu). Psychiatric treatment in medically ill patients is more difcult because of the risks posed by patients medical comorbidities, the averse effects of
medical and surgical treatments received, and drug-drug interactions. In this
issue, Drs. Robinson and Qaqish review the complexities of psychopharmacology in patients with HIV. Drs. Rasmussen, Rummans, and Richardson review
the use of electroconvulsive therapy in the medically ill. The illumination they
provide should help expand the use of effective but underutilized treatment
modalities in the medically ill.
Psychiatrists who care for the medically ill are at the frontiers of medicine.
Their clinical expertise and research contributions have had important implications inuencing new medical and surgical treatments. One example has been
the changes in policy and practice regarding liver transplantation for alcoholic
patients, reviewed by Drs. DiMartini, Weinrieb, and Fireman. Other frontiers
xii
PREFACE
addressed in this issue are the rapidly increasing use of herbal remedies and
nonherbal supplements (Drs. Crone and Gabriel) and designer drugs (Dr. Bialer).
The authors hope you nd this rich buffet of topics in psychiatric care of
the medically ill as lling and fullling as they did. Bon appetit.
West Hospital
1200 E. Broad St., 8th Fl., North Wing
Richmond, VA 23219
PREFACE
JAMES L. LEVENSON, MD
Guest Editor
xiii
PSYCHIATRIC PRESENTATIONS
OF NON-HIV INFECTIOUS
DISEASES
Neurocysticercosis, Lyme Disease, and
Pediatric Autoimmune Neuropsychiatric
Disorder Associated with Streptococcal
Infection
Robert K. Schneider, MD, Michael J. Robinson, MD,
and James L. Levenson, MD
Psychiatric symptoms are commonly a part of the clinical presentation of an infectious process. Psychiatrists of the medically ill are aware
of psychiatric aspects of classic infectious diseases, such as neurosyphilis,
and newer infectious diseases, such as HIV, but are less familiar with
non-HIV infectious agents; however, recent changes, such as increased
global mobility caused by rapid economic and cultural pressures, medical advances that alter immunity, and increased longevity, have created
an environment where new and seemingly unusual diagnoses need to
be considered. Also, evidence links certain infectious processes and
neuropsychiatric disorders (e.g., pediatric autoimmune neuropsychiatric
disorder associated with streptococcal infection [PANDAS]). Some of the
infections are not well known in the United States despite increasing
prevalence (e.g., cysticercosis). Little information is found in psychiatric
journals and textbooks because these illnesses are not considered psychiatric; however, psychiatrists in medical settings should be able to
evaluate the possibility of an infectious cause for secondary psychiatric
SCHNEIDER et al
Figure 1. Life cycle of Taenia solium. (From Garcia H, Del Bruttoo O [eds]: Taenia Solium
Cysticercosis. Infect Dis Clin North Am 14:1, 200, 97119; with permission.)
SCHNEIDER et al
The four forms of active NCC are (1) parenchymal, (2) ventricular,
(3) subarachnoid, and (4) spinal. The presentation of active disease can
take different forms depending on the part of the CNS involved and the
degree of involvement. Seizures are a common presentation when there
is parenchymal involvement. In fact, NCC is the leading cause of seizures in endemic areas worldwide. The seizures are often partial complex that can generalize.3 Ventricular NCC produces symptoms when
the cysticerci obstruct the ow of cerebrospinal uid and cause hydrocephalus. Subarachnoid involvement can cause seizures, hydrocephalus,
or stroke. Spinal involvement usually occurs when there is also cerebral
involvement.
The psychiatric presentation depends on not only the area of
involvement of the CNS but also the clinicians venue. In an outpatient
neurology clinic in Brazil, depression was the most common psychiatric
disorder; however, the diagnosis of NCC was already established.8 When
the diagnosis is unclear (i.e., at an acute medical center), psychosis or
delirium may be the most common presentation. Typically the patient
does not have a history of psychiatric disorders and has an acute decompensation. Often, the differential includes seizures. Shandera et al34 described a case of NCC involving a young woman who had recently
emigrated from Mexico. She presented with bizarre behavior (bathing
her neonate in olive oil) and paranoid ideation. She also had a history of
seizures. The differential diagnosis includes schizophrenia, postpartum
psychosis, and interictal seizures; however, given her origin of birth,
infectious causes, including tuberculosis and toxoplasmosis, should be
considered. In the case series studied by Shandera et al,34 8% of NCC
patients presented with either psychosis or dementia. Other dementias
are more common than the cognitive impairment seen in NCC, but
patients who are younger, have a more acute onset, have a country of
origin endemic for NCC, and have a history of seizures are more likely
to have NCC. The symptoms usually are related to hydrocephalus
caused by chronic ventricular NCC.45 In both presentations, psychosis
and dementia represent common symptoms found in the general population. Similarly, headache is a common symptom found with NCC in
endemic areas, but it represents a nonspecic nding.5 A high index of
suspicion and a careful workup are needed to catch these cases.
The only truly reliable gold standard for the diagnosis of NCC
is pathologic conrmation through biopsy. Given that this is usually
impractical, head CT scanning or MR imaging has become the default
gold standard. The head CT scan typically shows a round, high-density
lesion in the brain that is less than 1 cm in diameter (Fig. 2). In active
disease, a ring-enhancing lesion may be present, with a pathognomonic
scolex seen in the cyst. MR imaging can visualize the walls of the cysts,
but CT scans cannot (Fig. 3).22 When the subarachnoid or ventricular
spaces are involved, visualization of the organism becomes more difcult, and indirect signs (e.g., inammation and calcication) may be the
only radiographic clues.3 Laboratory studies are inferior to neuroimaging
but can help to conrm the diagnosis. It is important to clarify that
nding T. solium eggs in the feces indicates taeniasis (i.e., infection with
the tapeworm) but not cysticercosis or NCC. Serology is required to
determine whether infection or autoinfection with the cysticerci has
occurred. Enzyme-linked immunosorbent assay (ELISA) has been used
in the past, but the test of choice recommended by the Centers for
Disease Control and Prevention to detect antibodies from the larval cysts
of T. solium is the enzyme-linked immunoelectrotransfer blot (EITB).
EITB is more sensitive and specic than ELISA.31 EITB has reported
sensitivity and specicity of more than 90% for early stage NCC. The
sensitivity increases to 94% with two or more detectable lesions; however, patients with only single lesions or calcied lesions were less
likely to be EITB positive.46 Between clinical history, neuroimaging, and
serology, a presumptive diagnosis of NCC usually can be made.
Treatment of NCC depends on acuity of presentation and the cause
of the symptoms. If the patient presents with seizures and cerebral
edema, then the treatment is supportive, with antiepileptics and steroids.
If the presentation is cognitive decline and hydrocephalus, then surgical
shunting is indicated.45 Anthelminthics (e.g., albendazole and praziquantel) had been the mainstay of denitive treatment. These drugs can
increase pericystic inammation, aggravating neuropsychiatric symptoms, so steroids are recommended to be coadministered; however,
recent placebo-controlled trials question the use of anthelminthics because of the morbidity associated with their toxicity and questionable
efcacy. A recent review of four studies involving 305 patients concluded
that insufcient evidence exists to assess whether cesticidal therapy
SCHNEIDER et al
Figure 3. Pre-(A) and postcontrast (B) CT images showing the appearance of a right
parietal enhancing lesion. (From Garcia H, Del Bruttoo O [eds]: Taenia Solium Cysticercosis. Infect Dis Clin North Am 14:1, 2000, 97119; with permission.)
SCHNEIDER et al
Comments
Symptoms of the disorder rst become evident in the
majority of patients between 3 years of age and the
onset of puberty.
The patient must meet lifetime diagnostic criteria (DSMIIR or DSM-IV) for OCD or a tic disorder.
Clinical course is characterized by the abrupt onset of
symptoms or by a dramatic symptom exacerbation;
often, the onset of a specic symptom exacerbation
can be assigned to a particular day or week, at which
time the symptoms seem to explode in severity;
symptoms may resolve between episodes, or continue
at lesser severity.
Since streptococcal infections and tics are common in
childhood, conrmation of an association between
them can be made only by following the children
over time, observing at least two exacerbations
occurring shortly after GABHS infections (i.e.,
associated with positive throat culture or elevated
anti-GABHS antibody titres); of note, the temporal
relationship between the GABHs infection and the
symptom exacerbation may vary over the course of
the illness, often with a lag time of a several days to a
few weeks; fever and other stressors of illness are
known to increase symptom severity; therefore, the
symptom exacerbations should not occur excllusively
during the period of acute illness.
During symptom exacerbations, patients will have
abnormal results on neurological examination;
motoric hyperactivity and adventitial movements
(including choreoform movements and tics) are
particulary common; it is particularly important to
make the distinction between PANDAS and
Sydenhams chorea.
PANDAS pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection; OCD obsessive-compulsive disorder; DSM Diagnostic and Statistical Manual of Mental Disorders; GABHS group A -hemolytic streptococci.
Adapted from Swedo SE, Leonard HL, Garvey M, et al: Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections: Clinical description of the rst 50 cases. Am J
Psychiatry 155:264271, 1998; with permission.
Comments
Age-inappropriate behavior
Nighttime difculties
Attention decit hyperactivity disorder
Anorexia ?
10
SCHNEIDER et al
11
Figure 5. Lyme diseasereported cases, United States, 1997. In 1997, a total of 12,801
cases of Lyme disease were reported by 46 states and the District of Columbia. The 10
states with the highest incidence of Lyme disease cases per 100,000 population were
Connecticut, Rhode Island, New Jersey, New York, Pennsylvania, Delaware, Massachusetts, Wisconsin, Minnesota, and Maryland. These states accounted for 92% of the reported
Lyme disease cases in 1997. One dot one case, randomly placed within county of
residence. (Data from Summary of Notiable Diseases, United States 1997. MMWR
46:42, 1998.)
12
SCHNEIDER et al
13
14
SCHNEIDER et al
SUMMARY
Infectious diseases can cause an array of symptoms, including psychiatric symptoms. Psychiatrists serving the medically ill need to be
aware not only of classic infectious diseases (e.g., neurosyphilis and
HIV), but also of less commonly discussed infectious diseases (e.g.,
NCC, PANDAS, and Lyme disease). These examples represent an internationally endemic disease (e.g., NCC), a probable immunogenetic disease (e.g., PANDAS), and a frequently overdiagnosed and overtreated
disease (Lyme disease).
References
1. American College of Physicians: Guidelines for laboratory evaluation in the diagnosis
of Lyme disease. Ann Intern Med 127:11061108, 1997
2. Berthier ML, Kulisevsky JJ, Gironell A, et al: Obsessive-compulsive disorder and
traumatic brain injury: Behavioral, cognitive, and neuroimaging ndings. Neuropsychiatry Neuropsychol Behav Neurol 14:2331, 2001
3. Carpio A, Escobar A, Hauser WA: Cysticercosis and epilepsy: A critical review. Epilepsia 39:10251040, 1998
4. Centers for Disease Control: Lyme diseaseUnited States, 1999. MMWR Morb Mortal
Wkly Rep 50:181185, 2001
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5. Cruz ME, Cruz I, Preux PM, et al: Headache and cysticercosis in Ecuador, South
America. Headache 35:9397, 1995
6. Fallon BA, Nields JA: Lyme disease: A neuropsychiatric illness. Am J Psychiatry
151:15711583, 1994
7. Fix AD, Strickland GT, Grant J: Tick bites and Lyme disease in an endemic setting.
JAMA 279:206210, 1998
8. Forlenza OV, Filho AHGV, Nobrega JPS, et al: A study of 38 patients from a neurology
clinic in Brazil. J Neurol Neurosurg Psychiatry 62:612616, 1997
9. Garcia HH, Del Brutto OH: Taenia solium cysticercosis. Infect Dis Clin North Am
14:97119, 2000
10. Garvey MA, Giedd J, Swedo SE: PANDAS: The search for environmental triggers of
pediatric neuropsychiatric disorders: Lessons from rheumatic fever. J Child Neurol
13:413423, 1998
11. Garvey MA, Perlmutter SJ, Allen AJ, et al: A pilot study of penicillin prophylaxis for
neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry
45:15641571, 1999
12. Giedd JN, Rapoport JL, Garvey MA, et al: MRI assessment of children with obsessivecompulsive disorders or tics associated with streptococcal infection. Am J Psychiatry
157:281283, 2000
13. Kalish RA, Kaplan RF, Taylor E, et al: Evaluation of study patients with Lyme disease,
10-20 year follow-up. J Infect Dis 183:453460, 2001
14. Klempner MS, Hu LT, Evans J, et al: Two controlled trials of antibiotic treatment in
patients with persistent symptoms and a history of Lyme disease. N Engl J Med
344:8592, 2001
15. Krauss JK, Jankovic J: Tics secondary to craniocerebral trauma. Mov Disord 12:776
782, 1997
16. Logigian EL: Neurologic manifestations of Lyme disease. In Rahn DW, Evans J (eds):
Lyme Disease. American College of Physicians, Philadelphia, 1998, pp 89106
17. McCracken JT: Tic disorders. In Sadock BJ, Sadock VA (eds): Kaplan and Sadocks
Comprehensive Textbook of Psychiatry, ed 7. Philadelphia, Lippincott Williams &
Wilkins, 2000, pp 27112719
18. Murphy TK, Goodman WK, Fudge MW, et al: B Lymphocyte antigen D8/17: A
peripheral marker for childhood-onset obsessive-compulsive disorder and Tourettes
syndrome. Am J Psychiatry 154:402407, 1997
19. Nadelman RB, Nowakowski J, Fish D, et al: Prophylaxis with single-dose doxycycline
for the prevention of Lyme disease after an izodes scapularis tick bite. N Engl J Med
344:7984, 2001
20. Nadelman RB, Nowakowski J, Forseter G, et al: The clinical spectrum of early Lyme
borreliosis in patients with culture-conrmed erythema migrans. Am J Med 100:502
508, 1996
21. Nichol G, Dennis DT, Steere AC, et al: Test-treatment strategies for patients suspected
of having Lyme disease: A cost-effectiveness analysis. Ann Intern Med 128:3748, 1998
22. Noujaim SE, Rossi MD, Rao SK, et al: CT and MR imaging of neurocysticercosis. AJR
Am J Roentgenol 173:14851490, 1999
23. Osler W: On Chorea and Choreiform Affections. Philadelphia, HK Lewis, 1984, pp
3335
24. Perlmutter SJ, Garvey M, Castellanos X, et al: A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Am J Psychiatry
155:15921598, 1998
25. Perlmutter SJ, Leitman SF, Garvey MA, et al: Therapeutic plasma exchange and
intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in
childhood. Lancet 354:11531158, 1999
26. Peterson BS, Leckman JF, Tucker D, et al: Preliminary ndings of antistreptococcal
antibody titres and basal ganglia volumes in tic, obesessive-compulsive, and attentiondecit/hyperactivity disorders. Arch Gen Psychiatry 57:364372, 2000
27. Rahn DW, Evans J: Lyme Disease. Philadelphia, American College of Physicians, 1998
28. Ravdin LD, Hilton E, Primeau M, et al: Memory functioning in Lyme borreliosis. J
Clin Psychiatry 57:281286, 1996
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29. Salinas R, Prasad K: Drugs for treating neurocysticercosis (tapeworm infection of the
brain). Cochrane Database Syst Rev 2000, CD000215
30. Schantz PM, Moore AC, Munoz JL, et al: Neurocysticercosis in an orthodox Jewish
community in New York City. N Engl J Med 327:692695, 1992
31. Schantz PM, Sarti E, Plancarte A, et al: Community-based epidemiological investigations of cysticercosis due to Taenia solium: Comparison of serological screening tests
and clinical ndings in two populations in Mexico. Clin Infect Dis 18:879885, 1994
32. Schneider RK, Levenson JL: Infectious disease syndromes. In Stoudemire A, Fogel BS,
Greenberg DB (eds): Psychiatric Care of the Medical Patient, ed 2. Oxford, UK, Oxford
University Press, 2000, pp 857869
33. Seltzer EG, Gerber MA, Cartter ML, et al: Long-term outcomes of persons with Lyme
disease. JAMA 283:609616, 2000
34. Shandera WX, White AC Jr, Chen JC, et al: Neurocysticercosis in Houston, Texas.
Medicine 73:3752, 1994
35. Sigal LH, Zahradnik JM, Lavin P, et al: A vaccine consisting of recombinant Borrelia
burgdorferi outer surface protein A to prevent Lyme disease. N Engl J Med 339:216
222, 1998
36. Sorvillo FJ, Waterman SH, Richards FO, et al: Cysticercosis surveillance: Locally acquired and travel-related infections and detection of intestinal tapeworm carriers in
Los Angeles County. Am J Trop Med Hyg 47:365371, 1992
37. Steere AC, Bartenhagen NH, Craft JE, et al: The clearly clinical manifestations of Lyme
disease. Ann Intern Med 99:7682, 1983
38. Steere AC, Sikand VK, Meurice F, et al: Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med
339:209215, 1998
39. Swedo SE, Leonard HL, Garvey M, et al: Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections: Clinical description of the rst 50
cases. Am J Psychiatry 155:264271, 1998
40. Swedo SE, Leonard HL, Mittleman BB, et al: Identication of children with pediatric
autoimmune neuropsychiatric disorders associated with streptococcal infections by a
marker associated with rheumatic fever. Am J Psychiatry 154:110-112, 1997
41. Swedo SE, Rapoport JL, Cheslow DL, et al: High prevalence of obsessive-compulsive
symptoms in patients with sydenhams chorea. Am J Psychiatry 146:246249, 1989
42. Swedo SE: Sydenhams chorea: A model for childhood autoimmune neuropsychiatric
disorders. JAMA 272:17881791, 1994
43. Tager FA, Fallon BA: Psychiatric and cognitive features of Lyme disease. Psychiatr
Ann 31:172181, 2001
44. White AC Jr: Neurocysticercosis: A common cause of neurological disease worldwide.
Clin Infect Dis 24:101113, 1997
45. White AC Jr: Neurocysticercosis: Updates on epidemiology, pathogenesis, diagnosis
and management. Annu Rev Med 51:187206, 2000
46. Wilson M, Bryan RT, Fried JA, et al: Clinical evaluation of the cysticercosis enzymelinked immunoelectrotransfer blot in patients with neurocysticercosis. J Infect Dis
164:10071009, 1991
47. Zee CS, Go JL, Kim PE, et al: Imaging of neurocysticercosis. Neuroimaging Clin North
Am 10:391407, 2000
Address reprint requests to
Robert K. Schneider, MD
Department of Psychiatry
Division of Consultation-Liaison Psychiatry
Medical College of Virginia Campus of
Virginia Commonwealth University
P.O. Box 980268
Richmond, VA 23298-0268
e-mail: rkschnei@hsc.vcu.edu
THE USE OF
ELECTROENCEPHALOGRAPHY
IN PSYCHIATRY OF THE
MEDICALLY ILL
John Michael Bostwick, MD, and Kemuel L. Philbrick, MD
From the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
17
18
Their words point out the tendency of any brain injury to result in
electrical alteration, a concept that makes intuitive sense if the brain is
understood as an electrical organ. They remind us that, because electrical
signals attenuate in proportion to the distance they must travel from
deep structures, EEG surface leads primarily survey only shallow cortical layers. Signals originating in the brainstem or in orbitofrontal, mesial,
or deep temporal structures are for this reason notoriously difficult to
capture. Finally, slow, degenerative changes may not even register as
deranged electrical signals because dead-brain tissue sends no signal
at all.10
CURRENT APPLICATIONS OF
ELECTROENCEPHALOGRAPHY
The nonspecificity of EEG signal abnormalities helps to explain why
its promise as a screening tool for particular conditions affecting function
has not been realized. But Neylans observations, read in reverse, tell us
how EEG can be useful. When a patient has experienced a known insult
acutely that could have affected the neocortex, the nonspecific findings
on EEG have a high likelihood of correlating with the insults effect.
ELECTROENCEPHALOGRAPHY
19
20
For the EEG to be useful despite its anemic sensitivity and specificity, the importance of the psychiatrist gathering history from chart data,
patient interview, and collateral sources cannot be overemphasized. This
case illustrates this well. Each EEG must be read in its proper context
in relation to a particular problem of an individual patient, Kiloh7
writes, and full clinical details should be available, including the results
of other investigations. EEG is first and foremost a correlational tool,
powerful when deployed to clarify a drug-induced, metabolic, or convulsive state. Indications from history for ordering an EEG cluster around
the sudden, recent, discrete, or episodic mental status change. Indications for ordering an EEG include the following:
Helpful
Seizure disorder
Encephalitis
Delirium
Rapidly progressive dementia
Profound coma
Often abnormal, but unhelpful
Space-occupying lesions
Dementia
ELECTROENCEPHALOGRAPHY
21
22
condition, but can merely serve to diminish the probability of its existence, Kiloh7 warns. Serial EEGs days apart can help to resolve the
dilemma as the EEG changes with the resolution or worsening of the
delirium. In emphasizing the evanescent nature of some EEG findings,
Adams et al1 caution that an EEG is ordinarily recorded under restricted
circumstances . . . from several parts of the cerebral convexities (only)
during an infinitesimal part of a persons life. It is this concern that
leads to recommendations for serial tracings, up to months apart, or for
extended EEG observation in a video-monitoring unit in an attempt to
capture an event. While multiple investigators report what intuitively
makes sensethat serial tracings increase yieldspecific guidelines for
the appropriate intervals do not exist.2, 5, 8
Case 4: Partial Complex Seizures
Versus Behavioral Dyscontrol
Mr. R. was a 49-year-old man whose history of refractory seizures had
culminated in a right temporal lobectomy 1 year before his present psychiatric
admission. Postoperatively, his seizures had been well-controlled with carbamazepine and phenytoin, but he had begun experiencing vexing bouts of intense
anxiety associated with despondent mood. He was admitted to a medical psychiatry unit after antidepressants proved ineffective. He received bilateral electroconvulsive treatments nine times without benefit. In addition to his profound
anxiety and depression, he had periodic outbursts, sudden paroxysms of suicidality, and intermittent sexual impropriety. Staff became increasingly convinced
that these behavioral perturbations were consonant with a personality disorder.
He was referred to the epilepsy monitoring unit, however, where he was found
to have frequent partial complex seizures originating in the right frontal region
and frequently generalizing to the left frontal and right temporal regions. They
lasted 5 to 60 seconds, provoked significant sleep disruption, and correlated
with a variety of behavioral and cognitive abnormalities. After a more complex
anticonvulsant regimen had been instituted, the behavioral dyscontrol resolved.
Venlafaxine effectively treated remaining depressive and anxiety symptoms.
ELECTROENCEPHALOGRAPHY
23
before and during the study to maximize the likelihood inducing seizure
activity at the time that the tracing is made. These activating procedures
lower the seizure threshold in susceptible individuals. Sleep deprivation
for the night before a study can help to ensure that a patient will fall
asleep during the study. A patient with partial complex seizures, for
example, may have a normal tracing until asleep. Epileptic abnormalities
appear on 10% to 30% more EEGs in patients who sleep during the
examination.12
In addition to sleep, many activating procedures are used to bring
out abnormality on the EEG tracing, particularly when convulsive phenomena are suspected. Hyperventilation, typically at a rate of 20 times
a minute for 2 to 3 minutes, is especially helpful in elucidating petit mal
activity.2 A strobe light for photic stimulation, placed 37.5 cm (15 inches)
from a patients eyes and flashed at frequencies ranging from 1 to 20
times per second may bring on seizure activity. When it does not occur
spontaneously during a tracing, sedatives, such as barbiturates, or antipsychotics, such as chlorpromazine, may be administered to suppress
ascending reticular activity and help unmask abnormalities not present
on the EEG tracing in the awake subject.9 If patients report that a
particular stimulus (e.g., music) induces a seizure, exposure to that
stimulus during monitoring is recommended. Potentially confounding
medications, such as anticonvulsants or benzodiazepines, may need to
be discontinued in anticipation of the study.
