2002, Vol.25, Issues 1, Psychiatry in The Medically Ill

PSYCHIATRY IN THE MEDICALLY ILL
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
0193953X/02 $15.00 .00
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
From the Departments of Psychiatry and Internal Medicine, Division of Consultation-Liaison

Psychiatry, Medical College of Virginia Campus of Virginia Commonwealth University,
Richmond, Virginia (RKS, JL); and the Department of Psychiatry, Division of Consultation-Liaison Psychiatry, Queens University, Kingston, Ontario, Canada (MJR).
THE PSYCHIATRIC CLINICS OF NORTH AMERICA

VOLUME 25 NUMBER 1 MARCH 2002
SCHNEIDER et al
symptoms. The reader is referred elsewhere for a comprehensive review

of psychiatric symptoms of non-HIV infectious syndromes.32 This article
focuses on the psychiatric aspects of three non-HIV infectious diseases:
(1) neurocysticercosis, (2) Lyme disease, and (3) PANDAS.
RISKS FACTORS
An infectious process should be considered when evaluating psychiatric symptoms in any medical patient; however, an impaired or abnormal immune response or certain demographic and behavioral characteristics should place an infectious process higher in the differential
diagnosis. Compromised immunity is easily recognized in HIV infection
as well as in patients who are receiving immunosuppressive therapies
for malignancies, autoimmune disorders, or transplants; however, substance abuse, age (extremes of young and old), and genetics also may
inuence immune response. PANDAS is an example of an abnormal
immune response (probably genetically mediated) in which a bacterial
infection triggers an autoimmune response in children that results in
obsessive-compulsive disorder (OCD) and tics.
The most important demographic factors are geographic. Certain
regions of birth, residence, and travel affect the risk for particular infections, even within countries. Travelers are often equally vulnerable to
indigenous organisms compared with the local inhabitants. The major
difference between the two groups seems to be the length of time that
one is exposed to a region. Behavioral factors include recreational activity, occupation, and high-risk sexual behaviors.
NEUROCYSTICERCOSIS
Neurocysticercosis (NCC) is globally one of the most common neuroparasitic infections. With the increase of travel and immigration, NCC
is an issue not only in developing countries but also in developed
countries.44 In NCC, the larval form of Taenia solium (cysticerci) infects
the CNS. T. solium is also known as the pork tapeworm. Its life cycle
involves humans as the denitive host and swine as the intermediate
host. Typically, humans acquire the tapeworm infection by ingesting
cysticerci contained in undercooked pork. These cysticerci grow to mature tapeworms in the humans gut. Infection with the tapeworm does
not cause neuropsychiatric sequelae. For NCC to occur, a human must
ingest the eggs from the tapeworm (Fig. 1).9 This most commonly occurs
by eating foods that have been contaminated with the T. solium eggs
from swine or human fertilizer and were not properly cleaned. Also, T.
solium eggs can remain on the unwashed hands of a person with
cysticercosis. This can be especially dangerous if the person is a food
handler. Autoinfection can occur by this way or by having the eggs
regurgitated from the small intestine into the stomach, but this is uncommon. Once the eggs are ingested, they enter the bloodstream and deposit
PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES
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.)
themselves throughout the body. Wherever they end up they develop

into cysticerci; if the area is the CNS, then the disease is called neurocysticercosis. Cysticercosis is endemic in rural areas of Latin America, Asia,
and Africa. In the United States, regions where frequent immigration
from Latin America occurs are the most common areas for NCC (e.g.,
California, Texas, and other southwestern states)36; however, food handlers with the tapeworm infection may contaminate food of people who
have no contact with pork or otherwise uncontaminated foods. An
example of this occurred in an Orthodox Jewish community in New
York City.30
The full natural history and clinical outcomes of NCC are not
fully understood because a high percentage of NCC infections remain
asymptomatic or inactive and undiagnosed. Also, before the 1970s, the
diagnosis was rarely made antemortem. With the development of CT
scanning and MR imaging, the detection rates and understanding of the
disease process have increased.47
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
Figure 2. Noncontrast T1-weighted MR image showing multiple intraparenchymal cysticerci

with visible scolex. (From Garcia H, Del Bruttoo O [eds]: Taenia Solium Cysticercosis.
Infect Dis Clin North Am 14:1, 2000, 97119; with permission.)
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.)
in NCC is associated with benecial effects.29 Further research is needed

to direct clinical decisions.
PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC
DISORDER ASSOCIATED WITH STREPTOCOCCAL
INFECTION
Sir William Osler rst noted a certain perseverativeness of behavior among patients with Sydenhams chorea (a variant of rheumatic
fever), which suggests a possible association with obsessive-compulsive
behavior23; however, it was not until the 1980s that formal investigation
into this observation took place. Investigators at The National Institutes
of Mental Health (NIMH) concluded that approximately 70% of children
with Sydenhams chorea had obsessive-compulsive symptoms, which
had their onset typically shortly before the chorea began.41 The clinical
presentation of Sydenhams chorea implicates basal ganglia dysfunction
in the pathophysiology of this disorder.42 It has also been observed that
obsessive-compulsive symptoms are associated with Tourettes disorder.17 In addition, both tics and OCD may occur following acquired
brain injury to the basal ganglia.2, 15 Based on these and other ndings,
a hypothesis developed proposing that basal ganglia dysfunction could
explain a variety of neuropsychiatric symptoms, including OCD and tic
disorders.
Table 1 outlines the current inclusionary criteria required for the
label of PANDAS. PANDAS is not a diagnosis, but rather an acronym
that refers to the clinical characteristics of a subgroup of children whose
OCD and tic disorders seem to have been triggered by an infection.
Clinically, it has many features similar to childhood-onset OCD and tic
disorders; however, PANDAS has several unique features. First, the age
of onset for PANDAS seems to be approximately 3 years earlier than
previously reported for childhood-onset OCD and tic disorders. Second,
the clinical course of PANDAS is characterized by an abrupt onset with
a relapsing-remitting pattern. Childhood-onset OCD, however, typically
has a gradual onset with a more chronic waxing and waning pattern of
symptom severity. Third, there must be a temporal association between
group A -hemolytic streptococcal (GABHS) infection and symptom
onset or exacerbations. Ideally, this association is made prospectively by
identifying a GABHS infection during at least two symptom exacerbations. Much of the time, however, this is a retrospective observation.
Recent GABHS infection may be documented in a couple of ways (Table
2). The best way to demonstrate the association between recent GABHS
infection and PANDAS symptoms is documented by a rapid increase in
antistreptococcic titers and associated with symptom exacerbation. Because titers may remain elevated for months, it is also important to
demonstrate that a decrease in titers is associated with symptom resolution or improvement, which tends to occur more slowly; however, a lack
of evidence for a recent GABHS infection may not preclude the diagnosis
SCHNEIDER et al
Table 1. INCLUSIONARY CRITERIA FOR PANDAS

Inclusionary Criteria
Pediatric onset
Presence of OCD or tic
disorder
Episodic course of
symptom severity
Association with GABHS

infection
Association with neurologic

abnormalities
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.
of PANDAS. This is based on our knowledge of immune responses.

Primary immune responses are specic and slow, whereas secondary
responses may be more generalized and rapid. Thus, it is possible for
other illnesses, such as viral infections, to trigger symptom exacerbations. Fourth, children with PANDAS commonly have other associated
symptoms, which has led to speculation as to whether the denition of
PANDAS symptoms should be altered to reect these (Table 3).10, 24, 39
Investigations in the workup of a child who presents with OCD or
tics with an abrupt onset include a thorough medical history, followed
possibly by antistreptococcic titers or a throat culture. Some children
who have GABHS infection may not have a sore throat; rather, they may
Table 2. DOCUMENTATION OF RECENT GABHS INFECTIONS

Method
Comments
Positive GABHS throat culture
A positive throat culture is not sufcient evidence of a

recent GABHS infection, since some children may
simply be carriers of GABHS (i.e., carrier positive
throat culture without accompanying titre rise, or
lack of immune response).
Rising or elevated ASO or anti-DNAse-B titres is
indicative that a GABHS infection has occurred.
However, only an increase in titres is indicative of a
recent GABHS infection.
Rise in antistreptococcal titres

ASO
Anti-DNAse-B
ASO titres typically increase 36 wk following

GABHS infection.
Anti-DNAse-B titres typically increase 68 wk
following GABHS infection.
Some GABHS infections may stimulate an increase in
only one of these titres.
Prompt antibiotic response may alter or suppress the
expected increase in antistreptococcal titres.
GABHS A -hemolytic streptococci; ASO antistreptolysin O; anti-DNAse B antistreptococcal deoxyribonuclease-B.
present with the triad of headache, stomachache, and fever.39 Based on

preliminary neuroimaging research using the MRI, it is suggested that
the basal ganglia of patients with PANDAS may be enlarged; however,
in the PANDAS workup, the MRI is a research tool and not recommended as part of the clinical investigation.12 There are also proposed
markers for patients who may be susceptible to acquiring PANDAS. A
monoclonal antibody called D8/17 has been found to bind to the surface
of mononuclear cells in a high percentage of patients with rheumatic
fever. How this relates to the disease process is still poorly understood.
The relative frequency of cells bearing this marker seems to be an
inherited trait, suggesting that there may be an inherited susceptibility
to acquiring rheumatic fever. Given the association to the D8/17 in
rheumatic fever, the D8/17 marker has been studied in Sydenhams
Table 3. COMMON ASSOCIATED SYMPTOMS IN PANDAS

Motoric hyperactivity
Impulsivity
Distractibility
Emotional lability
Separation anxiety
Age-inappropriate behavior
Nighttime difculties
Attention decit hyperactivity disorder
Anorexia ?
PANDAS pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection.
10
SCHNEIDER et al
chorea and PANDAS. In a small study of 27 children with PANDAS, 23

(85%) were found to possess this marker, as well as 8 of 9 patients with
Sydenhams chorea (89%), versus only 4 of 24 volunteers (17%).40 In
addition, this marker has been found to exist in a high percentage of
patients with childhood-onset OCD and Tourettes syndrome.18 Despite
these preliminary ndings, D8/17 remains a research tool and is not
recommended in the clinical investigation of children suspected of having PANDAS.
The proposed theory regarding the etiopathogenesis of PANDAS
seems to be determined by both genetic and environmental factors.
Based on a clinical description of the rst 50 cases diagnosed with
PANDAS, a model for the pathogenesis of this disorder developed is
shown in Figure 4.39 This intuitively leads one to deduce that antibiotics
do not affect PANDAS symptomatology because they do not affect the
immune response, but rather target the pathogen; however, clinical
observation has shown that antibiotics (e.g., amoxicillin) have been benecial in improving symptom severity. Currently, clinical trials are underway at the NIMH examining the role of antibiotics in the treatment of
and prophylaxis against PANDAS symptom exacerbations.11 Perhaps
immunologic changes accompany antibiotic response. Based on the
pathogenic theory in Figure 1, immunomodulatory treatments investigated have included plasma exchange, plasmapheresis and intravenous immunoglobulin. Recent investigation of 30 children with PANDAS, randomized to receive intravenous immunoglobulin, plasma
exchange, or placebo showed marked improvements in obsessivecompulsive symptoms, anxiety, and overall functioning at 1 month for
both active treatment groups. Tic symptoms also were improved signicantly by plasma exchange. In 82% of these children who completed 1
Figure 4. Proposed pathogenesis of PANDAS (pediatric autoimmune neuropsychiatric

disorder associated with streptococcoal infection). GABHS group A-B-hemolytic streptoccoccus.
11
year of follow-up, treatment gains were maintained. Perlutter et al,

however, do not support the routine use of immunomodulatory treatments of OCD and tic disorders.25
LYME DISEASE
Lyme disease is caused by the spirochete, Borrelia burgdorferi, transmitted by deer ticks. A single (recognized) tick bite confers a risk for
Lyme disease of approximately 3%.19 In 1999, more than 16,000 cases
were reported in the United States, with more than 90% coming from
just nine states, in the Northeast (i.e., Connecticut, Rhode Island, New
York, New Jersey, Pennsylvania, Delaware, Massachusetts, and Maryland) and the northern Midwest (Wisconsin) (Fig. 5).4 The disease onset
is marked by erythema migrans, a characteristic large spreading rash
with central clearing. More than 90% of individuals who contract Lyme
Disease have had erythema migrans, although the characteristic central
clearing is found in just 40% or less.37 Acute disseminated disease occurs
during the rst month, with the most common symptoms being fatigue
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
(54%), myalgia or arthralgia (44%), headache (42%), fever or chills (39%),

and stiff neck (35%).20 In 20% of persons infected with B. burgdorferi who
do not receive antibiotic treatment, no other symptoms beyond erythema
migrans develop. Fifty percent of infected persons develop secondary
skin lesions similar to the primary erythema migrans. The description
of acute Lyme disease as ulike is misleading because Lyme disease
does not include any cough, sore throat, or other symptoms of upper
respiratory tract infection.27
If untreated, Lyme disease may disseminate to other organs and
produce subacute or chronic disease. Subacute symptoms developing
over months can include arthritis, secondary skin lesions, carditis, and
neurologic symptoms.27 The arthritis typically affects just one or a few
joints, most often the knee (60% of patients). Neurologic symptoms
occur in approximately 15% of patients and may include cranial neuropathies (most often the facial nerve, i.e., a Bells palsy), meningitis, or
painful radiculopathy.16 Carditis, typically manifested by conduction
disturbance, occurs in 5% to 10% of these patients. If still untreated,
patients may develop chronic complications, including dermatitis; arthritis; and neurologic and psychiatric disturbances (chronic neuroborreliosis), including a mild sensory radiculopathy, cognitive dysfunction, or
depression. Typical symptoms of chronic Lyme encephalopathy include
difculty with concentration and memory, fatigue, daytime hypersomnolence, irritability, and depression. Rarely, Lyme disease has included
chronic encephalomyelitis. Although these chronic syndromes are not
distinctive, they are almost always preceded by the classic early symptoms of Lyme disease, such as erythema migrans, oligoarticular arthritis,
cranial neuropathy (most often facial palsy), or radiculopathy.
Many different psychiatric symptoms have been reported to be
associated with Lyme disease, including depression, mania, delirium,
dementia, psychosis, obsessions or compulsions, panic attacks, catatonia,
and personality change6, 43; however, causality by Lyme disease has not
been clearly established for most of these symptoms. As discussed later,
a diagnosis of Lyme disease should not be made on the basis of positive
serologic testing alone. In many of the case reports, positive serology
(with or without a classic history of Lyme disease) may be coincidental.
Although higher rates of depression have been found among patients with chronic Lyme disease compared with normal controls, the
same association has been reported for many medical disorders. Association does not allow one to infer causation. In a recent study, evaluation
of patients with Lyme disease at 10- to 20-year follow-up showed no
signicant differences in symptoms or neuropsychological testing compared with normal controls; however, patients who had had acute facial
palsy but did not receive antibiotics had more sleep difculty and joint
pain compared with antibiotic-treated patients.13 The clearly established
causal relationship between another spirochetal disease, syphilis, and
psychopathology makes the possibility of B. burgdorferi causing psychiatric syndromes an area of great interest and controversy.
In chronic neuroborreliosis, cerebrospinal uid abnormalities occur
13
in more than 50% of patients, including increased cerebrospinal uid

protein and the presence of antibody to the organism. Electroencephalography is typically normal, whereas MR imaging shows white matter
lesions in approximately 25% of patients with neuroborreliosis. Neuropsychological assessment is useful in documenting and quantifying the
cognitive dysfunction found in chronic neuroborreliosis. Although it is
considered sensitive to cognitive dysfunction in chronic Lyme encephalopathy, the ndings are not specic.28 Positron emission tomography is
also not sufciently specic to be useful in diagnosing neuroborreliosis.
The differential diagnosis of neuroborreliosis in a patient presenting
with fatigue, depression, or impaired cognition includes bromyalgia,
chronic fatigue syndrome, other infections (e.g., babesiosis or ehrlichiosis), somatoform disorders, depression, autoimmune diseases, and
multiple sclerosis.6, 27, 43 Unfortunately, Lyme disease has been grossly
overdiagnosed in patients with nonspecic cognitive, affective, or other
psychiatric symptoms. As mentioned earlier, numerous cases have been
reported in the literature attributing a wide variety of psychiatric symptoms to neuroborreliosis, basing the diagnosis on positive serologic
testing. For reasons outlined later, this is inappropriate. Adverse consequences of overdiagnosis include reinforcement of somatization and
the creation of invalidism. Overdiagnosis leads to overtreatment. The
diagnosis of an infection that can be treated with antibiotics can be very
appealing to patients for whom depression or somatoform disorder are
unacceptable diagnoses, leading to inappropriate diagnostic procedures
and inappropriate treatments, especially extended prescription of antibiotics for a putative chronic CNS infection. Chronic antibiotic prescription
is not benign and leads to secondary infections (e.g., thrush and Clostridia
enteropathy; this latter complication has occurred frequently enough
to have been dubbed Lyme colitis). Even in patients with classic
symptomatic Lyme disease conrmed by serologic testing, if they have
received adequate antibiotic therapy, persisting symptoms usually are
explained by some illness other than chronic borreliosis. Although symptoms such as pain, fatigue, and difculty with daily activities are common among patients treated for Lyme disease years before, the frequencies of such symptoms are similar in controls without Lyme disease.33
Two recent controlled trials found no benet of intravenous ceftriaxone
for 30 days, followed by oral doxycycline for 60 days, in patients with
well-documented, previously treated Lyme disease who had persistent
pain, neurocognitive symptoms, or dysesthesia, often with fatigue.14
Lyme disease is a clinical diagnosis based on the characteristic
clinical features. Serologic testing can support a diagnosis of Lyme
disease, but the diagnosis should never be based on serology alone.1, 7, 27
Serologic testing is a two-step process with an initial ELISA test. If the
ELISA test is positive, it must be conrmed with a western blot test
because the frequency of false-positive results with ELISA testing is
high. Several limitations of serologic testing must be kept in mind. Both
tests may be negative early in infection. Early successful treatment with
antibiotics may block the development of an antibody response so that
14
SCHNEIDER et al
subsequent serologic testing is falsely negative even though the patient

really had Lyme disease early on. False-positives occur in other infections and with various autoimmune diseases. Finally, even a true-positive is not correlated with time or activity. In other words, a true-positive
test indicates that the patient has had Lyme disease at some point in his
or her lifetime, but no conclusion about current disease activity or extent
of infection can be drawn.
Treatment of acute Lyme disease is straightforward. Oral doxycycline or amoxicillin for 2 to 4 weeks is highly effective. For neuroborreliosis, intravenous ceftriaxone is recommended for 2 to 4 weeks. With
both regimens, complete recovery is the goal.27 Neither serologic testing
nor antibiotic treatment is cost-effective in patients who have a low
probability of having the disease (i.e., nonspecic symptoms and low
incidence region).21
Because the risk for contracting Lyme disease from any single tick
bite is quite low, antibiotic prophylaxis is not recommended after a tick
bite; however, a single, 200 mg dose of doxycycline given within 72
hours of the bite almost eliminates even the small risk.19 Individuals
engaging in higher-risk activities (e.g., camping or forestry work) in
endemic areas, especially during spring and summer, should cover up
and use adequate insect repellents (e.g., DEET). A vaccine has been
developed that provides 50% to 70% effective protection during the rst
year, increasing to 75% to 90% protection during the second year.27, 35, 38
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
0193953X/02 $15.00 .00
THE USE OF
ELECTROENCEPHALOGRAPHY
IN PSYCHIATRY OF THE
MEDICALLY ILL
John Michael Bostwick, MD, and Kemuel L. Philbrick, MD
The electroencephalogram (EEG) is one of the oldest tools in clinical

psychiatry. As the new millennium dawns, however, it is worth considering whether the EEG is also one of the most irrelevant. Although focal
electrical abnormalities can point to localized lesions, particularly when
acute, the advent of CT scanning in the 1970s and MR imaging in the
1980s has rendered EEG essentially obsolete as a diagnostic tool for
assessing structural damage.1 EEG still has significant merit in the medicalsurgical setting, however, even as the medical psychiatry literature
remains largely silent about it. This article offers guidelines to help
psychiatrists determine appropriate situations in which to request EEGs
and provides some ideas about how to understand and apply the information that comes back in the EEG report. It is not a primer on interpreting EEG tracings. In the authors opinion, the busy medical psychiatrist
best leaves that to the EEG technician.
Developed in the early twentieth century as a noninvasive method
for investigating both cerebral function and structure, the EEG was, for
decades, standard in the workup of brain disease.1 Despite poor sensitivity and specificity for identifying particular clinical conditions, it was
the only tool short of surgery and direct visualization of the brain that
reliably delivered information on the cerebral parenchyma. As a result,
a large body of literature exists, attempting to make pathognomonic
sense of the electrical tracings gathered from many clinical conditions.
From the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota

17
18
BOSTWICK & PHILBRICK
EEG failed as a diagnostic tool of functional alteration on many

grounds, however. Multiple studies of general psychiatric and healthy
populations debunked its value as a screening tool.2, 5, 8, 13 Not only do
most psychiatric conditions not have specific electrical patterns associated with them, but also nonspecific abnormalities appear on tracings
from both the psychiatrically ill and the well. Among healthy subjects,
10% to 15% have some EEG abnormalities.4, 9 In one study, 20% of
patients with bipolar disorder had marginally abnormal EEGs. One
fourth of patients with schizophrenia, and half of individuals with
sociopathy, had tracings with nonspecific abnormalities.9 Moreover, in
most general psychiatry cases, EEG adds nothing to the diagnostic
impression. In a review of 190 inpatient psychiatric charts of patients
who have had screening EEGs, Warner et al13 found that 36 of the
screening tracings contained abnormalities, but that only 2 of 36 provided additional information that resulted in a different diagnosis from
that based on non-EEG data alone.
To appreciate the value of EEG, it is necessary to understand its
limitations. Neylan et al10 summed them up as follows:
The EEG is a nonspecific indicator of cerebral function. Any pathophysiological insult to the central nervous system can result in alterations in
electrophysiology. Thus, with few exceptions, the EEG does little in providing a precise diagnosis. EEG abnormalities are most pronounced with
acute injuries of the outer cortex. Disorders that affect deep brain structure
or result in a chronic, indolent loss of neurons may show little or no
EEG changes.
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
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.
19
Case 1: Postoperative Delirium Versus

Problematic Personality
Mr. G. was a 62-year-old man who had undergone hip-replacement surgery
2 days prior. Before surgery, he was irascible and demanding. Since surgery, he
had demonstrated more of the same behavior, with the addition of the following
symptoms: instructed to remain in bed, he was found, on several occasions,
hobbling around his room despite his unstable hip; and, when interviewed
about his rehabilitation plans, he failed to pay attention, finally answering a
question about whether he would need a hospital bed after discharge with, the
skew of the angle interferes with the formation of the committee. The orthopedics team asked the psychiatrist whether Mr. G. was crazy. The psychiatrist
opined that Mr. G. probably had a challenging premorbid personality, and his
problem now was likely delirium in the context of general surgery and anesthesia. An EEG showed a grade 2 generalized dysrhythmia consistent with toxicmetabolic encephalopathy.
For the psychiatrist working in the medical-surgical setting, the EEG

remains an economic and generally available tool for assessing brain
activity.9 An abnormal EEG tracing in conjunction with a negative MR
imaging or CT study illustrates a truism often forgotten in this age of
exquisitely detailed imaging studies: All cerebral abnormalities cannot
be seen in the conventional sense. Even when an abnormality is
visible, it must be correlated with a functional measure, either from
history or clinical examination or another study. His words still true 2
decades after he wrote them, Itil6 reminds us that, the EEG is still the
only method able to provide information on cerebral function in a
continuous and noninvasive way that is also cost-efficient.
Medical psychiatrists work in situations in which many of their
patients have psychiatric presentations or acute mental status changes
secondary to brain dysfunction induced by a primary medical or surgical
condition. Fenton4 notes the value of the EEG as a noninvasive tool for
the investigation of organic mental syndromes and epilepsy. Lam et al8
broaden its applicability to include exploration of symptoms that mimic
psychiatric disorders but actually result from iatrogenic, metabolic, or
nonconvulsive seizure disorders. EEG is ideally suited to detect encephalitides, particularly herpes simplex encephalitis, with its pathognomonic periodic high-voltage, sharp waves and slow-wave complexes at
two to three per second in the temporal regions, and rapidly progressive
dementias, such as subacute sclerosing panencephalitis and CreutzfeldtJakob disease, with their characteristic periodic, high-amplitude bursts.
While causing localized slowing detectable on EEG, cerebrovascular
accidents and space-occupying lesions, such as tumors, typically are
identified these days on CT or MR imaging. As time passes from the
stroke, the EEG tends to normalize. Deep lacunar infarcts may never
register at all on a scalp tracing. If a tumor grows slowly or degenerates
insidiously, as in Alzheimers disease, the EEG may show little, if any,
change.2
Until specific anatomic or physiologic causes have been ruled out,
20
the depression, anxiety, psychosis, or conversion disorder that

commonly earns the medical-surgical patient a psychiatry consultation
initially should be regarded only as a phenotype consistent with mental
illness. Medical psychiatrists must convince themselves that there is no
cause for the abnormality other than the psychiatric condition.
Case 2: Iatrogenic Seizures versus Conversion Disorder
Ms. W was a 33-year-old woman with a complex medical history that
included congenital connective tissue disease, pheochromocytoma, and frontal
meningioma, the latter two in the context of von Hippel-Lindau syndrome. She
was admitted to a general neurology service for evaluation of multiple seizurelike events and was behaviorally polymorphous in presentation since having
gamma knife surgery for the meningioma 1 year ago.
Ms. Ws initial EEG failed to show epileptic activity, and her spells were
neither stereotypic nor classic in their description. In terms of her psychosocial
history, moreover, she and her estranged husband were engaged in an emotionladen custody battle, and she had multiple blood relatives with diverse psychiatric diagnoses. Given all of these factors, the neurology service consulted the
psychiatry department to rule out conversion disorder with pseudoseizures as its
manifestation. After ascertaining that Ms. W herself had no previous psychiatric
history and no characteristics of the typical conversion-disordered patient, the
psychiatrist encouraged the neurology team to pursue extended observation.
After several days off antiepileptic medication, while on continuous EEG monitoring, Ms. W had a grand mal seizure that resembled her presenting spells and
originated from the gamma radiation scar at the meningioma site.
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
21
Variable findings, therefore, unhelpful

Cerebral infarctions
Head injury
Acute psychiatric symptoms in a patient with a known neurologic
diagnosis, such as epilepsy or multiple sclerosis, especially call for an
EEG investigation. New-onset mental status abnormalities or localizing
neurologic signs also point to conditions that should be considered
functional only after the organic workup, including EEG, is negative.
An abnormal EEG may raise suspicion of a previously unsuspected
abnormality. Paradoxically, the key to clarifying the following case
turned on the EEG finding demonstrating why the psychiatrist could
not induce a desired seizure. The EEG findings also led to additional
investigations that revealed heretofore undiagnosed pancreatic and hepatic disease.
Case 3: Hepatic Encephalopathy Versus Recurrent
Major Depression
Mrs. A, an 80-year-old woman with a history of diabetes mellitus, recurrent
major depression, and remote ovarian cancer, was admitted to a medical psychiatry unit after failure to respond to adequate antidepressant trials. Having responded to electroconvulsive therapy (ECT) in the past, she consented to receive
ECT once again; however, a seizure could not be induced on several successive
days, even with the deployment of maximum energy, hyperventilation, an extender, and a change in anesthetic agents. Meanwhile, she became increasingly
withdrawn, mute, and disinterested in oral intake. Hoping to clarify whether
she had slipped into an apathetic, hypoactive delirium versus nihilistic progression of depression, an EEG was performed and demonstrated diffuse, generalized slowing consistent with metabolic encephalopathy. Additional laboratory
studies yielded elevated liver function tests. A liver sonogram revealed a large
pancreatic mass with metastases to the liver.
In ordering the EEG, medical psychiatrists must keep in mind

certain recommendations and caveats. In the setting of delirium, the
EEG is almost always abnormal if the patient has an altered level of
consciousness. Not only does the degree of EEG change correlate with
the severity of the encephalopathy, but also EEG changes reverse as the
causative condition resolves, thus permitting serial EEGs to track response to therapy.3 Complicating matters, however, is that an EEG may
be read as normal, relative to general parameters, when it actually
represents a change for that particular patient. Although an individuals
rhythm is consistent at one frequency, normal value can range from 8
to 13 Hz. Thus, a normal value for one patient may represent significant slowing for another. As a result, the presence of slowing as the
result of a syndrome such as delirium cannot be definitively inferred
without a baseline EEG for comparison to health.1, 11
Events such as seizures are typically sporadic, with the EEG tracing
normal between events. A normal EEG never excludes any clinical
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.
Detecting seizure disorders often requires technical adjustments as

well. Activating procedures and yield-enhancing techniques include the
following:
Activating Procedures
Hyperventilation
Photic stimulation
Sleep
Drug administration
Yield-enhancing Techniques
Alternate electrode placement
Replication of patient-specific provocations
Minimization of confounding variables (e.g., medications)
A single interictal tracing is normal in 20% of patients with absence
seizures and 40% with grand mal seizures.1 Serial tracings eventually
may show the suspected seizure, but the patient can be prepared both
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
sufficient time period without artifact or confounding factors present?