Given the shallow surveillance depth of surface leads, alternative
lead placements can put the electrode closer to the source in cases
in which temporal lobe seizures are suspected. Nasopharyngeal leads,
inserted into the nose, rest on the mucosa of the pharyngeal roof, several
centimeters closer to the temporal tissue inferiorly. Sphenoidal leads,
ensheathed in a lumbar puncture needle, can be angled into the cheeks
inferior to the zygomatic arches to the neighborhood of the foramen
ovale. These lead manipulations capture up to one third of patients with
partial complex seizures who have normal scalp tracings.12
Beyond these measures to enhance yield, it is also useful to minimize confounding factors that may attenuate the useful information that
can be gleaned from a tracing. Ideally, a patient should not fast before
an EEG because hypoglycemia can influence a tracing. Similarly, an
overly anxious or frankly uncooperative patient can introduce a variety
of motion artifacts. Recent electroconvulsive therapy or psychoactive
medications (e.g. sedatives, neuroleptics, tricyclics, or lithium carbonate)
also can influence the EEG tracing. The EEG technician should take such
details into consideration when attempting to extract relevant information from a compromised tracing.2
Once the EEG technician has read the EEG tracing and provided a
narrative report, the psychiatrist must interpret the findings. This process
of putting them in context is best accomplished by asking a series of
questions that confirm the adequacy of the tracing while translating the
findings into the psychiatric context.
Is the tracing adequate, that is, was the patient monitored for a
24
SUMMARY
The psychiatrist considering recommending an EEG should look for
acute changes in the history or examination suggestive of an organic
cause. If he or she judges that the EEG will help to clarify or confirm
the diagnostic impression already formulated, it is worth considering
whether adding provocative maneuvers could increase the yield. The
authors cannot overemphasize the importance of using the EEG in
ELECTROENCEPHALOGRAPHY
25
correlation to further inform old-fashioned clinical detective work already in process, particularly when the EEG could rule out a potential
organic contributor to a psychiatric phenotype. For routine screening
without an elevated index of suspicion or for thoughtless fishing expeditions, EEG results will surely disappoint.
References
1. Adams RM, Victor M, Ropper AH: Special techniques for neurological diagnosis. In
Principles of Neurology, ed 6. New York, McGraw-Hill, 1997, pp 1242
2. Boutros N: A review of clinical indications for routine EEG in clinical psychiatry.
Hospital and Community Psychiatry 43:716719, 1992
3. Brenner R: Utility of EEG in delirium: Past views and current practice. Int Psychogeriatr 3:211229, 1991
4. Fenton G: The electroencephalogram in psychiatry: Clinical and research applications.
Psychiatr Dev 2:5375, 1984
5. Hughes J: The EEG in psychiatry: An outline with summarized points and references.
Clin Electroencephalogr 26:92101, 1995
6. Itil T: The use of electroencephalography in the practice of psychiatry. Psychosomatics
23:799813, 1982
7. Kiloh LG, McComas AJ, Osselton JW, et al: Value and limitations of electroencephalography. In Clinical Electroencephalography. London, Butterworth, 1981, pp 272280
8. Lam RW, Hurwitz TA, Wada JA: The clinical use of EEG in a general psychiatric
setting. Hospital and Community Psychiatry 39:533536, 1988
9. Lishman W: Clinical assessment. In The Psychological Consequences of Cerebral Disorder in Organic Psychiatry. Oxford, Blackwell Science, 1998, pp 94148
10. Neylan TC, Reynolds CF III, Kupfer DJ: Electrodiagnostic techniques in neuropsychiatry. In Yudofsky SC, Hales RE (eds): American Psychiatric Press Textbook of Neuropsychiatry, ed 2. Washington, DC, American Psychiatric Press, 1992, pp 151164
11. Pro J, Wells C: The use of the electroencephalogram in the diagnosis of delirium. Dis
Nerv Syst 38:804808, 1977
12. Remick RA, Wada JA, Miles JE: Neuropsychiatric and electroencephalographic aspects
in the diagnosis of complex partial seizures. Can J Psychiatry 26:4952, 1981
13. Warner MD, Boutros NN, Peabody CA: Usefulness of screening EEGs in a psychiatric
inpatient population. J Clin Psychiatry 51:363364, 1990
Address reprint requests to
John Michael Bostwick, MD
Department of Psychiatry and Psychology, M-W11A
Mayo Clinic
200 First Street, SW
Rochester, MN 55905
e-mail: bostwick.john@mayo.edu
PSYCHIATRIC CONSEQUENCES
OF MOTOR VEHICLE ACCIDENTS
Richard A Mayou, BM, BCh, MA, MSc, MPhil
Unpublished work described in this article was supported by The Wellcome Trust
grant nos. 039203 and 048431.
27
28
MAYOU
29
also the article about traumatic brain injury [TBI] on pages 4369 of this
issue). Apparently, minor head injuries, causing bruising or abrasion
and perhaps very brief loss of consciousness, are much more common.
Posttraumatic amnesia is usually very brief, and in only a small proportion of cases is it prolonged. Mild TBI causes a spectrum of clinical
consequences, ranging from transient symptoms of impairment to persistent disability with cognitive decits, mood disturbance, and personality
change.35
Postconcussional symptoms are difcult to separate clinically from
acute psychological dissociation as described later. When persistent, it
seems probable that psychological and physical causes are both involved
and interact and that psychological factors become increasingly important over time.32
Patients with brief unconsciousness and amnesia have been shown
to be at the same risk for psychological sequelae: acute stress disorder
(ASD), PTSD, phobic travel anxiety, and other consequences.44 The specic posttraumatic syndromes also can occur after severer brain injuries
that are accompanied by prolonged unconsciousness and lengthy posttraumatic amnesia.9, 11 Intrusive memories may relate to islands of
memory of the MVA and to post-MVA events, such as hospital care.
30
MAYOU
31
with work and other aspects of everyday life. The content of the travel
anxiety reects the nature of the MVA, such that drivers are mainly
concerned about driving, and passengers, about traveling as a passenger.
Pedestrians and cyclists are largely phobic about those forms of travel;
however, in a small proportion of patients, travel anxiety generalizes to
other forms of transport and indeed to concern about other members of
the family, especially children, when they are traveling.
WHO IS AT RISK?
The small minority of victims with very severe injuries and prolonged physical consequences are at increased risk for all adverse medical outcomes, including hospital and primary care resource use. Severity
of injury is not a predictor for psychiatric outcomes, and the determinants of who does well and who does poorly are psychological and
social. Predictors differ according to the outcome being considered,40 but
published research has largely focused on PTSD. Predictors of PTSD include:
32
MAYOU
Type of Accident
Most published evidence about types of MVA has related to vehicle
occupants, but in the authors study of consecutive MVA attenders for all
types of MVA, there were considerable similarities in the consequences
between those who were drivers, passengers in vehicles, motorcyclists,
cyclists, and pedestrians. Inevitably, the pattern of travel anxiety reected the nature of the MVA itself.
Perception of Threat
Victims who perceive the MVA as having been very frightening and
perhaps life-threatening have signicantly poorer outcomes, including
the reported severity of pain and other physical symptoms.
33
34
MAYOU
Statistical Prediction
Analysis using multiple regression or logistic regression has largely
been concerned with prediction of long-term PTSD,2, 20 but the author
also has reported ndings for other outcomes.40 Predictors of travel
anxiety and of general anxiety and depression are similar to those
listed for PTSD,40 but slight differences exist; most notably, travel-related
variables (e.g., previous nervousness about driving) predict phobic anxiety about travel but no other outcome.
Chronic Pain
Chronic pain is commonly an issue in late referrals to orthopedic
and neurology clinics and is conspicuous in medicolegal practice; however, as described earlier, the evidence from the authors prospective
series suggests that it is problematic for no more than a small minority
of MVA victims regardless of whether compensation is an issue. Such
pain should be seen as one example of a much wider occurrence of
persistent pain in the general community.25 It is important to note the
increasing evidence for the importance of iatrogenic factors34 as contributors to the subjective severity and to the disability in those with severe
chronic pain, such as referrals to pain clinics. Neglect of psychological
and behavioral issues in standard medical care, even in physical rehabilitation programs, remains far too common.
35
36
MAYOU
37
38
MAYOU
Pharmacologic
Major depression needs to be recognized and treated vigorously in
the same way as that associated with other types of physical problem.
It is commonly regarded as an understandable, normal reaction rather
than pathologic, which may lead to prolonged delay in starting appropriate treatment.
Systematic reviews support the value of antidepressant medication
in the treatment of chronic pain.49 Antidepressant drugs, most especially
selective serotonin reuptake inhibitors (SSRIs), are the most widely used
pharmacologic treatment for PTSD. Evidence supports their effectiveness,1, 13, 23, 24 but small trial sizes and the use of very different populations
makes it difcult to compare ndings and draw conclusions. A recent
multicenter study has concluded that sertraline is a safe and effective
treatment compared with placebo.15 Current evidence suggests that drug
treatment may be less effective than the best forms of psychological
treatment and that there is a substantial danger of relapse when the
medication is ended.
39
References
1. Ballenger JC, Davidson JRT, Lecrubier Y et al: Consensus statement on posttraumatic
stress disorder from the International Consensus Group on Depression and Anxiety. J
Clin Psychiatry 61:6066, 2000
2. Blanchard EB, Hickling EJ: Who develops PTSD from motor vehicle accidents, and
who subsequently recovers? In Hickling EJ, Blanchard EB (eds): The International
Handbook of Road Trafc Accidents and Psychological Trauma: Current Understanding, Treatment and Law. Oxford, Elsevier Science, 1999, pp 185198
3. Blanchard EB, Hickling El, Taylor AB, et al: Psychiatric morbidity associated with
motor vehicle accidents. J Nerv Ment Dis 183:495504, 1995
4. Blanchard EB, Hickling EJ, Taylor AB, et al: Who develops PTSD from motor vehicle
accidents? Behav Res Ther 34:110, 1995
5. Blaszczynski A, Gordon K, Silove D, et al: Psychiatric morbidity following motor
vehicle accidents: A review of methodological issues. Compr Psychiatry 39:111121,
1998
6. Brewin CR: A cognitive neuroscience account of posttraumatic stress disorder and its
treatment. Behav Res Ther 39:373393, 2001
7. Bryant B, Mayou R, Lloyd-Bostock S: Compensation claims following road accidents:
A six-year follow-up study. Med Sci Law 37:4:326336, 1997
8. Bryant RA: Acute stress disorder. PTSD Research Quarterly 11:13, 2000
9. Bryant RA, Harvey AG: Postconcussive symptoms and posttraumatic stress disorder
after mild traumatic brain injury. J Nerv Ment Dis 187:302305, 1999
10. Bryant RA, Harvey AG, Dang ST, et al: Treatment of Acute Stress Disorder: A comparison of cognitive behavior therapy and supporting counseling. J Consult Clin Psychol
66:862866, 1998
11. Bryant RA, Marosszeky lE, Crooks J, et al: Posttraumatic stress disorder and psychosocial functioning after severe traumatic brain injury. J Nerv Ment Dis 189:109113, 2001
12. Cassidy ill, Carroll U, Cote P, et al: Effect of eliminating compensation for pain and
suffering on the outcome of insurance claims for whiplash injury. N Engl J Med
342:11791186, 2000
13. Davidson JRT: Pharmacotherapy of posttraumatic stress disorder: Treatment options,
long-term follow-up, and predictors of outcome. J Clin Psychiatry 61(suppl 5):5256,
2000
14. Davidson JRT, Connor KM: Management of posttraumatic stress disorder: Diagnostic
and therapeutic issues. J Clin Psychiatry 60:3338, 1999
15. Davidson JRT, Rothbaum BO, van der Kolk BA, et al: Mulicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch
Gen Psychiatry 58:485492, 2001
16. de Vries APJ, Kassam-Adams N, Cnaan A, et al: Looking beyond the physical injury:
Posttraumatic stress disorder in children and parents after pediatric trafc injury.
Pediatrics 104:12931299, 1999
17. Di Gallo A, Barton I, Parry-Iones W: Road trafc accidents: Early psychological consequences in children and adolescents. Br J Psychiatry 170:358362, 1997
18. Dionne CE, Koepsell TD, Von Korff M, et al: Predicting long-term functional limitations
among back pain patients in primary care settings. J Clin Epidemiol 50:3143, 1997
19. Ehlers A: A cognitive approach to the understanding and treatment of posttraumatic
stress disorder. In Hickling EJ, Blanchard EB (eds): The International Handbook of
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44. Mayou RA, Black J, Bryant B: Unconsciousness, amnesia and psychiatric symptoms
following road trafc accident injury. Br J Psychiatry 177:540545, 2000
45. Mayou RA, Bryant BM: Effects of road accidents on travel. Injury 25:457460, 1994
46. Mayou RA, Ehlers A, Hobbs M: Psychological debrieng for road trafc accident
victims. Three year follow-up of a randomised controlled trial. Br J Psychiatry 176:590
594, 2000
47. Mayou RA, Simkin S, Thelfall J: Effects of road trafc accidents on driving behaviour.
Injury 22:365368, 1991
48. McDonald AS, Davey GCL: Psychiatric disorders and accidental injury. Clin Psychol
Rev 16:105127, 1996
49. McQuay HJ, Tramer M, Nye BA, et al: A systematic review of antidepressants in
neuropathic pain. Pain 68:217227, 1996
50. Mirza KAH, Bhadrinath BR, Goodyer IM, et al: PTSD in children and adolescents
following road trafc accidents. Br J Psychiatry 172:443447, 1998
51. Morley S, Eccleston C, Williams A: Systematic review and meta-analysis of randomized
controlled trials of cognitive behaviour therapy and behaviour therapy for chronic
pain in adults, excluding headache. Pain 80:113, 1999
52. Murray GJL, Lopez AD: Global burden of disease. Cambridge, Harvard University
Press, 1996
53. Schrader H, Obelieniene D, Hovim G, et al: Natural evolution of late whiplash
syndrome outside the medicolegal context. Lancet 347:12071211, 1996
54. Shepherd I, Stein K, Milne R: Eye movement desensitization and reprocessing in the
treatment of post-traumatic stress disorder: A review of an emerging therapy. Psychol
Med 30:863871, 2000
55. Stallard P, Velleman R, Haldwin S: Prospective study of post-traumatic stress disorder
in children involved in road trafc accidents. BMJ 317:16191623, 1998
56. Stallard P, Velleman R, Haldwin S: Psychological screening of children for posttraumatic stress disorder. J Child Psychol Psychiatry 40:10751082, 1999
57. Taylor S, Koch WI: Anxiety disorders due to motor vehicle accidents: Nature and
treatment. Clin Psychol Rev 15:721738, 1995
58. Von Korff M, Harlow W, Cherkin D, et al: Effects of practice style in managing back
pain. Ann Intern Med 121:187195, 1994
59. Von Korff M, Gruman I, Schaefer I, et al: Collaborative management of chronic illness.
Ann Intern Med 127:10971102, 1997
60. Wessely S, Hotopf M: Is bromyalgia a distinct clinical entity? Historical and epidemiological evidence. Ballieres Clin Psychiatry 13:427436, 1999
61. White KP, Carette S, Harth M, et al: Trauma and bromyalgia: Is there an association
and what does it mean? Semin Arthritis Rheum 29:200216, 2000
Address reprint requests to
Richard A. Mayou, BM, BCh, MA, MSc, MPhil
University Department of Psychiatry
Warneford Hospital
Oxford OX3 7JX
United Kingdom
e-mail: richard.mayou@psych.ox.ac.uk
PSYCHIATRIC ASPECTS OF
TRAUMATIC BRAIN INJURY
Vani Rao, MD, and Constantine G. Lyketsos, MD, MHS
EPIDEMIOLOGY
Traumatic brain injury (TBI) is dened as brain damage secondary
to an externally inicted trauma. It is an ongoing pandemic with an
annual incidence of 2 million cases per year in the US.28 Of these,
approximately 500,000 require hospitalization and 80,000 suffer from
chronic disability of some kind.28 TBI is the leading cause of death and
disability in people younger than 45 years of age, with an overall
mortality rate of 25 deaths per 100,000. The age of peak incidence of
head injury is 15 to 24 years, with males being injured two to three
times more frequently than females.56, 99
Tables 180 and 255, 59 illustrate the causes and classication of head
injury. Advances in acute trauma care have improved survival signicantly. This has led to a substantial increase in morbidity in patients who
Table 1. CAUSES OF HEAD INJURY
Causes
Frequency (%)
50
21
12
10
Data from McAllister TW: Neuropsychiatric sequelae of head injuries. Psychiatr Clin North Am
15:395413, 1992.
From the Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, The
Johns Hopkins University, School of Medicine, Baltimore, Maryland
43
44
Mild
Moderate
Severe
1315
0.5 h
1h
912
124 h
124 h
8
24 h
24 h
*Severity of head injury can be classied by combining the GCS, LOC, and PTA.3 Other systems
of classication include use of GCS alone4 or use of LOC and PTA.5
Data from references 55 and 59.
45
b. Edema
c. Hypoxicischemic injury
d. Diffuse vascular injury
B. Secondary injury: indirect trauma related factors
1. Hypoxia
2. Anemia
3. Metabolic abnormalities
4. Fat embolism
5. Release of excitatory amino acids
6. Release of oxidative free radicals
7. Disruption of neurotransmitters
Primary Injury
Primary injury caused by direct mechanical impact of trauma might
be focal31 or diffuse.30, 51 Focal injuries include contusion, intracerebral
hematoma, intracranial hemorrhage, or focal hypoxicischemic injury.
Contusion is the most common focal injury and is the result of accelerationdeceleration forces and the angular and transitional movements of
the head, causing the brain to impact on the bony protuberances of the
skull producing coup (at the site of impact) and contre-coup (away from
the site of impact) injury.6
Of the diffuse injuries, DAI is the most common and is caused by
angular or rotational acceleration of the head producing shearing and
tearing of the axons.31 A diagnosis of DAI is suspected when there is a
history of acceleration injury with immediate loss of consciousness and
neuroimaging ndings of swelling, peticheal hemorrhages, subarachnoid
hemorrhage, or normal scan. The severity of the axonal damage can be
assessed by the depth and duration of coma, duration of posttraumatic
amnesia, and presence or absence of rostral brain stem signs.51 Brain
edema and swelling, hypoxic brain damage, and vascular injury are
other types of diffuse brain injuries well described by Katz and Alexander51 and Gennarelli and Graham.31
Secondary Injury
At the neuronal level, brain injury is a complex phenomenon, associated with a cascade of events from the time of injury and for a prolonged
period. Gennarelli and Graham31 have provided an extensive discussion
of the neuropathology of brain injury. The reader is encouraged to read
that article for a better understanding of this heterogenous disorder. This
article provides a brief summary. Calcium inux into the cells, free
radical damage, receptor damage, and inammation are the four distinct
but inter-related processes that occur after brain injury resulting in
vascular or neural injury with consequent focal or diffuse brain damage.31 The immediate cellular effect of trauma is mechanoseparation,
the transient separation of the lipid bilayers from the more rigid membrane inclusions, such as channels or receptors, causing a traumatic
46
defect in the cell membrane.31 The membrane defect may last a few
minutes to hours, with closure either by a passive process or by an active
processes, such as calcium-mediated lysolecithin patching or fusion of
the membrane.26
Other mechanisms, such as activation of voltage-dependent or receptor-mediated channels, cause delayed calcium entry into the cells.
Subsequently, following a pressure gradient, ions move into and out of
the cell, followed by an increase in intracellular calcium and leading to
deleterious effects, such as expression of immediate early genes and heat
shock proteins98 or activation of the N-methyl-D-aspartate receptors and
other secondary messengers causing alterations in cell metabolism,27
with resultant damage to the cytoskeletal and axonal elements.
Following the acute membrane defect, a cascade of neurochemical
events occurs, leading to disturbance in ionic homeostasis, cerebral metabolism, and blood ow. This results in activation of the excitatory
amino acidsglutamate and aspartate receptors,49 oxidative free radical
damage,54 release of cytokines,114 changes in the cholinergic system,90
catecholamine system,40 and serotonergic system.107 All of these disturbances contribute to short-term and long-term neuronal dysfunction
and, in some cases, neuronal death from necrosis.
Recovery from Brain Injury
Recovery from brain injury is a complex and dynamic process that
continues for a prolonged period from the time of injury. Little information is available on the exact duration of recovery, the factors inuencing
recovery, or the relationship between severity of injury and duration
and nature of recovery.
Animal studies suggest that, because of plasticity of the brain,
neuronal and axonal recovery occur within a few months after injury.20
Researchers have hypothesized similar mechanisms of recovery in the
human brain; however, this information cannot be translated directly to
humans because differences exist in the nature and severity of injury,
between human brain injury, and experimental brain injury.
In humans, recovery after focal brain injury differs from recovery
after diffuse brain injury. Location, size, site, and other pathophysiologic
features, such as hemorrhage, edema, and mass effect determine the
course of recovery in patients with focal lesions. The authors have
broadly divided the course of recovery from focal injury into three
phases: (1) an acute phase lasting from a few seconds to hours, in which
the patient is frankly confused; (2) a subacute phase, lasting two to
several days, characterized by gradual clearing of confusion but with
persistence of several emotional and cognitive sequelae (common symptoms include headache, dizziness, anxiety, depression, inattention, and
memory lapses); (3) a chronic phase, lasting for weeks to months and
characterized by gradual improvement in symptoms. In a small percentage of patients with focal TBI, some symptoms persist for months to
47
years after the injury. The reason for this is unclear but is probably due
to a combination of biological or psychosocial factors and premorbid
personality traits.
Recover from diffuse injury is often dependent on the amount
of diffuse axonal injury. The stages of recovery after such injury have
been described using the Rancho Los Amigos scale of cognitive
functioning.50, 52 These levels of recovery are neither clear-cut nor separated into well-dened stages. Overlapping between the stages is common, and, in general, the duration of the stages is proportional to the
severity of injury, with each stage longer than the previous stage.52 In
some cases, progress may stop abruptly in one or the other stage without
ever reaching the stage of complete independence. This scale is useful
for patients with severe head injury: but whether it can be applied to
people with mild to moderate head injury is unclear. Also, the scale
does not correlate well with the onset or resolution of psychiatric disturbances.
In the authors opinion, the stages of recovery, after mild to moderate diffuse head injury, are probably similar to what happens after focal
injury, with each stage more prolonged in duration and with residual
mood and cognitive or behavioral disability in the chronic stage in many
patients.
Recovery from brain injury is a complex and dynamic process, with
rapid improvement occurring over a few months after the injury, followed by gradual plateauing in recovery. No clear evidence shows when
recovery slows down or stops in patients with focal or diffuse injury.
Also, no linear relationship exists between the severity of head injury
and functional or emotional recovery.
CLASSIFICATION, ETIOLOGY, RISK FACTORS, AND
EPIDEMIOLOGY OF THE PSYCHIATRIC DISORDERS
ASSOCIATED WITH TRAUMATIC BRAIN INJURY
Classication
TBI is associated with several psychiatric disturbances that are not
always easy to classify. It may be possible to group together certain
signs and symptoms as specic syndromes, but others may occur in
isolation. Disturbances, such as irritability, insomnia, or fatigue, may be
secondary to a comorbid psychiatric disorder, such as major depression,
or may be a direct consequence of brain injury. Literature review also
reveals a lack of uniformity in classifying the psychiatric sequelae. Similar psychiatric disturbances have been classied differently by various
research workers. For example, impulsivity, aggressiveness, disinhibition, or cognitive decits occurring together have been classied by
some according to the anatomic site of damage as frontal or temporal
lobe syndromes,59 according to their clinical presentation as personality changes,60 or aggressive disorder,63 and according to the time
48
49
The authors have divided them into two: (1) highly signicant risk
factors, in which sufcient enough evidence suggests their role in the
development of psychiatric sequelae, and (2) less signicant factors, in
which the evidence is still controversial.
50
II.
III.
IV.
V.
VI.
VII.
The key components include obtaining a detailed history from the patient and collateral informants, and review of old medical records, performing a mental status, physical, and neurologic examination and conducting a brief test of global cognitive functioning, such as the MMSE.
This should help in formulating a working diagnosis. If deemed necessary and not done previously, other tests, such as neuropsychological
assessment to characterize cognitive decits, neuroimaging scans to assess neuroanatomic decits, and occupational therapy evaluation to
assess functional and motor skills and safety, also should be performed.
A complete diagnosis should include the type, nature, and severity
of brain injury, the associated neuropsychiatric sequelae, comorbid psychiatric diagnosis, medical illnesses that may be present, psychosocial
stressors, and current functional capacity. The patients stage of recovery
and short- and long-term prognosis also should be noted.51
51
52
Table 3. MEDICATIONS FOR PSYCHIATRIC DISORDERS FOLLOWING TBI
Medications
Depression
Mania
Apathy
Pathologic
Laughter/
Crying
Psychosis
Anxiety
Agitation/
Aggression
Cognition
Risk for
Adverse Side
Effects
Tricyclic antidepressants
Selective serotonin reuptake
inhibitors
Serotonin and norepinephrine
reuptake inhibitors
(venlafaxine)
Serotonin antogonists and
reuptake inhibitors
(trazodone)
Lithium
Carbamazepine and
valproate
Typical antipsychotics
Atypical antipsychotics
Psychostimulants
Amantadine
Dopamine agonists
Cholinesterase inhibitors
Benzodizopines
Buspirone
Beta-blockers
Potential benet; No/poor benet; Mild side effects; Moderate side effects; Severe side effects.
Adapted from Arciniegas DB, Topkoff F, Silver JM: Neuropsychiatric aspects of traumatic brain injury. Curr Opin Neurol 2:160186, 2000; with permission.
53
to education and hope, supportive psychotherapy should include recommendations on nutrition, regular exercise, importance of maintaining
routine, and scheduling daily activities. Patients should be encouraged
to attend brain injury support groups available in their area and to
maintain contact with the local and national brain injury associations.
It is beyond the scope of this article to discuss the extensive array
of psychotherapeutic measures; hence, only the common varieties of
therapy are named. Psychotherapy may be individual, group, or family
therapy, or a combination. The different types of therapies include occupational therapy, physical therapy, behavior therapy, cognitive rehabilitation, reality orientation, speech therapy, social skills training, recreation
therapy, vocational training, and substance abuse counseling. Even
though some of these interventions have been useful for some patients,
their use is largely empiric, with a lack of scientic validation. The big
problem is that no standardized criteria enumerate the indications, risks,
and benets of these forms of therapy. Cicerone et al13 conducted an
extensive literature review on the effectiveness of the different forms of
cognitive rehabilitation for people with TBI and stroke and have found
an overall effectiveness. The authors recommend this paper because it
provides information on the various types and effectiveness of cognitive
rehabilitation and methodologic success and aws of different studies.
Caregiver Support and Education
A caregiver may be the spouse, parents, family member, a friend,
or even a professional care provider. Whoever they may be, addressing
their needs is important because they often experience intense stress,
depression, and anxiety as a result of caring for a person with TBI.79
Often, these adverse effects are present for years after the TBI. The
frequency of psychiatric illness, such as anxiety and major depression,
among care providers of TBI patients ranges from 16% to 51%.89 In
addition, other problems, such as nancial difculties, role changes,
social isolation, and impaired family functioning79 are common. Hence,
support of the family and of the caregivers is an essential component of
treatment of the brain-injured patient. Each family is unique, and so are
their problems, and the needs should be addressed individually. The
general approach to caregiver support includes (1) providing education;
(2) instilling hope; (3) providing emotional support; (4) if symptoms of
anxiety or low mood are persistent, recommending professional help;
(5) encouraging the use of available resources, such as local and national
brain injury association centers; (6) discussing importance of respite care
and the need to have personal time; and (7) always providing emergency
contact numbers.
Clinical Features
This section discusses the common psychiatric disorders, which
include cognitive decits, mood disorders, anxiety disorder, apathy, psy-
54
55
56
57
58
Table 4. DIFFERENTIAL DIAGNOSIS OF MAJOR DEPRESSION
Signs and Symptoms
Depressed mood
Identiable stressor
Resolution of symptoms
Changes in sleep, appetite,
concentration
Changes in self-attitude
Feeling of hopelessness
Suicidal thoughts
Anhedonia
Initiation
Motivation
Major Depression
Adjustment Disorder
Demoralization
Apathy
Often transient
Often present
Symptoms resolve as
stressor terminates
Often transient
Often present
Symptoms resolve as
stressor terminates
Not present
Not present
Symptoms persist despite
termination of stressor
Often present
No change
No change
If present transient
May be present
May be decreased
May be decreased
Not present
May be present
May be decreased
May be decreased
Not present
Present and severe
Markedly decreased
Markedly decreased
59
60
61
dine8, 36, 58, 110 have found to be benecial in the treatment of apathy.
Again, only anecdotal reports and small case series studies are available.
Psychosis
Denition. Psychosis refers to disturbances in form and content of
thought, frequently associated with hallucinations and delusions.
Prevalence. Psychotic syndromes are more common among subjects
who sustain TBI than in the general population. In their review, Davison
and Bagley16 reported that 0.7% to 9.8% of subjects with TBI developed
schizophrenia-like psychosis. More recent studies have shown a prevalence of 3.4% to 8.9%.2 Davison and Bagley16 also found that 15% of
schizophrenics had sustained TBI before the onset of their rst psychotic
episode. In a study of multiple schizophrenia pedigrees, Malaspina et
al75 reported that a family history of schizophrenia is associated with
increased risk for TBI, with head trauma further increasing the risk for
TBI. In a retrospective study of 659 consecutive admissions to a psychiatric hospital, Wilcox and Nasrallah112 demonstrated that a history of head
trauma was signicantly more common among the schizophrenics than
among patients with major depression, mania, or surgical controls.
Clinical Picture. Post-TBI psychosis is a complex heterogeneous
disorder and may present with one or several of the core symptoms
of schizophrenia, such as delusions, hallucinations, abnormal thought
process, abnormal behavior, or negative symptoms. It may also manifest as impulsivity, aggressive behavior, expression of odd ideas, grimacing, inappropriate giggling, or ideas of reference. Psychotic symptoms
may be acute or delayed, relapsing or chronic, and might occur anytime
after TBI. They also may be seen in association with posttraumatic
amnesia,105 epilepsy,106 and mood disorders related to TBI.94, 103 Risk
factors for the development of psychosis include severe closed-head
injury, temporal lobe epilepsy,16 presence of a congenital neurologic
condition, and head injury before adolescence.29
Pathology. Both right69 and left hemisphere72 damage have been
associated with posttraumatic psychosis.
Treatment. Animal studies have shown impaired neuronal recovery
with the use of typical neuroleptics, such as haloperidol.25 Hence,
these agents should be used with caution and in low doses. Studies
about the effectiveness of atypical neuroleptics are few. Risperidone92
and clozapine91 have been found to be useful in the treatment of post-TBI
psychotic symptoms, such as hallucinations, delusions, and catatonia.
Our clinical experience also indicates that medications such as
risperidone, olanzapine and quetiapine can be used effectively to treat
paranoid delusions, auditory hallucinations and/or disorganized
thought process. Aggressive outbursts and delusion like signs and symptoms associated with cognitive impairment or behavior dyscontrol may
benet from dopaminergic agents.59
62
63
into their problem and may deny all complaints. The caregivers are
often overwhelmed and frustrated.
Pathology. The underlying abnormality probably is the result of
damage to the frontotemporal regions, causing emotional lability, executive dysfunctioning, disinhibition, memory lapses, and social inappropriateness.18, 36
Treatment. Management includes treatment of the patient and support and education of the caregiver. Pharmacologic interventions for the
treatment of behavioral dyscontrol includes use of high-dose -blockers,
dopamine agents, SSRIs, and mood stabilizers.36, 97 Silver et al95 have
reported the efcacy of high-dose blockers in the treatment of aggression
in chronically hospitalized inpatients. Carbamazepine has been shown
to be useful for the treatment of aggression in the acute12 and chronic70
phases of recovery. Several reports have suggested the benecial effects
of lithium in the treatment of aggression, but it is not favored secondary
to its potential neurotoxic side effects.7
Amantadine was rst used in the 1960s as an antiviral agent and
later as an antiparkinsonian agent; however, over the past decade, it has
been used as a frontal lobe agent secondary to its dopamine-enriching
property. The effectiveness of amantadine was studied by Gualtieri in
30 severely brain-injured patients approximately 2 to 144 months after
injury.37 Two thirds of them showed improvement in symptoms of agitation, emotional lablity, distractibility, and aggression.
Minor Variant. The authors have used the term minor variant to
describe the most common and controversial condition following
TBIthe postconcussion syndrome. It refers to a constellation of mood,
cognitive, and somatic signs and symptoms that occur soon after TBI of
any severity. Clinically, this condition resembles the major variant in
that patients present with a multitude of symptoms involving several
domains but differs in that, in most patients, the symptoms are often
not persistent and resolve spontaneously. Also, the other big difference
between the major and minor variants is the presence of aggressive
behavioral symptoms in the former and physical or somatic symptoms
in the latter.
Prevalence. Eighty to one hundred percent of patients who sustain
mild closed-head injury suffer from a multitude of symptoms affecting
several systems in the rst month of injury.64 The prevalence of this
disorder in patients with moderate and severe head injury is largely
unknown, although several researchers have reported their occurrence.
Numerous studies suggest that several of these symptoms spontaneously resolve by 3 and 6 months after injury; however, approximately
15% of patients with mild TBI have symptoms lasting longer than
1 year.83
Clinical Picture. The clinical picture of this disturbance includes:*
*Adapted from Rao V, Lyketsos C: Neuropsychiatric sequelae of traumatic brain injury.
Psychosomatics 41:95103, 2000; with permission.
64
Mood
Depression
Anxiety
Irritability
Cognition
Impaired memory
Decreased attention
Decreased concentration
Dysexecutive function
Conceptual disorganization
Somatic Symptoms
Headache
Nausea
Dizziness
Vertigo
Diplopia
Insomnia
Deafness
Tinnitus
Light sensitivity
Noise sensitivity
Fatigue
Dyscoordination
Drowsiness, blurred vision, nausea, and vomiting usually are seen
within the rst 48 hours. Other symptoms, such as headache, fatigability,
dizziness, impaired memory, poor concentration, depression, slow thinking, anxiety, and irritability often occur after 48 hours.101 Levin65 evaluated 155 patients 1 week after they had experienced a minor head injury
and found that headache and dizziness were reported by more than 50%
of patients. Somatic complaints, such as dizziness and visual disturbances, were also commonly reported symptoms but were more common among in females than males.66
Pathology. The underlying abnormality of this perplexing disorder
is unclear; however, a generally accepted hypothesis is that it may be
the result of rotational sheer strains and diffuse axonal injury.3 Interestingly, a number of patients have normal neurologic examination and
structural brain scans; however, single-photon emission CT and positron
emission tomography case reports have revealed focal abnormalities of
regional cerebral blood ow and glucose uptake.1, 35 More studies using
functional neuroimaging techniques need to be done to identify specic
abnormalities.
Treatment. It is crucial to maintain a practical and holistic approach.
Persistent emotional or cognitive problems requires a thorough psychiatric evaluation to rule out mood and anxiety disorders. Disruptive and
abnormal behavior should be redirected. Education, patient and family
support, and psychotherapy are other essential rehabilitative interventions.
65
SUMMARY
TBI is a complex heterogenous disease that can produce a variety
of psychiatric disturbances, ranging from subtle decits in cognition,
mood, and behavior to severe disturbances that cause impairment in
social, occupational, and interpersonal functioning. With improvement
and sophistication in acute trauma care, a number of individuals are
able to survive the trauma but are left with several psychiatric sequelae.
It is important for psychiatrists to be aware of this entity because an
increasing number of psychiatrists will be involved in the care of these
patients. Treatment should be interdisciplinary and multifaceted, with
the psychiatrist working in collaboration with the patient, caregiver,
family, other physicians, and therapists. The goal of treatment should be
to stabilize symptoms; maximize potential; minimize disability; and
increase productivity socially, occupationally, and interpersonally.
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Address reprint requests to
Vani Rao, MD
Osler 320
Neuropsychiatry and Memory Group
The Johns Hopkins Hospital
Baltimore, MD 21287
e-mail: vrao@mail.jhmi.edu
EPIDEMIOLOGY
Pain is dened by the International Association for the Study of
Pain81 as an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms of such
damage. Pain is a complex experience that integrates affective, cognitive, and behavioral factors with an extensive neurobiology.66 Pain is a
common problem in the general population and the most common
reason a patient presents to a physician for evaluation.51, 60, 61
In an 8-year follow-up survey, the US Center for Health Statistics
found that 32.8% of the general population suffered from persistent or
chronic pain symptoms.70 A World Health Organization (WHO) study
of over 25,000 primary care patients in 14 countries found that 22% of
patients suffered from pain that was present for most of the time for at
least 6 months.39 In a 24-year longitudinal study of chest, abdominal,
and musculoskeletal pain, symptoms increased with aging and women
reported more persistent and severe pain.8 In people 65 years of age or
older, musculoskeletal pain was associated with threefold the risk for
signicant difculty performing physical activities.92
In persons over the age of 75, more than two-thirds reported pain,
almost half reported pain in multiple sites, and a third rated pain as
severe in at least one location.7 Sixty-six percent of nursing home residents over the age of 65 reported chronic pain.99 Pain, not detected by
physicians in 34% of these residents, was associated with signicant
decreases in function and quality of life. The Study to Understand
From the Adolf Meyer Chronic Pain Treatment Programs and Department of Psychiatry
and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
71
72
73
74
75
Essence
Goal
Means
Accumulated
events produce
a unique
personal
narrative
Meaningful
connections
between past
events and
present
circumstances
Restore mastery
Understand
patterns,
appreciate
circumstances,
and reinterpret
meaning
Behaviors
Actions have an
underlying
design and
purpose
Goal-directed
behaviors
require choice
and free will
Restore
productivity
Stop behavior,
alter drives/
goals,
emphasize
responsibility
and relapse
prevention
Dimensions
Diseases
Dimensions
Obtain descriptions of who the patient was before the onset of illness
Supplement this information with standardized instruments
Quantify the amount of each trait a patient possesses
Identify the specic demands or situations that are evoking the
patients vulnerabilities
Provide new skills for decient traits and match strengths to new
tasks
Behaviors
Point out all problematic behaviors that need to stop
Focus on repeated actions that undermine the patients progress
Insist that the patient take responsibility for his choices and recognize the consequences
Emphasize productive behaviors and reinforce any positive change
Expect and plan for relapse
Diseases
Consider that the patients distress is caused by an unrecognized
clinical syndrome
Search for all possible broken parts causing pathologic processes
Fix as many broken parts as completely as possible to minimize disease
Select treatments that will minimize new damage and subsequent
disease
Use palliative treatments when cures are unavailable
76
Life Stories
As people live their lives, they encounters and experiences a number
of events in a variety of settings. As these events accumulate, people
become imbedded in a narrative. This narrative is a tapestry of meaningful connections specic to individuals from which they develop an
understanding of their own existence and set of assumptions about
their roles in the world. At times, people experience the unintended
consequences of past events. When life turns out differently from what
was expected, the outcome is demoralization and distress. This distress
is caused by a perceived loss of mastery over ones life. This loss is not
the result of the broken part of a disease but of an individual left
wanting something better from life.
Evaluation within the domain of life stories involves knowing more
of the personal story and appreciating the patients meaningful understanding of those events. In treatment, the patient is persuaded by the
physician to give up his current interpretation of those events for another. A new interpretation is not necessarily the correct or true
interpretation. An innite number of meanings can be generated for a
given set of historical life events. The importance of the new interpretation is that it tries to be useful and restore a sense of mastery for the
patient. If the patient can embrace a new understanding of his situation
and why it has occurred, he can go forward with a renewed sense of
control over his life that now again has the potential for success.
The patient who develops postherpetic neuralgia can be persuaded
that, even though he has a severe illness, he can contribute to the future
and be successful in his life. His contribution may be in ways previously
not considered, such as starting a support group with educational programs for patients with postherpetic neuralgia. Similarly, a patient who
presents feeling overwhelmed by a failure of a new medication for pain
would benet from discussing his commitment to treatment as a symbol
of hope for the future. Recognizing recurring patterns of events would
allow for changes to avoid future circumstances of the same kind and
restore the individuals sense of mastery.
The cognitive-behavioral model of chronic pain assumes individual
perceptions and evaluations of life experiences affect emotional and
behavioral reactions to these experiences.56 If patients believe that pain,
depression, and disability are inevitable and uncontrollable, then they
experience more negative affective responses, increased pain, and even
more impaired physical and psychosocial functioning. Patients are
taught to become active participants in the management of their pain
with methods that reframe their circumstances and minimize distressing
thoughts and feelings. Outcomes studies of such treatment for patients
with a variety of chronic pain syndromes have demonstrated signicant
improvements in pain intensity, pain behaviors, distress, depression, and
coping.54, 108, 109 Pain reduction and improved physical function have been
found to continue up to 6 months after the completion of active cogni-
77
78
79
pain).1 Treatment within the dimensional perspective identies the demands that are evoking the patients vulnerabilities and focuses on
enhancing the decient traits and nding new situations that will capitalize on the patients strengths.
Behaviors
Behaviors are goal-directed activities. Internally, behaviors are motivated by drives such as hunger or seeking relief from pain. These drives
provoke the behavior and then abate after some action is performed that
satises the drive, which then likely will re-emerge at some time in the
future. Externally, behaviors are meaningful because of the opportunities, self-imposed beliefs, and individual goals that lead to a person
making choices. Similarly, behavior has external consequences that are
reinforcing to the individual and involve learning over time how to
accomplish ones goals more effectively. A self-efcacy expectancy is a
belief about ones ability to perform a specic behavior while an outcome expectancy is a belief about the consequences of performing a
behavior.47 Individuals are considered more likely to engage in coping
efforts they believe are both within their capabilities and will result in a
positive outcome. Self-efcacy beliefs mediate the relationship between
pain intensity and disability in different groups of patients with chronic
pain.3, 4, 110 The lack of belief in ones own ability to manage pain,
cope, and function, despite persistent pain, is a signicant predictor of
disability and secondary depression in patients with chronic pain.
Traditional approaches to behavioral disorders have focused on
modifying drives and reinforcements to stop problematic actions, such
as pain behaviors, medication use, and excessive utilization of health
care services. Pain behaviors, such as grimacing, guarding, and taking
pain medication, have been found to be indicators of perceived pain
severity and functional disability.10, 37, 53, 90, 106 Behavioral treatments promote the adaptation of a person to their pain by encouraging healthy,
productive actions. Active physical therapy is a specic form of behavior
therapy directed at reducing pain behaviors by increasing muscle
strength and endurance as well as altering abnormal body mechanics
that have developed to compensate for a specic dysfunction. This
behavioral rehabilitation involves performing a series of exercises and
implementing postural changes with the goals of recovering normal
functional capacity throughout the body. These exercises also have a
psychological benet as patients learn to take an active role in a treatment that increases their functional capacity.122
In a study of patients attending a clinic specializing in pain, almost
90% of patients were taking medications.58 Opioid analgesics were prescribed to 70%, whereas antidepressants and benzodiazepines were being taken by only 25% and 18%, respectively. In this population, 12%
met DSM-III-R criteria for substance abuse or dependence; however, the
misuse and abuse of medications was not limited to just psychoactive
80
substances. In a study of patients with chronic low back pain, 34% had
a substance use disorder, but in all cases, such use was present before
the onset of their chronic pain.84 Those individuals with a history of
substance abuse were found to be at increased risk for substance abuse
during treatment for chronic pain and for further physical injury.91
Terms such as addiction, misuse, overuse, abuse, and dependence have
been used inconsistently to describe various medication seeking or taking behaviors. The under-reporting and inaccurate reporting of medication use complicates accurate assessment of actual use patterns by patients with chronic pain.31, 87 The mechanism of relapse back to substance
abuse in these patients is not well understood and probably involves
multiple factors; however, a cycle of pain followed by relief after taking
medications is an example of operant reinforcement of their future use.36
Studies investigating the risk for opioid abuse during treatment for
chronic pain have been reassuring. In one study of 12,000 medical
patients treated with opioids, only 4 patients without a history of substance abuse developed addiction to the medication.86 Other studies of
chronic opioid therapy found that patients who developed problems
with their use of the medication all had a history of substance abuse.85, 104
Even when the diagnosis of addiction is suspected in patients taking
opioids for chronic pain, maladaptive behaviors, such as stealing or
forging prescriptions, rarely occur.25, 93
Although the actual diagnosis of somatization disorder is rare in
patients with chronic pain, somatization is a common phenomenon in
the practice of medicine, manifests itself along a spectrum of severity
and can emerge from and is shaped by many factors both in and around
the patient. Somatization is a behavioral process and not a categorical
psychiatric diagnosis or a psychological trait.101 The process of somatization starts with symptom perception that varies along a continuum from
minimization to amplication of sensory information. Once the symptom
has been perceived, the individual attributes it to a cause, such as a
health problem. Finally, a decision is made about what to do for this
symptom. For example, patients with chronic pain are more likely to
consult a physician.2 Environmental forces, such as the societal stigma
of psychiatric disorders and the reliance of physicians on the biomedical
paradigm, have been correlated with increased rates of somatization.59, 116
Abnormal illness behavior may be manifested in other ways, such
as unexplained disability or high utilization of health care services, and
can be formulated in a similar fashion. The drives, behaviors, and goals
of choosing to use excessive medications, pursue diagnostic evaluations,
or failing to work full-time must each be determined. Ultimately, treatment moves beyond stopping the dysfunctional actions to altering these
associated drives and goals. These later steps focus on the components
of behavior to prevent relapse so that productive behaviors are not
subsequently overrun by the recurrence of problematic ones. The physician emphasizes that the patient must take responsibility and accept the
consequences of personal choices to make progress.
81
Diseases
The disease perspective uses the logic of cause and effect. It is a
linear approach most often described as the biomedical model. The
disease perspective assumes an abnormality in the structure or function
of a bodily part. This is an example of the power of nature to break
individuals. The broken part transforms physiology into pathophysiology and health into sickness. As a consequence, signs and symptoms of
the disease emerge and cluster together as a recognizable clinical syndrome. The patient either has a particular disease, or he does not. One
diagnosis is ruled in, and other diagnoses are eventually ruled out.
The disease perspective demands searching for the broken part that
results in pain. For example, a patient with burning pain in a particular
dermatome is examined and formulated as having the clinical syndrome
of neuropathic pain. Further examination attempts to determine what
abnormality is present, such as sensory loss, allodynia, and hyperalgesia.
The patient may have an inammation, infarction, or compression of the
involved peripheral nerve. Each of these abnormalities, for example
compression, has an associated list of potential causes of disease, such
as a tumor caused by increased cell division, an aneurysm caused by
weakened smooth muscle in a blood vessel, or excessive bone formation
caused by osteoblast activation. Some mental disorders are best explained as a disease such as dementia, schizophrenia, or major depression.
Studies of patients presenting to clinics specializing in the evaluation of pain have systematically assessed the prevalence of psychiatric
diseases, with affective and anxiety disorders being the most common.88
The relationship between pain and depression remains controversial.
Approximately 60% of patients with depression report pain symptoms
at the time of diagnosis.69, 114 The presence of a depressive disorder has
been demonstrated to increase the risk for chronic musculoskeletal pain,
headache, and chest pain 3 years later.64, 70, 71, 115 Among 1016 health
maintenance organization members, the prevalence of depression was
12% in individuals with three or more pain complaints compared with
only 1% in those with one or no pain complaints.17 Among groups of
patients with medically unexplained symptoms, such as back pain and
dizziness, two thirds of patients have a history of recurrent major depression compared with less than 20% of medically ill control groups.52, 101
In patients with chronic pain referred to comprehensive pain programs
for evaluation, 8% to 50% have a current major depression.98
In a comparison of measures of affective distress, self-reported depressive symptoms, and presence of major depression in 211 patients
with chronic pain in a university pain clinic, major depression was
signicantly related to self-reported disability and negative thoughts
about pain.38 Self-reported depressive symptoms also were highly related
to the evaluative or cognitive component of pain, but affective distress
was uniquely related to the sensory or emotional component of pain.
Alternative sets of diagnostic criteria for major depression in pa-
82
tients with chronic pain include disregarding symptoms that are caused
by medical problems, replacing somatic symptoms with nonsomatic
alternatives, and including all symptoms regardless of presumed
cause.121 The prevalence of major depression ranged from 19% to 36%,
with disregarding symptoms producing the lowest rate; however, patients that were excluded from diagnosis by this method were comparable to those patients diagnosed with depression across all methods.
These ndings support the use of inclusive criteria for major depression
to avoid neglecting the treatment of patients that have signicant distress
and disability.
Depression is not simply a comorbid condition but interacts with
chronic pain to increase morbidity and mortality. Patients with chronic
pain and depression reported greater pain intensity, less life control,
more use of passive-avoidant coping strategies and greater interference
from pain and exhibited more pain behaviors than did chronic pain
patients without depression.42, 69, 117 Depression has been shown to be a
signicant predictor of pain persistence and the best predictor of application for early retirement because of pain.41, 70
The consequences of unrecognized and untreated depression are
substantial. For example, patients suffering from chronic pain syndromes
including migraine, chronic abdominal pain, and orthopaedic pain syndromes report increased rates of suicidal ideation, suicide attempts, and
suicide completion.23, 27, 72 Oncology patients with pain and depression
were signicantly more likely to request assistance in committing suicide
and to actively take steps to end their lives; however, even if in pain,
when depression was not present, they were unlikely to request the
interventions of euthanasia and physician-assisted suicide.19 Depression,
not suicidal status, consistently predicted level of functioning, pain severity, pain-related disability, less use of active coping, and more use of
passive coping in patients with chronic pain on a university inpatient
unit.32 Depression should be treated aggressively and not simply understood as an expected outcome of suffering with chronic pain.