Does the report note that tracings were obtained with the patient asleep
as well as awake? If abnormalities are mentioned, are they generalized
and symmetric, indicating global dysfunction, or focal and asymmetric,
suggesting a specific site of injury? Are there general patterns of either
slowing, suggestive of encephalopathy, or acceleration, typically associated with sedativehypnotic or alcohol withdrawal? Are there focal
abnormalities, such as the spikes characteristic of seizures, or patterns
pathognomonic for particular encephalitides? Did the EEG technician
correlate any electrical aberrations with clinical history?
The EEG, finally, serves a useful purpose in resolving debates that
occur with unfortunate frequency in a medical environment that, nearly
400 years later, has still not bridged Descartes mindbrain split. When
Miss X suddenly began to exhibit bizarre behavior, as described in the
following case, it was the EEG that revealed the anatomic and physiologic underpinnings of the behavioral change.
Case 5: Frontal Lobe Status Epilepticus Versus
End-of-Life Personality Changes
Miss X was a 58-year-old woman who had been fighting breast cancer for
7 years. She had had a mastectomy, chemotherapy, and radiation over the
multiple recurrences of the disease, but its latest manifestationmeningeal
metastaseswas the most dire. The latest cancer recurrence had made planning
for the end of her life a prominent concern. She was undergoing palliative
whole-brain irradiation and discussing hospice placement with her inpatient
oncology team when her mental status dramatically changed. Where she had
formerly been practical, no-nonsense, and intimately involved in organizing her
care, she becameovernightuninterested in the details of her hospice care
plan. As if a switch had been turned on, she suddenly waxed grandiose, vague,
expansively spiritual in terms that fit no known religious practice. She intoned
in poetic and dramatic terms about the universe and her place in it but seemed
unable to discuss these ideas with an examiner who found it difficult even to
make eye contact with her as she gazed off into the middle distance. A neurologist and psychiatrist were consulted. The neurologist found nothing untoward
in her presentation and adamantly refused to authorize the EEG that the psychiatrist wanted, until the patient had a partial complex seizure witnessed by a
member of the neurology team. The patient was found to be in frontal-lobe
status epilepticus, a finding that explained her abrupt mental status change.
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
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
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
0193953X/02 $15.00 .00
PSYCHIATRIC CONSEQUENCES
OF MOTOR VEHICLE ACCIDENTS
Richard A Mayou, BM, BCh, MA, MSc, MPhil
THE SIZE OF THE PSYCHIATRIC PROBLEM

The World Health Organization has estimated that, by 2020, motor
vehicle accidents (MVAs) will be second only to ischemic heart disease
as a cause of years of life lost and third as a cause of disability after
ischemic heart disease and depression.52 This challenging public health
problem is at least as great in underdeveloped as in Western countries
because poor roads and bad driving result in very high MVA rates. This
problem is particularly difcult because of the large numbers of victims,
many of whom are not in contact with continuing medical care. The
forecast for 2020 is based on the estimated consequences of major physical injury and takes no account of the now compelling evidence of the
psychiatric impact of MVAs causing no physical injury. The lack of
awareness of the scale of disability has been accompanied by a lack of
recognition and lack of treatment in everyday clinical practice. It must
be an urgent task for psychiatry of the medically ill to promote the
understanding of the psychologically determined consequences of being
in an MVA and the ways in which they can either be prevented or
can be recognized and treated. This means educating nonspecialists;
providing information to victims, lawyers, and insurers; and providing
mental health care services.
Many of the psychiatric consequences of MVAs are similar to the
Unpublished work described in this article was supported by The Wellcome Trust
grant nos. 039203 and 048431.
From the Department of Psychiatry, University of Oxford, Oxford, United Kingdom

27
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consequences of other acute medical problems42 and include the whole

range of psychiatric disorders and their effects on the perception of
physical symptoms (e.g., pain) and on everyday life for the victim and
relatives. In addition, specic consequences relate to the nature of the
traumatic event. Before 1993, there were no more than case reports and
brief series57; since that date, the number of prospective studies has
increased. Although based on samples recruited in rather different ways
and with varied methodologies,5 it is evident that psychiatric complications are common and not closely related to the extent of any physical injury.
Research has largely focused on posttraumatic stress disorder (PTSD),
but other psychiatric disorders are also frequent. Studies of psychiatric
morbidity following MVA should be considered alongside other literature
on the psychiatric consequences of traumatic head injury, whiplash neck
injury,38 and seeking compensation. In addition, a small amount of literature of mixed quality reports on disability after different types of MVA
injury; for example, Holbrook et al30 have shown that disability after
multiple injuries is not closely related to physical impairment.
PSYCHIATRIC FACTORS CAUSING
MOTOR VEHICLE ACCIDENTS
The psychological factors that contribute to the causation of MVAs
include48:
Alcohol and other substance abuse
Major psychiatric disorder
Dementia
Depression
Schizophrenia
Prescribed medication
Attempted suicide and suicide
Personality disorder
Sleep disorder
It is likely that these factors also increase the risk for post-MVA
complications. The psychiatrist working in medical settings must be
alert to these factors in assessing any MVA victim because these factors
may require specialist treatment; alcohol abuse is of particular importance. Although the authors experience is that suffering an MVA (and
any legal penalties) has little salutary effect on drivers who were intoxicated with alcohol, it may nonetheless be an opportunity for brief and
effective intervention.
PSYCHIATRIC CONSEQUENCES
The Consequences of Head Injury
Severe brain damage is uncommon but may have permanent consequences often associated with other long-term medical problems (see
PSYCHIATRIC CONSEQUENCES OF MOTOR VEHICLE ACCIDENTS
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.
Immediate Psychological Reactions

It has long been a lay and medical belief that trauma victims
commonly suffer shock, but it is only very recently that there has
been systematic evidence.8 This, current interest in the later psychiatric
consequences has led to proposals for a specic acute syndrome.
ASD is dened in very different ways in the DSM and ICD-10.
Research has concentrated on the former denition. DSM sees this as
very similar to PTSD but occurring within one month after exposure to
an extreme traumatic stressor but places more emphasis on dissociative
symptoms. ICD uses the heading acute stress reaction to refer to a
severe but transient disorder in which the symptoms usually begin to
diminish after 2448 hours and are usually minimal after about three
days. ASD is common immediately after an MVA and is predictive of
later PTSD.26, 31 For example, Harvey and Bryant26 found that 78% of
patients who initially met criteria for ASD suffered PTSD 6 months later;
so did those with subclinical ASD (without dissociative symptoms). ASD
is not closely related to the nature of any physical injuries but is predicted by cognitive variables relating to the MVA perception and the
immediate reaction.8, 31 Adjustment disorder is also common.
Another immediate response of those who believe that they were
the innocent victims of bad behavior by others is anger, an emotion that
often persists and may be increased by subsequent events, including the
frustrating progress of legal procedures. Anger is associated with an
increased risk for psychiatric complications described later. It is likely
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that it can be diminished by sympathetic medical care and by early

treatment of psychiatric complications.
Later Psychiatric Complications
Current wider psychiatric interest in PTSD has led to some overemphasis about its signicance after MVAs compared with three other
types of psychiatric complication: (1) specic phobia about travel, (2)
general anxiety, and (3) major depression. These often overlap but may
occur alone or in any combination. Differences exist in their pre- and
immediately post-MVA predictors, their phenomenology, their treatment, and their prognosis.
PTSD has consistently been reported in all recent studies of MVA
victims.3, 20, 28, 39 Reported prevalence has varied over a wide range, but
review suggests a probable prevalence of approximately 20% to 25%
within the rst year after the MVA. Prevalence is highest in the early
months, slowly decreasing over a period of years.43 A number of cases
reported at later stages are of delayed onset. For example, in the authors
large, prospective study of consecutive attenders at an accident and
emergency department (ED), the prevalence of PTSD among 967 consecutive patients who attended an emergency clinic shortly after an MVA
was 23.1% at 3 months and 16.5% at 1 year.20 Just over 6% who did not
meet PTSD criteria at 3 months reported PTSD at 1 year. In a further
follow-up, the author found that the prevalence of PTSD at 3 years
was 11%.
Specic phobia about travel is also common and can be very disabling. Many MVA victims are more cautious about travel and more alert
to the behavior of other drivers and road users.45, 47, 57 Avoidance of
driving and of any reminders of MVAs is commonly reported. These
consequences include:
Increased alertness to other drivers
Caution when driving
Anxiety about travel
Change to safer vehicle or methods of travel
Avoidance
Travel situations similar to that of the MVA
Place of the MVA
Reminders of the MVA
Radio and television programs about accidents
Although phobic avoidance is a part of PTSD, patients who satisfy
criteria for specic phobia are an overlapping group, many of whom do
not describe intrusive thoughts.40, 57 In the authors prospective study,
22% suffered phobic anxiety disorder at 3 months, and 17%, at 1 year.
Phobic travel anxiety that satises diagnostic criteria commonly is
associated with severe limitations of travel that may greatly interfere
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.
OTHER PSYCHIATRIC COMPLICATIONS

The characteristics of general anxiety and depression40 are similar
to those occurring after other acute medical events and indeed stress in
general. Although major depression is less common than the specic
posttraumatic disorders, it may be severe and is often unrecognized.
Chronic, untreated depression is a common nding among patients who
undergo medicolegal assessment.
SOCIAL, FINANCIAL, AND FAMILY CONSEQUENCES

Social difculties in work, leisure, and everyday activities partly
reect the nature of the injury and also the severity of any travel
anxiety.38
Involvement in an MVA commonly has nancial consequences even
for those who have adequate insurance and who eventually obtain
personal-injury compensation.39 Such benets are usually long delayed
and are rarely substantial compared with the degree of loss. Financial
difculties are especially likely to be problematic in that many MVA
victims are young and do not have secure careers, homes, or family life
to cope with unexpected losses and an uncertain future.
MVAs can have marked effects on families regardless of whether
relatives were involved in the MVA. Relatives mental state, relationships, quality of life, and nancial and social circumstances all may be
affected adversely.
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:
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Previous psychological status

Accident threat
Severe medical injuries
Immediate severe distress and dissociation
Later psychological maintaining factors
Involvement in compensation proceedings
Continuing medical problems
Analyses of predictive factors for PTSD2, 4, 20 suggest that ndings
are consistent with those reported after other types of trauma.6 The most
powerful predictors at baseline relate to previous personality, perception
of the threat of the MVA, and the immediate emotional reaction. Later
maintaining factors include cognitive variables, continuing medical
problems, and involvement in compensation proceedings. Factors relating to the nature and severity of the injury are largely unimportant.
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.
Severity and Type of Injury

Apart from the most severe injuries, the type and severity of physical injury seems to be of little signicance as a determinant of long-term
psychosocial outcome.38 Overall, people with minor or no injuries have
similar outcomes to those with more major injuries, such as fractures or
severe soft tissue injury. This is consistent with the observation that
the greatest proportion of long-term disability after MVA is caused by
psychiatric complications of MVAs that are regarded as having medically
trivial consequences.
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
Immediate Emotional Reaction

Victims who are initially distressed or report dissociative symptoms
generally have a poorer outcome. As discussed earlier, ASD is a powerful predictor of later PTSD.
Maintaining Factors
Later events and processes are important in determining the course
of the psychological and other consequences. The maintaining factors
for PTSD (listed earlier) are all associated with an increased risk for
slower and less satisfactory psychological and physical recovery and include:
Cognitive variables. Beliefs about the meaning and implications
of the MVA and of persistent physical and psychological symptoms, such as thought suppression and rumination, anger, and
negative views of the long-term signicance of intrusive recollections, are all important predictors.
Continuing physical problems and their treatment. These act as
continuing reminders of the MVA and the emotions that it evokes
and thereby powerfully maintain psychological complications.
Litigation. Although conscious malingering and exaggeration are
uncommon, the frustrations and uncertainties of seeking compensation for personal injury seem to contribute to the psychosocial
determinants of outcome (see subsequent discussion).
COMPENSATION AND LEGAL PROCESSES
Argument about the signicance of compensation in relation to
recovery from personal injury has been long and acrimonious,36 especially in relation to chronic whiplash syndrome (see subsequent discussion). The author has followed up compensation claimants in two studies
of MVA victims. In the rst, he interviewed victims seeking compensation over a period of 6 years7; in the second, a large, prospective study,
the author has much less information for a larger number of people over
a period of 3 years.20 In both cases, it is striking that the outcome for
victims seeking compensation is very similar to that of victims who did
not seek it. Detailed review36 suggests that many victims who do not
seem to have been responsible for the MVA are not notably keen to
pursue compensation, and a very small number seem to behave in any
way so as to increase their likelihood of nancial gain. Research suggests
that deliberate, conscious behavior is uncommon; however, it does seem
probable that legal and insurance procedures and the whole pattern of
medical and other care after an MVA maintain both symptoms and
disability.12
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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.
PAIN AND PHYSICAL SYMPTOMS

Physical complaints, mainly musculoskeletal pain, are reported to a
much greater extent than might be expected from the trivial nature of
most injuries. For example, in the authors prospective study of consecutive attenders, 80% of victims suffered injuries classed in the ED as
medically minor, but at 1 year, 5% reported major physical problems,
and 39%, minor problems. Review of all available information suggests
that very few victims, probably approximately 1%, experienced persistent distress and disabling chronic pain that could be diagnosed as
somatoform pain disorder.
The predictors of pain38 in the authors series were largely psychological and social; injury variables made a small contribution at 3
months, but they were not statistically signicant at 1 year. These ndings of the interaction of psychological and physical variables are very
similar to those that have been described for back pain18 and other pain
syndromes. Arguments as to whether (1) pain causes psychological
distress or (2) distress is a cause of pain are unproductive in that
longitudinal evidence after MVAs and experience with other pain syndromes indicates two separate aspects of outcome that interact over time.
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
Chronic Whiplash Syndrome

Whiplash neck injury has attracted particular attention and controversy.37, 41 Despite the many assertions about the role of psychological
and social factors as causes of chronic whiplash pain and disability, little
prospective research has been performed. The few published studies
indicate that whiplash victims suffer patterns of psychiatric and other
complications similar to those described for MVA victims in general.38 It
may well be that the handicap and subjective severity of neck pain are
affected by psychological variables, but there seems to be no reason to
doubt an underlying pathology, the severity and course of which may
well be affected by secondary postural and behavioral effects of the
MVA and early symptomatology.
Also increasingly clear is that the nature of medial and legal systems
and of compensation procedures have important consequences. Thus,
the combination of an uncertain, bewildered, and angry MVA victim,
vague and cautious medical advice, and a frustrating compensation
procedure is likely to greatly increase the risk for severe, long-term
distress and disability. The signicance of social issues has been demonstrated by two widely cited studies. Fewer chronic problems have been
reported in Lithuania, where the legal and compensation issues are
insignicant53; improved symptomatic outcome has been reported in
Canada after a change to a no-fault compensation procedure.12
Fibromyalgia
Case reports and medicolegal reports suggest that so-called bromyalgia also can be a complication of MVAs. It is difcult to disentangle
the evidence related to this syndrome, seen very largely in rheumatology
specialist practice, for which no accepted pathology or etiology exists
but for which criteria originally formulated for research purposes exist.
Current evidence suggests that this syndrome is not a separate diagnostic entity60 but represents an extreme of severer and widespread chronic
pain, together with trigger points that are correlated with psychiatric
distress rather than evidence of underlying organic abnormality. It
clearly overlaps with chronic fatigue and other functional syndromes
reported from other medical settings. This view does not in any way
deny the reality of the symptoms, but it makes it impossible to suggest
simple etiologies in terms of simple relationships with trauma or any
other factor. Review of poor-quality prospective evidence does, however,
support clinical experience that bromyalgia-like symptoms may occur
after trauma in previously t people in such a manner as to suggest the
trauma had a key triggering role.61
CHILDREN
Several recent prospective studies have been published about children involved in MVAs and attending hospital EDs.16, 17, 21, 50, 55, 56 Despite
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considerable difculties in recruitment in all of these studies, it seems

probable that the pattern of outcome is generally similar to that described for adults, with a similar prevalence of PTSD. In a recent prospective study,38 the author found that, although only 11% of children
met strict DSM-IV criteria for ASD, one third scored above the recommended cutoff on the Impact of Events Scale. These discrepancies between measures indicate the current problems of denition of ASD and
especially the signicance of dissociative symptoms. One fth of the
children suffered PTSD at either 3 or 6 months, with 16% at 3 months
and 12% at 6 months. Adverse effects on travel were rather more
common, and more than one third suffered specic phobic travel
disorder37% at 3 months and 34% at 6 months.
Families reported considerable distress, and this was especially so
for parents for whom their own involvement in the MVA or receiving
the news of their childrens involvement in an MVA can be seen as a
traumatic event. Twelve percent of mothers met the criteria for ASD,
and 4%, at 3 and at 6 months. Apart from suffering PTSD and other
psychiatric consequences, parents may become anxious about their childrens travel and may impose restrictive rules.
TREATMENT
Awareness of the psychiatric consequences of MVAs has led to a
small number of clinical treatment programs and also to several randomized, controlled trials of psychological treatment, mostly derived from
experience with other types of trauma. Research has largely focused on
PTSD; however, it is clear that treatment provision is totally inadequate
for the scale of the psychological and psychiatric problems.
General Principles
Because of the large numbers of MVA victims, initial treatment in
busy EDs, and a general lack of awareness of the importance of the
psychological issues, the early management of both minor and major
MVA injuries is often rushed and inconsistent. Victims often receive
rather little general information or advice, and follow-up arrangements
may be unclear or involve several different disciplines. Later care of
common problems (e.g., whiplash neck injury) is uncertain. The legal
issues of prosecution for a driving offense and those associated with
personal injury and vehicle insurance claims add further frustration and
uncertainty.
The evidence described in this article indicates that there is a compelling argument for better-organized and more positive care directed
to appropriately rapid mobilization and to the prevention or detection
of psychiatric complications. Such rehabilitation is most effective when
it is informed by behavioral principles and takes account of patients
37
circumstances and beliefs. It may well need to be multidisciplinary and

collaborative, as has been well described for the care of back pain.58, 59
Because systematic review of multidisciplinary physical rehabilitation
programs for those with neck and shoulder pain has found little evidence for effectiveness,33 physicians need to promote more psychologically and behaviorally informed methods of care.
Psychological
It is widely believed that immediate psychological care may prevent
later problems and especially PTSD. Several immediate and intensive
techniques, derived from military experience, have been proposed and
are widely used after disasters for those such as police and ambulance
workers exposed to traumatic experiences and for other groups. Although such procedures, often called critical incident debrieng, have
been, and are still, widely recommended, randomized, controlled trials
after MVAs and other forms of trauma have found them to be ineffective
and indeed probably harmful.46
Cognitive-Behavioral Therapy
In contrast, a small study of a cognitive-behavioral therapy for ASD
found this rather different intervention at a later time than that for
debrieng to be benecial.10 It seems that the carefully controlled methods of aiding information processing enable the reduction of distress, in
contrast to the debrieng, in which memories are expressed and cause
distress but in which no resolution is effected.
Psychological methods involving exposure, cognitive methods, or
combinations of techniques have been evaluated widely and found
useful.14, 22, 23 Most randomized, controlled trials have been small and of
poor quality, however. Preliminary research evidence and considerable
clinical experience suggest that, after MVAs, cognitive-behavioral therapy is effective for PTSD and for associated phobic travel anxiety.29 The
author has found cognitive-behavioral concepts19 to be valuable in pilot
studies and in a current randomized, controlled trial. Improvement in
posttraumatic symptoms is accompanied by improvement in mood and
in subjective experience of pain.
Eye-Movement Desensitization and Reprocessing
It has been argued that eye-movement desensitization and reprocessing (EMDR) is an effective specic treatment.54 Although some
supportive evidence exists, it is highly probable that the value of this
treatment lies in its nonspecic cognitive and behavioral elements rather
than in an alleged specic rationalea rationale that has been heavily
criticized.27 No convincing theoretic or empirical evidence supports the
value of the eye-movement component.
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Psychological interventions are also valuable in the management of

chronic pain.51 It is important that they start early, before secondary
problems become severe; long-delayed treatment for chronic pain is
often unsuccessful, even in the most sophisticated pain-management
programs.
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.
THE CLINICAL PROBLEM FOR PSYCHIATRY OF THE

MEDICALLY ILL
Because most MVA victims suffer only minor injuries, they usually
are not evaluated in EDs; however, they may then attend primary care,
physiotherapy, or other treatment. Even so, there is little continuity, and
in only a minority of cases is there any opportunity for review to detect
persistent psychological complications that might require treatment. Recognition of complications must, therefore, depend on awareness among
those who provide emergency care and follow-up and those who may
be involved in medical care at later stages, together with allied health
professions, such as physical therapists, and of lawyers.
Treatment organization includes:
Sympathetic, immediate care with clear, positive advice
Identication of treatable psychiatric disorder and substance abuse
contributing to the causation of the MVA
Encouragement of mobilization
Handouts with general advice
Early follow-up assessment, regardless of whether signicant physical
39
injury is present, to detect psychiatric complications and chronic

pain
Well-organized psychologically and behaviorally informed continuing
medical and physiotherapeutic care
Access to specialist mental health care
References
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stress disorder from the International Consensus Group on Depression and Anxiety. J
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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
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44. Mayou RA, Black J, Bryant B: Unconsciousness, amnesia and psychiatric symptoms
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Injury 22:365368, 1991
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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
0193953X/02 $15.00 .00
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 (%)
Motor vehicle accidents

Falls
Violence
Sports or recreational activities
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
RAO & LYKETSOS
Table 2. CLASSIFICATION OF HEAD INJURY*

Test
Mild
Moderate
Severe
Glasgow Coma Scale (GCS)

Loss of consciousness (LOC)
Posttraumatic amnesia (PTA)
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.
survive TBI with psychiatric sequelae being central to their morbidity.

Although physical disabilities typically stabilize with time, mood, cognitive, and behavior changes become the more disabling long-term impairments because they frustrate the patient, overwhelm the caregiver, and
challenge the physician. Despite the common occurrence of psychiatric
disorders following TBI, very little literature about their epidemiology,
pathophysiology, and management is available. Almost no randomized
controlled studies about treatments for these psychiatric sequelae are
available.
This article reviews the common psychiatric conditions associated
with TBI, highlighting two features: (1) the link between psychiatry and
TBI and (2) the existing gaps in the literature regarding these disorders.
We begin with a discussion of the pathophysiology and recovery from
TBI. This is followed by classication of the psychiatric disorders associated with TBI and approaches to the evaluation and diagnosis of postTBI patients. We conclude with a discussion of the clinical features and
treatment of the psychiatric disorders.
PATHOPHYSIOLOGY AND RECOVERY
FROM TRAUMATIC BRAIN INJURY
This section is divided into (1) pathophysiology of brain injury and
(2) recovery from brain injury.
Pathophysiology of Brain Injury
Brain injury can be classied into two types, as follows:
A. Primary injury: direct impact of trauma
1. Focal injury
a. Contusion
b. Hematoma
c. Hemorrhage
d. Hypoxicischemic injury
2. Diffuse injury
a. Diffuse axonal injury (DAI)
PSYCHIATRIC ASPECTS OF TRAUMATIC BRAIN INJURY
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
RAO & LYKETSOS
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
RAO & LYKETSOS
of occurrence, duration, and functional dependency as delirium60 or

dementia.10 Similarly, the term postconcussive syndrome has been used
to describe certain presentations. This term is confusing and controversial because it is seen in a number of TBI patients with or without a
concussion. The authors prefer to classify the neuropsychiatric disturbances associated with TBI according to their phenomenology as follows:
1. Cognitive decits, 20% to 80% of patients
2. Mood disorders
a. Major depression, 6% to 77% of patients
b. Mania, 3% to 9% of patients
3. Anxiety disorders, 11% to 70% of patients
4. Apathy, 10% of patients
5. Psychosis, 2% to 20% of patients
6. Behavioral dyscontrol disorder
a. Major variant, 11% to 98% of patients
b. Minor variant, 80% to 100% of patients
The authors have reported this in one an earlier review article.88 The
authors have used the term behavioral dyscontrol disorder to describe a
constellation of cognitive, physical, and emotional signs and symptoms
that can occur together. The authors have subclassied this disorder into
major and minor variants based on the severity of the signs and symptoms. The clinical features of these disorders are discussed later.
Etiology and Risk Factors
for Neuropsychiatric Disorders
The etiology of the psychiatric disturbances after TBI involves interaction of postinjury biological changes, premorbid personality traits, and
psychosocial and environmental factors. Regarding premorbid personality factors, little information about the correlation between the different
personality traits and the post TBI psychiatric sequelae is available. Risk
factors17, 24, 74 for the development of psychiatric sequelae include:
A. Highly signicant risk factors
1. Preinjury history of psychiatric illness
2. Preinjury poor social functioning
3. Increased age
4. Alcoholism
5. Arteriosclerosis
B. Less signicant risk factors
1. Lower Glasgow Coma Scale
2. Lower Mini Mental State Examination (MMSE)
3. Marital discard
4. Financial instability
5. Poor interpersonal relationship
6. Pre-injury levels of education
7. Compensation claims
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.
Epidemiology of the Neuropsychiatric Sequelae

Depending on the study, 10% to 80% of people who sustain a TBI
suffer from a psychiatric disturbance at some point in their recovery
period.111 This wide range in estimates is probably the result of differences in dening various syndromes; lack of standardized diagnostic
criteria; differences in TBI severity among participants; and selection
differences with patients seen in various locations, such as community,
rehabilitation facilities, acute trauma centers, and psychiatric clinics. The
previous list reports the frequency of some of the common disorders.
The authors have listed the lowest and the highest quoted frequencies
so that the reader can get an idea of how common these disturbances
might be.
EVALUATION AND DIAGNOSIS OF

PSYCHIATRIC DISORDERS ASSOCIATED
WITH TRAUMATIC BRAIN INJURY
The psychiatric evaluation of an individual with brain injury should
be comprehensive and includes:
I. History
A. Demographic information
B. Family history of psychiatric illness
C. Personal history
1. Birth and development
2. Childhood health and behavior history
3. Education
4. Pre- and postinjury employment
5. Pre- and postinjury marital status
6. Pre- and postinjury living situation
D. Drug and alcohol history
E. Pre and post injury legal history
F. Medical history
G. Current medications
H. Past psychiatric history
1. History of hospitalization
2. History of outpatient treatment
3. History of self injurious behavior/suicide attempt
4. History of treatment with psychotropics
50
RAO & LYKETSOS
II.
III.
IV.
V.
VI.
VII.
I. Details regarding premorbid personality for collateral informants.