Although anxiety is a common and expected component of acute
pain, patients with chronic pain are also at increased risk for comorbid
anxiety disorders. Patients with a variety of pain syndromes ranging
from chronic low back pain, chronic neck pain after whiplash injury,
and chronic pain from prostate cancer have increased rates of both
anxiety symptoms and disorders.43, 63, 84, 120 Almost 50% of patients report
anxiety symptoms and 19% to 30% of patients have an anxiety disorder,
such as panic disorder and generalized anxiety disorder.15, 26, 88 One
prospective study of 1007 young adults found that a baseline history of
migraine was signicantly associated with an increased risk (OR 12.8)
for incident panic disorder.9 Conversely, 40% of patients with panic
disorder reported chronic pain symptoms, and more than 7% were using
analgesics on a daily basis.62
Although experimental trials have not been performed, the identication and treatment of specic psychiatric diseases, such as major
depression and panic disorder, would likely result in a signicant reduc-
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34. Flor H, Fydrich T, Turk DC: Efcacy of multidisciplinary pain treatment centers: A
meta-analytic review. Pain 49:221230, 1992
35. Folkman S, Lazarus RS, Gruen RJ, et al: Appraisal, coping, health status, and psychological symptoms. J Pers Soc Psychol 50:571579, 1986
36. Fordyce W, Fowler R, Lehmann J, et al: Operant conditioning in the treatment of
chronic pain. Arch Phys Med Rehab 54:399408, 1973
37. Fordyce WE, Lansky D, Calsyn DA, et al: Pain measurement and pain behavior. Pain
18:5369, 1984
38. Geisser ME, Roth RS, Theisen ME, et al: Negative affect, self-report of depressive
symptoms, and clinical depression: relation to the experience of chronic pain. Clin J
Pain 16:110120, 2000
39. Gureje O, Von Korff M, Simon GE, et al: Persistent pain and well-being: A World
Health Organization study in primary care. JAMA 280:147151, 1998
40. Hallberg LR, Carlsson SG: Anxiety and coping in patients with chronic work-related
muscular pain and patients with bromyalgia. Eur J Pain 2:309319, 1998
41. Hasenbring M, Marienfeld G, Kuhlendahl D, et al: Risk factors of chronicity in
lumbar disc patients: A prospective investigation of biologic, psychologic, and social
predictors of therapy outcome. Spine 19:27592765, 1994
42. Haythornthwaite JA, Sieber WJ, Kerns RD: Depression and the chronic pain experience. Pain 46:177184, 1991
43. Heim HM, Oei TPS: Comparison of prostate cancer patients with and without pain.
Pain 53:159162, 1993
44. Hellstrom C, Jansson B, Carlsson SG: Subjective future as a mediating factor in the
relation between pain, pain-related distress and depression. Eur J Pain 3:221233, 1999
45. Hellstrom C, Jansson B, Carlsson SG: Perceived future in chronic pain: The relationship between outlook on future and empirically derived psychological patient proles. Eur J Pain 4:283290, 2000
46. Hildebrandt J, Pngsten M, Saur P, et al: Prediction of success from a multidisciplinary
treatment program for chronic low back pain. Spine 22:9901001, 1997
47. Jensen MP, Turner JA, Romano JM: Self-efcacy and outcome expectancies: relationship to chronic pain coping strategies and adjustment. Pain 44:263269, 1991
48. Jensen MP, Turner JA, Romano JM: Correlates of improvement in multidisciplinary
treatment of chronic pain. J Consult Clin Psychol 62:172179, 1994
49. Jensen MP, Turner JA, Romano JM, et al: Coping with chronic pain: A critical review
of the literature. Pain 47:249283, 1991
50. Jensen MP, Nielson WR, Romano JM, et al: Further evaluation of the pain stages of
change questionnaire: Is the transtheoretical model of change useful for patients with
chronic pain? Pain 86:255264, 2000
51. Karlsten R, Gordh T: How do drugs relieve neurogenic pain? Drugs Aging 11:398
412, 1997
52. Katon W, Sullivan M: Depression and a chronic medical illness. J Clin Psychiatry
150(suppl):311, 1990
53. Keefe FJ, Crisson JE, Maltbie A, et al: Illness behavior as a predictor of pain and overt
behavior patterns in chronic low back pain patients. J Psychosom Res 30:543551, 1986
54. Keefe FJ, Caldwell DS, Williams DA, et al: Pain coping skills training in the management of osteoarthritic knee pain: a comparative study. Behav Ther 21:4962, 1990
55. Keefe FJ, Caldwell DS, Williams DA, et al: Pain coping skills training in the management of osteoarthritic knee pain: II. Follow-up results. Behav Ther 21:435447, 1990
56. Keefe FJ, Beaupre PM, Weiner DK, et al: Pain in older adults: A cognitive-behavioral
perspective. In Ferrell BR, Ferrell BA (eds): Pain in the Elderly. Seattle, IASP Press,
1996, pp 1119
57. Kerns RD, Rosenberg R, Jamison RN, et al: Readiness to adopt a self-management
approach to chronic pain: The Pain Stages of Change Questionnaire (PSOCQ). Pain
72:227234, 1997
58. Kouyanou K, Pither CE, Wessely S: Medication misuse, abuse and dependence in
chronic pain patients. J Psychosom Res 43:497504, 1997
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84. Polatin PB, Kinney RK, Gatchel RJ, et al: Psychiatric illness and chronic low back
pain. Spine 18:6671, 1993
85. Portenoy RK, Foley KM: Chronic use of opioid analgesics in non-malignant pain:
Report of 38 cases. Pain 25:171186, 1986
86. Porter J, Jick H: Addiction rate in patients treated with narcotics. N Engl J Med
302:123, 1980
87. Ready LB, Sarkis E, Turner JA: Self-reported vs. actual use of medications in chronic
pain patients. Pain 12:285294, 1982
88. Reich J, Tupin J, Abramowitz S: Psychiatric diagnosis in chronic pain patients. Am J
Psychiatry 140:14951498, 1983
89. Riley JL III, Robinson ME: Validity of MMPI-2 proles in chronic back pain patients:
Differences in path models of coping and somatization. Clin J Pain 14:324335, 1998
90. Romano JM, Syrjala KL, Levy RL, et al: Overt pain behaviors: Relationship to patient
functioning and treatment outcome. Behav Ther 19:191201, 1988
91. Savage SR: Addiction in the treatment of pain: Signicance, recognition and management. J Pain Symptom Manage 8:265278, 1993
92. Scudds RJ, Robertson JM: Empirical evidence of the association between the presence
of musculoskeletal pain and physical disability in community-dwelling senior citizens. Pain 75:229235, 1998
93. Sees KL, Clark HW: Opioid use in the treatment of chronic pain: Assessment of
addiction. J Pain Symptom Manage 8:257264, 1993
94. Skevington SM: Investigating the relationship between pain and discomfort and
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95. Slade PD, Troup JD, Lethem J, et al: The fear-avoidance model of exaggerated pain
perception: II. Behav Res Ther 21:409416, 1983
96. Slavney PR: Perspectives on Hysteria. Baltimore, Johns Hopkins University Press,
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97. Slavney PR: The mind-brain problem, epistemology, and psychiatric education. Acad
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98. Smith GR: The epidemiology and treatment of depression when it coexists with
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99. Stein WM, Ferrell BA: Pain in the nursing home. Clin Geriatr Med 12:601613, 1996
100. Stroud MW, Thorn BE, Jensen MP, et al: The relation between pain beliefs, negative
thoughts, and psychosocial functioning in chronic pain patients. Pain 84:347352, 2000
101. Sullivan M, Katon W: Somatization: The path between distress and somatic symptoms. Am Pain Soc J 2:141149, 1993
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104. Taub A: Opioid analgesics in the treatment of chronic intractable pain on nonneoplastic origin. In Kitahata LM, Collins JG (eds): Narcotic Analgesics in Anesthesiology. Baltimore, Williams & Wilkins, 1982, pp 199208
105. Turk DC, Stieg RL: Chronic pain: the necessity of interdisciplinary communication.
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106. Turk DC, Matyas TA: Pain-related behaviors: Communication of pain. Am Pain Soc J
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107. Turk DC, Meichenbaum D, Genest M (eds): Pain and Behavioral Medicine: A Cognitive-Behavioral Perspective. New York, Guilford Press, 1983
108. Turner JA: Comparison of group progressive-relaxation training and cognitive-behavioral group therapy for chronic low back pain. J Consult Clin Psychol 50:757765, 1982
109. Turner JA, Romano JM: Psychological and psychosocial techniques: Cognitive-behavioral therapy. In Bonica JJ (ed): The Management of Pain. Malvern, PA, Lea and
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110. Turner JA, Jensen MP, Romano JM: Do beliefs, coping, and catastrophizing independently predict functioning in patients with chronic pain? Pain 85:115125, 2000
111. Vendrig AA: The Minnesota Multiphasic Personality Inventory and chronic pain: A
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122.
PSYCHIATRIC ISSUES IN
PULMONARY DISEASE
Kathy Coffman, MD
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Interventions
Efforts to educate school personnel have encouraged better management during the day.164 The costs that may be harder to quantitate
include days lost from school, decreased exercise, decreased school performance because of interrupted sleep, and parental days missed from
work to care for the child as well as changes in housekeeping to minimize allergens. In teenagers, a lack of knowledge about asthma and
denial of symptoms may result in delays in seeking medical treatment.100
A study testing the predictive value of the 1993 Biobehavioral Family model in 22 asthmatic children showed that insecure fatherchild
relatedness, triangulation of the child in marital conict, and hopelessness correlated with vagal activation. Insecure motherchild relatedness correlated only with hopelessness.221 In children and adolescents
with asthma, the video intervention/prevention assessment (VIA)
method, giving children videocameras to document their daily lives,
resulted in an identication of environmental risk factors, medication
adherence problems, and illness beliefs and psychological states that
were not found through standard clinical history taking or tools. VIA
helped to make counterproductive behaviors understandable by putting
them in context of the adolescents experience of chronic illness and
health care.171
One study of 85 asthmatics showed a higher prevalence of selfreported noncompliance with treatment among those who were hospitalized or had been previously hospitalized than those that had never been
hospitalized. Emotional distress associated with disease and treatment
was related to noncompliance.165 Early intervention to identify and treat
depression in asthmatic children has been recommended to increase
medication adherence; improve outcome; and, it is hoped, decrease
mortality.74
Only two studies of randomized, controlled trials have compared
family therapy for children with asthma. Both showed improvement in
various measures, such as clinical pulmonary function and number
of functionally impaired days.154 The question of whether behavioral
interventions could affect asthma morbidity was investigated in a randomized, controlled study of 16 young, nonsteroid-dependent asthmatics who received biofeedback-assisted relaxation. Data indicated signicant improvement in FEV1/FVC after the test and decreased severity
of asthma and bronchodilator use with changes in white blood cell
populations over time, suggesting decreased inammation.106
Patient-education programs can reduce anxiety and improve selfmanagement. Tools such as problem checklists and patient diaries of
attacks can be useful in making patients aware of the signs of an attack,
triggers of attacks, helpful steps for the patient or others to take during
an attack, and the impact of the illness on social and academic development and family life.217
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Cystic Fibrosis
In the United States, CF affects more than 18,000 children aged less
than 18 years. This disease is inherited in 1 in 2500 children and is the
most common hereditary disease among white children. The disorder
also occurs in other races. In general, the disease results in chronic
progressive lung disease and pancreatic insufciency. Survival improved
from a median age of 12 years in 1966 to 28 years by 1997.39
The regimen of therapy necessary to maintain health in patients
with CF is time consuming and may involve the whole family, especially
in early childhood. The use of a nebulizer with bronchodilating medications followed by physiotherapy three times a day is necessary to loosen
up sputum so that it can be coughed up more easily. Antibiotic treatment
by portacath may be needed because intravenous (IV) sites are used up
quickly and the port can decrease the pain of frequent IV sticks. Pancreatic enzyme replacement by bills at mealtimes are needed during the
day. Inhalers may be used during the day. In cases of severe malnutrition, gastrostomy tubes with a kangaroo pump may allow for nighttime
feeding to gain the weight needed to improve strength and endurance
so that activities and schooling may be more normal.126
Psychodynamic Issues
Several investigators have described the experience of growing up
with CF from the childs perspective. This strategy is helpful to understand the different issues that arise during various stages of psychological development. For example, adolescents may come to grips with the
illness; put it into a new perspective because of their growing cognitive
abilities; and, it is hoped, assume responsibility for their health care.
Knowing the key issues involved can make design of therapeutic interventions more effective.39, 80, 126
A study by Christina and DAuria45 explored adolescent conceptualizations of their chronic illness and investigated how perceptions
changed throughout childhood. Although based on a small sample of
20 adolescents with CF, the subjects were interviewed in depth to learn
about their coping strategies. Interestingly, these adolescents did not
realize that they were ill until age 6 to 8 years old, around the time
when they left the family environment to begin school. The diagnosis of
CF did not have meaning for them at this time, and children recalled
being surprised that they were sick. Once children began school, their
symptoms brought unwanted attention from peers, who wondered why
they coughed and took pills. Much like the children with attentiondecit/hyperactivity disorder, who visit the nurse and take pills, they
felt stigmatized.
In middle childhood, children learned to keep the CF a secret out
of fear of being talked about or picked on. They felt unprepared for the
intensity of the negative responses from peers. Children minimized their
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illness on involvement in activities, such as running in gym class, climbing stairs, going out with friends, and being able to be up all day
without a nap.216 Parents lled out the Child Behavior Checklist.2 The
adolescents were involved in 9 weekly sessions involving cognitivebehavioral therapy for an hour each in their homes. At 3-month followup assessment, the adolescents showed decreased anxiety and perceived
functional ability but did not maintain the gains in coping with CFrelated problems.
Chronic Obstructive Pulmonary Disease
Estimates indicate that almost 16 million Americans are diagnosed
with chronic obstructive pulmonary disease (COPD) each year, with
roughly 14 million with chronic bronchitis and 2 million with emphysema. COPD ranks fourth as cause of death in the United States after
heart disease, cancer, and stroke. More than 112,000 people died from
COPD in 1998. Chronic bronchitis ranks ninth among chronic conditions
in the United States. Whereas many other types of lung disease affect
minority groups disproportionately, COPD alone shows a higher ageadjusted death rate for whites (21.9 per 100,000) than blacks (17.7 per
100,000). COPD ranked eighth among causes of death in blacks and
ninth for Hispanics, even though both groups have high rates of cigarette
smoking. Cigarette smoking is related to 82% of COPD deaths, and
cigarette smokers are 10-fold as likely to die from COPD than nonsmokers.
Pathologic changes in the lungs seen in COPD are not reversible
and cause airow obstruction and abnormalities in arterial blood gases,
including decreased partial pressures of oxygen and sometimes retention
of carbon dioxide. The changes in mentation seen in patients with
diminished oxygen content in the blood include confusion, disorientation, altered consciousness, and even muscle twitching or tremor. Seizures have been reported, which exacerbate hypoxia through increasing
demand for oxygen. If hypoxia is not sustained for long periods, no
lasting sequelae occur. Prolonged hypoxia can result in permanent memory decits or dementia or anoxic encephalopathy.124 Profound anoxia
can lead to parkinsonian symptoms, extrapyramidal symptoms, pseudobulbar palsy, or visual agnosia. Watershed infarcts of the cerebral
cortex from hypotension may present with unilateral weakness of the
arm or parietal lobe decits because these areas are supplied by the
conuence of the anterior and middle cerebral arteries. Hypoxia can
present with psychological changes, such as irritability, mental slowing,
impairment of memory with poor reasoning, and perseveration. Patients
show muscular incoordination, poor calculation ability, slow reaction
time, problems retaining new information, and emotional lability. If
hypoxia is accompanied by hypercapnia and respiratory acidosis, as in
emphysema or status asthmaticus, patients may be lethargic and have
auditory and visual hallucinations, especially with blood pH below 7.2
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dence. Patients may react to these groups in various ways. Patients with
social phobia symptoms may avoid the class if the chairs seem crowded
or the temperature is too hot or cold. Care must be taken to present the
material at a level appropriate for the patients. Some patients may take
offense if the material is too simple or too complex.60
Sarcoidosis
Sarcoidosis was rst reported by Jonathan Hutchinson in 1872.183
Although the cause has been suspected to be an atypical reaction to
tuberculosis and an immunologic basis has been postulated, the cause
of sarcoidosis is undertermined. Sarcoidosis causes granulomas and
affects the alveoli and bronchioles, ultimately reducing lung capacity.
Estimates of the prevalence of sarcoidosis today indicate that this
disease affects black patients disproportionately in the United States, 40
per 100,000 versus 5 per 100,000 whites. In Europe, Swedes and Danes
have high prevalence rates of sarcoidosis.6 Onset of the illness is between
the ages of 20 and 40 years, and the illness may show a relapsing and
remitting course, with recovery in 80% of patients. Fatality caused by
sarcoidosis occurs in approximately 5% of patients. Patients may be
asymptomatic but often have a dry cough, shortness of breath, fatigue,
and weight loss. Lesions can affect the skin, bones, joints, skeletal muscles, or heart. Fatal complications include pulmonary brosis, cardiac
disease, and renal failure.125
CNS Sarcoidosis
The rst case of peripheral nervous system sarcoidosis was described in 1905.218 Sarcoidosis affects the CNS in approximately 5% of
patients. Involvement of cranial nerve VII can lead to unilateral or
bilateral facial palsies. If the optic nerve is affected, blurred vision may
occur. As many as 32% of people with sarcoidosis may have ocular
involvement, which may mimic multiple sclerosis and other disorders.
Available data indicate that as many as 47% of neuro-ophthalmic sarcoidosis remits.43 Arachnoiditis may cause increased intracranial pressure and hydrocephalus, and granulomatous meningitis can cause headache. Tumorlike granulomas can cause personality changes, including
somnolence, obesity, and hyperthermia, together with memory changes.
Pituitary involvement may result in diabetes insipidus; hyponatremia;
or other endocrine problems, such as menstrual cycle changes or hypogonadism.30, 57, 138, 187
Various psychiatric symptoms have been noted, such as apathy,
irritability, neglect, hallucinosis, and residual dementia.95 Seizure may be
the presenting symptom with CNS sarcoidosis.210 CNS disease may cause
disturbance of orientation, sensorium, memory, and cognitive function-
99
ing.133, 189 CNS sarcoidosis has been mistaken for a depressive stupor,
Wernicke-Korsakoff psychosis, and a classic paranoid psychosis.95, 226, 202
Comorbidity with Psychiatric Disorders
Sarcoidosis has not been well investigated from the psychological
standpoint. One study of 17 patients found a relationship between
increased life stress at the outset of the study and impairment of lung
function during the study period. No consistent psychiatric symptoms
were associated with the disease, although the sarcoid patients had
symptoms similar to patients with agoraphobia, such as uncomfortable
bodily sensations, thoughts of embarrassing themselves or acting in a
strange manner, or avoidance of going places unaccompanied. Many
patients ultimately diagnosed with sarcoidosis have been mistakenly
labeled as having somatization disorder.56 Because of the role of the
immune system in sarcoidosis, relaxation training and stress-reduction
therapy have been suggested as adjuvant treatment in hopes of inuencing immune function and addressing isolation from agoraphobic symptoms. Interestingly, the only psychological variable that consistently correlated with lung function was the mean score for day-to-day hassles,
which may benet from relaxation exercises and stress management.110
Psychodynamics in Sarcoidosis
Because sarcoidosis arises in the 20- to 40-year-old age range, the
disease affects adults in their most productive years. Diagnosis may be
delayed either by failure to recognize the slowly progressive symptoms
until characteristic ndings are seen on chest radiography. Patients may
feel robbed of vitality at their physical peak. They may regret time
wasted when they were in better physical shape. They may be hesitant
to take on activities because of fears of becoming light-headed or having
to gasp for air. Patients may use shallow breathing to avoid the embarrassment and exertion of having a coughing t, much like those with CF.
Pulmonary Fibrosis
The cause of idiopathic pulmonary brosis (IPF) is unknown, but
the prevalence is roughly 3 to 5 per 100,000. IPF may be caused by
inhalation of various agents, such as asbestos, crystalline silica, beryllium, steel particles, nylon ocking used to make plush toys, cotton ber
(brown lung), alpha particles from radon progeny in uranium mining, or
oxidant gases.13, 27, 116, 215 IPF also may result from acute hypersensitivity
pneumonitis, such as chronic bird fanciers disease.150 IPF has been seen
with 1-antitrypsin deciency.109 Interstitial lung disease also may be
seen in rheumatologic disease, such as systemic sclerosis, primary Sjogrens syndrome, rheumatoid arthritis, and polydermatomyositis. In one
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103
driasis and hysteria and low on depression. If patients earn a living with
their voices, this disorder can end a career. In others, the embarrassment
may result in social withdrawal and isolation. Abnormal neurologic
ndings in 74% to 90% of patients suggest an underlying organic cause.15, 173
Factors noted to play a part in this disorder include a setting of psychosocial stress, rapid onset after an upsetting event, with strong dependency needs and fears of separation. Laryngospasm has been viewed as
a behavioral response to ward off dysphoric affect, and characterized as
a possible somatization disorder. Those with factitious disorder may not
benet from short term psychotherapy.198 The disorder may mimic
asthma, although in general, the wheezing is loudest over the larynx
and the chest is otherwise clear. These patients respond well to active
expiratory breathing in speech therapy and to short-term psychotherapy.41 Patients may show severe respiratory distress with hypoxemia or
relatively normal blood gas levels. Studies166 have shown that the disorder generally is not associated with hysterical conversion or intention to
deceive; only one fth had a factitious disorder in one study. A rapid
response to speech therapy has been described.166 In cases resistant to
speech therapy and other treatment, recurrent laryngeal nerve section
has had some success in years past.121 In recent years, botulinum toxin
injection has been used in treatment. One group investigated phonoscopic examination as a way to distinguish patients with spasmodic
dysphonia from those with psychogenic dysphonia. Although individual
behaviors did not differentiate the groups, patterns seen on videotaped
laryngeal imaging did show differences between the two groups. Only
two of the features, tremor and paradoxic movements, were exclusively
found in those with spasmodic dysphonia. Tremor of the vocal cords
was seen only in 3 of 24 patients with spasmodic dysphonia and in none
of the patients with psychogenic dysphonia. Paradoxic movements of
the true and false folds was seen in 8 of 24 patients with spasmodic
dysphonia and none of the patients with psychogenic dysphonia. The
patients with psychogenic dysphonia tended to show a single abnormal
laryngeal posture that did not vary across phonetic tasks. Abnormal
postures in the patients with spasmodic dysphonia was intermittent
across the tasks.120
Pulmonary Hypertension
Although the incidence of pulmonary hypertension is estimated to
be 2 to 5 cases per 1 million population, autopsy data indicates that a
more accurate incidence is closer to 1 in 1000. In general, the onset is in
the early to mid-30s, and women are more likely than are men to be
affected. The patient may present with obesity, with a disproportionate
degree of dyspnea and fatigue, and a history of migraines and sometimes syncope. Many of these patients are misdiagnosed as having
anxiety, with a resulting delay in treatment. The most common medical
conditions that may trigger pulmonary hypertension are autoimmune
disorders, catecholamine release, HIV infection, lung injury, portal hy-
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pertension, and high altitude. Drugs that can trigger pulmonary hypertension include anorexigens, such as dexfenuramine (Redux), now
withdrawn from the US market, cocaine, L-tryptophan, and rapeseed oil.
Diagnostic criteria include a mean pulmonary artery pressure of 25
mm Hg at rest and 30 mm Hg with exercise, no evidence of left-sided
heart disease, or lung disease, such as active vasculitis or pulmonary
emboli. Pathology typically shows pulmonary arteriolar hypertrophy.