J. History of patient illness
1. Details of head injury
a. Open versus closed
b. Mechanism of injury
c. Glasgow Come Scale at the time of injury
d. Duration of loss of consciousness (LOC)
e. Duration of past traumatic amnesia (PTA)
f. Hospitalization versus outpatient treatment
g. Treatment of surgical or medical complications
2. Details regarding current psychiatric illness
3. Review of old medical records
Mental status examination
Neurologic examination
Brief cognitive assessment (MMSE)
Neuroimaging studies
Neuropsychological tests
Occupational therapy assessment of functional skills and safety
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
CLINICAL FEATURES AND MANAGEMENT

OF PSYCHIATRIC SEQUELAE AFTER
TRAUMATIC BRAIN INJURY
This section provides an only overview of the psychiatric disturbances associated with TBI because it is beyond the scope of this article
to discuss in detail all the different psychiatric sequelae. The reader is
encouraged to read the textbook Neuropsychiatry of Traumatic Brain Injury,
edited by Silver et al96 for more information. This section has been
divided into two parts: (1) general guidelines on the management of
psychiatric sequelae and (2) clinical features.
51
General Guidelines on the Management

of Psychiatric Sequelae
Management of the psychiatric disorders of TBI is both complex
and challenging. Approach to care should be multifaceted and interdisciplinary, with the psychiatrist working in close collaboration with the
other physicians and colleagues of other disciplines. The treatment plan
should be holistic and practical and include (1) pharmacotherapy, (2)
psychotherapy, and (3) caregiver and family education and support.
Rabins et al87 have discussed the essential attributes of a treatment plan
in the care of patients with dementia. The authors suggest using the
same approach to the care of TBI patients with psychiatric disorders.
The essential elements include (1) having a rational and realistic plan
taking into account the severity of head injury, the stage of recovery, the
psychosocial situation, and psychiatric and medical complications; (2)
keeping the plan exible and dynamic according to the changing condition and needs of the patient and family; (3) anticipating problems or
changes and educating patient and family about these; (4) having a
cohesive and comprehensive plan focusing on the many needs of the
brain-injured patient; and (5) instilling hope and emphasizing the importance of maximizing the patients potential and minimizing disability.
This section briey outlines the general principles regarding (1) pharmacotherapy, (2) psychotherapy, and (3) caregiver education and support.
Pharmacotherapy
Knowledge regarding pharmacologic interventions in brain-injured
patients is derived mainly from the authors experience in caring for
patients with primary psychiatric disorders, anecdotal reports, and small
case series studies; however, unlike primary psychiatric disorders, psychiatric symptoms associated with TBI are not always syndrome specic,
and some of them may need to be treated independently. Therefore,
treatment can be aimed at observable symptoms or syndromes, based
on hypotheses regarding biological dysfunction, or both.68 In general,
TBI patients are very sensitive to medications; hence, one should follow
the golden rule of start low and go slow. Other rules include (1)
minimize medications; (2) avoid medications that may have a deleterious
effect on the CNS, such as phenytoin, halperidol, barbiturates, and
benzodiazepines25, 86; (3) monitor serum levels if necessary; and (4) always discuss indications, risks, and benets with patient and family
members. Table 3 depicts the various psychotropics based on their
clinical utility. Arciniegas et al5 have provided an extensive literature
review on the medications useful for the treatment of various psychiatric
disorders following TBI, which the reader is encouraged to read.
Psychotherapy
Psychotherapy is as important as pharmacotherapy in the rehabilitation of patients with psychiatric disorders secondary to TBI. In addition
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
RAO & LYKETSOS
chosis, and behavioral dyscontrol disorder. For each of these disorders,

its denition, prevalence, clinical picture, pathology, and pharmacologic
treatment are described in sequence.
Cognitive Decits
Denition. Cognition may be dened as the sum total of processes
involved in the acquisition, analysis, and management of information.
This includes acquiring data through sensory inputs, analyzing data
using a predened set of criteria, choosing alternatives by weighing the
pros and cons, and executing the chosen option.85
Prevalence. Cognitive decits are very common among TBI patients.
Almost anyone who sustains a brain injury, regardless of the severity,
suffers from some kind of cognitive decit; however, the actual frequency of these decits is unknown. Levin67 reported that memory
disturbance following closed head injury is the most common cognitive
decit; the prevalence ranges from 23% to 79%
Clinical Picture. Cognitive activities include attention, memory, language, abstraction, executive function, and perceptual skills. All of these
activities may be affected in brain injury to a varying degree, with
decits lasting for a variable duration. The common cognitive decits
that persist after the resolution of the acute confusional state and posttraumatic amnesia include disturbances of memory, attention, language,
and executive functions. Each of these decits is briey described.
Memory Disturbances. Memory loss is the most common complaint
of patients after TBI. Quantiable decits occur in both verbal and
nonverbal domains. The immediate postacute TBI phase is often associated with problems in the acquisition and retrieval of new information,
which often resolves as the confusion clears. Persistent memory change
is related to the severity of TBI and the diffuse nature of the injury.
Short-term memory decits, such as misplacing things, inability to recall
recent conversations, or trouble remembering grocery lists, are the most
common complaints during both the early and late recovery phases.
OShanick and OShanick85 found that, after TBI, memory impairment is
greater for effortful rather than incidental memory, with patients
doing better with open-ended questions rather than with ll-in-theblank questions. Neuropsychological tests in brain-injured patients reveal impaired episodic or declarative memory, with relative preservation
of procedural memory.22, 85
Disturbances of Attention. Attentional disorders are also common
in patients with brain injury and often predict return to work.82 Learning
is central for recovery after brain injury, and attention is the principal
component for adequate learning. Selective attention, sustained attention, and divided attention are some of the functions of the attention
system. Patients with brain injury often have problems with sustained
and divided attention.100 They often report problems with concentration,
difculty in focusing, easy distractibility, or inability to focus on more
than one task at a time. In some patients, the attention decit is probably
55
caused by impaired sensory gating or a sensation of shutting off in a

noisy environment.4 The P50 evoked waveform response to paired auditory stimuli is a useful test to measure auditory gating. Arciniegas et al8
compared 20 TBI patients with memory and attention problems to 20
control subjects and found that the P50 ratio was signicantly greater in
TBI patients indicating P50 nonsuppression or impaired gating. Cholinergic dysfunction has been hypothesized to be one of the key factors
responsible for the impaired gating mechanism.4 The Brief Test of Attention93 and the Paced Auditory Serial Addition Test34 are excellent tests
of divided attention, and both have been found to be useful measures
of recovery from brain injury and outcome.
Language Disturbances. Language problems are also common after
TBI and occur with both focal frontotemporal damage and or diffuse
brain injury.80 They may range from minor decits, such as a lack of
spontaneity of speech, to severe forms of expressive, receptive, or global
aphasia. Common language decits include motor and sensory prosodic
dysfunction, word-nding problems, difculty in expressing ideas, dysarthria, and inability to understand sarcasm or follow simple commands.63, 108, 109
Executive Disturbances. Executive function involves planning, organizing, and sequencing; concept formation; abstraction; and set shifting. Patients with executive dysfunction display perseveration, stimulus
bound behavior, concrete thinking, impulsivity, poor initiation, and motivation and a general unawareness of self and others.79
Pathology. Cognitive decits result from both focal and diffuse
cortical brain damage. These are believed to be the results of damage to
the anterior temporal and the orbitofrontal lobes, which are most vulnerable sites for injury secondary to their localization over the bony protuberances of the skull. The severity of cognitive decits depends on the
size and location of injury, the severity of injury, duration of posttraumatic amnesia, brain stem dysfunction, and the degree of diffuse axonal injury.60
Treatment. Dopamine agonists, psychostimulants, amantadine, and
cholinesterase inhibitors have been used to treat disturbances of attention, arousal, memory, and executive functions.8, 58, 102, 110 A single case
report and small case series studies have suggested the benecial effects
of methylphenidate and dextroamphetamine for the treatment of inattention, distractibility, disorganization, hyperactivity, hypersomnia, hypoarousal, and apathy.21, 38 Mood and cognitive improvement was noted in
a double-blind, placebo-controlled cross-over study using methylphenidate.21 The same agent has also been found useful in the postacute
recovery trauma period for the treatment of attention46 and cognitive
and physical function.84
Small, uncontrolled case studies also have suggested benecial effects of dopamine agents. Cognitive and behavioral improvement was
seen in open-labeled trial with L-dopa/carbidopa in 12 moderate or
severe brain-injured patients.61 Bromocriptine was found to be useful in
the treatment of apathy and executive dysfunction.81 Cognitive impair-
56
RAO & LYKETSOS
ment in patients with TBI have been hypothesized to be secondary to

acetylcholine deciency. Case reports are available on the effectiveness
of procholinergic agents to treat memory dects. Goldberg et al32 used
oral physostigmine (1.5 mg) and lecithin (20 g suspended in cranberry
juice) to treat posttraumatic amnesia. Improvement was seen in verbal
but not visual memory. Additionally, the risk for neurologic and cardiovascular side effects is high at this dose, and hence it may not be useful.
Taverni et al102 reported on the use of donepezil, which is a centralacting selective acetylcholinesterase inhibitor, in two patients with memory decits months after they had sustained severe head injury. Both
showed improvement in their memory problems at a dose of 5 mg, 3
weeks after the medication was started. Because cognitive decits are
the most common consequence of TBI, more studies need to be done to
prove the effectiveness, tolerance, and safety of these medications.
Mood Disorders
Disturbances of mood range from transient episodes of sadness or
happiness to persistent periods of low or elevated mood associated
with several neurovegetative symptoms. Major depression and bipolar
disorder are the two most common mood disorders, as described later.
Major depression should be differentiated from demoralization, adjustment disorder, apathy syndrome, and pathologic crying. Similarly, the
differential diagnosis for bipolar disorder includes behavioral dyscontrol
disorder and pathologic laughter.
Major Depression. Denition. Major depression is a persistent,
sustained feeling of sadness associated with neurovegetative and cognitive disturbances, such as changes in sleep; appetite; energy; concentration; interests; and feelings of worthlessness, guilt, hopelessness, or suicide.
Prevalence. The prevalence of major depression after TBI varies
widely because of a lack of standardized criteria in diagnosing depression. Fedoroff et al,24 in their longitudinal study of 66 inpatients with
acute TBI of mild, moderate, and severe degree, reported a cumulative
prevalence of 26% in the rst year after TBI using the DSM-IIIR diagnostic criteria for major depression.
Clinical Picture. The clinical picture of post-TBI depression is similar to that of primary depression. Post-TBI depression may be transient,
lasting for a few days to weeks, or enduring, lasting for months. The
diagnosis of post-TBI major depression is difcult because a number of
symptoms of major depression, such as changes in sleep, appetite, or
libido, could be secondary to the brain injury itself or a nonspecic
reaction to an acute medical illness. Jorge et al41 examined longitudinally
the specicity of depressive symptoms at 3 months and 1 year after
head injury and found that a lack of energy and symptoms related to
changes in self-attitude, such as a lack of self-condence, low selfesteem, feeling of hopelessness, poor interest in surroundings, and suicidal thoughts differentiated the depressed from the nondepressed
57
group. Suicide is of concern in patients with post-TBI depression because

approximately 65% report suicidal ideation.62 No data are available on
completed suicide in post-TBI, depressed patients. Major depression
should be differentiated from demoralization, adjustment disorder, and
apathy (Table 4).
Pathology. A number of studies have suggested that early onset
transient depression may be caused by the disruption of brain physiology associated with the injury, whereas prolonged, persistent depression
is probably a psychological reaction to physical and cognitive impairment.42, 74 Lesions in the left dorsolateral frontal or left basal ganglia
regions have been associated with early onset major depression (13
months after injury) but not late-onset depression (after 3 months of
injury)43; however, more studies need to be done to conrm or refute
this hypothesis. Until then, post-TBI depression should be considered to
have a multifactorial etiology associated with biological, psychological,
and environmental factors.
Treatment. Treatment of post-TBI major depression is very similar
to the treatment of primary depression. Case reports are available on
the successful use of selective serotonin reuptake inhibitors (SSRIs), such
as sertraline23 and uoxetine,11 trazadone;115 buspirone;39, 115 psychstimulants,38, 57 such as dextroamphetamine and methylphenidate; and even
electroconvulsive therapy (ECT).48 Fann et al23 reported improvement in
two thirds of mild TBI depressed patients treated with sertraline in a
single-blind, placebo run-in trial; however, no other randomized, placebo-controlled, double-blind studies support the effectiveness of any of
these medications.
Monoamine oxidase inhibitors and tricyclic antidepressants generally are not favored because of their drug food interactions and anticholinergic side effects. Agents such as venlafaxine and paroxetine have
been used with great success by the authors for the treatment of major
depression and insomnia, even though no studies guide the use of these
agents. ECT may be safely used for the treatment of psychiatric disorders
following TBI. Kant et al48 studied 11 closed-head injury patients with
various psychiatric disorders, such as major depression, mood disorder
secondary to TBI, chronic delirium, and delusional disorder. Eight responded to an index course of ECT; 2, to continuation ECT after the
index course; and 1 was a nonresponder. Cognitive side effects were not
signicant in any of the patients except for the nonresponder. Other
studies also have demonstrated the benecial effect and safety of ECT
in TBI patients with depression.14
Bipolar Disorder. Denition. Post-TBI bipolar disorder is dened
as intermittent periods of major depression and mania. A manic episode
is characterized by periods of persistent elevated or irritable mood
associated with increased energy, racing thoughts, decreased sleep, grandiose ideas, impulsivity, or aggressive behavior.
Prevalence. Literature on TBI-associated bipolar disorder is sparse.
Only case reports or small series studies are available. The largest series
is from Jorge,44 who studied 66 acute TBI patients for 1 year after their
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
Pervasive and persistent

Not always present
Symptoms persist
despite termination of
stressor
Often present
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
Often not present
Often not present
Often global and

persistent
Often global and
persistent
May be present
Present
Decreased
Decreased
Related to the stressor
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
injury. Approximately 10% (6 of 66) met the DSM-IIIR diagnostic criteria

for manic episode at some point during the follow-up. Only 1 met
criteria for bipolar disorder.
Clinical Picture. The symptoms displayed by the six patients who
developed mania secondary to TBI in Jorges study44 included expansive
mood (6 of 6), irritability, increased motor or verbal activity, and thought
disorder (5 of 6) increased sexual interests and aggressive behavior (3 of
6), decreased need for sleep (2 of 6), and grandiose delusions (1 of 6). In
general, the manic episodes lasted for approximately 2 months. Shukla
et al94 reported on 20 mild, moderate, and severe TBI patients referred
to psychiatric clinics for evaluation for mania or schizoaffective disorder.
Eighty-ve percent had an irritable form of mania, and 70% had a
history of assaultive behavior. Psychotic symptoms were found in only
15%. Other symptoms included impaired and decreased need for sleep
(100%), grandiosity (90%), pressured speech and ight of ideas (70% to
80%), and hyperactivity (65%). They found a signicant relationship
between mania and partial complex seizures (40%). Recurrent mania
without depression was found in 70% of patients. It is difcult to
distinguish mania from labile, aggressive, or disinhibited behavior secondary to TBI. Symptoms such as impulsivity, disinhibition, or aggression may be common to the two conditions; however, the core symptoms
of mania include persistent, elevated, or irritable mood; mental and
physical overactivity (e.g., increased energy, decreased need for sleep,
pressured speech with racing thoughts); and grandiose or persecutory
beliefs. Pathologic laughter is another common but less reported condition characterized by inappropriate and uncontrollable laughter outbursts. These outbursts are either not associated with changes in mood
or, if associated, is out of proportion to mood changes. The other neurovegetative symptoms of mania are usually not present.
Pathology. Anterior temporal lesions have been associated with a
greater risk for mania.44 Other studies of secondary mania have revealed
an association with lesions involving the right hemisphere, particularly
orbitofrontal regions, inferior temporal areas, thalamus or basal ganglia.89 No association has been found between mania and other factors,
such as family history of mood disorder, personal history of psychiatric
illness, severity of brain injury, degree of physical or cognitive impairment, social support, social functioning level, or posttraumatic epilepsy.44
Treatment. Literature is sparse in the treatment of mania following
TBI. Valproate or carbamazepine is preferable to lithium; the latter may
cause worsening of cognitive decits.59
Thus, post-TBI mania is relatively understudied despite its substantial frequency. More studies need to be done to elucidate specic risk
factors and to determine lesion location and effective treatment.
Anxiety Disorder
Denition. Anxiety is an intermittent or persistent feeling of apprehension or dread with or without associated cardiovascular, gastrointestinal, or autonomic signs and symptoms.
60
RAO & LYKETSOS
Prevalence. Anxiety is commonly reported after TBI (range, 11%

70%).53, 71 Epstein and Ursano19 compiled 12 studies comprising more
than 1000 head-injured patients and reported an overall prevalence of
anxiety disorder of 29%. Jorge et al,45 in their study of 66 TBI patients,
reported a syndrome of anxious depression in 11%.
Clinical Picture. All types of anxiety disorder including generalized
anxiety disorder, panic disorder, obsessive-compulsiv disorder, and posttraumatic disorder have been reported after TBI57, 73; however, the most
common post-TBI anxiety symptoms include free-oating anxiety, fearfulness, intense worry, generalized uneasiness, social withdrawal, interpersonal sensitivity, and anxiety dreams.71
Pathology. Both right33 and left72 hemispheric injuries have been
associated with the development of anxiety disorders. Jorge et al45 found
anxious depression to be associated with right hemispheric lesions and
major depression, with left-sided brain lesions suggesting that the two
disorders are different in their etiopathology.
Treatment. Small case series studies and anecdotal reports point to
the effectiveness of SSRIs, naltrexone,104 and buspirone39 in the treatment
of anxiety disorders. Antipsychotics25 and benzodiazepines86 should be
avoided secondary to adverse side effects, such as delayed neuronal
recovery, paradoxic rage, and memory impairment. No controlled studies of treatment for anxiety disorders after TBI are available.
Apathy
Denition. Apathy may be a symptom of major depression, delirium, or dementia (secondary apathy), or it may occur in isolation as a
separate syndrome (primary apathy).76 Marin dened primary apathy
as lack of motivation emotionally, cognitively, and behaviorally not
attributable to intellectual impairment, emotional distress, or diminished
level of consciousness.77
Prevalence. Kant et al,47 in a study of 83 patients with closed-head
injury attending a neuropsychiatric clinic, reported the prevalence of
(primary) apathy to be 10% and of apathy in association with depression
(secondary) to be 60% of all patients.
Clinical Picture. Apathetic patients usually do not complain of any
symptoms. They often are brought to treatment by a family member
with the history of laziness. On further questioning of both the patient
and the family member, symptoms such as disinterest, disengagement,
lack of motivation, reduced emotional responsivity, inertia, lack of curiosity, and decreased productivity become apparent. Table 4 compares
apathy to depression and depicts the salient features of these two conditions.
Pathology. Damage to the medial frontosubcortical circuit,15 basal
ganglia, and thalamus9 have been associated with the pathogenesis
of apathy.
Treatment. Psychostimulants, dopamine agonists and amanta-
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
RAO & LYKETSOS
Behavioral Dyscontrol Disorder

Denition. This is a complex syndrome characterized by disturbance in mood, behavior, and cognition. Because the core feature of this
syndrome is dyscontrol of emotion and behavior, the authors have
provided the term behavioral dyscontrol disorder. The authors have subclassied this disorder into two variants: (1) major variant, in which the
symptoms are chronic, persistent, and severe and (2) minor variant, in
which the symptoms are acute and transient. The authors describe the
prevalence, clinical features, and treatment of the two variants separately.
Major Variant. Prevalence. The prevalence of agitation, impulsive
behavior, and aggressive outbursts are very common after brain injury,
with a frequency ranging from 11% to 98%.6
Clinical Picture. The salient clinical features of this syndrome include:*
Mood
Irritability
Rage
Anger
Cognition
Impaired attention
Impaired memory
Poor executive function
Impaired judgment
Distractability
Conceptual disorganization
Behavior
Impulsivity
Aggressivity
Hyperactivity
Impaired judgment
Hyperphagia
Pica
Patients often are referred to a psychiatrist by their physician or family
members for the management of verbal or physical aggression, impulsivity, and anger or rage outbursts. This condition should be differentiated
from major depression, mania, and psychosis. The characteristic symptoms of these disorders were described earlier in the relevant sections.
The core feature of behavioral dyscontrol disorder is the intermittent,
uncontrollable outburst of mood or behavior in contrast to the persistence of symptoms in other disorders. Patients have very little insight
*Adapted from Rao V, Lyketsos C: Neuropsychiatric sequelae of traumatic brain injury.
Psychosomatics 41:95103, 2000; with permission.
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
RAO & LYKETSOS
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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Vani Rao, MD
Osler 320
Neuropsychiatry and Memory Group
The Johns Hopkins Hospital
Baltimore, MD 21287
e-mail: vrao@mail.jhmi.edu
0193953X/02 $15.00 .00
REFRACTORY CHRONIC PAIN

Michael R. Clark, MD, MPH, and Todd S. Cox, MD
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
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Prognoses and Preferences for Outcomes and Risks of Treatment

(SUPPORT) has demonstrated that pain, dyspnea, and fatigue are the
most prevalent symptoms experienced by patients with terminal illnesses at the end of life and 63% had difculty tolerating physical or
emotional symptoms.67
MULTIDISCIPLINARY TREATMENT
Patients with chronic pain, compared with those with almost all
other medical conditions, suffer dramatic reductions in physical, psychological, and social well-being, and their Health-Related Quality of Life
is lower.5, 6, 94 Substantial evidence shows that multidisciplinary pain
programs improve patient functioning in a number of areas.14, 28, 33 A
meta-analysis of 65 studies concluded that combination treatments were
superior to unimodal treatments or no treatment; treatment effects were
maintained over a period of up to 7 years; and improvements were
found not only on subjective but also objective measures of effectiveness,
such as return to work and decreased health care utilization.34 A more
recent review of 24 meta-analyses of nonsurgical, nonmalignant, nonheadache pain treatment found multidisciplinary pain facility treatment,
as well as single-modality treatments (e.g., antidepressants, capsaicin,
physical therapy, topical nonsteroidal anti-inammatory drugs, and cognitive-behavioral therapy), were consistently effective24; however, no specic subset of effective treatments within the treatment package offered
by a pain facility could be prescribed.
Refractory Chronic Pain
Ultimately, the goal of treating patients with chronic pain is to end
disability and return them to work or other productive activities. Although outcome studies are positive, many patients with chronic pain
are refractory to treatment, continue to suffer, and remain disabled.
Many factors can interfere with treatment including disease states, mental disorders, affective distress, personality traits, and personal beliefs.
For example, elderly patients often do not report pain because they fear
it means a deterioration of their condition, that it will distract physicians
from their underlying illness, or that it will upset others around them
who are concerned about their well-being.82 The formulation of refractory chronic pain simply as a symptom of a disease of the body fails to
appreciate the role of these factors and results in poor treatment outcome. The complexity of these conditions requires a more comprehensive
formulation than the biomedical paradigm can provide.
For physicians attempting to take care of patients with refractory
chronic disorders involving symptoms such as pain, the principal question often becomes whether to attribute the cause of the patients persistent suffering and disability to psyche or soma.97 This form of dualism
73
can be resolved by recognizing that both of these entities exist and

problems arise from both realms even though the connections between
the two are still unclear. The meanings generated by the mind and
mechanisms generated by the body remain distinct and cannot be
merged to form a unied eld theory of mental life and behavior.
Patients with chronic pain probably will not suffer problems from either
mind or body but almost certainly from both.
Even mechanism and meaning are inadequate to describe the whole
of human consciousness and behavior. As individuals can be affected
by their experiences in the external world and their interpretation of it,
these interpretations are shaped by their own drives, traits, and beliefs.
They make decisions about their suffering and take purposeful actions
to express their distress. The physicians initial role in the evaluation of a
patient with refractory chronic pain is to produce a more comprehensive
formulation and a differential diagnosis attempting to sort out to what
extent the patient is demoralized by a particular sequence of meaningful
events, frustrated by his own psychological trait vulnerabilities, upset
by the consequences of repeatedly choosing to engage in problematic
behaviors, or sick with a specic disease.1113
INTERDISCIPLINARY FORMULATION
The patient who presents to a physician with refractory chronic
pain is suffering and seeking help for a problem. Every approach to
solving problems must have an underlying organization and methodology.7679 The biopsychosocial approach attempted to dene a comprehensive model of the entire patient.2022 Unfortunately, it dened only the
elements of the systems of the patient and not an approach that could
be used to make a diagnosis, determine its causes, and direct treatments.
The vulnerability-diathesis-stress model for the pathogenesis of chronic
pain emphasized the need to understand the interaction among biological, psychological, and social risk factors,16 but this model lacks an
appreciation for the distinct mechanisms needed to describe different
types of disorder. Psychological treatment for chronic pain was pioneered using an operant conditioning behavioral model.36 The behavioral
approach is based on an understanding of pain occurring in a social
context. If pain behaviors are reinforced, pain and disability continue. In
treatment, productive behaviors are targeted for reinforcement and pain
behaviors for extinction.
The multidisciplinary approach of chronic pain management attempted to dene a comprehensive model of treatment for every
problem of the patient with chronic pain.105 A multidisciplinary approach
is a serial evaluation by multiple specialists. Usually, this process leads to
diagnoses by exclusion and implies a hierarchy of diagnostic importance.
Psychiatry is often the last specialty to evaluate the patient, reinforcing
the belief that pain is truly mysterious and just a gment of your
imagination. Even attempts at simultaneous evaluation by multiple
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CLARK & COX
specialists, including a psychiatrist, can be misconstrued as trying to

determine whether symptoms are real; however, the different disciplines usually end up in one of the two classic camps: (1) organic
problems get specic treatments and (2) functional problems get
symptomatic treatment. Despite the goal of covering all the bases with
more disciplines, Cartesian dualism still survives.
Interdisciplinary approaches are characterized by combining areas
of expertise to form a shared common view of chronic pain.105 Although
the individual team members are representatives of different elds of
study, they recognize that all illnesses can have a variety of causes and
are organized by specialty for clarity; however, the classication structure does not invalidate certain diagnoses, such as psychiatric disorders,
as a cause for the patients symptoms. This approach implicitly emphasizes that all diagnoses are real and can be made by any number of
specialists if properly trained. When a specic diagnosis cannot be made,
a cause for the patients symptoms has simply not yet been discovered.
Regardless, the patient can remain in treatment to receive symptomatic
interventions and the coordination of future evaluations. The patient is
no longer stigmatized as having a false condition but instead recognized as having a legitimate problem with understandable suffering.
If all patients with chronic pain are going to benet from the health
care system, a systematic interdisciplinary approach that produces a
comprehensive formulation and leads to an individualized treatment
plan needs to be made explicit. The fundamental reasons for the patients
suffering must be specied and can be organized using four perspectives: (1) life stories, (2) dimensions, (3) behaviors, and (4) diseases.80
Each perspective offers its own essential logic and method of reasoning,
beginning with the meaningful circumstances of the patients life and
progressing to the type of unique person involved; then the choices and
actions of that person; and, nally, the stereotypic diseases that can
afict him (Table 1). In this approach to patient care, life stories are what
people want, dimensions are what people are, behaviors are what people
do, and diseases are what people have. The physician should formulate
the case of a patient with refractory chronic pain by looking for and
thinking about the individual contributions from each perspective to the
overall presentation. A treatment plan to address each perspective can
then be designed. The step-by-step approach to the individual patient
with chronic pain includes:
Life Stories
Expand the history to include every aspect of the patients life
Understand what it means to the patient to suffer from chronic pain
Determine whether the patients distress is caused by events that
he has encountered
Reinterpret these events to provide new insights
Help the patient nd an answer to the question, What good does
life hold for me?
75
Table 1. SUMMARY OF THE PERSPECTIVES OF PSYCHIATRY

Life Stories
Logic
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
Personal features Causal

are quantied
relationships
along spectrums
dene
of measurement
categorical
diagnoses
Relative amounts Abnormal
of a trait
structure or
predisose to
function of a
inherent
bodily part
strengths and
vulnerabilities
Restore emotional Restore function
stability
Guide toward
Prevent, correct, or
settings that
palliate the
evoke strengths
abnormality
and avoid
provocation of
vulnerabilities
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
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CLARK & COX
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
tive-behavioral therapy.55 In a 30-month follow-up study of patients with

chronic pain receiving multidisciplinary treatment, employment status
was predicted by the patients voiced intent to return to work, as well
as the perception of a jobs dangerousness, excessive physical demands,
and potential for future injury.29, 30, 46
Treatment strategies in the life story perspective focus on instilling
in the patient a desire for a life that is more fullling. A negative
perception of the future by the patient with chronic pain leads to an
increase in distress, a sense of losing social support, and the use of
maladaptive coping skills.44, 45 Acceptance of pain is related to how
patients learn to live with chronic pain. Self-esteem and social support
are factors predictive of improved acceptance of various types of disability.66 Greater acceptance of pain has been associated with a variety
of factors including decreased disability and pain-related anxiety.73 In
addition, acceptance of pain predicted better overall adjustment to pain
and patient functioning independent of perceived pain intensity.75 As an
individual reects on his life, the process of understanding and adjustment should address the meaning of his illness, planning specic interventions to minimize any disability and nding opportunities to maximize quality of life.
Dimensions
The dimensional perspective is based on the logic of a continuous
distribution of individual variation. Traits are personal characteristics
and bodily processes that can be quantied along a continuum or distribution of measurement. Traits are aspects of who people are. Most
individuals possess an average amount of a particular trait; however, a
few individuals have very little or excessive amounts. The trait itself
conveys certain inherent strengths and weaknesses on the individual
that vary depending on the individual dose of the characteristic and
the task at hand, which places specic demands on the person. The
setting, which is usually typical and nontraumatic, evokes the vulnerability of the trait and causes a response, such as anxiety. Different
settings evoke different vulnerabilities for different traits. While the
responses are not abnormal in character, difculty is caused for the
patient when they occur more frequently, with more intensity, or for a
longer duration than usual.
Traits involve potentials and not destinies. Standardized assessments of traits can provide efcient and detailed information about an
individual; however, no one instrument has proven comprehensive and
relevant for all patients with chronic pain. Treatments within the dimensional perspective focus on emphasizing the strengths and weaknesses
that are the manifestations of particular characteristics and the settings
that evoke them, such as being anxious in unfamiliar situations. Specic
methods must be devised to compensate for the individual patients
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vulnerabilities, such as providing vocational training. With guidance and

new skills, success can be achieved by seeking out situations that are a
better match to the persons specic trait composition and capable of
evoking his strengths.
An example of a dimensional trait is found in the domain of affective temperament. Several studies have focused on the personality
characteristics and disorders of patients with chronic pain.112, 118, 119 Previous studies have identied Minnesota Multiphasic Personality Inventory
(MMPI) cluster proles such as the conversion V type and neurotic
triad with different multivariate relationships between other constructs,
such as somatization, coping strategies, depression, pain severity, and
activity level.89 Although patients with chronic pain differ from nonchronic pain controls in their scale proles on the MMPI, however, no
single personality type is associated with medically unexplained chronic
pain or chronic pain from organic diseases. Personality traits should
be appreciated as sustaining or modifying factors that have the potential
to complicate the treatment process rather than as causes of or the sole
explanation for chronic pain.111 The personality vulnerabilities, therefore,
contribute to the degree of potential disability that individuals experience by modifying their response to pain.
Coping has been dened as a persons cognitive and behavioral
efforts to manage the internal and external demands of the personenvironment transaction that is appraised as taxing or exceeding the
persons resources.35, 49 Higher levels of disability were found in persons
who remain passive or use coping strategies of catastrophizing, ignoring
or reinterpreting pain sensations, diverting attention from pain, and
praying or hoping for relief. In a 6-month follow-up study of patients
completing an inpatient pain program,48 improvement was associated
with decreases in the use of passive coping strategies. Negative selfstatements have been found to be predictive of general activity, pain
interference, and affective distress.100 The transtheoretical model of
change proposes that patients progress through specic stages as their
readiness to adopt new beliefs increases and subsequent coping responses improve.50, 57
The effectiveness of particular coping strategies is dependent on
many aspects of a patients experience with chronic pain.103 Higher
levels of pain-related anxiety are associated with greater pain severity,
interference of pain, and difculty with daily activities in men but not
women with chronic pain.18 Patients with bromyalgia compared with
work-related muscular pain reported higher levels of trait anxiety and
pain-related catastrophizing and low levels of abilities to control and
reduce pain.40 In the fear-avoidance model of exaggerated pain perceptions, fear of pain leads to avoidance of and escape from activities
that are perceived to increase pain and disability.65, 74, 95, 113 Dispositional
optimism is an intrinsic variable that affects types of coping with chronic
pain.83 Optimism increases the ability of patients to nd benets from
living with adversity, such as major medical problems (e.g., chronic
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
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CLARK & COX
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
CLARK & COX
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-
83
tion of both pain and disability. Treatment of a disease involves nding

a cure for the abnormality and restoring function to premorbid levels.
The cure may repair the broken part, prevent the initial damage from
occurring, or compensate for the affected physiology. Denitive cures
can be developed to combat specic causes when they are discovered.
The cause of many diseases is elusive, and treatments can be palliative
only, such as antidepressant medications.
SUMMARY
Refractory chronic pain is a signicant public health problem and
frustrating to everyone affected by it. All physicians can participate in
the care of these patients, but psychiatrists should take a leading role in
their care. A comprehensive approach offers hope and increases the
opportunities for successful treatment.
Each perspective of an interdisciplinary formulation has a unique
logic that denes specic methods for designing treatment for the patient
with refractory chronic pain.1113, 96 The patient does not have to t into
one theoretic approach or model to receive and accept treatment. The
patients diagnoses are based on the formulation, which then directs
treatment along rational directions. The linkages and interactions of a
patients diagnoses can then be investigated within a framework that
includes the entire person and not just his or her biochemistry.
If a patients suffering persists, other factors must be considered
that may have been overlooked before the treatment plan is abandoned
or modied. Usually these factors are within one of the perspectives
initially thought to be less important. A new combination of approaches
is then required to treat the patient successfully. The perspectives appreciate not only that the patient is struggling through important life
events but also that he is a person composed of vulnerabilities and
strengths, having made many choices and aficted by diseases.
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Michael R. Clark, MD, MPH
Department of Psychiatry and Behavioral Sciences
The Johns Hopkins Medical Institutions
Osler 320, 600 North Wolfe Street
Baltimore, MD 212875371
e-mail: mrclark@jhmi.edu
0193953X/02 $15.00 .00
PSYCHIATRIC ISSUES IN
PULMONARY DISEASE
Kathy Coffman, MD
Diseases of the lung afict millions of people worldwide. In view

of the broad nature of the topic of psychological issues in pulmonary
disease, a decision was made to take an evidence-based approach to
reviewing the clinical literature. The three main goals of this article are
(1) to discuss the major disorders that most clinicians see in practice, (2)
to provide an update on the surgically related topics of lung resection
surgery and transplantation, and (3) to provide some clinically relevant
suggestions about pharmacologic interactions between pulmonary and
psychotropic drugs.
Depending whether the onset of the disease occurs in childhood,
adolescence, early adulthood, midlife, or senescence, there may be a
different impact based on what developmental tasks are affected. In
general, those conditions, such as asthma and cystic brosis (CF), have
an early onset. Sarcoidosis may begin in early to midlife. Emphysema,
chronic bronchitis, and pulmonary brosis may be diagnosed in midlife
to senescence. Infectious diseases, such as tuberculosis, may affect people
of any age. Despite the number of people with lung disease, many
conditions have not been well studied from the psychological standpoint.
COMMON PULMONARY DISORDERS
Asthma
Asthma is now the most common chronic disease in the United
States. According to a recent text on asthma, 5% to 7% of Americans
From the Department of Psychiatry, Comprehensive Liver Disease Center, St. Vincent
Medical Center, Los Angeles, California

89
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COFFMAN
suffer from asthma, or roughly 17 million people.6, 19 The mortality rate

has risen steadily since the early 1980s. This illness affects nearly 5
million children per year in the US, with a cost of roughly $1000 per
child.119, 143 Contrary to the common wisdom, most people do not grow
out of this condition. In fact, of children with asthma, 85% of girls and
72% of boys continue to live with asthma throughout their lives. This
illness affects member of various racial and ethnic groups differently for
reasons that are not completely understood. Hispanics of Puerto Rican
descent have a rate of childhood asthma that is three fold as high as
that of non-Hispanic white children. The prevalence of asthma among
non-Hispanic blacks is twice that of non-Hispanic whites. The ageadjusted mortality rate for asthma varies among different ethnic groups,
as follows: Puerto Ricans, 40.9 per million; non-Hispanic blacks, 38.1 per
million; Cuban-Americans, 15.8 per million; non-Hispanic whites, 14.7
per million; Mexican-Americans, 9.2 per million.
Health care utilization may differ among groups even when the
insurance coverage is the same. For example, a study of patients in
managed care organizations showed that African-American patients
lled fewer prescriptions for inhaled steroids and were less likely than
whites to see an asthma specialist. The issue of patient education is
important because emergency departments generally are not geared
toward providing patient education about illness; rather they are geared
toward crisis intervention only. Managed care patients studied at the
Cleveland Clinic showed different patterns of health care use. White
patients were more likely to see a primary care doctor (70.2% versus
47.6%), and allergist, or pulmonary specialist (38.8% versus 27%) after
initial hospitalization for asthma compared with African Americans.
African-American patients made more emergency department visits
(45.2% versus 22.4%) compared with white patients. Seeking care for
asthma on a regular basis can prevent emergency department visits and
hospitalizations. More work needs to be done on investigating the reasons for these patterns to understand whether socioeconomic issues,
attitudes toward seeking health care or differences in caregiver services
are responsible for the disparity in care and outcomes.
Comorbidity with Psychiatric Disorders
The overlap of asthma symptoms with those of other disorders may
make the diagnosis difcult. One study using a methacholine inhalation
challenge test to assess airway hyper-responsiveness revealed that anxiety symptoms may be mislabeled as a respiratory condition. In 31% of
patients, the methacholine inhalation challenge test was negative. Anxiety symptoms in social settings were strong predictors of mislabeling
patients as asthmatic. Among the patients without bronchial reactivity,
social phobia was 10-fold more common than in the patients who actually had asthma. Therefore, clinicians should ask whether the symptoms
occur in certain circumstances, such as social settings.184 Three cases of
PSYCHIATRIC ISSUES IN PULMONARY DISEASE
91
factitious asthma have been reported, with self-produced wheezing but

no bronchial reactivity to a methacholine inhalation challenge.59
Some have reported a high comorbidity between panic disorder and
other anxiety disorders and asthma. Those with asthma and panic disorder have more perceived breathlessness after an inhalation challenge
test than those without panic disorder. In addition, use of bronchodilators has been linked to perceived discomfort rather than actual bronchoconstriction.184 Several recent studies have indicated that anxiety and
depression are more common among asthmatic patients that among
the general population, particularly women and those with less higher
education. Women hospitalized for emergency treatment of asthma had
a high incidence of anxiety.35 Another study suggested that male asthmatics reported signicantly more psychological distress and used fewer
physician services than female patients. In contrast, female patients use
of services and perceptions of health functioning were negatively affected by their marital partners level of psychological distress. This
suggested the need for inclusion of partners in treatment.3 A study of
230 outpatients with moderate asthma showed that almost half had a
positive screen for depressive symptoms and that those with more
depressive symptoms reported worse health-related quality of life even
though disease activity was similar to those with fewer depressive
symptoms.130
Psychodynamic Issues
Old psychosomatic theories about asthma proposed by French and
Alexander in 19391941 were based on the hypothesis that the central
conict revolved around subconscious dependency issues with the
mother and fear of separation.78 Interestingly, a study attempting to
relate temperament to later development of asthma showed no difference on the Brief Scale of Temperament between children that developed
asthma and those who did not.181 One group investigated whether a
repressivedefensive style could be reliably measured and whether this
coping style was related to physiologic reactivity under a stressful task.
The data cast doubt on whether the trait could be measured reliably.
Asthmatic children with the trait did not differ from those without the
trait on physiologic reactivity.142 Anxiety is increased by sudden and
unexpected attacks of asthma, anticipation of attacks in response to
certain triggers, and side effects of medications for treatment of asthma.
Anxiety can affect the patients response to an attack, as well as use of
medications and quality of life.205
The vagus nerve is thought to mediate airway reactivity to emotion.102 The upper airways innervated by cholinergic neurons may be
affected more by suggestion and emotion than smaller airways.118 Recent
research has shown that various emotions and types of stress can increase respiratory resistance in asthma.172
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COFFMAN
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
93
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
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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COFFMAN
differences by not disclosing the name of the illness. At times this

backred as the other children incorrectly assumed that the patients
had AIDS. Coughing raised concerns about whether the patient was
contagious. Children with CF found that by not telling the teachers their
diagnosis, they could compete in sports. They learned to pace themselves to appear as normal as possible. Some children avoided athletics
from fear of adverse effects on their health. Hiding visible differences
allowed friendships or romantic relationships to develop; however, keeping secrets created distance and undermined intimacy. Siblings and old
friends helped by telling the diagnosis to new friends to spare the
patient potential rejection. Adolescents with CF especially valued camp
and hospital experiences where they met other teens with CF and shared
experiences. In this setting, they realized that their self-esteem suffered
by comparing themselves to healthy peers. They found their own standard and realized that comparison to healthy peers was not the right
standard for their lives. Camp experiences relieved feelings of coping
with CF alone.
Adolescents often did not adhere to medication schedules for fear
of appearing different at a time of life when tting in socially is the
ultimate goal. On dates, adolescents with CF often skipped the pancreatic enzymes, although they had abdominal pain later. Friends who
showed unconditional regard were an important source of support.
Younger children found the disease difcult to understand and hard to
explain to their peers. Adolescents viewed their main tasks as learning
how to disclose their CF, learning not to let reactions of others upset
them, learning to take their medications, and learning to make close
friendships.
Interventions
Surprisingly little has been written about psychological intervention
with children with CF; however, one small program used cognitivebehavioral interventions with ve adolescents. Some studies have shown
psychiatric problems in 50% to 60% of CF patients, mainly anxiety
related.80 Increased depressive symptoms have been seen in older adolescents and young adults.24 Noncompliance with the medical regimen has
been estimated to be 35% or more.50 The intervention used in the study
by Hains et al80 used cognitive restructuring and problem-solving skills.
The Spielberger State-Trait Anxiety Inventory form was used to assess
change in trait anxiety from baseline. The KIDCOPE, a 10-item coping
checklist, was used by the adolescents to rate 10 commonly used cognitive and behavioral coping strategies.197 The adolescents coped with
school-related items: homework, grades, sports participation, peer conicts, and dating issues. Issues at home included ghts with siblings
and job issues. Problems related to CF included coughing in social
situations, wheezing at night or during sports activities, missing school
and falling behind in homework, and nonadherence with treatment. The
Functional Disability Inventory was used to measure the impact of the
95
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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COFFMAN
or pCO2 of more than 100 mm Hg. If pH falls below 7.1 or pCO2

increases to more than 120 mm Hg, the patient may progress into coma
and cerebral vasodilation may result in increased intracranial pressure.124
When investigating psychological symptoms in patients with physical conditions, confounding variables are problematic. One study of
COPD patients showed that those patients with more severe physical
symptoms had more negative mood. In particular, fatigue was found to
account for 28% of the variance on the Negative Mood Scale.191 Dyspnea,
congestion, and peripheral-sensory disturbances did not enter into the
equation. Another study found that COPD patients had symptoms similar to those of agoraphobic patients, although not as intense.110
Dudley et al60 observed that when patients and physicians face
chronic disease, they may feel impotent. The patient may be viewed by
others as weak and lacking motivation. Physicians may be seen as
lacking clinical competence when a patient cannot be cured. The patient
and family may be angry and frustrated that this illness cannot be xed.
Patients may feel guilty if smoking resulted in the disease. They may
feel like a burden to their spouses and families. Patients may avoid
strong emotions to minimize the demands on the lungs. Denial, suppression of affect, repression, and isolation frequently are used as coping
strategies in COPD patients.60 Consequently, the patients spouse or
family may feel that the patient is emotionally distant and unavailable.
They may view the patient as unwilling to address issues that they bring
up, not recognizing that this strategy is viewed by the patient as necessary for survival. Family members may experience the patients rigid
avoidance of affect and conict as rejection of them. This may perpetuate
a cycle of confrontation and avoidance, leading to unresolved anger and
despair because neither the needs of the patient nor those of the family
are met.
Patients may fear loss of control or loss of independence. They may
have many losses to contend with because of their COPD, such as loss
of their job, social status, role in the family, or changes in their appearance. Use of steroids with the resulting weight gain, with moonface,
potbelly, striae, or a buffalo hump can challenge self-image. Chronic
steroid use also may exacerbate depression, emotional lability, or irritability, which may cause alienation of family and friends. Chronic depression can push supports away because as the clinging behavior may set
up a cycle of avoidance and guilt in the family members and friends.
Recognition of major depression is more difcult because of the confounding effects of pulmonary medication. Bronchodilators may cause
tremor, palpitations, anxiety, and insomnia. Rating scales that are less
tied to the physical symptoms of depression, such as the Beck Depres-
97
sion Inventory or the Inventory or Depressive Symptomatology, may be

more useful. Evaluation of medical causes of depression should be a
part of a psychiatric evaluation because concomitant medical conditions
or medications may result in depression. Some patients cannot engage
in sexual intercourse because of physical limitations. Other patients may
still be capable of sexual intercourse and feel disappointed or rejected if
a spouse shows less interest after the diagnosis of COPD is made. Like
spouses of cardiac patients, the spouse of a COPD patient may fear
harming the patient through vigorous sexual activity.
Another issue is dependence on supplemental oxygen, which can
be socially embarrassing or make the patient feel less attractive. They
may fear that the oxygen tank is a liability in business, particularly if
the patient is in sales. Some simply cannot accept the need for oxygen
because of denial about the illness. Others become psychologically dependent on oxygen, even exceeding the amounts necessary against the
directions of the doctor. This can be dangerous for patients who retain
carbon dioxide because their respiratory drive may be suppressed, leading to lethargy and worsening of the condition. Many patients prefer
liquid oxygen tanks because the newer models last longer. Patients also
may need a wheelchair for family outings. Many public venues now
rent out electric scooters. Scooters are perceived as less stigmatizing than
a wheelchair and may give the patient more independence and a greater
sense of control; however, the cost of renting a scooter may be prohibitive for some patients.
Interventions
COPD is a chronic and terminal disease that limits the lifestyle and
progressively compromises the quality of life. The goals of treatment are
to relieve symptoms, provide physical rehabilitation, and improve the
patients coping skills.191 The patient may have little prospect of regaining ground that is lost after a bout of pneumonia without a rehabilitation program. Physical therapy groups may help patients to practice
breathing techniques. Exercise may allow the patient to build endurance
and improve their range of activities. Learning to pace oneself is essential. Patients may interpret dyspnea as a signal to avoid all activity and
become homebound and isolated. Some patients avoid exercise groups
to avoid confronting their illness or to avoid seeing others who may be
sicker, which may foreshadow their own eventual decline. These patients
may do better with individual physical therapy. Through work with a
structured exercise program, the patient may gain more control and
learn that mild dyspnea is not necessarily life-threatening. A treatment
plan with realistic and attainable goals and rewards can counter the
sense of helplessness.
Educational group meetings to discuss the disease process and the
impact on lifestyle in a matter-of-fact way can be helpful. Question-andanswer periods may increase patient participation. Training in relaxation
techniques to manage anxiety and panic are helpful in restoring con-
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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
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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study of patients with rheumatologic disorders, 41.2% were found to

have abnormal lung ndings on high-resolution CT versus 18.7% with
plain chest radiography.180 In systemic sclerosis, IPF is the most common
respiratory disorder, seen in 80% of patients, and is the primary cause
of mortality caused by respiratory insufciency in 20% to 60% of cases.
Unfortunately, clinical signs are seen only after at least 50% of the lung
parenchyma has been affected. Cyclophosphamide and corticosteroids
have been used in treatment.131 Outcome in IPF can be estimated with
80% sensitivity and 85% specicity by rating brosis through highresolution CT and pathology brosis scores.75
Psychiatric Comorbidity
One study investigated health-related quality of life in patients with
IPF. Dyspnea was the most important factor in determining quality of
life in these patients. BDI scores correlated with quality of life variables,
as did FVC, FEV-1, and arterial pH. Mean pO2 was 67, and mean pCO2
was 37 in this group.
Tuberculosis
The incidence of tuberculosis (TB) had been decreasing for more
than 70 years, and began to increase again over the past decade in the
United States, Western Europe, Asia, and Africa. Causes for this trend
include the rise of AIDS, disruption of society with increasing homelessness, as well as a failure to fund the public health systems to provide
treatment. The World Health Organization statistics indicate there are
2.9 deaths per year and nearly 8 million new cases per year world-wide.
Approximately 1.7 billion people worldwide, or approximately one third
of the world population, are infected with Mycoplasma tuberculosis and
are at risk for the disease. Roughly one fth of all adult deaths in
developing nations are caused by TB.26
In general, involvement of the psychiatrist with patients infected
with TB comes in the consultationliaison setting, in which patients
are conned for observed treatment of resistant TB. These patients are
generally from urban settings and often may have major psychiatric
disorders that compromise their ability to adhere to the TB regimen,
such as schizophrenic or bipolar patients, or those who are involved in
alcoholism or drug abuse.
Hyperventilation
Hyperventilation was rst recognized in 1871 by DaCosta. Hyperventilation is a common presenting complaint in emergency departments
leading to psychiatric consultation.147 These patients increase the rate
and depth of breathing briey for a few minutes and may have dizziness
101
or syncope from the respiratory alkalosis and cerebral vasoconstriction

that results. Accompanying symptoms of carpopedal spasm, myoclonic
jerks, or paresthesias may frighten relatives and result in visit at the
emergency department.
The incidence of hyperventilation syndrome (HVS) is estimated as
between 6% to 11% of the general population.114 Three elements characterize the diagnosis of HVS: (1) that the patient hyperventilates and has
a low pCO2, (2) that somatic diseases causing hyperventilation have
been ruled out, and (3) that the patient has somatic complaints related
to hypocapnia.72 One article179 points out hazards of labeling patients
with HVS in the emergency department. The suggested evaluation included chest radiography, blood chemistries, a complete blood count,
and thyroid functions. The validity of the hyperventilation provocation
test has been challenged because various groups have not found any
correlation between symptoms and physiologic criteria for HVS.195
Differential diagnosis for HVS includes medical problems and psychiatric disorders. Medical problems to exclude include acute porphyria,
bronchial asthma, carbon monoxide poisoning,190 diabetic ketoacidosis,211
right atrial thromboembolus,92 epilepsy, hypoglycemia, ingestion of
salicylates,176 Me nie` res disease, pheochromocytoma, and vasovagal
phenomena. In HVS patients unilateral symptoms, often left-sided, may
mimic a cerebrovascular accident (CVA). Bilateral somatosensory evoked
potentials show no difference between the affected and unaffected
arm.151 Neurologic causes of hyperventilation include left posterior thalamic infarct with unilateral right hemiparesthesia,186 Cheyne-Stokes
breathing,123 vestibular hyperreactivity after whiplash injury,71 and
Hirschsprung disease with primary central hyperventilation syndrome.16
Hyperventilation may occur with normocalcemic tetany, and chronic
magnesium decit.61, 86
HVS may mimic acute cardiopulmonary disease. One paper asserted that HVS is present in as many as 50% of patients with cardiac
chest pain.85 One patient with angina and hyperventilation produced
coronary artery vasospasm, with dizziness and breathlessness.73 A patient with chronic HVS, syncope, and coronary vasospasm was reported
on by another group.34 One heart transplant recipient developed HVS as
a result of fears about the donor organ.31 As noted previously, HVS has
been cited as a precipitant to asthma attacks. Education and bronchodilator treatment may be helpful in these patients.58 One patient with hyperventilation had hereditary mesenchymal dysplasia.104 Both hypoxemia
and hypercapnia may occur in patients with HVS, with no other diagnosed disease.38
Environmental causes of HVS include anaphylaxis caused by a
wasp sting,200 heat in glass bangle workers,168 chronic hypobaric hypoxia
in miners, and photochemical air pollution causing mass psychogenic
HVS in Japanese schoolchildren.11, 128 Medications reported to cause central hyperventilation include carbamazepine and topiramate. Topiramate
inhibits carbonic anhydrase isoenzymes II and IV in the CNS. Central
HVS resolved promptly within a day or two after discontinuation of
these drugs.116, 139
102
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Psychiatric disorders to rule out include anxiety attacks, borderline