On physical examination, an increased jugular pulse, right ventricular
heave, and S4 gallop may be appreciated. ECG may show signs of right
ventricular hypertrophy or a right axis deviation and may be misread
as an anteroseptal infarct. Mitral valve prolapse is common because of
the dilation of the right ventricle. The prognosis can be correlated with
the stage of heart disease that occurs, with New York Heart Association
(NYHA) class I or II disease surviving approximately 6 years, NYHA
class III surviving approximately 2.5 years, and NYHA class IV surviving
6 months. Factors that correlate inversely with survival include right
atrial pressure, mean pulmonary artery pressure, and NYHA class. The
worst prognostic factor is presence of a large pericardial effusion on
echocardiography. Workup includes echocardiography, ventilation
perfusion scan, and possibly pulmonary angiography. Pulmonary function tests may be normal until late, when in NYHA class III or IV, there
may be a decreased diffusing capacity and mild restrictive pattern.
Potential benets of calcium channel blockers or epoprostenol (Flolan) can be determined by a cardiologist experienced with treatment of
pulmonary hypertension. Epoprostenol has been shown to improve
short-term survival in patients with NYHA class III or IV disease. This
drug can be administered by an indwelling catheter by continuous pump
on an ambulatory basis. Even if the initial response to epoprostenol is
not positive, there may be a lag time caused by vascular remodeling,
slow changes in right ventricular function with digitalis, or decreased
thrombosis. Treatment with epoprostenol offers hope to those who may
be candidates for lung or heartlung transplantation, who may wait for
more than 18 months for organs. Survival in lung transplantation for
pulmonary hypertension is roughly 85% 1 year and 50% 5 year, with
better outcomes in those with NYHA class I and II disease.
Supportive psychotherapy is directed toward coping with a life-threatening disease, learning pacing to conserve energy, and stress management.
Family supports can inuence outcome. Pregnancy is not recommended,
and oral contraceptives are contraindicated because estrogen may worsen
primary pulmonary hypertension and increase the risk for thrombosis.
Weight control through calorie restriction is helpful because patients have
poor exercise tolerance. Low fat and low salt diet are recommended.170
Lung Cancer
Lung cancer is the most common cancer worldwide. The incidence
of lung cancer has surpassed breast cancer in women. Smoking tobacco
is the primary cause of most lung cancers.
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spite the use of newer agents, such as gemcitabine and a novel antifolate,
Alimta, the survival with nonsmall cell lung cancer is still poor, with
response rates of 15% to 30% and a mean survival of 8 to 9 months.
Median 1-year survival rates are roughly 30% to 40% with 2-year survival rate of approximately 10% to 15%.65 Not much has been written
about psychological aspects of nonsmall cell lung cancer.94, 115
One study noted four common coping strategies among 50 patients
with stages III and IV adenocarcinoma of the lung, including seeking
social support, problem-solving, self-control, and positive reappraisal.
No correlation was found between coping, mood, or perceived stress
and the side effects of chemotherapy.37 Very little has been published on
the QOL of women with lung cancer. One study compared women with
lung cancer with a normative sample of women with other cancers. This
study concluded that women with lung cancer had more global problems with QOL because of fatigue, problems with household chores,
worry about ability to care for oneself, and worry about progression of
cancer. QOL was affected disproportionately in women aged less than
65 years, those with recurrent disease and low-income women.182
Terminal Weaning
Any discussion of psychological issues in pulmonary disease must
address terminal weaning. Patients with end-stage pulmonary disease
caused by amyotrophic lateral sclerosis, COPD, CF, IPF, lung cancer, or
other diagnoses may request terminal weaning to avoid futile interventions. The term terminal weaning has been viewed by some as an oxymoron for several reasons. The term terminal implies that the withdrawal
of ventilator support inevitably ends in death, but the word weaning
carries the implication of achieving independence from the ventilator.
The phrase discontinuation of ventilator support may be preferred when
talking with the patient, family, and staff caring for the patient.10 Others
have used the phrase withdrawal of mechanical ventilation.51 Ethicists concur that competent patients have the right to refuse either life-saving
treatment or that which prolongs life. Experts agree that no moral
difference exists between not initiating treatment and withdrawing treatment in a futile situation; however, physicians may nd withdrawing
treatment more difcult because this is viewed as a more active intervention, which may cause a greater sense of culpability.
The ethical process used to make such decisions involves weighing
the moral principles, which favor action and those which preclude
action. The opposing principles in decisions regarding terminal weaning
are autonomy and benecence. To honor a patients right to autonomy
the patient must be deemed competent to make medical decisions, such
as choosing terminal weaning. In general, if patients are able to state the
risks and benets of a procedure and the consequences of refusing
treatment, they are considered to be competent to make medical decisions. The patient must be aware of the most likely outcome when
ventilator support is discontinued and make the decision after due
109
110
COFFMAN
111
or 1-antitrypsin deciency emphysema. Nonfunctional lung parenchyma is resected with the goal of increasing lung elastic recoil, respiratory muscle function, and ventilationperfusion matching. The expected
benets of surgery include decreased dyspnea, increased exercise time,
and increased quality of life (QOL).136 Exclusion criteria generally include
isolated bulla because these patients are referred for bullectomy. Other
exclusionary factors cited include chronic bronchitis, concurrent malignant disease, excessive steroid dependence, hypercapnia, previous thoracotomy, malnutrition or obesity, psychiatric illness, and pulmonary hypertension.129
One study148 addressed the issue of LVRS in patients with hypercapnia. This group found no difference in mortality between eucapnic
and hypercapnic patients after LVRS. Both groups showed signicant
improvements in FVC, residual volumes, 6-minute walking distance,
and QOL after LVRS. The study concluded that hypercapnia should
not be an absolute exclusionary factor, although the long-term benets
remained to be seen.
Studies generally agree that the procedure is more effective when
done bilaterally than unilaterally. A large study on bilateral LVRS versus
unilateral LVRS with follow-up data on 671 patients showed that bilateral treatment was associated with greater improvement on spirometry,
lung volumes, and QOL.127 The staple method is better than the laser
method because patients undergoing laser treatment had signicantly
more episodes of delayed pneumothorax.89 The results for patients with
smokers emphysema were better than for patients with 1-antitrypsin
deciency emphysema. Only one study showed an increased life expectancy at 3 years after LVRS over patients treated medically. Most reports
indicate that outcome with heterogeneous distribution of emphysema is
better.207
The mortality rate in patients during a preoperative pulmonary
rehabilitation program ranged from 2.7% to 4.0%. The perioperative
mortality rate has been listed as ranging from 4.1% to 9.4%.49, 81, 129, 214
Duration of improvement is not known. Some programs have observed
rapid declines in gains after LVRS over 14 to 20 months after surgery.
There may be more gains with bilateral surgery, but some have noted
more rapid declines in gains after surgery with bilateral surgery.108, 207
One group122 showed that Sickness Impact Scores improved signicantly
3 months after LVRS, and this correlated with the decrease in hyperination and decreased steroid requirement. Although forced expiratory
volume in 1 second (FEV-1) and RV improved, no change in oxygenation
was found. Another group8 found that, although there was an initial
improvement in FEV-1 at 3 months, this was not maintained at 6 or 12
months, and scores on a visual analog scale for dyspnea were unchanged
postoperatively; however, improvement in QOL scores were maintained
at 6 and 12 months, although none of the physiologic variables were
related to QOL. One group46 found that unilateral LVRS resulted in
signicantly improved FEV-1, RV, total lung capacity (TLC), 6-minute
walking test, and QOL on the Nottingham Health Prole. Improvement
in domains of emotions, energy, mobility, pain, and social involvement
112
COFFMAN
113
70% or more than 130% of ideal body weight. Other factors considered
to be absolute contraindications include active alcoholism, drug abuse
or cigarette use, severe psychiatric illness, or noncompliance with treatment. Consideration of factors once thought to be absolute contraindications have been revised. These include transplant in those on more than
20 mg/d of corticosteroids, patients on mechanical ventilation, those
with active collagen vascular disease, or CF patients colonized with panresistant bacteria. Some centers may consider infection with Burkholderi
cepacia as an absolute contraindication because of the high postoperative
mortality rate. Finding Aspergillus on a respiratory tract culture before
transplantation is not necessarily predictive of later infection unless
evidence of invasive colonization is found.14, 193, 155
In general, lung is allocated differently than other solid organs, such
as heart and liver. Severity of disease is not considered; only waiting
time is factored into the equation. One exception is that patients with
idiopathic pulmonary brosis are given a 90-day credit at the time of
listing to offset the greater mortality rate of this group during the
waiting period.83
Although four main approaches to lung transplantation exist, including bilateral sequential transplantation, heartlung transplantation,
single-lobe donation from living donors, and single-lung transplantation,
the latter is the most commonly performed.12 In general, in patients with
CF or bronchiectasis, bilateral lung transplantation is preferred, and the
infected lungs are removed. In CF patients, transplantation of lobes from
two donors with compatible blood types has been done. One clinical
series20 with 120 donors reported no deaths and four severe complications requiring repeat surgery. Loss of one lobe only decreased the lung
volume by 15%, which does not impact long-term activity in the donor.
Data reported in 1997 touted 1-year, 3-year, and 5-year actuarial
survival of 70.7%, 54.8%, and 42.6%, respectively. Median survival time
was 3.7 years. For comparison, both heart and liver transplant 5-year
actuarial survival rate is approximately 70%. For patients with CF or
IPF, there seems to be an increased survival rate compared with the
natural history of the underlying illness; however, for those with emphysema, no survival advantage could be demonstrated, although the transplantation does seem to improve QOL and functional ability. These
patients have a reduced risk for early death after transplantation because
the surgery is technically easier with emphysema. Factors associated
with a risk for early death after transplantation include a preoperative
diagnosis of pulmonary hypertension, ventilator dependence before
transplant, or a recipient or donor of age greater than 50-years. Longterm survival rate is lower in recipients age 55 or older and for those
with IPF. Survival does not differ between recipients with unilateral
lung transplantation versus bilateral lung transplantation.9
Benets of transplantation include improvement on pulmonary
function and gas exchange as well as hemodynamics in those with
pulmonary vascular disease. Exercise capacity returns, and approximately 80% of recipients report no limitations in activity within 1 year
114
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115
116
COFFMAN
117
118
COFFMAN
sertaline, are effective and have few drug interactions that are problematic in pulmonary patients. In one series of patients at a regional weaning
center, 3.4% of patients seen for psychiatric consultation had prolongation of the QT interval on ECG. One case of prolonged QT interval was
seen in a patient on citalopram therapy. Because many pulmonary patients are elderly with comorbid condition and may be on other medications that can prolong the QT interval, review of the ECG may be
prudent when considering treatment with an antidepressant. Cardiac
drugs, such as amiodarone, bepridil, disopyramide, procainamide, quinidine, and sotalol, have been reported to cause Torsades de pointes
tachyarrhythmia. In addition, chloral hydrate, tetracycline, thioridazine,
and TCAs have been reported to cause Torsades de pointes, as has the
use of IV erythromycin or pentamidine.222 Patients on diuretics may
hypokalemia or hypomagnesemia that may predispose to Torsades de
pointe.141 In the elderly, nortriptyline or desipramine are preferred over
the more sedating tertiary amines, which may cause delirium or hypotension. Although protriptyline may promote respiratory drive, this drug
has a very long half-life of 54 to 92 hours, a three- to fourfold longer
half-life than nortriptyline.7 Regardless of the antidepressant used, starting low and titrating slowly in elderly pulmonary patients is a prudent
strategy. Sedation with mirtazepine and high-dose venlafaxine has been
seen in elderly pulmonary patients. The use of monoamine oxidase
inhibitors with sympathomimetic bronchodilators may be dangerous.192
With pulmonary patients, the use of steroids is ubiquitous. Clearly,
patients may become euphoric, hypomanic, or manic on steroids. When
tapered, steroids may cause lability of emotions or depression. The other
side effects of steroids, such as cushingoid appearance, gastritis, and
osteoporosis, may affect the QOL of the patient. Psychotic symptoms
may be seen increasingly with prednisone dosages more than 40 mg/d.
The use of low-dose haloperidol may be helpful for steroid-induced
psychosis, hypomania, or mania.
SUMMARY
This article has attempted to provide an overview of the clinical
literature regarding the psychological issues facing patients with pulmonary disease, depending on when the illness begins in the life span,
because different developmental tasks are disrupted. Patients must contend with side effects of medication that may mimic or exacerbate
psychiatric disorders. The main drug interactions for psychiatrists to be
aware of in this patient population occur between rifampin, or theophylline and psychotropic medications. In lung transplant recipients on cyclosporine therapy, the antidepressant drug nefazadone may cause increased cyclosporine levels. Psychiatrists must be aware of the risks,
benets, and survival statistics; educate patients; and ascertain whether
the patient is competent to make medical decisions regarding treatment
procedures.
119
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Address reprint requests to
Kathy Coffman, MD
Comprehensive Liver Disease Center
St. Vincent Medical Center
2200 West Third Street, #500
Los Angeles, CA 90057
e-mail: ChristinaT@CHW.edu
129
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cess to hot surfaces (e.g., nonvehicle radiators, space heaters, and pressing irons), scalding hot water, ames, and ammable liquids14, 44, 80 are all
to blame. Also, depressive illness and behavioral disturbances, parental
psychopathology, careless smoking, and cigarette lighters are often contributory. Neglect or abuse occurs in 6% to 20% of cases68, 83 and are
more likely to occur with boys than with girls who have burns. Tell-tale
signs include sharply demarcated, often posteriorly located burn areas,
inconsistent history, numbness to pain, depression, and other signs of
abuse or neglect (e.g., poor grooming, previous injuries, and failure to
thrive). The clinician has a duty to report suspicious cases to Protective
Services. Young ( 20 years) and poorly educated ( high school)
mothers with three or more young children have been identied as more
likely to be associated with res fatal to children.76 Such children are
also more likely to be living with a single parent from a lower socioeconomic class.50, 59
The National Burn Information Exchange reports that, apart from
childhood, the next peak of risk for burns is over age 60 years, when
the average TBSA is greater than for any other age group. The most
common causes of burn accidents in older adults are from ame or
scalding, lighting trash res or a furnace, bathing, and falling asleep
while smoking. The National Fire Protection Agency84 found that seniors
aged 75 years or older are most likely to die in house res. Elderly and
demented adults living in supervised homes may suffer burns as a result
of negligence of caregivers. A peculiar form of spousal abuse (to the
husband by the wife) with scalding hot water has been reported6 and
often is unsuspected by physicians and unreported by victims.
Patients with epilepsy are at increased risk for burn injury. Josty et
al42 reported that 1.6% of patients in a busy burn unit had an association
with seizures. Fifty-four percent were from scalds and tended to be deep
but small ( 2% TBSA). Seizures (including status epilepticus) may
continue into or recur during the postburn period and be a cause for
delirium. Also, children with preexisting sensorimotor decits constitute
a special risk group, composing more than 2% of patients at the Shriners
Hospital in Galveston, Texas, over a 30-year period.67
The following case illustrates many of the factors that predispose to
and inuence the outcome of burns, as well as common clinical events
that mark the course of recovery from burn injury.
Case 1
Mr. P is a 47-year-old, right-handed, white man admitted with 37% TBSA
burns affecting his right chest area, right axilla anterior abdominal wall, and left
lower limb. Consultation was requested on the fourth day of hospitalization for
aggressiveness and history of ethanol abuse. His blood ethanol level was 370
mg/dL on admission.
He was status post skin graft to right torso. He claimed that the burns
were sustained while attempting to rescue children from a neighbors burning
apartment.
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Subsequent information revealed that the burns were sustained when his
apartment burned while he was smoking and drinking. He had a history of
unspecied psychosis, but he denied any current or recent psychotic symptoms
or use of antipsychotic medications. He also had a history of alcohol-withdrawal
delirium and admitted to a binge pattern of ethanol use.
He was unemployed, lived on public assistance, and lived with a girlfriend
who also had a similar psychosocial prole. His family did not visit until after
2 weeks of hospitalization because his alcohol use had alienated him from his
rather higher functioning family.
On examination, he was agitated and disoriented to time and place. He was
asking to go home. A diagnosis of ethanol withdrawal delirium was made.
Multiple grafts marked his hospital course. His right shoulder was held in
an awkward aero plane splint. Pain was a continual problem, especially
because his surgeons worried about giving him too much pain medication for
fear of another addiction. Later in the course of his hospitalization, he complained of poor night sleep, waking up with cold sweats, and preoccupation not
only with being burned but also with property losses sustained and with his
altered appearance secondary to scarring and hyperpigmentation. He mourned
the long-standing loss of his closeness with his family: They dont want to be
bothered with me.
A second diagnosis of acute stress disorder (ASD) was made.
He was treated for delirium; the surgical team had put him on daily
intravenous (IV) thiamine, 100 mg; folate, 5 mg; multivitamins; and lorazepam,
2 mg every 4 to 6 hours as needed. After clarifying his alcohol-use pattern and
severity of risk for withdrawal, staff initiated scheduled doses of chlordiazepoxide, 75 mg by mouth every 8 hours, titrated off the lorazepam, and later tapered
and discontinued the chlordiazepoxide. Staff also initiated contact with and
evaluated his girlfriend and family, drawing them into the treatment circle
within the limits of their comfort level. ASD was treated with sertraline, 50 mg,
support, and cognitive orientation to the objective limits of his physical disability
that affected mainly his right arm. At discharge, more surgery was planned to
release scar tissue that limited his shoulder movements.
ACUTE PHASE
Acute psychiatric syndromes after burn injury include substancewithdrawal delirium, burn delirium (i.e., burn encephalopathy), acute
pain, ASD, and any acute primary psychiatric symptoms that may cause
burn injury (e.g., acute suicidality or delusional states). There is also the
task of assuaging distress of family members, co-opting them as partners
in the care of the patient or sometimes fending off bad relationships in
order to optimize care. Families often show a bewildering mix of shock,
denial, anticipatory mourning, and anger but are often emotionally
supportive of the patient.7 As shown by the earlier mentioned case,
patients are often initially lucid enough to deploy their usual defense
mechanisms and may sacrice candor to ego defense. This may momentarily delay needed safety measures or medications, but collateral history
from family may be time saving if not lifesaving.
Burn delirium occurs approximately 1 to 2 days after burn injury. It
133
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Mild
Moderate
Initial
30 min
30 min
30 min
30 min
2 mg/5 mg/2mg
20 mg/20 mg/2 mg
5 mg/10 mg/2 mg
20 mg/20 mg/2 mg
Severe
10
20
20
20
mg/2mg
mg/2 mg
mg/mg/2 mg
*A lower starting dose of 0.5 mg and similar incremental amounts are used in the elderly.
Repeat last dose alternating without and then with lorazepam until patient stabilizes.
135
rently awaits FDA approval for the treatment of agitation but has not
yet been tested for efcacy in delirium.
Withdrawal delirium, usually caused by alcohol withdrawal, is
treated fairly proactively because a full-blown withdrawal delirium has
additional negative consequences for wound healing. It is helpful to be
familiar with risk factors for developing withdrawal symptoms, which
include27:
Age of more than 40 years
Male gender
Ethanol use of more than one fth daily (i.e., 20 drinks)
Drinking around the clock
Persistent excessive drinking for 10 years or more
Tremors and anxiety within 6 hours of cessation of drinking
History of hallucinations seizures, delusions, or delirium tremens (DT)
Presence of acute medical problems, such as pneumonia
Blood ethanol level of more than 250 mg/dL
The presence of seven to nine of these factors is thought to represent
high risk; three to six, moderate risk.27 Experience at the authors center
indicates that the main tasks for the psychiatric consultant are diagnosing unrecognized withdrawal symptoms and assessing their severity
and treating complicated or prolonged withdrawal. The surgical team is
usually comfortable with benzodiazepine detoxication and essential
vitamin replacement.
Analgesia
Opioid withdrawal may not appear as such because of the use of
opioid analgesia but may present as excessive demand or need for pain
medications. The evaluation by the psychiatric consultant anticipates
this need and prevents it from progressing into a disruptive demand or
delirious agitation. Patients already enrolled in methadone clinics need
to have their doses conrmed and resumed in the hospital so that the
primary team can concentrate better on treatment of acute pain. FDA
guidelines also allow for the use of reasonable doses of methadone for
opioid detoxication under these circumstances provided that the period
of detoxication does not exceed 2 weeks.
The use of a visual analogue scale facilitates collaborative evaluation
and longitudinal tracking of pain severity and relief in both children
and adults (Table 2). In infants, as well as adults who are nonverbal,
behavioral (i.e., facial expression, body movement, or moaning or crying)
and vital signs, oxygen-consumption changes, and acute stress hormone
evaluations provide useful clues regarding the severity of the pain.80
Morphine sulfate most often is used for acute pain. Guidelines suggest
0.05 mg/kg/h, with as-needed boluses of twice as much every 2 hours
in children; 5 to 10 mg intramuscularly or IV every 1 to 4 hours in
adults. Other parenteral options include meperidine, hydromorphone,
methadone, oxymorphone, and fentanyl. Fentanyl has been recom-
136
Table 2. PARENTERAL ANALGESIC EQUIVALENCIES*
Analgesics
Equivalents
SC/IM/IV
Morphine sulfate
(MS) (IM, IV, SC)
Dolophine
(Methadone) (IM, IV)
Hydromorphone,
(IM, IV)
Oxymorphone,
(IM, IV, SC)
10 mg
10 mg
1.5 mg
1 mg (PR)
Fentanyl (IV)
0.25 mg
(based on IV/h)
Meperidine
(Demerol) (IM, IV)
75 mg
137
mended for dressing changes and debridement because of its rapid onset
and short duration of action92; however, fentanyl and meperidine have
anticholinergic metabolites that increase the risk for delirium. Fairly
often, the psychiatric consultant is required to suggest analgesic dosage
equivalents for opioid-dependent patients who may not be taking orally.
Some guidelines are listed in Table 2.
Other Measures
Physical restraints (e.g., poseys, vests, padded bandages, and leathers) often are applied before the psychiatric assessment is obtained and
are difcult to use because of skin denudation. Usual hospital safety
guidelines are followed for the application of physical restraints. Psychosocial measures (e.g., sitters, family presence, orienting cues, and
direct and clear communication) may be helpful.
RECONSTITUTIVE PHASE
In the reconstitutive phase lasts from the end of acute surgical
interventions and delirium to the time of discharge. Pain management
is crucial at this stage. Mourning for lost body image, property, and
loved ones takes a toll. ASD and PTSD, adjustment disorders, and mood
disorders are major psychopathologic concerns. Some of the observations
of Lindemann51 on survivors of the Cocoanut Grove re disaster include
avoidance, physiologic reactivity, and survivor guilt that straddle both
grief and ASD categories. These observations were made decades before
the latter syndrome was given ofcial recognition in DSM-IV. Preinjury
mental health is a stronger predictor of postburn adjustment than is the
extent of the burn.65
The reported prevalence of stress syndromes has varied partly because of changing denitions, variability of the contributory factors in
different settings, and the point in time when studies were done. Estimates have ranged from 7.7% to 43.0%.15, 64 The lower estimate was
associated with a high diagnostic rate for adjustment disorders (77%),
suggesting an overlap with the diagnosis of ASD. Some studies suggest a
trend toward increasing incidence of PTSD with the passage of time,60, 72
whereas others show a uctuating course with exacerbations during
periods of stress.45
Since then, many studies have sought to isolate crucial factors in
the causation and prognosis of PTSD after burn injuries. Scarring, especially in the most visible parts of the body, associated with body and
self-image have been highlighted.15 The emphasis on scarring as a cause
of continuous traumatic stress disorder32 is important, but it seems
that the impact on self-image is even more important. Bryant15 suggested
postinjury factors (e.g., avoidance, also a symptom of PTSD) as a crucial
predisposing factor for PTSD. Some clinicians consider uncontrolled
pain (from tissue damage, debridement, dressing change) to be the core
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139
avoided the hospital and often missed clinic appointments. He could not use
the underground parking lot because it reminded him of being in a coma or
being restrained in bed. Clinic visits involved an elaborate arrangement to walk
him into the premises from a surface parking area some distance from the
hospital grounds. Problems with his ancee simmered throughout his recovery,
but whether they were related to burn sequelae was unclear. He slept well
initially with doxepin, 75 mg, but beneted most from nefazodone, 150 mg/d.
He returned to work despite mild depressive symptoms and changed to a more
acceptable job during the 18 months he was followed up. The PTSD symptoms
eventually subsided to an easily tolerated level.
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141
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143
million. Sometimes providers and hospitals have to bear the costs when
reimbursement sources run out. Payment for psychiatric services provided in tandem with surgical services sometimes are denied. Psychiatrists in this setting may need to fund their services through research,
nonreimbursed care, and budgets or funded programs. This is especially
applicable in urban outpatient burn clinics, which often cater to predominantly uninsured persons.