personality disorder, conversion disorder, histrionic personality disorder,
panic disorder with agoraphobia, phobic disorders, and obsessional
symptoms.105 A study of 102 general hospital patients who had HVS
showed 36 had panic, and scored higher on state anxiety, depression,
generalized anxiety, agoraphobic anxiety, and avoidance.195 Estimates of
the overlap between HVS and panic disorder are between 35% and 50%,
and in one study, 83% with panic disorder with agoraphobia and 82%
with generalized anxiety disorder.47, 55, 43 Some have called HVS a chimera
and assert that HVS is not synonymous with panic disorder but is more
closely associated with asthma.21 A study of 35 patients with HVS
showed a Minnesota Multiphasic Personality Inventory (MMPI) prole
similar to pseudoepileptic patients.28 Loss of consciousness and pseudoseizures caused by hyperventilation may be misdiagnosed as absence
of seizures.145, 158
HVS occurs at any age. Adolescents with functional somatic complaints may benet from exploration of stressful life events, peer relations, and self-esteem.82, 91, 175, 177 Elderly patients may have HVS also,
as noted in a 92-year-old Japanese woman treated with paper bag
rebreathing.206 HVS attacks are recurrent in half of patients and recurred
for more than 3 years in 10% of patients.90
Various treatments for HVS have been tried over the years, such
as IV sedatives,90 antidepressant medications,178 metoprolol, progressive
muscle relaxation and autogenic training,98, 203 abdominal breathing and
relaxation techniques,53, 54, 163 hypnosis,44 resolution of grief through psychotherapy,157 and group therapy.70 A placebo-controlled, randomized,
crossover trial of bisoprolol, 5 mg/d, in 60 patients with HVS showed a
signicant (P 0.05) decrease in attacks with bisoprolol,213 for patients
with hyperventilation and vestibular hyperreactivity, a calcium channel
antagonist, unarizine, 10 mg per/d, was successful.208
Vocal Cord Dyskinesia
Vocal cord dyskinesia has been called by various names: episodic
laryngeal dyskinesia, adductor spastic dysphonia, and functional upper airway
obstruction. A US textbook described the syndrome in 1842 as hysterical
croup. Terms used in the US literature include Munchausens stridor
and factitious asthma.166 In 1871, Traube described this disorder as a
spastic form of nervous hoarseness. Although thought to be rare, the
incidence and prevalence are unknown. The sex ratio is thought to be
equal. The disorder may present at any age, but typically around age 50
years, with a range of 20 to 80 years.
For many years, this disorder was considered a conversion disorder.
Although no symbolic meaning was discovered, the reaction was though
to be a barricade against self-revelation. On the MMPI, these patients
showed low scores on hypochondriasis and hysteria and high scores on
depression. Patients with conversion aphonia scored high on hypochon-
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-
104
COFFMAN
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.
105
The concept of the cancer-prone personality has been questioned

in recent years. The traits described included suppression of negative
emotions, self-sacricing behavior, and reluctance to voice personal
needs even in the face of severe life stress. A large, prospective study of
230 patients with breast tumors and 75 patients with suspected lung
cancer before biopsy investigated the cancer-prone personality concept
using semistructured interviews. The conclusion was that the psychological phenomena in cancer patients was found to be the result of the
disease and not the cause.185 Another study found that patients that
attributed the cancer to psychological factors were more depressed and
pessimistic. The group postulated that the so-called cancer-prone personality may be a result of how coping with the belief that one has
cancer, rather than a character type predisposing one to cancer.69
A review of QOL in lung cancer patients from 1970 to 1995 was
published in 1998.140 This article noted that more than 80% of lung cancer
patients die within 1 year of diagnosis because many are diagnosed late.
More than 50 instruments have been used to measure QOL in patients
with lung cancer. Methodologic problems with QOL studies in cancer
patients include problems with standardization, availability of rating
scales or staff to administer them, and patients being too ill or noncompliant to participate in a study.96 Those who are most depressed are
least likely to complete rating scales because of apathy, lack of energy,
or poor concentration.
Proxy measures, such as weight loss, have been used to study QOL.
Psychological distress and lower QOL have been correlated with even
moderate weight loss.153 Some use functional status, such as the Karnofsky Performance Scale as a proxy for QOL, because this measure has
prognostic value in predicting length of survival; however, Karnofsky
score alone can not give a multidimensional description of the patients
QOL beyond the stage of the disease, number of metastatic sites, or
amount of weight loss. The KPS did not correlate with other measures
of QOL, such as the European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire (EORTC QLQ C-36 or C-30).
Other commonly used instruments included the Hospital Anxiety and
Depression Scale (HADS), the Functional Living Index-Cancer (FLI-C),
and the Daily Diary Card (DDC). The DDC focuses on treatment-related
side effects, and compliance is low with a daily measure. The Lung
Cancer Symptoms Scale (LCSS) is rather narrow as well, scoring symptoms of lung cancer and the effects of these on functional status. The
Functional Assessment of Cancer TherapyLung (FACT-L) is a self-rated
instrument that measures ve dimensions of QOL: physical, social and
family, emotional, functional well-being, and relationship with the physician on part 1, and lung cancer symptoms on part 2. Both the LCSS and
FACT-L are highly reliable and provide internal consistency and content
validity. The FLI-C independently predicts length of survival even when
corrected for possible confounding variables, such as performance status,
stage of illness, metastases, and weight loss. One study using the Therapy Impact Questionnaire demonstrated that problems with activities
106
COFFMAN
with daily living had prognostic value in predicting survival. Another

study showed that tumor response correlated with Sickness Impact
Prole scores and anxiety.25 In addition, the EORTC QLQ questionnaire
has been used to compare QOL in patients treated with a standardized
protocol versus palliative treatment. Wolf et al220 found that, although
patients on standard treatment had better tumor response and QOL than
did those on palliative treatment, the group on standard treatment had
more severe side effects from the treatment. Whether the survival rate
is higher has been disputed. Therefore, when no proven extension of life
is found with one treatment versus another, the deciding factor may be
the impact on QOL. For example, survival in those with small-cell lung
cancer was better for those receiving chemotherapy, radiotherapy to the
primary tumor, and prophylactic cranial radiation; however, the increased toxicity resulted in a decreased QOL compared with patients
receiving chemotherapy alone.4
Although psychological outcomes with spouses of patients with
cancer have not been very well studied, the use of rating scales, such as
the Bereavement Risk Index and Brief Symptoms Inventory, may allow
for early identication of those likely to have negative bereavement
outcomes.174
A number of recent studies have attempted to dene the prevalence
of psychiatric disorders in patients with cancer. Although some studies
may not show a high percentage of newly diagnosed lung cancer patients meeting criteria for affective disorders, many had symptoms that
may benet from systematic evaluation and treatment. For example, one
study (N 52) showed that newly diagnosed lung cancer patients had
symptoms including insomnia (52%), loss of libido (48%), loss of interest
or ability to work (33%), concerns about their families (29%), and poor
concentration (19%).76
A large sample (N 4496) of cancer patients was surveyed225 to
determine whether the site of cancer affects the prevalence of psychological distress. The rate of distress ranged from 43.4% for lung cancer
patients to 29.6% for gynecologic cancers. Those with pancreatic cancer
had the highest mean scores for depression and anxiety, whereas Hodgkins patients scored highest on hostility. Therefore, cancer patients
should not be viewed as homogenous, but should be screened to identify
high-risk patients and target interventions to the specic problems of the
patient.225 Approximately 20% to 40% of cancer patients show emotional
distress.1
One study posed the question, How successful are oncologists in
identifying patient distress, social support and need for supportive counseling? Results showed that oncologists identied only 36.6% of severely
distressed patients, and referrals for counseling did not correlate with
patient reports of distress or amount of social support, but rather with
the progression of disease and less denial behavior.194
The prevalence of fatigue in cancer patients was studied to determine the key factors involved. Although 15% of newly diagnosed patients with breast cancer and 16% of newly diagnosed patients with
107
prostate cancer reported severe fatigue, 50% of those with inoperable

nonsmall cell cancer reported severe fatigue. Severe fatigue was reported in 78% of inpatients receiving palliative care from a specialist.
Key factors included the disease burden, dyspnea, pain, and psychological distress.201
Roughly 40% of patients in a small study of cancer patients (N
36) had depressive symptoms before starting chemotherapy. Depression
scores declined over the rst 6 months.137 Some researchers have asked
whether psychological factors alter survival of cancer patients. One
study examined 103 patients after diagnosis with cancer and before
treatment using the Depression Scale of von Zerssen and the Freiburg
Questionnaire on Coping with Illness. At 5-year follow-up, the best
predictor of survival was the interviewer rating of active coping, equal
in power to the Karnofsky performance status.67 On 8-year follow-up,
self-rated depressive coping was signicantly correlated with decreased
survival (P 0.007).68
Aside from survival, psychological factors may inuence response
to treatment in other ways. For example, one small study (N 26)
concluded that neurosis, anxiety, or depression as rated using the Cornell
Medical Index, Manifest Anxiety Scale, and Self-Rating Depression Scale,
increased the nausea scores in response to chemotherapy.204 Another
study found that factors predicting psychological distress in ambulatory
lung cancer patients included being female, living alone with no children
as condants, relying on nursing staff as condants, and a helpless or
hopeless coping style.5
Type of lung cancer may inuence the rate of depression. One study
compared 526 patients with poor prognosis small cell cancer with 461
patients with good prognosis nonsmall cell cancer using the self-rated
HADS and QOL items from the Rotterdam Symptom Checklist. The case
rate of depression was nearly threefold higher in those with small cell
cancer (25%) than in those with nonsmall cell cancer (9%). The most
important risk factor for depression was functional impairment.97
Paraneoplastic syndromes have been observed with several types of
cancer, notably small cell cancer of the lung and ovarian cancer. One
case report described a man with numbness of the right leg, followed
by polyneuropathy, cerebellar dysfunction, and psychological symptoms
ultimately attributed to a small cell lung cancer with anti-Hu antibody
production. Treatment of the cancer with carboplatin and etoposide
yielded some response, but the neurologic symptoms were not reversible.113 Despite the grim survival time with lung cancer, have some
reported long-term survival beyond 30 months. Sequelae included neurologic impairment in 13%, pulmonary brosis in 18%, and cardiac
disorder in 11%, and 13% had a second cancer within 58.6 months.
Predictors of survival past 30 months included age of less than 60 years
at diagnosis, chest radiotherapy, and absence of relapse.103 In one series
of 1478 patients with lung cancer, 223 8.6% were superlong-term survivors more than 15 years after surgery. The death rate of smokers was
signicantly higher than among the nonsmoking group, P 0.05. De-
108
COFFMAN
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
deliberation. The principle of benecence may be summarized as, First,

do no harm. The dilemma is how to honor a decision that may lead to
death and preserve the duty to promote good and not harm the patient.
What is good in this situation should be dened by the patient. The
highest good to the patient could mean freedom from painful interventions, such as blood drawing, IV lines, or having frequent suctioning.
Other ideals include preserving dignity and independence and being
able to speak with loved ones. Mechanical ventilation may be viewed
by the patient as an intolerable intrusion that diminishes QOL and
renders death the preferred option.51
Several recent papers outline an approach to withdrawal of mechanical ventilation. The patients goals should guide the process of withdrawing interventions.88 If the patient shows ambivalence about terminal
weaning, or staff is concerned that the patients mental state is interfering with making a well-thought-out decision, consultation from a psychiatrist may be helpful. Some patients may be depressed and agree to a
trial of antidepressants before nalizing the decision for terminal weaning. Others may choose terminal weaning because of concerns about
burdening the family with medical costs. A visit from the social worker
to clarify insurance benets may change the patients mind. Input from
hospital chaplains, ethicists, the bioethics committee, and from the
nurses, dietician, or respiratory therapists caring for the patient may be
helpful in deciding whether the patients decision is the right course of
action. A brief delay after the decision has been made to withdraw the
ventilatory support may reassure staff that the patient made a decision
not subject to temporary frustration or discomfort.
The patient should be told that the weaning process may be stopped
at any time if he or she wishes. The patient may decide who will be
present during the weaning process. Family members should be asked
whether they want to be present if the patient is comatose or unresponsive. Timing of weaning may be geared to arrival of relatives from out
of town. Withdrawal of the ventilator may follow the withdrawal of
pressors, antibiotics, and enteral feedings.29 In a comatose patient whose
family does not wish to be present, the physician may opt for extubation.
In a patient who is conscious, the approach suggested by Grenvik79 in
1983 may be preferred: a gradual decrease in FO2, with decreased PEEP,
and decreased respiratory rate over several hours. A study of ventilator
withdrawal in 152 patients done at Detroit Receiving Hospital33 considered the presence of a cough reex, volume of secretions, duration of
intubation, and level of consciousness before deciding whether to extubate. In this study 8% of patients survived and were discharged.
No matter which method is used, adjunctive medication may alleviate distress. Morphine or fentanyl has been used for pain relief, to
decrease gasping, coughing, or the sensation of shortness of breath,
provide sedation and decreased anxiety in the patient. Opiates can be
given as an IV bolus then as a drip during the procedure. Careful
documentation of the physicians intent in administering opiates is important to show that the medication is being used as a comfort measure
and not to hasten death. One protocol suggests giving an IV bolus of 5
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COFFMAN
to 10 mg morphine, followed by a drip of 2.5 to 5.0 mg/h of morphine.

Although dosages of up to 70 mg/h have been reported, two deaths in
Minnesota were ruled homicides caused by morphine poisoning by the
medical examiner because the intent of the physician was not adequately
documented. Benzodiazepines may decrease anxiety and prevent myoclonus or twitching that may be unsettling to the family.66 Phenobarbital
may control twitching not relieved by benzodiazepines. IV haloperidol
may be used for anxiety not relieved by benzodiazepines or if the patient
is delirious. Use of antiemetics, antipyretics, or anticonvulsants for neuropathic pain can be used as symptoms dictate. The family should be
educated before the procedure that, although the patient may have
reexive gasping or twitching, the medications used prevent the patient
from having awareness of these bodily events and may induce euphoria.
Although patients in a persistent vegetative may grimace when extubated, without higher cortical function, there is no awareness of discomfort.
Families should be told that death cannot be predicted with certainty. Patients may die within minutes or days, although in one series,51
11% of terminally weaned patients survived and were discharged. The
use of paralytic agents is discouraged because these may prevent the
patient from signaling distress. In patients who retain carbon dioxide,
decreasing tidal volume or respiratory rate on intermittent mechanical
ventilation may allow the carbondioxide to gradually increase, resulting
in drowsiness, at which point mechanical ventilation may be stopped.
The process should take place over a few hours, preventing a prolonged
bedside vigil that is exhausting to the family. The comfort of the family
should be considered. Seating should be provided, together with ample
tissues. The family may wish to dim the lights. The patient and family
may prefer to have monitors turned off because constantly beeping
alarms may be disruptive. In particular, the ECG monitor may prove
upsetting to family members watching for that last heartbeat, rather
than focusing on the face of their loved one. Distractions may disrupt
normal grieving behavior, such as saying goodbye, praying, or family
members comforting one another. Staff members should remain at the
bedside in a supportive, unobtrusive way, to attend to the patient and
provide comfort to the family. Even though the patient may be obtunded,
the family may appreciate the physician explaining what is about to be
done. Expressions of concern about how the withdrawal of ventilatory
support is affecting family members may be welcomed. Physicians
should take cues from the family and may want to step out occasionally
to allow for privacy or religious ceremonies to be performed without
interference.23, 51
Lung Volume Reduction Surgery
Lung volume reduction surgery (LVRS) has been investigated as a
palliative procedure for patients with severe emphysema from smoking
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
was shown 3 months after unilateral LVRS. Although more long-term

data are needed to determine whether sufcient gains are retained to
warrant this procedure, LVRS may be used as an alternative to medical
treatment of emphysema and may be used as a bridge to lung transplantation.
Lung Transplantation
The rst lung transplant was performed in 1963, but it was 20 years
before the rst successful operation in 1983.149 For the 19971998 cohort,
the 1-year survival rate for lung transplant recipients was 77%, and for
the graft, was 76%. Lower survival rates were found in recipients aged
11 to 17 years and 65 years of age or older. The largest obstacle remains
the shortage of donor organs. In 2000, 73,951 patients were waiting for
organs, and only 21,693 organs were transplanted. The gap has widened
considerably since 1990, when 20,481 patients were waiting and 15,004
transplants were done. With the improvement in survival rate with
transplantation, the demand has increased, but the organ supply has
not grown accordingly. For example, 1451 lungs were retrieved for
transplantation in 1999, up a bit from the year before, when 1391 lungs
were recovered. Of those recovered, 50% of those not used were the
result of organ damage or poor function.212 The median waiting time in
1999 was approximately 18 months.9
The most common indication for lung transplantation is COPD
(which includes those with emphysema from -1-antitrypsin deciency)
and accounts for approximately 45% of lung transplants. 99 Transplants
also are done for those with CF, Eisenmengers syndrome, IPF, and
primary pulmonary hypertension. Less commonly, those with bronchoalveolar carcinoma, collagen vascular disorders, drug-induced or radiation-induced pulmonary brosis, eosinophilic granuloma, lymphangioleiomyoma, or sarcoidosis may require lung transplantation.64
Patients generally are referred when their QOL has declined and
transplantation would convey a survival benet, given the waiting time
of up to 2 years once the patient is listed for transplantation. Selection
of candidates must take into consideration disease-specic guidelines
for referral, such as an FEV-1 of less than 25% of predicted after bronchodilators for COPD, or less than or equal to 30% for CF patients. For
CF patients with FEV of more than 30% with rapid decline in lung
function, frequent exacerbations, or progressive weight loss, referral is
indicated. Patients with primary pulmonary hypertension or Eisenmengers syndrome must be classied as NYHA class III or IV for referral.134
Guidelines may vary from one transplant center to another.
Absolute contraindications include medical conditions, such as renal
insufciency with creatinine clearance of less than 5 mL/min, hepatic
dysfunction resulting in portal hypertension or coagulopathy, or active
or recent cancer with likelihood of recurrence. Other comorbid infections, such as HIV, hepatitis B virus, or hepatitis C virus, are contraindications. Extremes of nutrition may add risk, such as weight of less than
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
COFFMAN
of transplantation. Only 4% of lung recipients require total care at 1 year

after transplantation. QOL remains stable if the course is uncomplicated,
but those who develop bronchiolitis obliterans show a sharp decline in
QOL. Despite the improvement in exercise tolerance and QOL, only
approximately 40% or less of lung transplant recipients return to work.
This may be the result of bias against workers with severe medical
conditions, a fear of losing health insurance or benets, or a change in
priorities after a life-threatening event.156
Several complications may occur after lung transplantation. Primary
graft failure occurs in approximately 15% of cases. Factors involved
include reperfusion injury, surgical trauma, and lymphatic disruption.
Severe hypoxemia in the rst 72 hours after transplantation with inltrates on chest radiography in the absence of infection, rejection, vascular
occlusion, or pulmonary edema is diagnostic. A 60% mortality rate has
been reported, and efforts to retransplant emergently have had poor
outcomes.40, 146 In the early years of lung transplantation, complete dehiscence of the bronchial anastomosis was a dreaded complication but
now occurs in less than 15% of patients. Repair or retransplantation
must be done immediately. Partial ehiscence is managed noninvasively,
with a reduction of steroids. Stenosis of the anastomosis is now the most
common airway complication, may occur within weeks or months of
transplantation, and may require stent placement by bronchoscopy.
The exposure of the lung to the outside environment results in a
higher rate of infectious complications with lung transplant recipients
than other solid organ recipients.112 Early after transplantation, bacterial
pneumonia often occurs. Other pathogens include cytomegalovirus, and
Aspergillus. Cytomegalovirs can be treated with ganciclovir, and efforts
are made to prevent transmission to the recipient by using donor organs
and blood products from seronegative individuals. Aspergillus infection
of the airways can be treated with itraconzole or IV or inhaled amphotericin B. Invasive and disseminated Aspergillus can be problematic in
immunosuppressed patients, especially who that received large amounts
of blood products or were admitted when construction was being done
in the hospital. Patients may appear depressed, delirious, or apathetic
when infected with Aspergillus, which may take several weeks to be
detected as brain abscesses on CT or MR imaging. Invasive Aspergillus
carries a high mortality rate despite treatment with itraconazole or
amphotericin B. In lung recipients, invasive Aspergillus has been reported
to cause fatal erosion into the pulmonary artery.
Differentiating infection from rejection may be more difcult in lung
recipients than other solid organ recipients. The incidence of rejection is
greatest in the rst 100 days after transplantation and declines over
the rst year.18 Symptoms may be nonspecic when present, and a
transbronchial lung biopsy may be positive for rejection in up to 39% of
asymptomatic patients. The use of spirometry for early surveillance for
rejection may be helpful because a 10% fall from baseline often occurs
with rejection; however, spirometry does not differentiate rejection from
infection and is less useful in single-lung recipients because of the
115
inuence of the native lung.22, 152 Treatment of rejection generally includes

a bolus of 1 g of solumedrol, and may be followed by an increase in
steroids followed by tapering the dose. Histologic appearance of rejection on biopsy is typied by perivascular lymphocytic inltration, with
invasion of the interstitial and alveolar spaces in severe rejection.224
Chronic rejection is more common among lung transplant recipients
than among recipients of other solid organ transplant. Sequelae include
pathologic and physiologic changes. Histologically, chronic rejection appears as a broproliferative process, targeting small airways and causing
submucosal brosis and obliteration of the lumen or bronchiolitis obliterans. Biopsy is accurate in as little as 17% of cases. Therefore, the bronchiolitis obliterans syndrome may be diagnosed by observing a sustained
decrease in the FEV-1 of less than 80% of the peak value after transplantation.36, 43 Risk factors suggested for this syndrome include airway
ischemia, cytomegalovirus infection, and human leukecyte antigen mismatching.65 The incidence at 5 years after transplant is 60% to 70%. The
disease presents with dyspnea and cough. The mortality rate after 2
years is 40%.17, 77, 87, 219 Although various immunologic strategies have
been tried to slow the progress of the disorder, none has been superior.
Preventive strategies have included cytomegalovirus prophylaxis to delay the onset of chronic rejection, and the use of tacrolimus, but followup was less than 2 years.52, 62, 107, 101 The future of lung transplantation
depends on overcoming the donor shortage. Several strategies have been
considered, including the use of nonheart-beating donors, the use of
nonoptimal donors, and xenotranplantation.84
PHARMACOLOGY
Drug Interactions Between Psychotropic and
Pulmonary Drugs
A few interactions should be noted when prescribing psychotropic
medications to those with pulmonary disease. The interactions are based
on the human liver microsomal cytochrome system. For example, uvoxamine inhibits the metabolism of theophylline by cytochrome (CY)P1A2. Marijuana can induce metabolism of theophylline, as can omeprazole. Theophylline can reduce serum lithium levels by 20% to 30%,
which could result in relapse; therefore, the lithium dose must be increased and monitored to accommodate for this interaction. Theophylline can also decrease carbamazepine levels and worsen seizure disorder
or alter mood stabilization in bipolar patients. Theophylline preparations, administered concurrently with electroconvulsive therapy (ECT),
can prolong seizure duration, especially if the theophylline level is above
the accepted therapeutic range, even if the level is below that typically
associated with seizures.159 Therefore, precautions may be taken to decrease the risk for prolonged seizures or, rarely, status epilepticus, such
as lowering the theophylline level or, if possible, discontinuing the
116
COFFMAN
theophylline preparation before ECT. Although a course of ECT can be

safely undertaken in severely depressed, medication-refractory patients,
Rasmussen and Korumsky169 discussed precautions that can decrease the
risk for prolonged seizures.
Rifampin has several signicant interactions. Rifampin can induce
metabolism of amitryptiline by CYP 2C9. Rifampin induces metabolism
of diazepam and desmethyldiazepam, donepezil, amitriptyline, chlomipramine, imipramine, and monoamine oxidase A inhibitor moclobemide
by CYP 2C19. Notably, omeprazole can inhibit metabolism of these
drugs by the same enzyme. Rifampin also can act as a substrate at CYP
3A4 and compete with various antidepressants, such as amitriptyline,
imipramine, uoxetine, sertraline, buproprion, nefazodone, venlafaxine,
and trazodone. Rifampin also competes with haloperidol, tegretol, the
benzodiazepines, and zolpidem at this site.7 If sedation is needed in an
asthmatic patient, morphine is contraindicated because of the potential
release of histamine.
Dextromethorphan may compete with tricyclic antidepressants
(TCAs), paroxetine, haloperidol, risperidone, and thioridazine at CYP
2D6. Several drugs can inhibit the metabolism of these substrates,
namely, uoxetine, paroxetine, sertraline, and quinidine.
Delirium in the Pulmonary Patient
Careful review of the patients chart may offer clues to delirium.
Hypoxia or hypercapnia may cause confusion. Metabolic problems often
are seen as a result of treatment of comorbid conditions, such as diabetes,
congestive heart failure, or cancer. Sepsis is a common cause of delirium
in pulmonary patients and may be bacterial, fungal, or viral. The incidence of delirium is higher in those who are ventilator dependent.
Cimetidine can cause delirium. Metabolism of secondary and tertiary
amine TCAs may be blocked by cimetidine. Ranitidine also is a common
cause of delirium, particularly in elderly patients with renal insufciency. In general, omeprazole or famotidine are preferred because they
produce fewer CNS effects. Antihistamines and anticholinergic drugs
frequently cause delirium in elderly pulmonary patients. Benzodiazepines, especially in withdrawal, are also common causes of delirium.
Discontinuation of these drugs and the use of low-dose haloperidol for
agitation generally allows the delirium to resolve over several days. The
use of sitters or soft restraints to prevent falls is important because many
pulmonary patients are elderly.
Treatment of Anxiety Disorders in Pulmonary Disease
Many drugs used to treat pulmonary disease may cause anxiety.
Theophylline, a methylxanthine, can cause nausea, tremor, and restlessness. Theophylline levels may be reduced from 50% to 80% by tobacco
117
smoking. Marijuana also may increase theophylline clearance. Nicotine

gum does not have this effect. Alcohol can reduce clearance of theophylline up to 30% for up to 24 hours. Larger doses of benzodiazepines may
be needed with theophylline. Theophylline blocks adenosine receptors,
whereas benzodiazepines increase CNS adenosine, which is a CNS depressant. Lithium increases renal theophylline clearance. Estrogen and
disulram decrease theophylline clearance.161
Terbutaline is a -adrenergic agonist bronchodilator often used in
treatment of asthma. This drug can cause marked anxiety and increase
in heart rate in 35% of patients and tremor in 15% of patients. This drug
has been reported to cause prolongation of the QT interval, although
the signicance of this observation is not known. Use of terbutaline
within 2 weeks of discontinuation of TCAs or monoamine oxidase
inhibitors may potentiate the vascular effects of terbutaline, and extreme
caution is advised.162 Montelukost sodium (Singulair) also can cause
anxiety in susceptible patients and can cause headache. Montelukast
sodium is metabolized through CYP 3A4 and 2C9 and so may cause
interactions similar to those of rifampin.
Beta-blockers cannot be used for anxiety in asthmatic patients because they cause bronchoconstriction. In anxious, pulmonary patients
with hypercapnia, buspirone is preferred for treatment of anxiety. If the
patient does not retain carbon dioxide, then shorter-acting benzodiazepines with no active metabolites, such as lorazepam or oxazepam, are
preferred. If the patient is not elderly, and has panic disorder, then
longer-acting benzodiazepines, such as clonazepam may be used for
better control. Selective serotonin reuptake inhibitors (SSRIs) may be
helpful in treating panic symptoms. Buspirone has no efcacy in treating
panic disorder.188 High doses of buspirone, 10 to 20 mg/kg body weight,
can increase ventilation and respiratory rate in animal studies.135 Buspirone does not depress the respiratory response to inhaled carbon dioxide
as diazepam does.167 For generalized anxiety in patients with severe
chronic lung disease, buspirone may be the drug of choice.48
Behavioral methods are another possible intervention for panic. If
panic does not respond to these measures, then haloperidol may be
effective in low doses. In very high doses, more than 100 mg/d, haloperidol may cause laryngospasm or paradoxic intercostal muscle movements. Bear in mind that pulmonary patients may be especially vulnerable to akathisia with drugs such as compazine and metoclopramide. One
series of patients at a regional weaning center showed a 7.6% incidence
of akathisia. Drug-induced parkinsonian symptoms also may occur with
compazine, metoclopramide, and amiodarone. Extrapyramidal symptoms may occur with these drugs. With amiodarone, chewing movements and shoulder girdle movements may occur.
Treatment of Depression in Pulmonary Disease
Treatment of depression includes consideration of the CYP 450
interactions mentioned earlier. In general, SSRIs, such as paroxetine and
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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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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
0193953X/02 $15.00 .00
PSYCHIATRY OF THE MEDICALLY

ILL IN THE BURN UNIT
Sunny T. Ilechukwu, MD, DPsych
In the United States, approximately 5500 people died as a result of

re and burns in 1991, and 51,000 required hospitalization of an overall
1.25 million persons burned.13 The Centers for Disease Control and
Prevention caution that, of all developed countries, the United States
still has the highest death rate from res (2.1 per 100,000).17
Nonetheless, and in marked contrast to pre-1970s medical era, more
people now survive massive traumaincluding burn trauma. Before
1970, a burn involving more than one third total body surface area
(TBSA) was almost always fatal.77 The question has been raised of
whether the psychological needs of patients are being adequately met
especially as more disgurement has arisen from more severely damaged persons being saved. The wisdom of saving the lives of massively
burned children (i.e., 70% TBSA) has become a health policy and
ethical question.30
The psychiatric burn consultant may be involved in the provision
of care for patients during any of the usually recognized three phases of
burn care: (1) acute, (2) reconstitutive, and (3) long-term adjustment
phase (LTAP).91 The effectiveness of the consultant is enhanced by an
appreciation of the risk factors in burn injury.
PSYCHIATRIC RISK FACTORS IN BURN INJURY
The medical literature has consistently documented that patients
with burn injury often face increased demands for adaptive functioning
From the Medical Psychiatry Clinical Research Division, Department of Psychiatry and
Behavioral Neuroscience, Wayne State University, Detroit, Michigan

129
130
ILECHUKWU
after burn injury, encumbered with psychiatric illness, substance abuse,

or cognitive impairment. Although many victims of structural res are
innocent victims of circumstance, most victims of individual burn injuries have important predisposing factors.
MacArthur and Moore52 had found that 59% of female and 38% of
male burn inpatients had signicant predisposing factors to burn injury.
Drug and alcohol abuse was the most prevalent factor. Twenty-one
percent of this predisposed group suffered senile dementia, and 20%,
schizophrenia or manic-depressive illness. Predictors of mortality in
burn injury included extremes of age, extent of inhalational injury, TBSA,
and ethanol use.55 This study also found greater TBSA, more common
inhalational injury, and a higher mortality rate among substance abusers
than among controls. One study of 155 adult patients with burn injury8
found an increased mortality rate among patients with a diagnosis of
personality disorder, schizophrenia, or ethanol intoxication on admission. Suicidal ideation; a diagnosis of personality disorder, schizophrenia, or senility; self-destructive behavior during burn care; and an inability to care for oneself also were found to prolong hospital length of stay.
These ndings have been widely replicated.35, 62, 84 Haum et al35 found
an increased mortality rate among alcoholics with burn injury compared
with nonalcohol abusers (31.5 % versus 18.1%) but found no difference
between intoxicated versus nonintoxicated alcoholics. These data emphasize the need to obtain a careful history rather than just rely on laboratory
ndings. Ilechukwu et al40 reported abuse of ethanol alone or in combination in 55% of all patients with burn injury referred to psychiatry. The
prevalence of alcohol and substance abuse in this population has been
estimated at 20% to 80%.12, 38, 89 Bernstein et al,7 at the New York Burn
Center, estimated that 20% of patients with burn injury had alcoholrelated problems. Swenson et al84 reported a trend of increasing substance
and alcohol abuse (especially psychostimulants) among all patients with
burn injury. Substance abuse in the home and involvement in the substance-using subculture also carries considerable risk for burns. For example, 25% of all psychiatry consultations at the Detroit Medical Center
Burn Unit involved intoxicated spouses, lovers, friends, and relatives or
disputes over drug deals and purchases.40 Self-immolation often provokes
especially strong countertransference reactions but should be regarded as
one form of attempted suicide. Sonneborn and Vanstraelen78 found a
psychiatric history in 70% of self-immolation patients, among whom 55%
had previously attempted suicide.
BURN EPIDEMIOLOGY IN CHILDREN
In the United States in 1994, res alone claimed 3.75 to 4.99 lives
per 100,000 child years and accounted for 17.3% of all injury deaths in
children aged less than 5 years.76 A combination of developmental and
environmental factors are responsible for increased risk for burn injury
in children. Increased exploratory activity, unsupervised or careless ac-
PSYCHIATRY OF THE MEDICALLY ILL IN THE BURN UNIT
131
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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ILECHUKWU
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
is marked by disorientation, agitation, assaultiveness, pulling out of life

support tubes and IV lines, attempts to leave the hospital against medical
advice, falls, and displacement of skin grafts. Early estimates indicated
an occurrence of delirium in 18% to 70% of patients.3, 4, 11 Current estimates are lower. Delirium was associated with electroencephalographic
abnormalities2, 4 and was a poor prognostic indicator. The cause of burn
delirium is multifactorial. The most often mentioned causes are burn
catabolic states, smoke inhalation, hypoxia, carbon monoxide poisoning,
infection, CNS and other undetected injury, and opioid medications
given to reduce pain.
Because many of these patients also have ethanol and other substance dependence, characteristic substance withdrawal also may occur.
Alcohol withdrawal tends to occur a few days later but often is difcult
to differentiate from burn delirium.
ASD is a relatively new diagnostic category in the DSM-IV1 that
describes acute symptoms that have lasted less than 1 month and resolve
before they reach the 1-month threshold for posttraumatic stress disorder
(PTSD). Clearly, a good proportion of the 20% of patients with burn
injury estimated to have PTSD3 would have had ASD. How many of
them had ASD and how many that progressed to PTSD and under what
circumstances is unclear. The majority of stress syndromes emerge in
the reconstitutive and LTAP of recovery.
Pain is also a great concern in the acute phase, but pain thresholds
vary among patients. Dressing changes and debridement are particularly
sore times, and patients surmising that staff are indifferent or callous
often lose condence and mistrust caregivers,54 especially when physicians have unrealistic fears about addiction63 and undermedicate. Pain
always should be considered when assessing the cause of violent and
disruptive states after burn injury.
Two conicting psychological issues predominate in the acute
phase: (1) denial of disgurement and (2) the need to know.91 Other
psychological issues include bewilderment by the strange, high-tech,
and ever-busy intensive care unit; projection; regression; mourning;
and coping.7
Treatment Measures in the Acute Phase

Delirium
The objectives of the treatment of delirium are reduction of cognitive
impairment and subjective distress, minimization of disruption of lifesupport gadgets (e.g., IV lines and ventilatory tubes), skin grafts, and
facilitation of further evaluative and rehabilitative procedures; however,
psychiatrists in the burn unit have to remind themselves to be a lot
more involved in making medical recommendations than on general
medical units, where much more medical support is available. They
need to take the initiative for requesting other consultants and laboratory
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ILECHUKWU
test recommendations to determine the specic causes of delirium (e.g.,

hypoxia, seizures, hypoglycemia, or head trauma) and should refer
directly to the appropriate specialists. The psychiatric consultant takes
specic leadership in the pharmacologic management of burn delirium,
withdrawal delirium, and pain relief.
Management of agitation associated with burn delirium most commonly follows the guidelines of Cassem and Murray16 or a modication
of them. Table 1 represents such a modication.
The IV route for haloperidol is usually widely employed even
though it is not FDA-approved and requires monitoring for QTc prolongation and ventricular arrhythmia. (Some psychiatrists in the Veterans
Administration care systems have reported opposition to IV use and so
may restrict care to the slower-onset intramuscular route). When agitation subsides after dosing but reemerges later, one approach is to divide
the total dose of haloperidol that has controlled agitation into scheduled
6-hourly doses while retaining as-needed doses of haloperidol and lorazepam. This is a strategy analogous to that used for insulin sliding-scale
dosing. If a patient remains calm over the next 24 hours and does not
require as-needed dosing, it usually makes sense to begin taper of both
medications. Because the aim of use of haloperidol in this context is to
calm the patient as quickly as possible, some clinicians have run it as an
infusion, 10 to 25 mg/h.28 Large, single-bolus doses ( 200 mg) and
daily doses ( 1600 mg) have been reported16; however, prolongation of
QTc interval ( 0.450 ms) and increases the risk of sudden death caused
by torsades de pointes also have been reported.39 The risk is thought to
be higher in female patients and in hypokalemia. The American Psychiatric Association treatment guidelines for delirium recommend cardiac
monitoring and serum magnesium and potassium monitoring during IV
haloperidol use.86 Many other parenteral antipsychotics are available but
also carry the potential for signicant adverse events and are not FDAapproved for delirium. Chlorpromazine is a potent -adrenergic blocker
associated with severe hypotension but is an alternative that does not
require benzodiazepine adjunct because of its sedative effects. Droperidol has been used but has been withdrawn from the market in Europe
for reasons related to its cardiotoxicity. Intramuscular olanzapine curTable 1. SCHEDULE FOR MANAGEMENT OF AGITATION IN THE BURN UNIT*
Medications (Haloperidol/Lorazepam)
Time
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
*Comparisons are based on im data and taken as equivalent to IV.

Dilaudid hydromorphone; Numorphan oxymorphone.
IM intramuscularly; IV intravenously; SC subcutaneously; MS morphine sulphate; PR per rectum.
Data from Derby S, Chin J, Portenoy RK: Systemic opioid therapy for chronic cancer pain. Practical guidelines for converting drugs and routes of administration. CNS
Drugs 9:99109, 1998.
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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ILECHUKWU
trauma associated with PTSD.75 Other factors cited as precipitating or

predisposing include the patients negative subjective appraisal, presence of physical versus nonphysical injury (20% versus 3.5%),36, 61 and
alexithymia31 (even though this also taps into the emotional-numbness
criterion of PTSD). After prolonged use of short-acting benzodiazepines,
discontinuation may lead to a subclinical, PTSD-like withdrawal syndrome that is specically responsive to benzodiazepines or carbamazepine.46 Some factors thought to be mitigating, such as debrieng
after disaster88 and rapid and focused psychological treatment,53 may be
exploited preemptively and therapeutically. PTSD also may affect more
than 50% of mothers of burned children, impairing their capacity to
provide supportive care.69 Risk factors for maternal PTSD include large
TBSA, being burned themselves, and having more than one child
burned. Also important in the reconstitutive phase are sleep disturbances48 and various adjustment disorders. The following case illustrates
reconstitutive challenges after burn injury.
Case 2
Mr. G is a 40-year-old, white man seen initially for competency determination. The patients ancee had claimed power of attorney said to have been
obtained the previous day, in the hospital. Mr. G and his two teenage children
from a previous marriage lived with his ancee, who had ve children of her
own. Mr. Gs sister disputed this power of attorney. Workers compensation was
involved, and his medical insurance was good.
Mr. G had 40% TBSA burns that affected his torso and lower extremities
sustained more than 4 weeks before psychiatric consultation. He had also suffered smoke inhalation. Burns were sustained in a work accident. He was under
a large truck, trying to loosen a stuck bolt with a blowtorch, when an explosion
occurred. In the hospital, the patient suffered anoxic encephalopathy, pneumonia, and adult respiratory distress syndrome and required tracheostomy and
ventilatory support. He had also received multiple skin grafts. He had a history
of depression, but alcohol and substance abuse were denied. The patient was
described as a slow learner in school. On examination, he was disoriented in
place and time and was unable to communicate consistently both verbally and
nonverbally. The psychiatric consultant made a diagnosis of delirium of multiple
causes and recommended guardianship.
Reevaluation was requested 1 week later, again for competency. He was
found to be more verbal and recalled the details of the accident. He was
tearful and reported nightmares and re-experience of the re incident. Cognitive
functions were much improved. A diagnosis of PTSD was made, as were recommendations to re-empower the patient to resume decisions for himself.
After discharge, he was followed up in the outpatient clinic and readmitted
later for left ulnar nerve entrapment secondary to heterotopic bone formation
that required neurolysis and transposition. The only visible scars were few and
conned to the neck area. No deformity or limitation of movement functions
was present.
He continued to display weepy spells, ashbacks, dissociation, free-oating
anxiety, and marked avoidance behavior. Fresh road tar evoked memories of
burning tires during the accident, making road use often quite distressing. He
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.
The following case illustrates rehabilitative challenges after burn injury.

Case 3
Ms. M is a 24-year-old, white woman admitted with TBSA 80% burns and
smoke inhalation 2 months before psychiatry consultation was sought. Burns
were sustained when the father of her daughter set her and her daughter ablaze.
Also, a telephone cord was wrapped around her neck when the police found
her. She was pregnant at the time but had had a miscarriage after the burn
injury. Her daughter was admitted to a childrens hospital burn unit at the same
time and bilateral below-knee amputations were required. Urine drug screen
was negative, and there was no history of alcohol abuse. Ms. M had multiple
skin grafts and later required left-arm amputation. Her face was badly burned
and, despite plastic-surgical repair, still looked quite grotesque. She was deaf
and dysphonic from her injuries. She refused to use her hearing aids because of
association with headaches. Communication was done by writing board and lip
reading. Consultation was sought for depression. She admitted sleep difculties
secondary to pruritus but denied depression, death fantasies, nightmares, and
ashbacks. She was angry with her assailant and wanted justice to take its
course. A diagnosis of adjustment disorder with depressed mood was made.
Her sleep improved on trazodone, 75 mg.
During another of her many admissions, psychiatric consultation was requested specically to consider the use of methylphenidate for apathy and lack
of participation. She rejected any antidepressants. She was seen several times
over a 3-year period for adjustment issues or for anxiety preceding the many
surgical procedures she had to undergofor example, for release of contractures
of both lower extremities, reconstruction of eyelids, myocutaneous trapezius ap
to the neck, and so on. Pruritus was a continual problem. Phantom ngers was
a source of annoyance. She needed help even for intimate activities of daily
living (ADL) but often displayed remarkable and sometimes robust humor. Her
father was her primary care provider. She had two separate admissions into
acute rehabilitation for gait training and independence with ADL. She initially
required a lot of encouragement to attend support group meetings for burn
victims but later attended regularly even after discharge. Sometimes she attended with her preschool-aged daughter, who played around uninhibitedly on
her prosthetic legs.
The cases of Mr. G and Ms. M illustrate the clinical psychiatric

challenges presented at various stages of recovery from burn injury.
The acute and restitutive phases have been discussed. These vignettes
illustrate many of the problems of the LTAP.
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ILECHUKWU
LONG-TERM ADJUSTMENT PHASE AND

LONG-TERM OUTCOME
Clinical work in the area of LTAP has been guided by studies that
measured quality of life (QOL), return to work (RTW), and return to
school (RTS). The Burn Specic Health Scale (BSHS), originally consisting of 114 items9 and now abbreviated to an 80-item scale,57 has
become a major research tool. Initial research experience with the longer
version led workers to these conclusions:
The psychological performance of patients with major burns lags
behind their performance in other areas.
The BSHS can be used to determine both individual and group performance and needs for intervention.
Postburn recovery is dynamic and undergoes marked changes for a
prolonged period of time, at least 1 year after hospitalization.
Currently available data56 link BSHS scores (as a measure of QOL)
to preinjury educational level, postinjury stress disorder, and predictability of RTW. One surprising conclusion is that total burn size has little to
do with QOL after burns. Also, the initial better adjustment of a nodiagnosis group compared with a positive-diagnosis group (e.g., mood,
anxiety, and substance use) did not hold after 4 months of discharge.26
Using the BSHS, Jones et al41 tried to predict psychosocial outcome
and physical functioning from degree of burn, location of burn, and
hospital length of stay. Some ndings were counterintuitive but consistent with other researchers ndings. At the predischarge stage, the
degree of burn severity strongly predicted the patients functioning;
however, patients with rst-degree burns reported lower physical and
psychological functioning on the BSHS. Conversely, during the acute
phase, patients with third-degree burns reported higher psychological
functioning in mental and social domains.
Other specic factors identied as contributory to QOL of patients
with burn injury include scar formation and deformity. Development
and maturation of scars are inuenced not only by individual and racial
differences but also by psychological factors.47 Perceived reduction in
sexual attractiveness often is attributed to scars but may be more related
to PTSD and should be treated with all approaches, including medications that are often blamed for sexual dysfunction.20
Pressure therapy (pressure garments), is regarded as effective in the
management of visible scars.18 Pressure suits are made of nylonspandex.
They are custom made for the healing body parts and sized to the
individual. The experience of wearing them has been compared with
that of wearing tight bike shorts. The garment has a molding effect on
scar tissue as it is being formed and so affects the appearance of the
scars; however, the inconvenience and impaired (mummylike) appearance associated with these garments are major drawbacks to compliance,
especially among young patients. One attempt to improve compliance
141
was a choice of colors and involvement of patients in choosing personal colors.

Previous psychiatric illness predicts postburn depression fairly well.
The role of continued substance abuse in the long-term outcome of burn
injury has not been studied much, but the well-accepted impact on
general psychosocial function suggests that ethanol and substance abuse
would be expected to have deleterious effects.
RTW is a complicated index of outcome. Multivariate analysis of 15
variables in a recent study of 225 patients after 12 months of discharge
identied four variables as signicant93:
Being white
Not blaming oneself
Receiving workmens compensation
Being employed before injury
Preinjury employment was the most powerful predictor of RTW
after burn injury. Other studies72 suggest that persons with health insurance were more likely to return to work, whereas those covered by
Medicaid and those involved in injury-related lawsuits were less likely
to do so.
CHILDREN AND BURNS
Burn injury can delay developmental milestones.81 Sleep disorders
are reported to be especially prevalent37% for nightmares and 24%
enuresis.48 Regression to an earlier childhood pattern of daytime napping
also was reported in 63% of patients. In one study, 51 children (average
age, 27 months) showed developmental language delay for up to 1 year
despite good physical and functional outcome.34 RTS has been used as
an outcome measure.79 After an average of 30.8 days in hospital (i.e., 22
missed school days), children with burns were back in school within 7.8
days (mean) and showed good or even better grades compared with
preinjury performance. Pre-reentry interventions may have been the
difference and should be highly encouraged. Difculty in RTS correlated
positively with preinjury school problems. Burn camps provide one way
of facilitating RTS and resocialization in this vulnerable group.22
Although long-term follow-up in burned adults is not associated
with an increased incidence of major depression,3 burned children have
an increased risk for anxiety and mood disordersa 10% to 20% 5-year
prevalence according to Herndon et al.37 There are also reports of burned
children exhibiting higher self-esteem than normative groups.49 Satisfaction with life may be expressed even though QOL may be decreased.47
This optimistic outlook may be a necessary defense mechanism and
needs to be supported rather than confronted.49 This nding of positive
self-image is sustained even in severely burned children with 80% or
more TBSA; however, the parents show higher parental stress scores
compared with control parents.10
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Burned adolescents face additional problems of coping because

body image changes and peer group acceptance are particularly important to this age group. Facial disgurement is the greatest factor in
predicting poor postburn adjustment in adolescents.74
One useful conceptual model for working with survivor children
and adolescents was derived from a content analysis of a 30-item,
sentence-completion inventory administered to a sample of survivors
(Robert et al70). They described ve themes about postburn life:
1. Preoccupation with health (example: I want to know whether the
surgery will work, versus I want to know when I am going
home.)
2. Struggle for internal acceptance (example: There is nothing worse
than being burned, versus There is nothing I cant do.)
3. Reconstruction of ones life map (example: I am afraid of not
being successful, versus I know I can be just as good as the
other kids.)
4. Awareness of changing relationships (example: I am afraid to let
my friends know Im not going to be like I was before, versus
People are always supportive, asking what happened.)
5. Redening the world (chaos versus meaning) (example: I am
afraid of natural disasters, versus I want to know why I had to
get burned.)
Each of the themes manifest ambivalent trends such that therapy
work could consist of encouragement of the healthy trends.
SUPPORT GROUPS FOR BURN VICTIMS
Support groups for burn victims have become indispensable assets
for surviving burns. They are characteristically self-help and inspirational. Burn Survivors On-Line,24 for example, asserts that you will
never nd a stronger willed person than the Burn Survivor, for they
have suffered the worst injury to the human body any one can endure
and survived. Survivors nd the culture in which everyone you meet
has burn scars . . . an incredibly empowering experience.24 The bestknown group is Phoenix.
Many support groups are available on the World Wide Web and are
easily accessed. One notable effort also attempts to inuence burncare providers,58 especially because many workers insist that the real
revolution in burn care is the organization of care delivery and the
dissemination of burn-care information and guidelines at appropriate
levels of care.47
BURN PREVENTION, COSTS, AND ETHICS
Treatment of burns is one of the most expensive areas of health
care. Individual patients have easily run up costs of more than $1
143
Resources Provided by Phoenix

Provision of peer support
Provision and dissemination of information about burns
Referrals to surgical rehabilitative and psychological resources
Running of reentry programs for work and school
Participation in research
Advocacy
Disaster relief
Legislative lobbying
Organization of a Burn Survivor Sunday
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
144
ILECHUKWU
Poor supervision of children and impaired elderly persons

Careless handling of ammable materials
Many clinical syndromes, such as delirium, ASD, acute psychosis,
suicidality, and pain need to be addressed by the consulting psychiatrist
to facilitate surgical treatment of the burn injury. Other psychiatric
disorders, such as PTSD, major depression, and adjustment disorder,
need to be treated to expedite long-term adjustment. Hospital length of
stay and RTW/RTS are major outcome variables. The psychiatry consultant can positively affect both variables substantially using both pharmacologic and psychosocial measures. The important role of psychiatric
issues both before and after burn injury support the need for more
consistent and comprehensive medical insurance coverage for psychiatric consultation to burn units and clinics. Burn Support Groups are an
invaluable asset.
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Sunny T. Ilechukwu MD, DPsych
6 Hudson, Harper University Hospital
3990 John R
Detroit, MI 48201
e-mail: Sunday@med.wayne.edu
0193953X/02 $15.00 .00
PRACTICAL
PSYCHOPHARMACOLOGY IN
HIV-1 AND ACQUIRED
IMMUNODEFICIENCY SYNDROME
Michael J. Robinson, MD, and Roula B. Qaqish, PharmD
Psychiatric disorders, including mood disorders, anxiety disorders,

substance use disorders, cognitive disorders, personality disorders, psychotic disorders, and delirium, are highly prevalent among patients
infected with HIV-1. HIV-1 infection rates among patients with psychiatric disorders also appear to be high. Psychopathology may have an
important impact on treatment adherence, quality of life, HIV-1 risk
factors, social and adaptive functioning, and possibly HIV-1 illness progression. For these reasons, psychiatrists treating patients infected with
HIV-1 have many important roles, as listed in Table 1.
The psychopharmacologic treatment of patients infected with HIV1 follows the same principles of using psychotropics in other medical
populations. Patients with HIV-1/acquired immunodeciency syndrome
(AIDS) may be at increased risk for side effects and drugdrug interactions with combination antiretroviral regimens and other commonly
used medications (e.g., antituberculous agents, antifungal agents, antimicrobial agents). This article reviews the psychopharmacologic treatment
of major psychiatric syndromes in patients infected with HIV-1. The rst
section outlines the use of psychotropic medications for depression,
anxiety, mania, psychosis and delirium, and cognitive disorders. The
second section specically focuses on known, potential and theoretic
drugdrug interactions between psychotropics and antiretrovirals. A
discussion of potential psychotropic drugdrug interactions with other
From the Division of Consultation-Liaison Psychiatry, Department of Psychiatry, Queens

University, Kingston, Ontario, Canada (MJR); and the Division of Pharmacy, St. Louis
College of Pharmacy, St. Louis, Missouri (RBQ)

149
150
ROBINSON & QAQISH
Table 1. POTENTIAL ROLES OF THE PSYCHIATRIST IN CARE OF THE HIVINFECTED PATIENT

Establishing and maintaining a therapeutic alliance
Collaboration and coordination of care with other mental health and medical providers
Diagnosing and treating all associated psychiatric disorders
Facilitating adherence to the overall treatment plan
Providing education about psychological, psychiatric and neuropsychiatric disorders
Providing risk reduction strategies
Maximize psychological and social adaptive functioning
Considering the role of religion and spirituality
Preparing the patient for issues of disability, death and dying
Advising signicant others/family regarding sources of care and support
Adapted 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.
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.
Table 2. RANDOMIZED TRIALS

Study
Year
Medication
Antidepressants and Stimulants

2000 Dextroamphetamine
Wagner GJ, et al85
Placebo
Schwartz JA, et al77 1999 Fluoxetine

Desipramine
Effect
Size*
Depression
Measures
1.66 (11) SCID (DSM-IV),

0.84 (11)
HAM-D, BSI,
BHS, VAS,
CGI
1.50 (8)
0.60 (6)
Rabkin JG, et al68
1999 Fluoxetine
Placebo
2.79 (81)
2.04 (39)
Markowitz JC, et
al51
1998 Imipramine (SWI)

IPT
Supportive psychotherapy
CBT
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
At baseline, 53% major depression, 13% dysthymia, 35% minor

depression or subthreshold major depression; 73% of the
dextroamphetamine group and 27% of the placebo group
responded to treatment; Note: dextroamphetamine was less
effective in those who had major depression compared with
those who had more mild depression.
SCID (DSMStudy participants were women only, with advanced HIV
IIIR), HAM-D,
disease, and most had prior depressive episodes by history;
CGI
insufcient power to detect differences between treatment
groups; 38% of uoxetine group and 33% of desipramine
group had a partial response dened as 50% reduction in
HAM-D score at 6 weeks, whereas 25% and 17%
respectively for full response dened as HAM-D score 8.
CGI, HAM-D,
In completers there was a 74% response rate to uoxetine, and
BSI
a 47% response rate to placebo; Intent to treat analysis,
however, showed no signicant difference (57% vs. 41%).
SCID (DSMOnly 53% of the sample met DSM-IIIR criteria for depression
IIIR), BDI,
on SCID, and about half the sample population had an axis
HAM-D, PDE
II disorder and a lifetime substance abuse history; scores on
HAM-D decreased signicantly for all groups, and BDI
scores fell signicantly only for IPT and SWI groups.
SCID (DSMOf the 79% who completed the trial, 64% of uoxetine treated
IIIR), HAM-D,
vs. 23% of placebo had a 50% decrease in HAM-D score.
BDI-13, CGI-I,
Differences were particularly apparent for those whose
CGI-S
depressive episodes were rated as severe (HAM-D 24).
Table continued on following page
151
152
Table 2. RANDOMIZED TRIALS (Continued)
Study
Elliot AJ, et al
Year
16
Medication
1998 Paroxetine
Imipramine
Placebo
Fernandez F, et al23 1995 Desipramine

Methylphenidate
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.
Rabkin JG, et al69
2000 Testosterone
Placebo
Rabkin JG, et al67
1999 Testosterone
Placebo
0.80 (38) SCID (DSM-IV),