Regarding questions raised about the ethics of saving severely disgured victims, rather than allow them to die with dignity,30 the literature documents how severely burned individuals sustain normal selfesteem despite perception of impairment.47, 49 Ms. M (see previous case
vignette) was such a person, but she nds meaning in her life because
she remains the only concrete reference point that her daughter will
have as she grows up.
SUMMARY
Clinical experience and burn survivor testimony show that the
experience of being burned can be associated with catastrophic stress
and lead to drastic permanent body image changes from scarring and
limb-function loss. Close relatives, if not killed in the re, often also
experience clinically signicant bystander stress. Closeness of relationships may be lost, and self-image may suffer. Property damage and loss
of crucial resources may be associated with res. Although many burns
result from accidents, most result from preventable causes associated
with psychiatric disorders, which include mood disorders, psychoses,
cognitive disorders, and substance-use disorders. Burns then result from:
Deliberate self-harm
Impaired judgment and poor coordination associated with substance
intoxication
Risk-taking behavior
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Address reprint requests to
Sunny T. Ilechukwu MD, DPsych
6 Hudson, Harper University Hospital
3990 John R
Detroit, MI 48201
e-mail: Sunday@med.wayne.edu
PRACTICAL
PSYCHOPHARMACOLOGY IN
HIV-1 AND ACQUIRED
IMMUNODEFICIENCY SYNDROME
Michael J. Robinson, MD, and Roula B. Qaqish, PharmD
149
150
medications commonly prescribed for HIV-1 infected patients (e.g., antimicrobials and antifungals) is beyond the scope of this article.
PSYCHOTROPIC MEDICATIONS FOR PSYCHIATRIC
SYNDROMES
Depressive Disorders
In the absence of delirium, clinical depression in HIV-1 patients
should be treated, regardless of the stage of disease, and a trial of an
antidepressant is usually warranted. Antidepressants have been underused in HIV-1/AIDS patients, as in other severely medically ill patients, because some clinicians overascribe depressive symptoms to a
normal reaction to illness. Many studies (i.e., randomized, controlled
trials; open-labeled trials; case series; and case reports) of the treatment
of depressive disorders in HIV-1 infection support safety and efcacy of
many antidepressant agents61; however, potential drugdrug interactions
always should be considered when prescribing antidepressants to a
patient with HIV-1 (see section on drugdrug interactions).30 Many of the
treatment trials to date were completed before currently recommended,
complex, highly active antiretroviral therapy (HAART). Thus, the generalizability of antidepressant safety under HAART remains to be determined. Table 2 summarizes the randomized, controlled trials, with effect
size calculations, in the treatment of major depression in HIV-1 infection.
Data from randomized trials support efcacy with a calculated high
median effect size; however, the effect size for placebo response is also
fairly high, as is typical of trials in uncomplicated depression. Literature
from uncontrolled clinical trials of several newer antidepressant agents
(e.g., uoxetine, uvoxamine, paroxetine, sertraline, nefazodone, mirtazapine, and venlafaxine) also supports their reported efcacy and tolerability.*
*References 2, 15, 17, 18, 26, 30, 32, 48, 61, 64, and 65.
Year
Medication
Effect
Size*
Depression
Measures
1999 Fluoxetine
Placebo
2.79 (81)
2.04 (39)
Markowitz JC, et
al51
1.55
1.89
0.98
1.13
Zisook S, et al89
1998 Fluoxetine
Placebo
1.89 (25)
0.69 (22)
(26)
(24)
(24)
(27)
Findings
151
152
Table 2. RANDOMIZED TRIALS (Continued)
Study
Elliot AJ, et al
Year
16
Medication
1998 Paroxetine
Imipramine
Placebo
Rabkin et al65
1994 Imipramine
Placebo
Testosterone
Grinspoon S, et al34 2000 Testosterone
Placebo
Effect
Size*
Depression
Measures
Findings
Not
SCID (DSMOnly 45% of the subjects completed the 12-week trial. Of the
readily
IIIR), HAM-D,
group that completed treatment, response rates ( 50%
calculated CGI
reduction in HAM-D) were 62%, 64%, and 90% for placebo,
paroxetine, & imipramine respectively after 12 weeks of
treatment. Rates for full response (HAM-D 8),
respectively, were 23%, 55%, and 80%. No signicant
difference in response rates for paroxetine and imipramine.
3.18 (10) DSM-IIIR,
47% of the DMI group and 43% of the MPD group had a
1.98 (10)
HAM-D,
50% reduction in HAM-D score at 6 weeks; signicant side
POMS, BSI,
effects were reported by 22% of the DMI group and 16% of
MMPI
the MPD group, with treatment emergent side effects more
common for MPD early in treatment, and later for DMI.
2.14 (47) SCID (DSM-IIR), 74% of IMI group versus 26% of the placebo group responded
1.00 (42)
HAM-D, CGI,
according to HAM-D and CGI scores; of the placebo
BSI, BHS
nonresponders, open treatment with IMI led to 53%
response rate after 6 weeks; no consistent relationship
between response rate and illness severity, as measured by
CD4 count; IMI had no adverse effect on immune status as
measured by CD4 count; Note: nearly 20% of IMI
responders chose to discontinue treatment before 6 months
secondary to side effects.
0.73 (26) BDI,
57% with BDI 18 were hypogonadal by free testosterone
0.67 (26)
antidepressant
levels, versus 24% with BDI 18; The BDI score was not
use was
different between treatment groups; the BDI score decreased
recorded
signicantly in testosteone group, but not among patients
receiving placebo.
2000 Testosterone
Placebo
1999 Testosterone
Placebo
2.02 (203)
1.82 (21)
0.73 (101)
0.84 (214)
1.51 (51)
*Effect sizes for depression scores were calculated for open trials and randomized trials in the same according to the following formula ((Mean(pre-test) Mean(post-test)/
standard deviation(pre-test)) within each treatment condition. The sign of the effect sizes was adjusted so that a positive effect size reected improvement on the measure. For
uniformity across randomized trials and open trials, estimates of standard deviation were not pooled across conditions. As a check, effect sizes in the randomized trials were
calculated using estimates of the standard deviation pooled across the pre-tests of all conditions in the study. This approach produced similar results.
Effect sizes adjusted so that the larger value reected the greatest retained improvement following the cessation of treatment in the discontinuation trial.
SCID Structured Clinical Interview for DSM; DSM Diagnostic and Statistical Manual of Mental Disorders; HAM-D Hamilton Depression Rating Scale; BDI Beck
Depression Inventory; BDI-13 Beck Depression Inventory-13 Item Short Version; BSI Brief Symptom Inventory; BHS Beck Hopelessness Scale; CGI Clinical Global
Impression; VAS Visual Analog Scale; MMPI Minnesota Multiphasic Personality Inventory; PDE Personality Disorders Examination; POMS Prole of Mood States:
IMI Imipramine; DMI Desipramine; MPD Methylphenidate; CBT Cognitive-behavioral therapy; IPT Interpersonal psychotherapy; SWI Supportive
psychotherapy with imipramine.
153
154
155
Nefazodone
Anxiety Syndromes
Anxiety, as a symptom, is prevalent in the HIV-1/AIDS population,
and may be multifactorial in etiology. It may be a symptom of an anxiety
disorder, adjustment disorder, depressive disorder, delirium, or other
cognitive disorder. In addition, anxiety may be a side effect of medications used in patients with HIV-1/AIDS. Psychopharmacologic treatment
options for anxiety states include benzodiazepines (BDZs), non-BDZ
anxiolytics (buspirone), antidepressants (particularly trazodone), and
neuroleptics. Neuroleptics generally are preferred for severe anxiety
states associated with delirium and other cognitive disorders.
BDZs may be used in patients with HIV-1/AIDS, as in other patients
with medical illnesses. They are best used for short periods to minimize
the risk for habituation, tolerance, abuse, and dependence. BDZs with
156
157
and has a more chronic course, few spontaneous remissions, and frequently relapses with cessation of treatment. Treatment of secondary
mania differs in some regards, as is discussed later. Finally, evaluating a
patient with HIV-1 infection who presents with manic symptoms, one
also should consider a medical cause (e.g., AIDS-associated CNS infection or neoplasm) or a side effect of medications (e.g., didanosine or
zidovudine).11, 14, 49, 88
Lithium commonly is used to treat primary mania of bipolar disorder in HIV-1 patients. The use of lithium may be complicated because
of unstable uid status with diarrhea, dehydration, and poor uid
intake. These patients also may develop HIV-1 nephropathy, a generally
irreversible condition, which may impair lithium clearance.2 Lithium
levels and renal function need to be monitored closely. Although it
does not require hepatic metabolism and is therefore free of signicant
metabolic drugdrug interactions, the previously mentioned difculties
limit its clinical use. Because of the risks of toxicity, even in small doses,
lithium should generally be avoided in the treatment of secondary or
HIV-1associated mania.
Valproic acid (or divalproex sodium) is a common mood stabilizer
used in the treatment of manic syndromes. Valproic acid may be used
for manic syndromes in HIV-1 with some caution. Recently, its use has
been questioned because of in vitro evidence that valproate may lead to
activation of HIV-1 and cytomegalovirus replication and thus acceleration of viral disease; however, the clinical relevance of this interaction is
unclear.36, 40, 41, 42 A retrospective review of 11 HIV-1 patients treated with
valproate and adequate antiretrovirals found no evidence of increased
viral load in these patients.50 Therefore, the use of valproate in HIV-1
patients receiving antiretroviral should be with caution until further
data are available. Until further study, the authors recommend regular
monitoring of viral load in patients receiving valproic acid or divalproex
sodium. It is also well known that valproic acid may cause hepatic
toxicity, usually asymptomatic and transient. Recently, a case of hepatitis
caused by the use of valproic acid, ritonavir, and nevirapine in a patient
with HIV-1 was reported.13 The frequency of liver function monitoring
should be individualized. As with any medication that is primarily
metabolized through the liver, there are potential drugdrug interactions
with antiretroviral medications.
Carbamazepine is now less commonly used as a treatment alternative for mania, especially in patients with HIV-1, and generally should
be avoided in the treatment of secondary mania. Because of its potential
for bone marrow toxicity (leukopenia or aplastic anemia), it should be
avoided in patients who are immunocompromised. Carbamazepine has
potent effects on the cytochrome P-450 system that may cause signicant
drugdrug interactions in patients with HIV-1.38
Gabapentin, lamotrigine, and topiramate are additional alternative,
off-label mood-stabilizing therapies for mania. No data are available
about the use of these agents for mania HIV-1infected patients. In other
populations, gabapentin is fairly well tolerated, with the main side
158
159
160
the authors have successfully used olanzapine in the treatment of delirious patients with advanced HIV-1. General clinical pearls guiding the
use of neuroleptics in the context of HIV-1/AIDS are listed in Table 4.
HIV-1Associated Cognitive Disorders
Potential CNS manifestations of HIV-1 infection are numerous. Cognitive disorders in HIV-1 mainly consist of HIV-1associated dementia
and HIV-1associated minor cognitive motor disorder. Diagnostic criteria
for these disorders are displayed in Tables 5 and 6, respectively. An
extensive review of the neuropsychiatric aspects of HIV-1associated
cognitive disorders, including epidemiology, pathogenesis, staging, diagnosis, neuropathology, neuroimaging, and treatment, can be found in
the article by Whitaker.86 There have been four major treatment approaches
are (1) antiretroviral drugs, (2) interventions that affect inammatory
mediators and neuroprotective therapies, (3) neurotransmitter manipulation, and (4) nutritional therapies. Most of the research to date has
focused on antiretroviral drugs; however, over the past few years, the
optimal treatment of HIV-1 has changed drastically with HAART, and
this makes it difcult to draw conclusions from earlier research. Also,
Table 4. CLINICAL PEARLS FOR PRESCRIBING NEUROLEPTICS IN PATIENTS WITH
HIV-1
Medication
General
Conventional
neuroleptics
Atypical
neuroleptics
Clinical Pearl
HIV-infected patients are at increased risk for side effects, including
EPS, NMS, and TD; use lowest effective dose; always be aware of
potential drugdrug interactions; Low potency conventional and
atypical (clozapine, olanzapine, and quetiapine) neuroleptics,
increased risk for postural hypotension which may be a
signicant problem in dehydrated or weak HIV patients.
High potency, increased risk for EPS; those with high
anticholinergic properties may worsen confusion, precipitate
delirium, and dry mucous membranes presdisposing to oral
candidiasis; molindone may be useful and well tolerated, based
on four case reports; low potency, increased risk for postural
hypotension which may be a signicant problem in dehydrated
or weak HIV patients.
Appear to be effective and better tolerated than conventional
neuroleptics; limited data other than uncontrolled trials and case
reports; risperidone has been safe and effective; potential
undesirable hematological side effects of clozapine and
remoxipride, use with caution; olanzapines muscarinic
antagonistic properties theoretically may make this unfavorable
for use in patients with cognitive dysfunction, but it is now
available in a orally disintegrating tablet formulation that may be
helpful in patients who are unable to take medication per os;
quetiapine may be the least likely to cause EPS.
161
Description
From American Psychiatric Association, Work Group on HIV/AIDS: Practice Guideline for the
treatment of patients with HIV/AIDS. Am J Psychiatry 157:162, 2000; with permission.
162
the populations studied have varied widely in both diagnostic denitions and clinical severity. Recently, increased understanding of the
neuropathology of HIV-1associated cognitive disorders has led to increased research involving anti-inammatory and neuroprotective therapies as adjuncts to viral suppression with antiretrovirals.86
Zidovudine has been found to be effective in the treatment of
cognitive disorders or dysfunction in HIV-1. This comes from two randomized, placebo-controlled trials that demonstrated improvements in
neuropsychological impairment, as well as open-labeled trials.76, 78 Other
antiretroviral drugs that have been studied in the treatment of HIV1associated cognitive disorders include stavudine, nevirapine, didanosine, and abacavir. A key question is whether antiretroviral agents penetrate the blood brain barrier sufciently to adequately suppress HIV-1
replication, and if so, what dosage of medication is required to achieve
this.53, 56, 86 Theoretically, if there is incomplete suppression of viral replication, then there may be the potential for antiretroviral resistance to
develop within the CNS and potentially worsen neurocognitive disorders. This also raises the possibility of resistant viral reseeding from the
CNS to the peripheral circulation.2 This explains the preferred use of
antiretroviral agents with good CNS penetration (e.g., zidovudine, stavudine, abacavir, and nevirapine). Combination antiretroviral treatments
have been shown to improve tests of neurocognitive function compared
with no treatment.24 Whether antiretroviral treatment helps to prevent
HIV-1associated cognitive disorders remains unclear, although a few
clinical trials have suggested that this may be the case.12, 35, 81
It has been postulated that HIV-1associated neuronal injury may
result from activation of voltage-dependent calcium channels and Nmethyl-D-aspartate (NMDA) receptor -operated channels. This has led
to the investigation of NMDA antagonists (e.g., memantine, see
www.memantine.com/inhalte/s1.html for more information), and calcium channel blockers (e.g., nimodipine).39, 86 Nimodipine has signicantly reduced HIV-1associated cognitive decits.28, 59 Still other neuroprotective therapies studied include antioxidants (e.g., OPC-14117 and
thioctic acid) and platelet-activating factor antagonist (e.g., lexipafant).75
Few treatment trials have involved interventions that are thought to
exert their effect through modulating inammatory mediators. These
have included peptide T, inhibitors of tumor necrosis factor- (e.g.,
pentoxifylline and thalidomide), interleukin-1 receptor blockers, and
interferon- inhibitors (e.g., naloxone).86 A detailed discussion of these
therapies is beyond the scope of this article.
Nutritional therapies also have been used as possible interventions
in the treatment of HIV-1associated cognitive disorders. These have
included vitamin B12, vitamin B6, and zinc. Vitamin B12 has been found
to be low in many HIV-1-infected individuals. Deciencies can be associated with impairments on tests of neurocognitive functioning, and normalization can lead to improvement. Zinc deciency has been found to
be associated with a more rapid general progression of HIV-1, which
163
includes CNS progression. Other nutritional therapies may include vitamin E, an antioxidant.2, 86
Other treatments that have been found to be helpful in the treatment
of HIV-1associated neurocognitive disorders include agents that manipulate neurotransmitter systems. Psychostimulants are used as palliative
agents in the care of patients with HIV-1associated dementia or minor
cognitive motor disorder. They are effective at relieving symptoms of
fatigue, apathy, decreased concentration, and memory decits.2 The use
of psychostimulants is outlined in the section on depression. When using
psychostimulants in patients with HIV-1associated cognitive disorders,
one must beware of the potential to exacerbate psychotic symptoms,
especially as dementia progresses. Psychostimulants also may exacerbate
the risk for seizures and movement disorders. Of the psychostimulants
used in the treatment of HIV-1associated cognitive disorders, methylphenidate is considered rst line, followed by dextroamphetamine and
pemoline. Other dopaminergic-enhancing agents are currently being investigated for use in HIV-1associated cognitive disorders (e.g., pramipexole, as dopamine agonist).2 Selegiline, a MAOI-B, which enhances
dopamine, has been shown to reverse decits in mild HIV-1associated
cognitive impairment.72, 74 Serotonin 5-hydroxyindoleacetic acid has been
found to be decreased in the cerebrospinal uid as HIV-1 progresses.
Theoretically, the administration of serotonergic agents, such as selective
serotonin reuptake inhibitors (SSRIs), may be useful in the treatment of
HIV-1associated cognitive dysfunction. Some recent evidence indicates
that some serotonin reuptake inhibitors (e.g., paroxetine, femoxetine
[not available in North America]) inhibit HIV-1 replication but require
further study.43
PSYCHOTROPIC-ANTIRETROVIRAL DRUGDRUG
INTERACTIONS
Drugdrug interactions are pharmacodynamic or pharmacokinetic
in nature. Pharmacodynamic interactions involve alterations in the pharmacologic response to or effect by a drug without pharmacokinetic
changes. Pharmacokinetic interactions include altered absorption, distribution, metabolism, or excretion and can result in changing the drug
concentration in tissues.
Hepatic metabolism is divided into phase 1 and phase 2 reactions.
A group of monooxygenase enzymes, called the cytochrome P-450
(CYP450) enzyme system, catalyze phase 1 reactions and are responsible
for most of the metabolic drug interactions. Eleven CYP450 enzyme
families exist, of which three are important in humans (e.g., CYP1,
CYP2, and CYP3). The families are subclassied into subfamilies that
are identied by a capital letter (i.e., CYP3A). The subfamilies are further
subclassied into isozymes based on the homology between the subfamily proteins and are denoted by a number following the capital letter
(i.e., CYP3A4). A substrate is an agent or a drug the metabolism of
164
165
2B6
2C9
Substrates
Clomipramine
Clozapine
Fluvoxamine
Haloperidol
Imipramine
Mirtazapine
Olanzapine
Zotepine
Bupropion
Efavirenz
Nevirapine
Diazepam
2C19
Diazepam
Nelnavir
2D6
Amitriptyline
Chlorpromazine
Clomipramine
Clozapine
Desipramine
Fluoxetine
Fluvoxamine
Haloperidol
Imipramine
Methylphenidate
Mirtazapine
Alprazolam
Amprenavir
Buspirone
Carbamazepine
Citalopram
Clomipramine
Clonazepam
Delavirdine
Efanirenz
Imipramine
Indinavir
Lopinavir
Lorazepam
3A4
Inhibitors
Olanzapine
Paroxetine
Perphenazine
Risperidone
Thioridazine
Trazodone
Trimipramine
Venlafaxine
Zotepine
Midazolam
Nefazodone
Nelnavir
Nevirapine
Pimozide
Quetiapine
Ritonavir
Saquinavir
Temazepam
Trazodone
Ziprasidone
Zotepine
Inducers
Fluvoxamine
Paroxetine
Olanzapine
Ritonavir
Ritonavir
Nevirapine
Efavirenz
Ritonavir
Efavirenz
Fluoxetine
Ritonavir
Fluoxetine
Fluvoxamine
Nelnavir
Noruoxetine
Olanzapine
Paroxetine
Perphenazine
Ritonavir
Sertraline
Venlafaxine
Ziprasidone
Amprenavir
Delvirdine
Efavirenz
Fluvoxamine
Indinavir
Lopinavir
Nefazodone
Nelnavir
Noruoxetine
Ritonavir
Saquinavir
Thioridazine
Carbamazepine
Efavirenz
Nevirapine
Ritonavir
St. Johns wort
166
167
Antidepressants
TCAs
Amitriptyline,
clomipramine,
desipramine,
imipramine,
nortriptyline,
trimipramine
Non-TCAs
Fluoxetine
(noruoxetine),
uvoxamine,
mirtazapine
paroxetine,
sertraline,
trazodone,
venlafaxine
Citalopram,
nefazodone
Bupropion
Mechanism of
Interaction with the
Protease Inhibitors
or the NNRTIs
Comment
Documentation
Inhibition of CYP2D6
by the PI, ritonavir
Potential; minimal
documentation
Inhibition of CYP2D6
by the PI, ritonavir
Potential; minimal
documentation
Inhibition of CYP3A4
by uoxamine and
noruoxetine
Theoretic
Inhibition of CYP3A4
by all the PIs and
or NNRTIs,
delavirdine, and
possibly efavirenz
Theoretic interaction
between
citalopram and
the PIs and
NNRTIs; minimal
documentation on
interation
between ritonavir
and nefazodone
Induction of CYP3A4
by the NNRTIs,
nevirapine, and
efavirenz
Theoretic
interactions for
both
psychotropics
Inhibition of CYP3A4
by nefazodone
Nefazodone is an inhibitor of
CYP3A4, thus may increase
the levels of the PIs or
NNRTI resulting in a
increased toxicity of the PI or
NNRTI.
Theoretic
Induction of CYP2B6
by the NNRTI,
nevirapine
Theoretic
Inhibition of
metabolism by
ritonavir
Potential; minimal
documentation
CYP cytochrome P-450; SSRI selective serotonin reuptake inhibitor; NNRTI non-nucleoside reverse
transcriptase inhibitor; PI protease inhibitor; TCA tricyclic antidepressant.
168
Mechanism of
Interaction with the
Protease Inhibitors or
the NNRTIs
Comment
Documentation
Inhibition of CYP3A4 by
all PI, delavirdine,
and possibly efavirenz
Potential
Induction of CYP3A4 by
nevirapine and
efavirenz
Theoretic
Inhibition of CYP3A4 by
all PIs, delavirdine,
and possibly efavirenz
Well
documented
Inhibition of CYP3A4 by
all PIs, delavirdine,
and possibly efavirenz
Potential;
minimal
documentation
Induction of CYP3A4 by
nevirapine and
efavirenz
Theoretic
Lorazepam,
oxazepam,
temazapam
Induction of glucuronyl
transferase by
ritonavir and
nelnavir
Potential
Diazepam
Induction of CYP2C9 by
ritonavir
Theoretic
Inhibition of CYP2C9
and 2C19 by efavirenz
Theoretic
Buspirone
Benzodiazepines
Midazolam,
triazolam
Alprazolam,
clonazepam,
lorazepam,
temazepam
NNRTIs non-nucleoside reverse transcriptase inhibitors; PIs protease inhibitors; BZD benzodiazepine; CYP
cytochrome P-450.
169
Neuroleptics
Typical
CYP2D6 substrate
Chlopromazine,
haloperidol,
perphenazine,
thioridazine
CYP3A4 substrate
Pimozide
Atypical
CYP1A2 substrate
Clozapine,
olanzapine,
zotepine
CYP2D6 substrate
Clozapine,
risperdone,
zotepine
CYP3A4 substrate
Quetiapine,
ziprasidone,
zotepine
Mechanism of
Interaction with the
Protease Inhibitors or
the NNRTIs
Comment
Documentation
Inhibition of CYP206 by
the PI, ritonavir
Potential
Induction of CYP3A4 by
NNRTIs, nevirapine
and efavirenz
Theoretic
Inhibition of CYP3A4 by
all PIs, delavirdine,
and possibly efavirenz
Contraindicated combination
serum concentrations of
pimozide may increase
resulting in increased
cardiotoxicity risk (QTc
prolongation).
Potential
Induction of CYP1A2 by
ritonavir
Theoretic
Inhibition of CYP2D6 by
the PIs, ritonavir
Theoretic
Inhibition of CYP3A4 by
all PIs, delavirdine,
and possibly efavirenz
Potential
Induction of CYP3A4 by
NNRTIs, nevirapine
and efavirenz
CYP cytochrome P-450; EPS extrapyramidal side symptoms; NMS neuroleptic malignant syndrome;
NNRTI non-nucleoside reverse transcriptase inhibitors; PI protease inhibitor.