0.49 (32)
HAM-D, BDI,
BSI
Of the 26 completers with current syndromal mood disorder,

58% randomized to testosterone and 14% randomized to
placebo were mood responders based on CGI score.
Mood disordered patients randomized to testosterone showed
signicantly more improvement on all measures of HAM-D
than placebo treated except the affective subscale.
Note: patients taking antidepressants were included in the
trial.
1.50 (37) SCID (DSM56% had depressed mood at study baseline, and of these 54%
0.03 (40)
IIIR), HAM-D,
had major depression and the remaining had elevated
CGI, BSI
scores on HAM-D, but no current axis I depressive disorder;
during open treatment phase, 79% with axis I depressive
disorder showed signicant improvement in mood; during
double-blind discontinuation phase, measures of mood
showed no decline in those receiving testosterone versus a
quick and signicant decline for those on placebo.
Median effect size

Antidepressent
Stimulant
Testosterone
Placebo
CBT/IPT
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.
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Newer antidepressant agents (i.e., uoxetine, sertraline, paroxetine,

uvoxamine, citalopram, venlafaxine, nefazodone, and bupropion) are
often better tolerated than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), but side effects may still limit their
use. Side effects from serotonergic agents may result from stimulation
of 5-HT2A (e.g., insomnia, anxiety or agitation, and sexual dysfunction),
5-HT2C (e.g., irritability and decreased appetite), and 5-HT3 (e.g., nausea,
vomiting, and headache) receptors. Side effects from newer agents also
may result from noradrenergic receptor stimulation (e.g., tachycardia,
blood pressure effects, dry mouth, and sweating) and from interactions
at other receptors, including muscarinic, histaminergic, and postsynaptic
1-adrenergic receptors (e.g., dry mouth, sedation, postural hypotension).70 It is important to keep these potential side effects in mind when
choosing an antidepressant for a patient with HIV-1/AIDS. In particular,
if patients are on HAART, with a large pill burden, selecting an agent
that is well tolerated with low risk for drugdrug interactions is important to promote medication adherence. Clinical pearls regarding the
use of antidepressants in patients with HIV-1 are listed in Table 3.
In addition to traditional antidepressant agents, testosterone treatment has been found to be effective for depressive symptoms, which
occur in the context of men with hypogonadal symptoms (e.g., diminished libido, depressed mood, low energy, and depleted muscle mass).
Table 2 summarizes the results from randomized trials. Their efcacy
also is supported in nonrandomized trials.
Psychostimulants, including methylphenidate, dextroamphetamine,
and pemoline, may be useful in the treatment of HIV-1infected patients
for depression with or without cognitive impairment and for pain syndromes. In advanced HIV-1 disease, psychostimulants have been shown
to improve cognitive performance, apathy, fatigue, withdrawal, anorexia,
suicidal ideation, and self-care.52 Stimulants are preferable to traditional
antidepressants in terminally ill HIV-1 patients because of their quicker
onset of action. Based on reports of the development of irreversible
abnormal involuntary movements in depressed patients with HIV-1
associated dementia, the current recommendation is to avoid dextroamphetamine in this population.20 Methylphenidate can be given by mouth,
feeding tube, or suppository. The advantage of pemoline is its availability in a tablet form that can be dissolved in the mouth and absorbed
through the buccal mucosa for patients who are on NPO (nothing-bymouth) restrictions.82 Potential disadvantages of pemoline are delayed
onset of action (23 weeks) and need to monitor liver function because
of idiosyncratic toxicity.9 Side effects may include movement disorders,
psychosis, and seizures. Although clinical experience with psychostimulants in the medically ill, including HIV-1/AIDS, suggests a low tendency toward tolerance and abuse, all psychostimulants have abuse
potential and should be used judiciously in patients with a history of
substance abuse.
PRACTICAL PSYCHOPHARMACOLOGY IN HIV-1 AND AIDS
155
Table 3. USING NEWER ANTIDEPRESSANT AGENTS IN PATIENTS WITH HIV/AIDS,

CLINICAL PEARLS
Medication
Clinical Pearls in HIV/AIDS Patients
Nefazodone
Inhibitor of CYP3A4use caution when combining with protease

inhibitors (see section on drug interactions for more information).
Venlafaxine
Higher rates of nausea and anorexia may not be well tolerated by patients
with HIV/acquired immunodeciency syndrome (AIDS); dosedependent increase in blood pressure.
Bupropion
Use with caution in patients with intracranial pathology (e.g.,
toxoplasmosis, CNS lymphoma, CMV) as there may be an increased
seizure risk; no longer contraindicated with protease inhibitor Ritonavir
Mirtazapine May promote weight gain (useful in patients with signicant AIDS
wasting). May alleviate nausea (by way of its 5-HT23 blockade); useful
for patients with poor sleep; now available in an orally disintegrating
tablet, which may be useful in severely ill patients; lack of sexual
dysfunction, minimal GI side effects.
Fluvoxamine One study in HIV patients found that it was poorly tolerated despite
showing efcacy; may not be a rst-line agent.
Fluoxetine
Well tolerated and clinically effective in studies to date; due to its
activating properties, it may not be rst line medication in patients with
signicant comorbid anxiety or insomnia; no reported effect on immune
function, when studied.
Paroxetine
Mild secondary muscurinic-antagonistic properties may make this drug a
second-time choice in an HIV/AIDS patient with cognitive impairment.
Sertraline
Well tolerated and clinically effective in studies to date; no reported effect
on immune function, when studied.
Citalopram
Most selective SSRI, with no secondary properties which limits nonserotinergic side effects.
TCAs
Anticholinergic side effects may cause urinary retention, paralytic ileus,
dry mouth (which may increase risk for oral opportunistic infections
such as candidiasis), cognitive dysfunction and may worsen confusion;
other side effects may be problematic including orthostatic hypotension,
and cardiac arrythmogenicity.
MAOIs
Avoid due to the complex, often changing drug regimen and the potential
for fatal hypertensive crisis, and drugdrug interactions.
CYP cytochrome P-450; CNS central nervous system; CMV cytomegalovirus; 5HT 5hydroxytryptamine; GI gastrointestinal; SSRI selective serotonin reuptake inhibitor.
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
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short to intermediate half-lives are preferred to decrease the potential

for accumulation and side effects, such as oversedation, disinhibition,
cognitive impairment, and confusion. The biggest concern when using
BDZs is the potential for drugdrug interactions.30
Buspirone, an alternative to BDZs, was found to be tolerated in
patients with HIV-1 for the treatment of generalized anxiety.5 It has the
advantages of being nonsedating and nonaddictive, and it has few
known drugdrug interactions in patients with HIV-1/AIDS. Disadvantages include a slow onset of action (usually 2 to 3 weeks), and it has
not been well studied in the medically ill in general. One case of
buspirone-induced psychosis with manic features in a patient with HIV-1
has been reported.83 Other cases of buspirone-induced mania in patients
without HIV-1 also have been reported.54, 55, 63 Despite these limited case
reports, it seems to be a reasonable alternative in treatment of general
anxiety in HIV-1/AIDS.
The antidepressant trazodone, in low dosage (25 to 200 mg/d), is
useful for the treatment of anxiety, agitation, and insomnia. It is usually
well tolerated, with an immediate sedating and calming effect, unlike
buspirone. Although it poses a small risk for priapism, it generally lacks
signicant systemic side effects, although in higher doses, the risk for
hypotension and sedation is increased.
Other antidepressants to consider for the treatment of generalized
anxiety include venlafaxine, which has received a clinical indication for
generalized anxiety disorder from the US Food and Drug Administration. The suggestions outlined in the preceding section on depression
are also appropriate when treating other anxiety disorders in which
antidepressant medications are often rst-line treatments (e.g., panic
disorder, obsessive-compulsive disorder, social anxiety disorder, and
posttraumatic stress disorder).
Manic Syndromes
Manic syndromes in patients with HIV-1 may be considered primary or secondary. Primary manic syndromes are those that occur in
HIV-1 patients with a preexisting personal or family history of bipolar
disorder and may occur at any time during the course of HIV-1 infection.
Treatment of primary mania is not substantially different from the usual
treatment of bipolar mania in patients without HIV-1. Secondary mania
(HIV-1associated mania, or AIDS mania) most often occurs late in the
course of HIV-1 infection and is thought to result from HIV-1 brain
involvement. HIV-1associated mania may be differentiated from primary mania in HIV-1infected patients by its late onset in the course of
HIV-1 infection and its common association with cognitive decline or
AIDS dementia. Frequently, no prior personal or family history of bipolar disorder is found. Of course, it is also possible for an HIV-1 patient
to have a manic episode that has primary and secondary characteristics.
Clinically, HIV-1associated mania tends to present with more irritability
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
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effects including sedation, fatigue, and dizziness. It is not metabolized

by the liver or protein bound, and is devoid of signicant drugdrug
interactions; however, it is entirely renally excreted, and therefore its
dosage may need to be adjusted if creatinine clearance is reduced.7
Gabapentin has been used successfully in patients with HIV-1 to treat
neuropathic pain.60 Lamotrigine has been used effectively as a moodstabilizing, or anticycling, agent in patients without HIV-1.19 Its use in
HIV-1 may be complicated by severe dermatologic side effects and the
potential for drugdrug interactions. Lamotrigine too has been used
successfully in patients with HIV-1 for the treatment of HIV-1associated
neuropathy.79 Gabapentin and lamotrigine, although used as mood stabilizing, or anticycling, agents, have not been shown to be effective individually in the acute treatment of mania in bipolar disorder. Topiramate,
in preliminary studies of nonHIV-1 patients, shows more promise as
both an adjunctive anticycling and antimanic agent.44 Potential side
effects of concern for the HIV-1 population include psychomotor slowing
with impaired concentration, somnolence, and fatigue. Other potential
side effects include confusion, memory problems, and increased irritability. Topiramate also may cause decreased appetite with weight loss, a
potentially undesirable side effect in the HIV-1 population. The authors
cannot currently recommend its use in this population until additional
research is performed.
The treatment of secondary mania deserves special attention. Because it typically occurs in patients with advanced HIV-1 infection,
management is more difcult. Single-agent therapy is a goal to minimize
the risk for potential drugdrug interactions and to promote treatment
adherence. Low-dose, high-potency neuroleptics and atypical neuroleptics (e.g., risperidone, olanzapine, and quetiapine) may be effective in
secondary mania.14, 80 For more information about the details of using
these neuroleptics in patients with HIV-1, please see the next section on
treatment of psychotic syndromes. Some emerging evidence shows that
antiretrovirals that have good CNS penetration may provide some protection against the development of secondary mania.58
Psychosis and Delirium

Psychotic symptoms may occur in HIV-1 infection either as a primary disorder, such as schizophrenia, or as part of mania, delirium, HIV1associated dementia, or other organic syndromes. The treatment of
new-onset psychotic symptoms in HIV-1infection always should begin
with thorough medical and neurologic evaluation. Psychopharmacologic
treatment primarily includes neuroleptics.
In patients with asymptomatic HIV-1 infection whose immune function is competent and who are not receiving antiretroviral medication,
the use of neuroleptics is no different that in the nonHIV-1 population.
For all patients who are receiving antiretroviral medication, particularly
159
the protease inhibitors (PIs), it is important to be aware of potential

drugdrug interactions with neuroleptics.
The risk for neuroleptic-induced extrapyramidal symptoms (EPS) in
patients with advanced HIV-1 infection is much higher than in patients
without HIV-1.37, 58 Patients with HIV-1 are also at higher risk for movement disorders, such as Parkinsonism and dystonia, unrelated to neuroleptic exposure, perhaps because of damage to the basal ganglia.2 Therefore, atypical neuroleptics are preferred, especially in patients with HIV1associated dementia. Baseline examination for a abnormal movements
always should be performed before initiating any neuroleptic. It is
important always to use the lowest effective dose of either a conventional or atypical neuroleptic.
With conventional neuroleptics, high-potency agents may pose
greater risk for EPS, but low-potency neuroleptics have much greater
anticholinergic activity. This may increase the risk for worsening confusion and may precipitate delirium, particularly in those with HIV-1
associated dementia; however, one study comparing chlorpromazine
(average maintenance dosage, 36 mg/d) and haloperidol (average maintenance dosage, 1.4 mg/d) in the treatment of delirium in patients with
AIDS found no statistically signicant difference in treatment emergent
side effects.10 Also, molindone was reported to be effective and well
tolerated in four patients with HIV-1 infection and psychosis of various
causes, refractory to conventional neuroleptic treatments, and suffering
from severe EPSs.22 In addition to EPSs, neuroleptic malignant syndrome
has occurred in HIV patients with both conventional and atypical neuroleptics.8, 25, 73 HIV-1infected patients seem to be at higher risk for neuroleptic malignant syndrome.
Atypical neuroleptics seem to be better tolerated in patients with
HIV-1 during both early and advanced infection, but no systematic
studies of atypical neuroleptic use in patients with HIV-1 have been
performed.6, 80 Therefore, recommendations are drawn mainly from clinical experience in HIV-1 and other medically ill populations and from
limited case reports and uncontrolled clinical trials. To date, the literature
supports tolerability and efcacy of risperidone. One case of neuroleptic
malignant syndrome in HIV-1 with risperidone, possibly secondary to a
drugdrug interaction with PIs ritonavir and indinavir, has been reported.45 This highlights the vigilance regarding potential drugdrug
interactions that one needs to maintain when prescribing any medication
to patients with HIV-1 who are on complex multidrug regimens. Atypical neuroleptics, clozapine, and remoxipride (not available in North
America), have been used successfully in patients with HIV-14, 46; however, they should be used with caution because they can produce undesirable hematologic side effects, such as agranulocytosis and aplastic
anemia, respectively. Weight gain, a common side effect among many
atypical neuroleptics, may be less problematic, even an advantage, in
patients with anorexia or HIV-1related wasting syndromes. Less is
known about the use of olanzapine, quetiapine, ziprasidone, and zotepine (not available in North America) in patients with HIV-1. Clinically,
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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.
NMS neuroleptic malignant syndrome; EPS extrapyramidal symptom; TD tardive dyskinesia.
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Table 5. DEFINITIONAL CRITERIA FOR HIV-1ASSOCIATED DEMENTIA

Criterion
Description
1. Acquired abnormality in at least two of

the following cognitive abilities (present
for 1 month):
Attention/concentration; speed of
processing; abstraction/reasoning;
visuospatial skills; memory
learning; speech/language
Cognitive decline veried by history and

mental status examination; when
possible, history should be obtained
from an informant and examination
should be supplemented by
neuropsychological testing; the cognitive
dysfunction must cause impairment of
work or in activities of daily living, with
impairment not attributable solely to
severe systemic illness
Abnormality veried by physical
examination, neuropsychological tests,
or both
2. At least one of the following:

A. Acquired abnormality in motor
function or performance
B. Decline in motivation or emotional
control or change in social
behavior
3. Absence of clouding of consciousness
during a period long enough to
establish the presence of criterion 1
4. Exclusion of another etiology by history,

physical, and psychiatric examination
and appropriate laboratory and
radiologic tests
Change characterized by any of the

following: apathy, inertia, irritability,
emotional lability, or new-onset
impaired judgment characterized by
socially inappropriate behavior or
disinhibition
Alternate possible etiologies include active
central nervous system opportunistic
infections or malignancy, psychiatric
disorders (e.g., depressive disorders),
active substance abuse, or acute or
chronic substance withdrawal
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.
Table 6. DEFINITIONAL CRITERIA FOR HIV-1ASSOCIATED MINOR COGNITIVE/

MOTOR DISORDER
Criterion*
1. Acquired cognitive/motor/behavioral abnormalities, veried by both a reliable
history and by neurologic tests
2. Mild impairment of work or activities of daily living
3. Does not meet criteria for HIV-1 associated dementia or HIV myelopathy
4. No other cause present
*A probable diagnosis must meet all four criteria.
A possible diagnosis of MCMD can be given if criteria 13 are present and either (1) an alternate
etiology is present and the cause of number 1 is not certain or (2) the etiology of criterion 1 cannot be
determined because of an incomplete evaluation.
Adapted from American Psychiatric Association, Work Group on HIV/AIDS: Practice Guidelines
for the treatment of patients with HIV/AIDS. Am J Psychiatry 157:162, 2000; with permission.
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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
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ROBINSON & QAQISH
which is catalyzed by CYP isozymes. An inducer is an agent or a drug

that increases the catalytic activity of the enzyme, allowing for increased
rate of metabolism, whereas an inhibitor decreases the catalytic activity
of an enzyme, resulting in the opposite effect on the enzyme. Phase 2
reactions are conjugation reactions, which couple oxidized substrates to
glucuronate for excretion (e.g., glucuronidation).62
The three classes of antiretroviral agents used to treat HIV-1 infection are shown in Table 7. Many of the clinically relevant pharmacokinetic interactions involving psychotropics and the PIs or the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolic in nature.
The nucleoside reverse transcriptase inhibitors (NRTIs) are eliminated
by the kidneys, thus involving fewer pharmacokinetic interactions.62
Many psychotropic agents are metabolized (e.g., substrates) by the
CYP3A4 and the CYP2D6 isozymes. Table 8 includes a list of psychotropic and antiretroviral substrates, inducers, and inhibitors of the
most relevant isoenzymes. The HIV-1 PIs and NNRTIs are substrates of
CYP3A4. In addition to being substrates of CYP3A4, nelnavir is substrate of CYP2C19, ritonavir is a substrate of CYP2D6, and efavirenz
and nevirapine are substrates of CYP2B6. The PIs inhibit the CYP3A4
isozymes at varying degrees. Ritonavir is the most potent inhibitor of
CYP3A4, followed by indinavir, amprenavir, and nelnavir as moderate
inhibitors and saquinavir and lopinavir are the weakest inhibitors. The
combination of lopinavirritonavir (Kaletra) may have greater inhibitory
effects on CYP3A4 because of the ritonavir component. In addition,
ritonavir inhibits CYP2D6, which is an important isoenzyme for the
metabolism of many psychotropics (Table 8), CYP2C9 and CYP2C19.
Ritonavir and nelnavir are weak inducers of CYP3A4 and glucuronyl
transferase, whereas ritonavir is also an inducer of CYP1A2, CYP2C9.
Table 7. HIV-1 ANTIRETROVIRAL MEDICATIONS BY CLASS

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (ABC) (Zigen)
Didanosine (ddI) (Videx)
Lamivudine (3TC) (Epivir)
Stavudine (d4T) (Zerit)
Zalcitabine (ddC) (Hivid)
Zidovudine (ZDV or AZT) (Retrovir)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Delavirdine (DLV) (Rescriptor)
Nevirapine (NVP) (Viramune)
Efavirenz (EFV) (Sustiva)
Protease Inhibitors (PIs)
Amprenavir (APV) (Agenerase)
Indinavir (IDV) (Crixivan)
Lopinavir/Ritonavir (Kaletra)
Nelnavir (NFV) (Viracept)
Saquinavir mesylate (SQV) (Invirase)
Saquinavir (SQV) (Fortovase)
Ritonavir (RTV) (Norvir)
165
Table 8. PSYCHOTROPIC AND ANTIRETROVIRAL* SUBSTRATES, INHIBITORS AND

INDUCERS OF THE CYTOCHROME P-450 ISOENZYMES
CYP Isoforms
1A2
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
*Italics antiretroviral medications.

CYP cytochrome P-450.
The NNRTIs efavirenz and nevirapine are substrates of CYP3A4 and

CYP2B6. Both are inducers of CYP3A4 and nevirapine is an inducer of
CYP2B6. In vitro, efavirenz seems to be an inhibitor of CYP3A4, CYP2C9,
and CYP2C19, whereas delavirdine is a potent inhibitor of CYP3A4.29
Many of the potential metabolic interactions between the psychotropics
and the antiretrovirals have not been studied; however, based on the
current understanding of how the psychotropic agents are metabolized,
166
ROBINSON & QAQISH
the potential for interactions with these antiretrovirals exists. Practical

management recommendations concerning the documented and theoretic interactions are summarized in Tables 9 to 11.
Antidepressants
Many of the TCAs and non-tricyclic antidepressants (non-TCAs) are
substrates of the CYP2D6 isoenzyme. The TCAs have minimal inhibitory
effects on the CYP450 isoenzyme pathway. The PI ritonavir is a substrate
and an inhibitor of CYP2D6; thus, interactions between the TCAs and
many of the non-TCAs can be predicted. Ritonavir was found to double
the serum concentration of desipramine.1 Therefore, patients receiving
the combination of ritonavir and any of the TCAs should be monitored
carefully for side effects of TCAs (e.g., dry mouth, urinary retention,
sedation, and blurred vision), delayed cardiac conduction, and orthostasis. Although the SSRIs are generally well tolerated, their coadministration with ritonavir may lead to serotonin syndrome, presumably by
inhibiting CYP2D6.30 Although the SSRIs can inhibit CYP2D6 to a lesser
extent than can ritonavir, patients still should be monitored for increased
ritonavir toxicity (i.e., gastrointestinal disturbances). The remaining PIs
and the NNRTIs have minimal or no effects on CYP2D6; thus, metabolic
interactions are unlikely. Conversely, nefazodone and citalopram are
substrates of CYP3A4; thus, a potential for interactions with the all PIs
and the NNRTIs exists. Nefazodone, uvoxamine, and the metabolite of
uoxetine (noruoxetine) are inhibitors of CYP3A4 isoenzyme.84 Thus a
decrease in the metabolism of all PIs and the NNRTIs is possible,
and patients should be monitored for side effects of these agents. The
coadministration of venlafaxine and indinavir has resulted in a decrease
in indinavir serum levels. Based on the established metabolic pathways
of these agents, how such an interaction occurred is unclear. Likewise,
whether the same could happen (e.g., a decrease in serum levels) with
the other PIs or any of the NNRTIs is unknown. Nonetheless, the
combination of indinavir and venlafaxine should be avoided at this time,
and patients receiving venlafaxine and other antiretrovirals should be
monitored for virologic control.47 Previously, bupropion was thought to
be a substrate of CYP2D6; however, recently it has been shown that it is
metabolized by CYP2B6.71 Because the NNRTI nevirapine is a substrate
and inducer of CYP2B6, a decrease in bupropion serum levels is predicted, thus potentially limiting its efcacy.
Anxiolytics and Sedative-Hypnotics
The BDZs and buspirone are substrates of CYP3A4. The NNRTIs,
nevirapine and efavirenz, may decrease the serum levels of buspirone
and the BDZs by inducing CYP3A4. Conversely, metabolic interactions
involving the PIs, NNRTIs, delavirdine, and perhaps even efavirenz, and
167
Table 9. ANTIDEPRESSANT AND ANTIRETROVIRAL DRUG-DRUG INTERACTIONS
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
Coadministration with ritonavir

may increase serum
concentrations of TCAs,
resulting in TCA toxicity.
Potential; minimal
documentation
Inhibition of CYP2D6
by the PI, ritonavir
Coadministration with ritonavir

may increase serum
concentrations of SSRIs,
resulting in SSRI toxicity.
Fluvoxamine and noruoxetine
are inhibitors of CYP3A4,
thus may increase the levels
of the PIs or NNRTI resulting
in increased toxicity of the PI
or NNRTI
Potential; minimal
documentation
Inhibition of CYP3A4
by uoxamine and
noruoxetine
Theoretic
by all the PIs and
or NNRTIs,
delavirdine, and
possibly efavirenz
Coadministration with any of

the protease inhibitor,
delavirdine or efavirenz may
increase serum concentrations
of SSRIs, resulting in SSRI
toxicity.
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
Administration with nevirapine

or efavirenz may decrease the
serum concentration of the
SSRI, resulting in decrease in
response to the SSRI.
Theoretic
interactions for
both
psychotropics
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
Coadministration with the

NNRTI, nevirapine, or
efavirenz, may decrease the
serum concentrations of
buproprion, compromising
the response to buproprion.
Theoretic
Inhibition of
metabolism by
ritonavir
Coadministered ritonavir may

increase serum concentrations
of bupropion, potentially
increasing risk for seizures.
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
ROBINSON & QAQISH
Table 10. ANXIOLYTIC/SEDATIVE-HYPNOTIC AND ANTIRETROVIRAL DRUGDRUG

INTERACTIONS
Anxiolytic and
SedativeHypnotics
Mechanism of
Protease Inhibitors or
the NNRTIs
Comment
Documentation
Inhibition of CYP3A4 by
all PI, delavirdine,
and possibly efavirenz
Coadministration may increase

buspirone, resulting in
buspirone toxicity.
Potential
Induction of CYP3A4 by
nevirapine and
efavirenz
Coadministration may decrease

buspirone, resulting in
subtherapeutic buspirone.
Theoretic
all PIs, delavirdine,
Both are contraindicated with

PIs, efavirenz, and
delavirdine because of a
signicant rise in serum
levels of these agents and
increased excessive sedation
and respiratory depression.
Well
documented

BZD serum concentration,
resulting in excessive
sedation and respiratory
depression
Potential;
minimal
documentation
nevirapine and
efavirenz

resulting in BZD withdrawal.
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

resulting in excessive
sedation and respiratory
depression.
Theoretic
Buspirone
Benzodiazepines
Midazolam,
triazolam
Alprazolam,
clonazepam,
lorazepam,
temazepam
NNRTIs non-nucleoside reverse transcriptase inhibitors; PIs protease inhibitors; BZD benzodiazepine; CYP
cytochrome P-450.
buspirone or the BDZs occur presumably by the inhibition of the

CYP3A4 isozymes. The combination of midazolam or triazolam is contraindicated with the PIs and the two NNRTIs, efavirenz and delavirdine, because of the potential for excessive sedation resulting in respiratory depression.2, 57 Initially, low-dose ritonavir seems to decrease the
clearance of the BDZ alprazolam,33 but chronically, ritonavir increases
the clearance of alprazolam, resulting in a 10% to 15% decrease in its
expected serum levels.27 Thus the use of ritonavir in a patient already
on alprazolam may initially cause BDZ toxicity and, later, signs of BDZ
169
Table 11. NEUROLEPTIC AND ANTIRETROVIRAL DRUGDRUG INTERACTIONS
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
Protease Inhibitors or
the NNRTIs
Comment
Documentation
Inhibition of CYP206 by
the PI, ritonavir

serum concentrations of the
typical neuroleptics, resulting
in increased risk of EPS and
NMS.
Potential
NNRTIs, nevirapine
and efavirenz

pimozide resulting in
subtherapeutic levels.
Theoretic
Contraindicated combination
pimozide may increase
resulting in increased
cardiotoxicity risk (QTc
prolongation).
Potential
ritonavir

serum concentration of
neuroleptic; Monitor for
clinical response.
Theoretic
Inhibition of CYP2D6 by
the PIs, ritonavir

neuroleptic serum
concentration, resulting in
excessive side effects;
increased clozapine serum
concentrations, monitor for
agranulocytosis.
Theoretic

serum levels of those
neuroleptics; monitor for
increased side effects; use
caution when
coadministering with
zotepine and possibly
ziprasidone for potential risk
of increased serum levels and
QTc interval.
Potential
NNRTIs, nevirapine
and efavirenz

serum levels of neuroleptics,
thus monitor clinical
response.
CYP cytochrome P-450; EPS extrapyramidal side symptoms; NMS neuroleptic malignant syndrome;
NNRTI non-nucleoside reverse transcriptase inhibitors; PI protease inhibitor.
170
ROBINSON & QAQISH
withdrawal. Ritonavir and nelnavir are inducers of the phase 2 enzyme

glucuronyl transferase and might decrease serum levels of the BDZs that
undergo glucuronidation (e.g., oxazepam, lorazepam, and temazepam).30
Mood Stabilizers
Carbamazepine and valproate may be used in HIV-1infected patients with bipolar disorders. The metabolism of valproate is not fully
understood, but valproate has been found to inhibit the phase 2 enzyme
glucuronyl transferase. The nucleoside reverse transcriptase inhibitor
zidovudine is glucuronidated using this enzyme; thus, combination with
valproate may result in decreased zidovudine clearance and increased
zidovudine toxicity (i.e., bone marrow toxicities).
Carbamazepine is a substrate of CYP3A4 isozyme. Like some other
anticonvulsants (e.g., phenobarbital and phenytoin), carbamazepine is a
potent inducer of CYP3A4. Thus, theoretically, carbamazepine could
enhance the clearance of the PIs and the NNRTIs and perhaps result in
decreased serum concentration of the antiretrovirals, thereby decreasing
viral suppression. Therefore, the viral load should be monitored closely.
In the other discussion, the PIs could decrease the metabolism of carbamazepine, thereby increasing its serum concentration and toxicities.
Thus, patients receiving carbamazepine in combinations with antiretrovirals should undergo regular monitoring of carbamazepine serum concentrations.2
Newer anticonvulsants have been used off-label for the treatment
of mood disorders in HIV-1 patients. These include gabapentin, lamotrigine, and topiramate. As mentioned earlier, metabolic interactions with
gabapentin are minimal. Lamotrigine is metabolized by glucuronyl
transferase, which is induced by the PIs ritonavir and nelnavir. This
theoretically could lead to increased metabolism of lamotrigine and
decrease its serum concentrations. Although topiramate is primarily
renally eliminated, the authors do not recommend its combination with
the antiretrovirals at this time (see section about manic syndromes).
Lithium carbonate has been used in HIV-1 patients with primary
bipolar disorders. Similar to gabapentin, lithium is primarily renally
eliminated and hepatic metabolism is not required. This in turn results
in insignicant metabolic interactions with HIV-1 antiretrovirals; however, it should be avoided in patients with AIDS mania or advanced
HIV because of the increased risk for toxicity in this population (see
section about manic syndromes).
Neuroleptics
The typical neuroleptics, haloperidol, chlorpromazine, perphenazine, and thioridazine, are substrates of CYP2D6 that are inhibited by
the PI ritonavir. Because serum levels of these agents may be increased
171
by ritonavir inhibiting CYP2D6, the risk for EPSs also is exacerbated.