170
171
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1998
Address reprint requests to
Michael J Robinson, MD
Division of Consultation-Liaison Psychiatry
Kingston General Hospital
76 Stuart Street, Connell 4, Room 2-486
Kingston, Ontario K7L 2V7
Canada
e-mail: mjr4@post.queensu.ca
ELECTROCONVULSIVE THERAPY
IN THE MEDICALLY ILL
Keith G. Rasmussen, MD, Teresa A. Rummans, MD,
and Jarrett W. Richardson, MD
This work was supported by National Institutes of Health grant no. MH55484-05.
From the Departments of Psychiatry and Psychology, Mayo Medical School, Rochester,
Minnesota
177
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RASMUSSEN et al
strongly encouraged to apply the principles contained in the APA Committee on ECT report,4 which has excellent sections on ECT in medically
ill patients.
CARDIOVASCULAR DISEASES
Cardiac complications represent the most common source of signicant morbidity and mortality during ECT. Even so, deaths are extremely rare, and the majority of cardiac patients can be given ECT with
a low risk of complications.2 There are several fundamental points in
providing safe ECT to such patients. The rst is accurate pre-ECT identication, through history, physical examination, and screening laboratory
tests, of those patients with cardiovascular disease. The next step is preECT cardiology consultation. The purpose of this is to determine the
severity of cardiac disease and may include functional or structural
cardiac imaging studies. The cardiology consultant can also recommend
any modication of the patients current treatment regimen to provide
further stabilization of the cardiac condition (e.g., an increase in diuretic
dosage in a patient with congestive heart failure that is not optimally
controlled). Finally, the medical consultant can recommend strategies
that may reduce cardiac risk during the ECT treatments, such as the
administration of -blockers to lessen the ECT-induced decrease in cardiac rate-pressure product. A third important strategy for safe administration of ECT to cardiac patients is careful vigilance throughout the
ECT course, both at the times of treatment and in the intertreatment
period, for any treatment-emergent complications so that prompt intervention can prevent deterioration of a minor complication into a major
one.
An elegant demonstration of the importance of these points is
provided by two reports from the Payne Whitney Clinic. Gerring and
Shields27 reported on a series of 17 cardiac patients given ECT in 1975
1976. None of the patients had pre-ECT medical consultations, electrolyte
studies, or digitalis levels, even though 13 of the patients were on this
medication. Most patients did not get continuous ECG monitoring during their treatments, nor were pretreatment antihypertensive medications given. There were four life-threatening cardiac complications and
one death in this series. In contrast, Rice et al75 reported on their experience at the same institution treating 26 cardiac patients with ECT in
19901991. All of the technical disadvantages described earlier for the
earlier cohort had been reversed, so that routine pre-ECT laboratory
and ECG studies were performed, most patients had pre-ECT medical
consultations, and ECT technique followed modern standards, including
continuous ECG monitoring and the availability of cardiac medications
at the time of treatment. No major cardiac complications occurred in
this cohort of patients. The following sections consider the aspects of
ECT technique in patients with specic types of cardiovascular disorders.
179
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RASMUSSEN et al
Hypertension
Despite the transient, peri-ictal increase in blood pressure, ECT does
not result in sustained increases in blood pressure and in fact may result
in a decrease in blood pressure.88 Common sense dictates that optimum
blood pressure control be attained in hypertensive patients pre-ECT.
Antihypertensive medications (except for diuretics, which could result
in a full bladder that may rupture during the seizure) should be given
with a small sip of water in the mornings of treatments. If there are
signicant risks to the patient for even brief periods of hypertension
(e.g., vascular aneurysms, cardiac aneurysm, severe left ventricular or
valvular compromise), premedication with antihypertensive agents is
indicated, selecting the drug that is most appropriate to the patients
clinical situation. Short-acting drugs (e.g., esmolol) administered at the
time of anesthesia induction may be preferable to avoid delayed hypotension that can occur with longer-acting drugs (e.g., labetolol). Although -blockade shortens seizure length during ECT,92 no direct evidence shows that this interferes with therapeutic efcacy.
181
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RASMUSSEN et al
185
186
RASMUSSEN et al
187
188
RASMUSSEN et al
189
able data consist largely of cases and case series, ECT is effective in
treating psychopathology despite the comorbidity. With appropriate precautions and monitoring during and after ECT, complications can be
minimized.
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193
LIVER TRANSPLANTATION IN
PATIENTS WITH ALCOHOL
AND OTHER SUBSTANCE
USE DISORDERS
Andrea DiMartini, MD, Robert Weinrieb, MD,
and Marian Fireman, MD
EPIDEMIOLOGY
The need for transplantable human organs far exceeds current organ
availability in the United States. As of April 2001, 17,520 Americans
were awaiting liver transplantation (LT), whereas only 4934 received a
liver in the previous year.4 Of the many antecedent causes of end-organ
damage, heavy alcohol and illicit drug use are more likely to result in
the need for LT compared with other organs. The lifetime prevalence of
alcohol dependence in the United States is approximately 13%,24 and of
those who drink the equivalent of 12 or more beers per day for greater
than 10 years, nearly 20% require LT.1 Not surprisingly, alcohol-related
liver disease (ALD) is the most common type of liver disease in the
United States and accounts for the largest proportion of LTs performed
in the US (nearly 27% in 1995).7 Although 25% of US adult LT recipients
undergo LT for hepatitis C virus (HCV), 32% of those undergoing LT
for ALD in 1995 also had HCV listed as their primary liver disease.7
Hepatitis C may be contracted through blood transfusions, tattoos,
sexual contacts, and intranasal drug use but is often contracted through
injection drug use. Before 1991, no specic screening tests for HCV
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DiMARTINI et al
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to learn that the LT team would not abandon them because of their
alcohol use. On the other hand, it is important not to condone or dismiss
small amounts of alcohol use. What may seem supportive may be
distorted by patients with addiction and become an excuse to drink
more regularly. Interestingly, a recent study done in Birmingham, England, found that only 59% of patients undergoing LT for ALD recalled
receiving pre-LT advice on post-LT alcohol consumption, and a surprising 23% claimed that they were advised that drinking in moderation
was acceptable.36 Tringali et al37 have found few patients with alcoholism
who could control their alcohol use or return to social drinking.
Therefore, the authors recommend total alcohol abstinence for patients
undergoing LT for ALD.
RATES OF RETURN TO ALCOHOL CONSUMPTION
(RELAPSE VERSUS SLIP)
Clarifying the rates of alcohol and substance use are essential to
identifying factors that predict relapse and associating these drinking
episodes with subsequent medical morbidity and mortality. The identication and denition of drinking episodes as either a relapse or a slip
are crucial but depend on the methods and frequency of post-LT patient
monitoring. While there is a lack of consistency in dening drinking
rates in the LT population, the results of studies can be roughly categorized into an isolated episode of a small amount of alcohol use (i.e., a
slip) and rates of repetitive drinking of larger quantities that are
potentially more harmful (i.e., a relapse). Using the criteria of any
alcohol use, studies show 1-year post-LT drinking rates (i.e., the percentage who used any alcohol by 1 year after LT) ranging from 8% to 22%.21
Rates of cumulative alcohol use are estimated to be between 30% to 40%
by 5 years after LT.29 Some of the variability in rates may be related to
the stringency with which use is monitored, as some investigators may
only identify alcohol use once it becomes problematic.6 Similarly, DiMartini et al15 reported a cumulative rate of 37% of post-LT patients having
at least one drink, whereas only 15% went on to repetitive drinking
episodes (dened as 10 or more episodes). Fortunately, the rates of
alcohol use seem to attenuate with the passage of time post-LT10, 11;
however, most concerning was the rapidity with which some patients
resumed alcohol use after LT, with 15% having had their rst drink
within the rst 6 months after LT.18 This highlights the importance of
early and intensive clinical follow-up.
Currently, Weinrieb et al39a are studying the rate of relapse and
medical consequences in patients who choose to drink nonalcoholic
beer and wine beverages before and after LT. Although these products
contain only small amounts of alcohol (ethanol content, 0.5% by
volume), the use of these beverages can result in relapse to alcohol use
and even uncontrolled drinking in vulnerable patients. While the authors
are aware of no data on the medical consequences of such drinking after
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LT, these beverages can have negative consequences before LT. For
instance, the authors have seen a pre-LT patient who drank four nonalcoholic beers and experienced an episode of severe hepatic encephalopathy. In another case, a patient with end-stage ALD drank a large volume
of nonalcoholic beer and was able to obtain a detectable blood alcohol
level.17 Furthermore, the authors do not consider pre-LT use of nonalcoholic beverages to be consistent with stable sobriety. Thus, the authors
require patients with ALD to abstain from nonalcoholic beverage use
before LT and recommend that they also avoid them after LT.
PREDICTORS OF THOSE AT HIGH RISK
FOR RELAPSE
For the general alcoholic population, investigations have attempted
to identify those at risk for drinking by looking at a variety of behavioral
and psychologic factors acting concurrently with or as antecedents to the
alcohol use.30 Unfortunately, studies performed in the non-LT, alcoholic
population have not found reliable predictors of relapse by 1 year after
addiction treatment.30 Given the complexities in predicting drinking in
non-LT alcoholics, it is not surprising that no single factor can consistently predict the risk for relapse in LT alcoholics.33 While prospective
studies are underway,15, 40 data are not yet available using post-LT behavioral or psychologic factors to predict relapse. Most research has relied
on pre-LT variables to predict post-LT alcohol use, in part because these
variables may be more readily available from the pre-LT evaluations.
Despite these limitations, addiction research suggests that pre-LT factors,
such as duration of sobriety, chronicity of the alcohol addiction, family
history of alcohol dependence, rehabilitation experiences, personality
disorders, affective disorders, and stable social supports, may be fruitful
areas to explore. In one longitudinal study of 63 patients undergoing LT
for ALD, a history of drug use at any time before LT was signicantly
associated with post-LT alcohol use relapse (P 0.0003).23 These investigators also found two factors predictive of post-LT abstinence: (1) the
absence of an illicit drug use history and (2) a life insurance policy
held by the recipient (believed to represent stable relationships and
employment).23 In a prospective study of post-LT alcohol use, DiMartini
et al15 explored demographic, socioeconomic, and pre-LT psychiatric and
addiction history variables. A lack of residential stability and employment were not associated with alcohol use. In addition, neither specic
variables of the addiction history (i.e., quantity, frequency, duration, and
length of sobriety) nor psychiatric variables (i.e., prior IV drug use,
affective disorders, or psychotic disorders) predicted alcohol use. Only
a family history of alcoholism and prior rehabilitation experience
(thought to represent those with a more severe addiction) were associated with post-LT alcohol use (P 0.05). A history of substance use was
associated with a higher, but not statistically signicant, risk for alcohol
use after LT.15 Of the group that drank any alcohol, 92% had a pre-LT
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of two regional VA transplant centers serving the Veterans Health Administration System for the entire United States. Since 1988, the combined program has evaluated over 1200 candidates for LT, and nearly
600 have undergone LT. Similar to most programs in the United States,
it is estimated that nearly 50% of the OHSU patients have histories of
alcohol and/or other substance use disorders, but nearly 70% of the
VAMC patients have such histories. Approximately two thirds of these
patients have alcohol dependence alone, and the remainder have polysubstance use disorders. Patients with polysubstance use disorders have
used alcohol in conjunction with at least one other substance of abuse.
The other substances most often used by these patients include marijuana, heroin, cocaine, and amphetamines. A retrospective chart review
of the OHSU patients revealed that approximately 20% of patients with
alcohol dependence alone have used any alcohol after LT, whereas 10%
have demonstrated a return to pathologic drinking (dened as a pattern
consistent with the diagnosis of alcohol dependence).22 In comparison,
38% of patients with polysubstance use disorders have used any substance or alcohol after LT, with most of these patients demonstrating
ongoing substance use.
Fireman22 studied the VAMC patients prospectively and in more
detail. Of 116 patients who underwent LT between 1988 and 1999 and
were diagnosed preoperatively with alcohol and/or other substance use
disorders, 77 were diagnosed with alcohol dependence alone, and 39,
with polysubstance dependence. Ninety-four patients who survived the
initial post-LT hospitalization and at least 1 year after LT were included
in the study. Patients with alcohol dependence alone did not differ from
those with polysubstance dependence for amount and number of years
of heavy use (alcohol or substance), length of pre-LT abstinence, reasons
for discontinuation of alcohol or substance use, or acceptance of the
diagnosis of their alcohol or substance use disorder; however, several
signicant differences were observed between these two groups. Patients
with polysubstance dependence tended to be slightly younger than
alcohol-dependent patients (average age, 42 versus 49 years, respectively). Patients with polysubstance dependence were twice as likely to
have multiple prior episodes of substance abuse treatment. Although
the groups had similar rates of comorbid depression and posttraumatic
stress disorder, the polysubstance dependence group was threefold more
likely to be diagnosed with personality disorders, especially from the
cluster B type (i.e., antisocial, narcissistic, histrionic, and borderline). The
polysubstance-dependent group was less likely to have stable housing,
a consistent work history, or stable social support.
These factors are traditionally considered to predict relapse risk in
the general population of chemically dependent persons. Approximately
22% of the patients with alcohol dependence relapse with any alcohol
use, and approximately 9% return to a pattern of drinking that is consistent with the diagnosis of alcohol dependence. Among patients with
alcohol dependence alone, those who have comorbid untreated psychiatric disorders, a history of multiple treatment episodes, and a lack of a
LIVER TRANSPLANTATION
203
stable living situation show an increased risk for relapse after LT. In
contrast, 76% of patients with a history of polysubstance dependence
relapse with the use of alcohol or any substance, and they tended to
develop a pattern of chronic use consistent with a diagnosis of substance
dependence. For the polysubstance-dependence group, comparisons
were made for numerous pre-LT variables between those who did and
did not relapse after LT.22 No signicant differences were found for age,
duration of pre-LT sobriety, amount and number of years of heavy
substance use, history of prior treatment, incidence of psychiatric illness,
or social stability factors. Post-LT variables for average duration of
survival, incidence of medical complications, and mortality rate compared favorably with the general transplant population at that center. In
no case was death directly attributable to the observed relapse.
THE TREATMENT OF ALCOHOL AND DRUG USE
DISORDERS IN LIVER TRANSPLANTATION
Alcohol Use Disorders
Research has shown that alcoholic LT candidates differ from nonLT alcoholics in some clinically signicant ways. For example, most quit
drinking on their own, without sensing the need for working on their
recovery.39, 43 In fact, many patients undergoing LT evaluation for ALD
have had no formal alcoholism treatment or even attended an Alcoholics
Anonymous (AA) meeting ( 50% at some centers).18, 43 That 30% to
50% of patients undergoing LT for ALD return to some drinking after
LT,29 and that nearly 10% relapse heavily, encountering severe medical
complications attributable to their drinking,44 attests to the need for
specic treatment strategies for this unique population. In an attempt to
address these issues, Wagner et al39 described the potential utility of
using relapse-prevention therapy for LT candidates with substance abuse
disorders. These investigators provided a thorough description of the
strengths and drawbacks of relapse-prevention therapy in this population; however, to date, no completed formal studies exist in the medical
literature of alcoholism treatment in LT patients.
One type of pre-LT treatment strategy is the use of contingency
contracting. Nelson et al31 give a thorough clinical guide describing the
theory and implementation of contingency contracting for alcoholic LT
candidates. They recommended that alcoholic LT candidates sign a contract assuring lifelong abstinence from substances of abuse to secure
wait-listing for LT. Although such contracts can have therapeutic value
and are believed to support abstinence, no studies have assessed the
potential benet of this recommendation. Despite this, in a survey of 69
LT programs, 45% of the programs endorsed this practice as very
important for listing a patient for LT.20 The authors believe that the use
of such contracts is controversial. It may not be ethical to refuse LT if a
patient refuses to sign such a contract. For example, a contract on
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LT.28 Of the 56% of programs that reported accepting patients for evaluation who were in MMT, an astonishing 32% required patients to discontinue their methadone use before LT. Even more concerning is the lack
of experience with such patients (i.e., only 10% of these programs had
experience with more than ve such patients). Although no studies of
this practice in LT patients have been performed, an abundance of
evidence shows that tapering methadone in stable, methadone-maintained opioid addicts results in relapse to illicit opiate use in as many
as 82% of patients.5 Relapse to opiate use places a previously stable
recovering opiate addict at risk for fatal overdose or contracting and
spreading HIV, HBV, or one of the many subtypes of HCV. In the
authors opinion, an attempt to taper a recovering opiate addict from
methadone should not be made at a time when patients are struggling
with the stresses and pain associated with end-stage liver disease. Until
data to the contrary emerge, requiring methadone tapering in stable
opiate dependents as a prerequisite for LT candidacy could be considered unethical. This strategy potentially heightens the risk for relapse,
and those who relapse would be declined from LT.
Other Health Behaviors That Affect Outcome
While patients undergoing LT for ALD have a survival rate comparable to that of patients undergoing LT for other types of liver disease
in the early post-LT years, decreasing long-term survival may be caused
by not only alcohol use21 but also other health behaviors. Beyond the
known direct negative effects on the liver, alcohol use can impair patients ability to comply with medical directives. In the cohort of Jain et
al27 of 185 patients who underwent LT for ALD and were followed up
over a 4-year period, only one died as a result of the direct toxic effects
of alcohol on the liver; however, three others died from organ rejection
and failure because of nonadherence with medications, laboratory testing, and clinic appointments.27 In addition, the recent identication of a
higher rate of post-LT death caused by lung cancer in the alcoholic
population27 suggests that other health behaviors, such as exposure to
tobacco use, may be crucial to long-term survival. In this same cohort of
patients undergoing LT for ALD, the rate for oropharyngeal cancer was
25-fold higher, and for lung cancer, 3.7-fold higher than that in the
general population, a risk not found in the non-ALD LT control group.
SUMMARY
It is unfortunate that LT is not the ultimate sobering experience. LT
patients can and do relapse; however, relapse to alcohol or substance
use should no more be considered a failure of LT than the recurrence of
HCV after LT. It is a phenomenon of their addiction. As a group, the
survival and outcomes of patients undergoing LT for ALD are not
LIVER TRANSPLANTATION
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Address reprint requests to
Andrea DiMartini, MD
University of Pittsburgh Medical Center
Western Psychiatric Institute
3811 OHara Street
Pittsburgh, PA 15213
e-mail: dimartiniaf@msx.upmc.edu
In recent years, complementary medicine has grown into a multibillion dollar annual industry. These medicines often are used by patients
to augment conventional medical care. One important aspect of this
trend is nutritional supplements, which are readily available to interested consumers. Herbal supplements are derived from plant sources,
such as St. Johns wort, garlic, and ginseng. Nonherbal supplements
refer to a complex group of agents, many naturally found in the human
body and necessary for physiologic functioning. S-adenosyl-L-methionine (SAMe), omega-3 fatty acids (OFAs), and coenzyme Q10 are a
few of the most popular nonherbal supplements. As a whole, these
supplements are purported to offer benets in a wide array of physical
and mental disorders, including:
Alzheimers disease
Acetyl-L-carnitine (ALC)
Gingko biloba
Huperzine
Anxiety
Kava kava
Valerian
From the Department of Psychiatry, Inova Transplant Center, Falls Church, Virginia (CCC),
Department of Psychiatry, Georgetown University Medical Center, Washington, DC
(CCC); and the Department of Geriatric Psychiatry, Walter Reed Army Medical Center,
Washington, DC (GG)
211
212
Asthma
Chinese medicines
Gingko biloba
Ma huang
OFAs
Saiboku-to
Atherosclerosis
Chromium picolinate
Garlic
OFAs
Soy
Bipolar disorder
OFAs
Cancer
Green tea
Mistletoe
Shark cartilage
Diabetes
Bitter melon
Chromium picolinate
Fenugreek
Ginseng
Human immunodeciency virus
Glutamine
L-Carnitine
N-acetylcysteine
St. Johns wort
Osteoarthritis
Chondroitin sulfate
Glucosamine sulfate
SAMe
213
Risks for adverse side effects and interactions with prescription agents
only add to concerns about patient safety. Unfortunately, physicians
regularly fail to ask their patients about possible supplement use and
lack the information necessary to guide their patients toward informed
decisions about nutritional supplements.
The past decade has seen increasing recognition of the comorbidity
between physical and mental disorders. High rates of anxiety and depression have been found in patients with cancer, HIV, and rheumatologic disorders.61, 116 Likewise, patients with severe mental illness are at
higher risk for cardiovascular and pulmonary diseases.73, 87 Because of
this overlap, psychiatrists can expect to be caring for patients facing
concurrent physical and mental disorders. This situation will continue
to increase as the general population ages. With factors such as chronic
illness, poor health, emotional distress, and quality of life inuencing
the desire for complementary medicine, patients with comorbid medical
and psychiatric problems seem likely to turn to this approach.19, 36, 48
Thus, psychiatrists need to become more informed about alternative
treatments.
Given the popularity of herbal and nonherbal supplements for the
treatment of medical and psychiatric conditions and the lack of knowledge about them among clinicians and their patients, this article provides psychiatrists with an overview of their risks and benets.
ALZHEIMERS DEMENTIA
Ginkgo biloba has been used throughout Europe to treat cerebral
insufciency, a loosely dened condition with a presentation similar to
dementia.95 Actions of the components of gingko include antioxidant
properties, vasodilation, antagonism of platelet-activating factor, and an
increase in density of muscarinic receptors.89, 110 The clinical effects of
ginkgo are most likely the results of a combination of these actions. The
active components of ginkgo extracts seem to be the avonoids and
terpene lactones, including the ginkgolides.26, 95
A recent review53 of nine randomized, double-blind, controlled studies suggested that ginkgo extract is more effective than placebo in the
treatment of Alzheimers dementia (AD), vascular dementia, and mixed
types. Le Bars et al105 conducted a placebo-controlled, double-blind,
randomized trial of gingko (EGb 761) extract (120 mg/d) for a 52-week
period in outpatients with mild to severe dementia of various types.105
Results suggested that EGB 761 was able to stabilize or improve measures of cognitive function for a period ranging from 6 to 12 months;
however, because of high dropout rates, the study partially relied on
intent-to-treat analysis, which may have distorted the degree of cognitive
decline.105 Wettstein184 compared placebo-controlled studies of available
cholinesterase inhibitors with studies of EGB 761 and found similar
periods of delay in disease progression. In a randomized, double-blind,
placebo-controlled study, van Dongen et al173 failed to demonstrate any
signicant treatment effect from EGB 761 in 214 subjects with mild
214
215
GABA (A) receptors to produce anxiolytic and sedative effects, but this
remains unproven.33, 72, 118 Most studies to date have demonstrated a
general trend supporting the use of valerian as a hypnoticsedative
that decreases sleep latency, increases slow-wave sleep, and improves
subjective sleep quality.149, 181 In a double-blind study,98 it seems that
valerian reduced the subjective experience of arousal without modication of actual physiologic activation. Isolated cases of hepatoxicity associated with valerian used in combination with skullcap have been reported, and a case of possible withdrawal with cardiac complications
has been reported.62, 111
ASTHMA
Asthma is a chronic respiratory disorder characterized by recurrent
episodes of reversible airway obstruction, bronchial hyper-reactivity, and
airway inammation. It affects 5% of the US population and accounts
for more than $6 billion in annual health care costs.43 Limiting the
synthesis of inammatory mediators, such as leukotrienes and interleukins, with drugs or nutritional supplements is one approach to managing
asthma symptoms. OFAs, derived from fatty sh or plants, form leukotrienes with less activity than those normally derived from arachidonic
acid.131, 175 A few randomized trials have noted benets in asthma patients given OFAs, but results are inconsistent.6, 70, 97, 131, 175 Also, OFAs
should be used cautiously with anticoagulant or antiplatelet agents
because of an increased risk for bleeding. Chinese herbal medicines for
asthma consist of several botanical agents, with ma huang being the most
common ingredient.13 Ma huang contains adrenergic agents, which relax
bronchial smooth muscle. Some prescription inhalers have similar, although more, selective adrenergic activities. Both can produce problems
with nervousness, jitteriness, tachycardia, and hypertension. Gingko biloba may be found in some Chinese asthma medicines but is more
popular in Europe as an antiasthmatic agent.13 Gingko reduces airway
inammation by antagonism of platelet-activating factor.13 A small number of clinical trials have shown mixed results despite positive ndings
in animal studies.13, 74, 107 Saiboku-to is a popular traditional medicine in
Japan and China; however, Ernst74 could locate only one published,
randomized, controlled trial for a systematic review of herbal medicines
in asthma. Reports of inammatory pneumonitis and alveolitis have
raised concerns about the safety of using Saiboku-to.49
ATHEROSCLEROSIS
Because cardiovascular disease is the leading cause of death in the
US, demand for ways to reduce the risk for atherosclerosis is not surprising. One approach involves the use of dietary supplements. Epidemiologic studies rst reported an inverse relationship between sh intake
216
217
have been reported in patients primarily taking OFA preparations derived from axseed oil.94, 164, 166
CANCER
Despite advances in treatment and early detection, the diagnosis of
cancer still provokes signicant fear and apprehension. The desire to
reduce the risk for cancer has led to the increased use of green tea.
Case studies have shown an inverse relationship between green tea
consumption and the risk for various types of cancers, leading some to
suggest that green tea offers cancer-preventive effects.81, 82, 189 Research
using cancer cells and animal models have shown that polyphenols in
green tea possess antineoplastic effects.18, 85, 172 In fact, polyphenols are
strong antioxidants and free radical scavengers, which also can inhibit
tumor growth and development.18, 172 Despite these ndings, prospective
population studies have failed to conrm a link between green tea use
and reduced risk for cancer.76, 172 A recent study that followed of a large
Japanese population for 8 years did not show an association between
green tea intake and a reduced risk for gastric cancer.172 In addition,
another study reported an insignicant increase in the risk for gastric
cancer.61
Shark cartilage is a popular nutritional supplement for the adjunctive treatment of cancer, and its use is partly based on the mistaken
premise that sharks do not get cancer. Bovine and shark cartilage present
can inhibit tumor angiogenesis.125 Investigators also have noted immunomodulatory and direct cytotoxic effects.125 Although abstracts are available about clinical human trials using cartilage treatments, only three
studies have been fully published in peer-reviewed, scientic
journals.119, 125, 136, 139 One is a case series, whereas the other two are phase
1 and 2 trials involving patients with various forms of cancer.119, 136, 139
Only the case series reported clear positive results.136 Despite this, unpublished data regarding an aqueous shark cartilage extract, AE-941,
have led the US food and Drug Administration to approve phase 3
trials.125 Adverse effects are usually mild to moderate, but generalized
weakness, hyperglycemia, hypercalcemia, and hepatitis have been reported.125
Mistletoe extracts have been used as natural cancer treatments
because of their ability to stimulate the immune system. Lectins are the
primary components thought to activate lymphocytes and macrophages,
leading to increased numbers and cytokine production.86, 126 Other compounds may be responsible for inducing apoptosis in cancer cells studied
in vitro.126 Although research has shown that mistletoe extracts stimulate
the immune system, this has not necessarily translated into anticancer
effects. Clinical studies have reported positive results, but most have
been of poor quality.54, 86, 96 Recent trials seem to be of better design but
have not yielded positive results.59, 126, 161 For example, a prospective
218
219
SAMe seems to have few side effects and is generally well tolerated.
Administration of SAMe has been demonstrated to cause hypomanic
and manic symptoms in patients with bipolar disorder, and its use in
patients with mood disorders with psychotic features has not been
adequately studied.25 While SAMe has been used in the treatment of
patients with Parkinsons disease and depression, it may cause rigidity
and hypokinesia.29, 30
St. Johns wort (Hypericum perforatum) is widely used as both a
prescription and an over-the-counter medication in the treatment of
depression. It has various effects on neurotransmitters, receptors, and
enzyme systems commonly associated with clinical depression.34, 124, 171
Which component or combination of components of the hypericum
extract is responsible for the clinical effects is unclear; however, it has
been suggested that hypericin and hyperforin may have the antidepressant actions.101 A meta-analysis109 of randomized trials of St. Johns wort
in the treatment of depression suggested that it is probably more effective than placebo in the treatment of mild to moderate depression;
however, dosages, outcome parameters, diagnostic criteria, and patient
selection varied widely among the different trials. In a review of Englishlanguage studies between 1980 and 1998, four randomized, double-blind
studies demonstrated greater improvement in HAM-D scores in the
treatment group with compared the placebo group.63 A randomized,
multicenter, controlled trial185 comparing St. Johns wort (500 mg/d) to
imipramine (150 mg/d) concluded that St. Johns wort was therapeutically equivalent to imipramine in the treatment of mild to moderate
depression and produced fewer adverse reactions; however, in another
multicenter, randomized, placebo-controlled trial, Shelton et al154 failed
to demonstrate a treatment effect for St. Johns wort in patients diagnosed with major depressive disorder. Multiple drug interactions have
been associated with the use of St. Johns wort, including decreased
cyclosporine, digoxin, indinavir, warfarin, and theophylline levels.83, 128,
134, 142
St. Johns wort seems to induce cytochrome P-450 3A4 and 2C9
enzyme systems while inhibiting 1A2.52, 88, 142 Because of case reports of
serotonin syndrome, caution must be exercised when St. Johns wort is
used in combination with other serotonergic compounds.67, 77 Induction
of hypomania and mania have been reported with its use.123, 129
DIABETES
The role of chromium in glucose regulation was initially suggested
by observations that diets decient in this element often resulted in
glucose intolerance and diabetes.3, 27 Recent reports have indicated that
the mechanism of action for chromium is mediated by the binding of a
low molecular weight chromium complex (chromodulin) with the insulin receptor and amplication of the receptor kinase activity.176, 177 Most
studies to date have indicated that chromium supplementation may be
220
221
222
Ma huang
Mistletoe
S-adenosyl-L-methionine
Saiboku-to
St. Johns wort
Shark cartilage
Valerian
223
Supplement
Hemorrhage
Increased coagulability
Hypoglycemia
Hyperglycemia
CNS depression
Severe headache
Serotonin syndrome
Cardiac glycoside
toxicity
Reduced drug level
Reduced drug level
(alters P-glycoprotein)
Reduced effectiveness,
drug level (CYP3A4
induction)
Prescription Drug
Warfarin, heparin, NSAIDs,
platelet aggregation
inhibitors
Warfarin
Insulin, oral hypoglycemic
agents
Insulin, oral hypoglycemic
agents
Alcohol, benzodiazepines,
hypnotic agents, opiates
Nitroglycerin
Clomipramine, SSRIs
Digoxin, other glycosides
Carbamazepine
Calcium channel blockers,
chemotherapy agents,
cyclosporine, digoxin
Azole antifungals,
cyclosporine, nonnucleoside reverse
transcriptase inhibitors,
oral contraceptives,
protease inhibitors
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generally more organized and more expensive than are raves, and the
attendees are usually a little older. Alcohol is usually more readily
available than at raves; however, the drugs that are used and the accompanying complications are basically the same. A survey of 173 people
attending a circuit party on Fire Island, New York, in 1998 reported that
the following substances were used on the day of the party (S. Lee,
MD, personal communication, 2001): ecstasy (71%), ketamine (53%),
methamphetamine (31%), alcohol (25%), cocaine (19%), -hydroxybutyric acid (GHB, 12%), benzodiazepines (11%), marijuana (10%), and
LSD (2%). The mean number of substances used on the day of the party
was 2.4. Although a variety of drugs and alcohol may be used in the
context of raves and circuit parties, the designer drugs that are the focus
of this article are ketamine, methamphetamine, ecstasy, and GHB.
KETAMINE
Ketamine was developed in the early 1960s by Parke-Davis as an
anesthetic alternative to phencyclidine, to which it is chemically related.15
Its advantage as an anesthetic was that it could produce profound
analgesia and amnesia with relatively little respiratory suppression or
loss of consciousness. It gained popularity as a eld anesthetic during
the Vietnam War; however, people receiving the drug often complained
of hallucinations and dissociative experiences during recovery, and its
use in adults became limited. Because of these effects, ketamine became
known as a dissociative anesthetic. It is still widely used in veterinary
medicine, which sometimes serves as a source for the illegal sale of the
drug. Ketamine also occasionally is used as an anesthetic for children
because children seem to experience fewer side effects.4
The dissociative effects are also the primary allure for the recreational use of ketamine. On the street and in clubs, it is known as K, ket,
kit-kat, lady K, special K, vitamin K, and cat Valium. Trade names are
Ketaset and Ketalar. The liquid form is usually dried in a microwave
oven and sold as a powder that is snorted. It can also be taken orally
(PO) in tablet form or injected (IV). The onset of action can range from
1 minute (IV) to 30 minutes (PO). The total duration of effect also
depends on the route of administration, lasting from 30 minutes for
parenteral intake to 3 hours for PO ingestion. Ketamine is metabolized
by the P-450 system, with an elimination half-life of approximately 2
hours.4, 33 The effective dosage ranges from 15 to 300 mg, and it sells for
$25 to $50 per gram on the street. Ketamine is a noncompetitive
N-methyl-D-aspartate (NMDA) receptor antagonist that produces calcium channel blockade. It also stimulates release of CNS dopamine and
endorphins, acts as a mild - and -adrenergic agonist, and produces a
mild muscarinic block.4
Other NMDA antagonists, such as phencyclidine, have been shown
to produce schizophrenic-like symptoms and cognitive decits when
given to normal volunteers, and this has also been demonstrated with
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rock candy. Much of the crystal meth that is available on the black
market is produced in large, illegal labs in Mexico; however, instructions
to synthesize crystal meth from pseudoephedrine or ephedrine can easily
be obtained over the Internet.
The onset of action ranges from 40 minutes if taken orally to 10
minutes if smoked, to immediate with IV injection. Its elimination halflife is approximately 4 to 6 hours. The average dose ranges from 50
to 200 mg, and tolerance builds quickly. Similar to other stimulants,
methamphetamine is a dopamine agonist and may have some serotoninuptake inhibitory activity.55
The desired effects from methamphetamine include euphoria, decreased need for sleep, increased mental alertness, and decreased appetite. When smoked or injected, users report an intensely pleasurable
experience referred to as a rush or ash. Some have likened it to
smoking crack cocaine except that the effects last longer. In the circuit
party scene, where much sexual activity occurs, many participants use
crystal meth to increase their sexual pleasure or to enhance the experience47; however, repeated use of the drug is much more likely to produce
disturbing and even dangerous effects. Chronic users can become aggressive and violent and may develop an amphetamine psychosis, with
persecutory delusions and hallucinations similar to someone suffering
from paranoid schizophrenia.7 Other effects of chronic use include insomnia, anxiety and increased psychomotor activity, involuntary movements, malnutrition, tachycardia, and elevated blood pressure sometimes
resulting in myocardial infarction or stroke.18
Discontinuing chronic use of methamphetamine produces a withdrawal syndrome. The severity of the withdrawal depends on the length
and magnitude of abuse.
The most common symptom of withdrawal is moderate to severe
depression. Other symptoms include disturbed sleep marked by alternating hypersomnia and insomnia, extreme hunger, exhaustion, psychosis, and intense craving for more methamphetamine. Flashbacks or
spontaneous recurrence of paranoid-hallucinatory states among methamphetamine users have been reported.36 Evidence of persistent, if not
permanent, damage to dopaminergic and serotonergic neurons from
repeated use of methamphetamine is increasing.7, 17 Neuroleptics are
probably the treatment of choice for acute psychotic behavior, agitation,
and aggressiveness. It has been suggested that atypical neuroleptics,
such as risperidone or olanzapine, may be preferred because of their
combined serotonin- and dopamine-antagonist properties.37, 38 How effective antidepressants are in treating the depression caused by methamphetamine withdrawal is unclear, and in some cases, the depression may
resolve spontaneously after many weeks of abstinence.
ECSTASY
The structural name of ecstasy is 3,4-methylenedioxymethamphetamine (MDMA). It is known on the street as X, XTC, E, M, Adam, bean,
235
roll, clarity, and essence, among others. As its name implies, it bears some
structural similarity to methamphetamine but also chemically resembles
the hallucinogen mescaline.
MDMA was rst synthesized in 1912 as an appetite suppressant but
was not found to be very effective and was never commercially produced. In the 1950s MDMA was mentioned in the psychoanalytic literature as a potential aid to analysis or psychotherapy by helping people
to overcome resistances and to get in touch with their feelings.52 By the
1980s, its recreational use was increasing in association with the growth
of raves and circuit parties. The FDA classied MDMA as a Schedule I
drug in 1985, but its illicit use has continued to grow over the past
decade, particularly among adolescents and young adults.
The use of ecstasy has spread beyond the club scene to high schools
and colleges. A survey by National Institute on Drug Abuse (NIDA)
showed that, in 1999, 5.6% of twelfth graders, 4.4% of tenth graders, and
1.8% of eighth graders had used ecstasy in the past year.10 A 5% lifetime
prevalence of use has been reported among youths aged 18 to 25 years;
however a study from Seattle indicated that 41% of gay men aged 20 to
29 years surveyed had used ecstasy at some time in their lives.10 Much
of the ecstasy available today is produced overseas or in Mexico. United
States Customs reported seizure of more than 5 million tablets of ecstasy
in 1999 compared with only 750,000 in 1998.10 Organized crime has
become involved in its distribution and sales in New York, and ecstasy
can now be purchased on the streets alongside heroin and crack cocaine.
Ecstasy is most commonly ingested orally in tablet form, but there
have been reports of the tablets being crushed into powder and then
smoked, snorted, or injected. The tablets are often imprinted with logos
taken from popular culture, such as the X-Files, Versace, Nike, or Warner
Brothers, among others. Most tablets contain 60 to 120 mg of MDMA and
sell for $10 to $40 each; however, because of their illegal manufacture,
contamination is common, such as with heroin, LSD, or methamphetamine. The onset of action is 30 to 45 minutes after PO ingestion, and
the effects generally are reported to last from 2 to 6 hours. Club goers
often take two or three tablets over the course of an evening. Physiologically, MDMA seems to produce its effects by ooding the brain with
serotonin. It both stimulates the release of serotonin and then inhibits its
reuptake, causing a depletion of as much as 80% of central stores of
serotonin.25 This produces rapid tolerance to the effects of ecstasy, and
users rarely experience the same pleasurable feelings with repeated hits.
Coadministration of uoxetine or citalopram have been shown to block
serotonin-depleting effects of ecstasy.25 MDMA also has been shown
to inhibit tryptophan hydroxylase, the rate-limiting step of serotonin
synthesis, for up to 2 weeks, which may explain why users often wait
at least 2 weeks between doses.25 MDMA is metabolized by P-450 2D6.
The pleasurable effects that ecstasy produces have been described
as enatogenesis, which means a sense that all is right with the world,
or empathogenesis, which is dened as emotional closeness to others.47
Ecstasy also has been reported to increase the senses of touch, taste,
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smell, vision, proprioception, and self-awareness. MDMA is also a stimulant, making it appealing to people attending all-night parties.25 A common side effect of ecstasy is bruxism, which leads to gum chewing or
the use of paciers at raves to counteract this effect.
Despite the reputation in the club scene of ecstasy as a safe, even
benecial, drug, many toxic effects have been reported. These include
delirium, tachycardia, tachypnea, profuse sweating, hyperthermia, acute
renal failure, cardiovascular collapse, disseminated intravascular coagulation, hepatic failure, hyponatremia, cerebral infarct or hemorrhage, and
death.45 Given its underlying mechanism of action, it is not surprising
that the toxic effects resemble serotonin syndrome.14 While most of the
toxic effects have been related to overdoses in the context of raves and
circuit parties, people who are decient in P-450 2D6 or taking drugs
that inhibit this enzyme may be at high risk even when taking therapeutic doses of MDMA. At least two cases have been reported of fatal
or near-fatal outcomes in men taking ritonavir as a part of an antiretroviral regimen and then ingesting ecstasy in a club.26, 27 Repeated use of
ecstasy may lead to chronic mood instability, cognitive impairment,
increased impulsivity, or psychosis.5, 23, 25, 42, 43 In addition, animal and
human studies using single photon emission CT and positron emission
tomography indicate that MDMA use may result in a prolonged decrease
in CNS serotonin and damage to serotonergic neurons.45, 46, 50 Delayed
hepatotoxicity, sometimes fulminant, also has been reported in association with MDMA ingestion.2a, 30a
For most patients, the management of acute ecstasy intoxication
includes basic supportive care. More intensive medical care may be
indicated according to the problems that develop. Neuroleptics and
selective serotonin reuptake inhibitors should be avoided in the management of acute intoxication, but benzodiazepines may be used to treat
agitation.14, 25 Although cyproheptadine, a nonselective serotonin antagonist, may be helpful in treating the serotonin syndrome,22a no evidence
supports for its use in treating MDMA intoxication. The use of antidepressants or neuroleptics for the treatment of chronic problems resulting
from MDMA use has not been studied. No withdrawal syndrome from
MDMA has been reported.
GAMMA HYDROXYBUTYRIC ACID
GHB is a club drug that is gaining notoriety among emergency
departments (EDs), addiction services, and consultationliaison services
because of some severe, life-threatening reactions in overdose and in
withdrawal. GHB is a naturally occurring, endogenous neurotransmitter
that was rst synthesized in 1960 for use as an anesthetic.21, 31, 40 Its
acceptance as an anesthetic was limited, however, because of side effects
that included petit mal and grand mal seizures. In the 1970s, GHB was
studied as a therapy for narcolepsy because of its ability to increase
rapid eye movement sleep in narcoleptics; research in this area continues
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Many of the qualities mentioned thus far, especially the hypnotic, amnestic, and hypotonic effects, have made GHB an ideal candidate for use as
one of the date-rape drugs.
Unfortunately, GHB has a relatively low therapeutic index, and the
toxic dose is close to the euphorigenic dose. Toxic effects that have
been reported include dizziness, nausea and vomiting, myoclonic jerks,
confusion, agitation, hallucinations, seizures, Cheyne-Stokes respirations, coma, and death.9, 31 Explosive and unexpected violent behavior
in patients who otherwise seem sedated has been reported.21, 39 Similar
adverse events also have been reported with the ingestion of the GHB
precursors, -butyrolactone and 1,4-butanediol.59 No known antidotes
for GHB poisoning exist.57 Management of acute intoxication depends
on the clinical presentation but usually consists of airway protection and
supportive observation for a few hours until the substance is metabolized and cleared. Ventilatory support may be necessary depending
on the depth of coma.39 Most reports indicate that patients recover
spontaneously within 7 hours.31, 39
For some who use GHB or its precursors regularly, tolerance and
dependence seem to build rapidly. Severe withdrawal reactions have
now been reported.1, 11, 19, 20, 28, 29, 48, 59 The authors experience recently
with three such patients at Beth Israel Medical Center in New York has
highlighted the importance for clinicians to be aware of the potential
dangers of GHB withdrawal.
Case 1
A 34-year-old man who had been using GHB for at least 3 years was
admitted to a medical service for detoxication. He began using it on the advice
of his brother, who lived in Texas and supplied the patient with the drug as a
bodybuilding aide. At the time of admission, the patient had been ingesting
approximately 1 oz of GHB every 2 to 4 hours for at least 6 months. His wife
urged him to come in to be detoxied after he tried on his own to taper the
drug but failed. He was tremulous on admission, with a heart rate of 140 beats
per minute (bpm) and a blood pressure of 160/90 mm Hg and was given an
intramuscular (IM) injection of phenobarbital, 130 mg, with minimal effect. He
was also started on a regimen of clonazepam, 1 mg three times a day, that was
to be tapered over the next 4 days. His condition deteriorated rapidly, and he
was diaphoretic, tremulous, hallucinating, and paranoid. A psychiatric consultation was requested, and the resident physician on call recommended an immediate dose of haloperidol, 5 mg IM, and lorazepam, 2 mg IM. Over the next 12
hours, the patient received an additional 2 mg of haloperidol and 7 mg of
lorazepam PO. His vital signs continued to uctuate, and he scored only 5 of 30
points on the Mini-Mental State Examination. Opisthotonus and cogwheel rigidity were noted, and he was given amantadine, 100 mg, and then transferred to
the neurology service for further treatment. His creatine phosphokinase (CPK)
level was elevated, at 4285 mg/dL. Over the next 24 hours, he was treated with
clonazepam, 1 mg three times a day, and he was more lucid. On the third day
after his admission, however, he became very suspicious of the staff and tried
to elope. He was brought back to his room and given haloperidol, 1 mg IM
(despite advice from the psychiatric consultant not to use neuroleptics based
239
upon the elevated CPK and the previously noted dystonic reaction), and lorazepam, 2 mg IM, with mild effect. A few hours later, he became explosively
agitated and threw a bedside table at his one-to-one companion. He then jumped
through a window and fortunately landed on a ledge one oor below without
suffering any further injury. He was brought back into the hospital and admitted
to the intensive care unit (ICU), where he was quickly sedated with a midazolam
drip of 35 mg/h. After 24 hours of stabilization, the midazolam dosage was
lowered to 25 mg/h. This was subsequently switched to a lorazepam drip of 8
mg/h several hours later. At this time, the patient was more alert, conversant,
and oriented to person and place. His vital signs remained stable and within
normal limits; the CPK level had decreased to 53 mg/dL and, other laboratory
test results were unremarkable. The next day, the lorazepam drip was decreased
to 3.5 mg/h, and the patient was started on lorazepam PO, 10 mg every 4 hours.
The IV lorazepam was discontinued the following day. After 1 week in the ICU,
the patient was transferred to the psychiatry unit for further tapering of the PO
lorazepam. Valproic acid was added as an adjuvant to the detoxication, which
was completed 10 days after his admission to psychiatry. Although his MiniMental State Examination score had improved to 26 of 30, he was unable to
recall the events that led to the incident of jumping out the window. He was
discharged to home, with follow-up arranged at a drug treatment program.
Case 2
A 30-year-old man was found unresponsive on the oor by his landlord
and brought into the ED, where he was extremely agitated, with elevated heart
rate and blood pressure. His girlfriend provided the history that the patient had
been using GHB, 1 to 2 oz every 4 hours for at least 2 years because he
found it relaxing. She said that the patient also frequently used many other
substances, including ketamine, LSD, and marijuana. He was admitted to the
medical ICU (MICU) and started on a lorazepam drip that was titrated to his
heart rate and blood pressure. As the dosage of the drip increased rapidly, the
patient was electively intubated. Abnormal laboratory test results included an
elevation of CPK and liver enzyme levels. A dosage of 25 mg/h of lorazepam
was required to maintain a heart rate of 90 bpm or less. Any attempts to taper
the lorazepam within the rst 3 days resulted in autonomic instability. The
patient was extubated after 2 days, and PO clonazepam was added to his
regimen. The ICU staff was reluctant to add valproic acid to the regimen because
of the elevated liver enzymes. After 15 days in the ICU, the patient was switched
over to a PO regimen of clonazepam, 30 mg/d in divided doses, and transferred
to the psychiatry unit for continued taper and detoxication. Initially, he had no
memory of the time in the ICU and denied having any problems related to his
GHB use. He eventually accepted some of the explanations of what seemed to
be a life-threatening withdrawal from GHB, and when he was discharged 17
days after admission to the psychiatry unit, he said he would try going to yoga
classes to address his anxiety. He refused referral for continued drug treatment
and acknowledged that he would probably continue to use illicit substances
despite this current experience.
Case 3
A 28-year-old women was brought to the ED by her husband, who stated
that she had been trying to detoxify herself from GHB by substituting beer but
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that she kept passing out. He estimated that she had been ingesting almost
12 oz/d of GHB for the past year. In the ED, her heart rate was elevated to 104
bpm, but other vital signs were within normal limits. She was treated for mild
agitation with 4 mg IV lorazepam and admitted to the MICU. Her condition
rapidly deteriorated, with extreme agitation and autonomic dysfunction. She
was given repeated doses of IV lorazepam and propofol according to her level
of agitation and heart rate. Within the rst 24 hours of admission to the ICU,
she required 98 mg of lorazepam and 80 mg of propofol, and she was electively
intubated . She was then maintained for the next 2 days on a lorazepam drip of
30 mg/h and a fentanyl drip of 50 g/h. She was extubated on this regimen of
lorazepam and fentanyl and was described as sedated but easily aroused and
confused. Any attempts to lower the rate of lorazepam infusion resulted in
elevation of her heart rate. Valproic acid was added and increased to a dose of
500 mg twice a day. Over the next 4 days, the lorazepam and fentanyl drips
were tapered, and she was simultaneously switched over to clonazepam, 10 mg
every 6 hours. Tapering of the clonazepam continued, and her mental status
improved, although she stated that she had no idea how she ended up in the
hospital. After 15 days in the ICU, she was transferred to a regular medical oor
on a regimen of clonazepam, 5 mg every 8 hours, and valproic acid, 500 mg
twice a day. The clonazepam dose was tapered, but she signed out of the
hospital against medical advice 5 days later, before the taper could be completed.
At that time, she was still taking 9 mg/d of clonazepam.
241
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