Therefore, patients should receive lower doses of these agents and be
monitored for EPS. The neuroleptic pimozide is a substrate of CYP3A4;
thus, its metabolism can be inhibited by all the PIs, delavirdine, and
possibly efavirenz. Consequently, this could result in increasing pimozide serum levels and cardiotoxicity (e.g., QTc prolongation); thus, the
combination of pimozide with any of the PIs, delavirdine, and efavirenz
are contraindicated.
Atypical antipsychotics are better tolerated than antipsychotics in
the HIV population. Clozapine and olanzapine are primarily metabolized by CYP1A2, of which ritonavir is a weak inducer, whereas risperidone and, to a lesser extent, clozapine are metabolized by CYP2D6
(inhibited by ritonavir).84 Thus, patients receiving the combination of
ritonavir and olanzapine or clozapine should be monitored for antipsychotic response. Conversely, the combination of ritonavir with clozapine
or risperidone may result in increased side effects.
SUMMARY
HIV-1 infection poses a challenge for psychiatrists of the medically
ill. Many factors concerning the care of HIV-1infected patients need to
be considered when prescribing psychotropics. These include careful
diagnosis, taking into account medical disorders associated with HIV-1
that can present with psychiatric symptoms, as well as medications that
HIV-1 patients may be taking that can cause a variety of neuropsychiatric
side effects. Another important issue is the potential for drugillness
interactions. In general, HIV-1 patients seem to be more sensitive to the
development of adverse drug reactions than do nonHIV-1 patients,
especially as the illness progresses. It is also important to be cognizant
of the complex multidrug regimens that many HIV-1 patients are on to
avoid known drugdrug interactions and be on the alert for other
potential interactions when using psychotropic medications.
ACKNOWLEDGMENT
The authors would like to acknowledge the assistance of Paul R. Davidson, PhD,
CPsych, from the Department of Psychiatry at Queens University, for his help in the
development of Table 2.
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63. Price WA, Bielefeld M: Buspirone-induced mania. J Clin Psychopharmacol 9:150151,
1989
64. Rabkin JG, Wagner G, Rabkin R: Effects of sertraline on mood and immune status in
patients with major depression and HIV illness: An open trial. J Clin Psychiatry
55:433439, 1994
65. Rabkin JG, Rabkin R, Harrison W, et al: Effect of imipramine on mood and enumerative
measures of immune status in depressed patients with HIV illness. Am J Psychiatry
151:516523, 1994
66. Rabkin JG, Rabkin R, Wagner G: Effects of uoxetine on mood and immune status in
depressed patients with HIV illness. J Clin Psychiatry 55:9297, 1994
67. Rabkin JG, Wagner GJ, Rabkin R: Testosterone therapy for human immunodeciency
virus-positive men with and without hypogonadism. J Clin Psychopharmacol 19:19
27, 1999
68. Rabkin JG, Wagner GJ, Rabkin R: Fluoxetine treatment for depression in patients with
HIV and AIDS: A randomized, placebo-controlled trial. Am J Psychiatry 156:101107,
1999
69. Rabkin JG, Wagner GJ, Rabkin R: A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry
57:141147, 2000
70. Robinson MJ: Are newer antidepressants really better tolerated? Can J Psychiatry
46:286287, 2001
71. Rotzinger S, Bourin M, Akimoto Y, et al: Metabolism of some second- and fourthgeneration antidepressants: Iprindole, viloxazine, bupropion, mianserin, maprotiline,
trazodone, nefazodone, and venlafaxine. Cell Mol Neurobiol 19:427442, 1999
72. Roesler R, Quevedo J, Walz R, et al: A randomized, double-blind, placebo-controlled
trial of deprenyl and thiotic acid in HIV-associated cognitive impairment. Neurology
52:19201921, 1999
73. Rosebush P, Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant
syndrome. Am J Psychiatry 146:717725, 1989
74. Sacktor N, Schitto G, McDermott MP, et al: Transdermal selegiline in HIV-associated
cognitive impairment: Pilot, placebo-controlled study. Neurology 54:233235, 2000
75. Schitto G, Sacktor N, Marder K, et al: Randomized trial of the platelet-activating
factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological
AIDS Research Consortium. Neurology 53:391396, 1999
76. Schmitt FA, Bigley JW, McKinnis R, et al: Neuropsychological outcome of zidovudine
(AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med
319:15731578, 1988
77. Schwartz JA, McDaniel JS: Double-blind comparison of uoxetine and desipramine in
the treatment of depressed women with advanced HIV disease: A pilot study. Depress
Anxiety 9:7074, 1999
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78. Sidtis JJ, Gatsonis C, Price RW, et al: Zidovudine treatment of the AIDS dementia
complex: results of a placebo- controlled trial. AIDS Clinical Trials Group. Ann Neurol
33:343349, 1993
79. Simpson DM, Olney R, McArthur JC, et al: A placebo-controlled trial of lamotrigine
for painful HIV-associated neuropathy. Neurology 54:21152119, 2000
80. Singh AN, Golledge H, Catalan J: Treatment of HIV-related psychotic disorders with
risperidone: A series of 21 cases. J Psychosom Res 42:489493, 1997
81. Swindells S, Zheng J, Gendelman HE: HIV-associated dementia: new insights into
disease pathogenesis and therapeutic interventions. AIDS Patient Care STDs 13:153
163, 1999
82. Thompson D, Dimartini A: Nonenteral routes of administration for psychiatric medications. A literature review. Psychosomatics 40:185192, 1999
83. Trachman SB: Buspirone-induced psychosis in a human immunodeciency virusinfected man. Psychosomatics 33:332335, 1992
84. Tseng AL, Foisy MM: Signicant interactions with new antiretrovirals and psychotropic
drugs. Ann Pharmacother 33:461473, 1999
85. Wagner GJ, Rabkin R: Effects of dextroamphetamine on depression and fatigue in men
with HIV: A double-blind, placebo-controlled trial. J Clin Psychiatry 61:436440, 2000
86. Whitaker R: Neuropsychiatry of HIV-associated dementia. Psychiatric Times 17:5761,
2001
87. White JC, Christensen JF, Singer CM: Methylphenidate as a treatment for depression
in acquired immunodeciency syndrome: An n-of-1 trial. J Clin Psychiatry 53:153
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1998
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
0193953X/02 $15.00 .00
ELECTROCONVULSIVE THERAPY
IN THE MEDICALLY ILL
Keith G. Rasmussen, MD, Teresa A. Rummans, MD,
and Jarrett W. Richardson, MD
Three questions face the practitioner who is treating a patient with

combined medical and psychiatric illness for whom electroconvulsive
therapy (ECT) is being considered:
1. Is ECT effective in such patients?
2. Does ECT cause deterioration of the underlying medical condition or signicant side effects?
3. Is modication of ECT technique indicated to lessen the risk of
adverse outcomes?
To answer these questions denitively, prospective trials are needed
in which the severity of both the medical and the psychiatric illness are
blindly rated in a systematic manner before, during, and after treatment.
Such trials are generally lacking. Furthermore, in relying on case reports,
one must consider that these publications tend to be biased either in
favor of excellent results or unexpectedly poor outcomes; however, a
large body of case reports and case series published over several decades
do inform the ECT clinician about a reasonable approach to patients
with a wide array of medical disorders. This section focuses on medical
conditions in which ECT has a direct physiologic effect and therefore
places the patient at risk for complications. These include cardiovascular,
neurologic, respiratory, and other disorders. In addition, the reader is
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.
ELECTROCONVULSIVE THERAPY IN THE MEDICALLY ILL
179
Coronary Artery Disease

Cardiac complications during ECT are more common in those with
coronary artery disease (CAD) than with other cardiac conditions.102 ECT
induces increases in pulse and blood pressure that result in a 200% to
300% increase in myocardial oxygen consumption during and for a few
minutes after the seizure24; however, ECT can be safely administered to
the majority of patients with CAD. For patients with known CAD, preECT cardiology consultation is recommended to assess the stability of
the patients cardiac status and to assist with risk-reduction strategies.4, 5
The most important of such strategies is optimal stabilization of cardiac
status before treatment.2 Pretreatment cardiac imaging is commonly
requested to assess the stability of the patients myocardial capacity
during stress. Any cardiac medications the patient is taking, with the
exception of diuretics or lidocaine-type agents, should be given with a
small sip of water the mornings of treatment. A further strategy is the
intravenous administration of -blockers immediately pretreatment to
dampen the increase in myocardial oxygen consumption.8 If pretreatment -blockade is used, then an anticholinergic agent, such as glycopyrrolate or atropine, should also be given to minimize the risk of vagally
mediated prolonged asystole or bradycardia, which sometimes occur
early in the seizure or if no seizure is elicited by the electrical stimulus.43
Depression commonly accompanies the postmyocardial infarction
periodhence, the question of how long to wait until ECT is safe.
Consideration should be given to the severity of the patients depression
and cardiac stability. A patient a few weeks out of a mild myocardial
infarction with stable myocardial function may be safer to treat than a
patient many months or years out of myocardial infarction with a
very low ejection fraction or with exercise-induced ischemic changes on
cardiac imaging. Close communication between psychiatrist and cardiologist is essential in these circumstances.
Dysrhythmias, Pacemakers, and Implantable
Debrillators
Patients with asymptomatic, uncomplicated cardiac conduction delays, such as rst degree heart block or bundle branch block, can be
safely treated with ECT without special precautions. Patients with atrial
brillation also usually can be treated safely59; however, pretreatment
cardiologic consultation can ensure optimal stabilization and treatment
of the dysrhythmia. In particular, ventricular rate should be normalized.
Occasionally, conversion to normal sinus rhythm occurs during ECT, so
pretreatment anticoagulation would be considered optimal.59 Patients
with any type of malignant ventricular arrhythmia are at higher risk
for hemodynamic instability during ECT, so pretreatment cardiology
consultation is mandatory for risk assessment and risk-reduction strategies. Lidocaine in antiarrhythmic doses has potent anticonvulsant prop-
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erties, so it should not be given before an ECT treatment unless truly

necessary and no alternative antiarrhythmic is available.
Patients with pacemakers usually do not need any special adjustment or attention aside from ensuring that monitoring and other equipment are well grounded.2 Consultation with a cardiologist is indicated,
and some older types of pacemakers may need to be turned from
demand mode to xed mode before treatment.2 The use of transesophageal atrial pacing during ECT for patients at signicant risk for asystole
has been described.89 Patients with implantable cardiodebrillators usually can be safely treated with ECT, but pretreatment consultation with
a cardiac electrophysiologist is recommended.4, 61
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.
Vascular Malformations and Anticoagulation

ECT has been safely administered in the presence of known cardiac14
and aortic aneurysms,12 although a case of cardiac rupture during ECT
has been reported.3 Pretreatment consultation with a vascular surgeon
in cases of known aneurysms or other vascular malformations (e.g.,
arteriovenous stula) is important in assessing the risk of rupture during
ECT. Risk-reduction strategies may include pretreatment with antihypertensive agents to reduce shear force against the aneurysm.
For patients who are on anticoagulation for deep venous thrombosis, valvular heart disease, atrial brillation, or another indication, it is
prudent and safe to continue it during ECT with close attention to
maintaining the proper PT or PTT.4
181
Congestive Heart Failure and Valvular Heart Disease

As ECT causes a temporary but sharp increase in cardiac ratepressure product, patients with congestive heart failure are at risk for
decompensation during a course of ECT72; however, successful administration of ECT to patients with stable low cardiac output has been
described.86 ECT has been successfully administered to patients with
stable valvular heart disease.32, 68, 72 As with the other cardiac conditions
discussed, the most important aspect of management in such cases is
careful pre-ECT cardiologic evaluation and risk assessment. In particular,
patients with congestive heart failure should have their medical management optimized, with very careful ongoing assessment during the course
of ECT looking for signs of congestive decompensation.
NEUROLOGIC DISORDERS
A large body of case reports and case series published over several
decades do inform the ECT clinician about a reasonable approach to
patients with a wide array of neurologic disorders. This section considers
such patients grouped by type of neurologic illness. A thorough consideration of all published papers is beyond the scope of this article, but
the interested reader is referred to various reviews published over the
years (see references 2, 18, 36, 81, 84, and 103).
Dementia
A vexing problem regarding the literature on ECT in demented
patients is the lack of standardized criteria for the establishment of a
dementia syndrome independent of depression-related cognitive dysfunction.87 In fact, in routine clinical circumstances, it is often difcult to
determine whether the patient with coexisting severe depression and
cognitive dysfunction has a separate dementing illness or depressionrelated cognitive dysfunction.87 A further problem with this literature is
the lack of long-term cognitive follow-up in most reports. Nevertheless,
the extant literature does provide guidance on safe, effective ECT in the
depressed, demented patient.
Numerous case reports indicate that ECT can be efcacious in
depressed and demented patients for the depressive symptoms without
causing undue or long-lasting increases in memory disturbance.67 Several
case series provide more substantial information. In a prospective study,
Reynolds et al74 systematically followed depression ratings in a group of
three demented depressives. Two of these patients had an excellent
antidepressant response to ECT without cognitive worsening, whereas
one had no antidepressant response and a sharp reduction in minimental state exam (MMSE) score. Gaspar and Samarasinghe26 reported
data on three patients with a diagnosis of primary dementia and depres-
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RASMUSSEN et al
sion. Similarly, two showed a good antidepressant response, and one

did not. None of the patients were believed to have sustained a longlasting (i.e., more than a few days) worsening of their baseline cognitive
status, although no systematic cognitive evaluations were done.
In a larger series, Nelson and Rosenberg55 reported their experience
treating 21 depressed and demented patients with ECT. Global antidepressant efcacy ratings based on chart review were similar to those of
a depressed but nondemented ECT cohort. Post-ECT confusion was
believed to be greater in the depressed and demented group. No efcacy
or cognitive follow-up data were presented.
In the largest series to date of depressed and demented patients
given ECT, Rao and Lyketsos67 described 31 patients, 16 diagnosed with
vascular dementia, 4 with Alzheimers dementia, and 11 with dementia
of uncertain cause. Half the patients were believed to suffer delirium
(criteria not specied) with ECT. Two thirds were believed to have a
good response in terms of depression. MMSE score actually increased
an average of 1.62 points by treatment end. This indicates the benecial
effect of ECT on attention and concentration after clearing of the acute
post-treatment confusion, even in demented patients. Of note, one patient had tardive seizures in the recovery room after ECT. No efcacy or
cognitive data were presented separately for the different demented
groups.
To summarize, several dozen depressed ECT patients believed to
have a separate dementing illness have been described in the literature.
Approximately two thirds obtained noticeable antidepressant benet,
with approximately half showing greater than usual confusional states.
Sorely needed is a trial with systematic cognitive evaluations in patients
diagnosed with dementia by standardized criteria, and subclassied by
dementia type, compared with nondemented ECT controls and with
depressed and demented patients treated with medications. Finally, in
an effort to spare excess memory disturbance, consideration should be
given to treating depressed and demented patients with right unilateral
or bifrontal electrode placement and twice-weekly treatment frequency.
Parkinsons Disease
A variety of case reports, small series, and one sham-ECTcontrolled
trial document that ECT is highly effective for depression in Parkinsons
disease and may improve motor function as well52, 69; however, delirium
is common during ECT,22 as is treatment-emergent dyskinesia,15 but posttreatment cognitive function may be improved.63 The duration of ECTrelated antiparkinsonian effects has been variable, but long-term followup data have been presented. For example, Fall et al19 systematically
followed up 16 nondemented, nondepressed patients with advanced
Parkinsons disease before, immediately after, and for up to 1.5 years
after courses of mostly unilateral ECT. Fifteen subjects experienced some
183
improvement in the motor symptoms of PD, which was dramatic in

some cases. Half of the patients had sustained improvement for 3 to 18
months after ECT, without maintenance ECT. Approximately one third
developed severe confusional states during ECT, the duration of which
was a few days to 2 weeks. Interestingly, 4 of these 5 patients went on
to have long-lasting (i.e., at least several months) motor improvement.
Baseline increases in cerebrospinal uid (CSF)-to-serum albumin ratios,
which were thought to reect violation of the bloodCSF barrier, accurately predicted the 5 subjects who developed interictal delirium. None
of the 11 subjects who did not develop interictal delirium had pre-ECT
increases in this ratio, indicating that violation of the bloodCSF barrier
before ECT predisposes to ECT-induced confusion.
In another series, Pridmore et al65 treated seven advanced, nondepressed PD patients with only four unilateral ECT treatments. Immediate
post-ECT and 2-week post-ECT ratings in all spheres of motor function
indicated improvements. Four patients developed severe, although temporary, confusion. One patient developed a dyskinesia responding to
lowering of the levodopa dose. In a follow-up report on these and
several other such patients given index (but not maintenance) ECT, three
of nine initial ECT responders had improvements lasting 2 to 10 weeks,
whereas the other six responders had improvements lasting 10 to 35
months.64
Attempts have been made to prolong the acute ECT-induced improvement in motor symptoms of Parkinsons disease using maintenance ECT, in which treatments are given every few weeks for variable
lengths of time.1, 20, 34, 83, 98, 101 In these reports, a total of 13 patients with
Parkinsons disease given maintenance ECT are described. Several of the
patients had had several courses of index ECT with good, although
relatively short-lived, motoric improvement. In each case, maintenance
ECT seemed to extend this period of improvement, in some cases for up
to 1 year. The frequency of such treatments was highly variable, depending on the length of each patients improvement, and was balanced
against cognitive impairment.
Several summary points can be made regarding the use of ECT in
Parkinsons disease patients:
It is highly effective for the severe depression so often seen in
such patients.
In a substantial proportion of patients, a variety of extrapyramidal
signs (EPS) phenomena also may improve, often faster than the
depression.
The duration of this antiparkinsonian benet may be from a few
days to years.
Maintenance ECT may extend the period of improvement in patients who can tolerate it from a cognitive standpoint.
Treatment emergent dyskinesias and delirium are relatively common15, 22 and may be helped by careful reduction of dopaminergic doses.
184
RASMUSSEN et al
Twice-weekly treatment frequency and right unilateral or bifrontal

electrode placement should be considered as methods to reduce
memory impairment.
Neuroleptic-Induced Movement Disorders
Variable results have been reported with the use of ECT in patients
with tardive dyskinesia. For example, Yassa et al100 found ECT helpful
in reducing dyskinetic movements in only one of nine such patients
treated. Furthermore, Holcomb et al35 reported increased signs of tardive
dyskinesia in a parkinsonian patient who had good resolution of his
parkinsonism with ECT. DeQuardo et al10 even found temporary spontaneous dyskinesias after ECT in a patient with Wilsons disease. These
results, combined with the known increase in levodopa-related dyskinesias occurring commonly in patients with Parkinsons disease treated
with ECT,15 indicate that ECT is unlikely to help dyskinetic movements
in patients with tardive dyskinesia and may even aggravate them. Interestingly, several cases of improvement in tardive dystonia with ECT
have been reported,39, 44, 62 which is not surprising given the similarity
of this syndrome to parkinsonian extrapyramidal signs, although one
negative outcome has been reported.30
Neuroleptic malignant syndrome, one form of malignant catatonia,60
often is treated, after withdrawal of the neuroleptic, by administering
dopamine agonists, such as bromocriptine, and muscle relaxants, such
as dantrolene or lorazepam. ECT may represent a lifesaving option for
patients who do not respond to these measures.56, 60 It may be the most
effective treatment for neuroleptic malignant syndrome, particularly
when it occurs in a patient who was already catatonic.
Cerebrovascular Disease
Several isolated case reports11, 96 of safe use of ECT in poststroke
patients have been published. Murray et al53 and Currier et al,9 describing experience at Massachusetts General Hospital from 1969 to 1991
giving ECT to poststroke patients, indicated that, of 34 such patients, 32
improved signicantly with ECT. Neither location of stroke, whether
rightleft or corticalsubcortical, nor time since stroke ( l month to 12
years) was associated with clinical response. Five of six patients showed
improvement in their preexisting cognitive impairment with ECT without neurologic worsening.
Martin et al47 compared 14 poststroke ECT patients with 14 nonstroke ECT patients and found a similar incidence of 4 of 14 in each
group developing interictal delirium. Interestingly, all 4 of the poststroke
patients developing such delirium had caudate strokes, buttressing the
investigators contention that basal ganglia lesions predispose to ECTrelated delirium. The poststroke ECT patients had a good clinical re-
185
sponse without neurologic worsening. Of note, the more ECT treatments

given after the delirium became apparent, the longer the delirium lasted.
In addition to patients with a history of cerebrovascular accident
(CVA), those with known intracerebral aneurysms or vascular malformations would be expected to have a high risk with ECT. At least two
cases of patients safely administered ECT after cerebral aneurysm repair
have been reported,21, 38 and numerous cases of patients with known
aneurysms that have not been surgically corrected pre-ECT have been
reported; in none of those has a bleed occurred.* To the authors knowledge, however, two cases of ECT-associated intracerebral hemorrhages
have been reported,76, 97 both in patients without known pre-ECT cerebrovascular disease. Most investigators reporting on ECT in patients with
known aneurysms used antihypertensive treatments to dampen the ECTrelated increase in blood pressure. Drop et al17 consider intracerebral
aneurysms at high risk for rupture during ECT and recommend that
appropriate antihypertensive measures (e.g., -blockade and sodium
nitroprusside) and monitoring should be undertaken during ECT in
such patients.
To summarize the literature on ECT in patients with histories of
stroke or intracerebral aneurysm, numerous reports of safe ECT administration exist to provide some condence to the clinician; however, caution must be exercised, and measures to control excessive blood pressure
increases should be considered.17
Epilepsy
Giving ECT to epileptics is cause for concern; however, ECT potently increases the seizure threshold during the course of treatments,
and seizure lengths progressively shorten, indicating that ECT has an
anticonvulsant action.78 Early ECT clinicians knew about this effect and
put it to use in treating epileptics with intractable seizure disorders. For
example, Taylor91 reported on 19 epileptics given ECT at a state hospital.
One patient had no change in spontaneous seizure frequency, one had a
modest reduction, and 17 of 19 had a complete resolution of such
seizures while they were being treated with weekly ECT sessions.
Caplan,7 in a similar population and using the same ECT method (i.e.,
thrice-weekly ECT for a few weeks, followed by weekly maintenance
treatments), also found a reduction in the patients spontaneous seizure
frequency. Both investigators found good psychopathologic improvement in psychosis, mood disorders, and aggression. In Caplans report,7
when ECT was stopped, spontaneous seizure frequency returned within
1 month to the pre-ECT levels, indicating that the anticonvulsant action
of ECT is temporary. Wolff99 and, more recently, Sackeim et al,78 Griesemer et al,28 Regenold et al,73 Schnur et al,82 and Viparelli and Viparelli94
have all described cases of patients with well-dened epilepsy using
modern diagnostic criteria who had highly refractory seizures in whom
*References 6, 16, 25, 37, 42, 54, 79, and 93.
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RASMUSSEN et al
substantial, although usually temporary, reductions in seizure frequency

were accomplished with ECT. In addition, occasional reports document
that status epilepticus can occur, fortunately rarely, after ECT, even in
nonepileptics.29, 31, 66
In the modern era, with highly sophisticated and extensive antiepileptic treatments available, it would be extremely rare that an epileptic
patient would be given ECT for the purpose of reducing seizure frequency. More commonly, such patients are given ECT for a mood,
psychotic, or behavioral dyscontrol disorder. Surprisingly, no large series
of such patients describing outcome, both therapeutic and cognitive, visa`-vis nonepileptic ECT patients exists. Such a series would be a welcome
addition to the ECT literature. At present, it can be condently stated
that epilepsy itself does not present a contraindication to ECT, and no
evidence shows that spontaneous seizure frequency increases with ECT.
It would be prudent to maintain antiepileptic medication at therapeutic
levels during ECT to avoid withdrawal-associated status epilepticus.33 If
seizure induction becomes impossible during the course of treatment
because of the anticonvulsant action of ECT, however, then careful,
temporary downward adjustment of the patients anticonvulsant medication may be warranted, in consultation with a neurologist, taking into
account the nature and severity of the patients seizure disorder.
Intracranial Tumors
The original report of Shapiro and Goldberg84 describing neurologic
deterioration after ECT in six patients subsequently found to have brain
tumors led to the belief that brain tumors constituted an absolute contraindication to ECT. This viewpoint was supported in the review by
Maltbie et al,46 in which 35 patients who had brain tumors found after
ECT were described. In that series, the rates of neurologic morbidity
and mortality were quite high. Mattingly et al,49 however, reviewed 10
cases in which presence of the tumor was known in advance of ECT.
None of the patients had focal neurologic ndings, increased intracranial
pressure (ICP), or papilledema before treatment. Neurologic deterioration was not noted with ECT, and none of the patients died within 1
month after treatment. In 8 cases, the tumors were meningiomas, and in
2 cases, they were metastatic breast cancers. The investigators concluded
that, in the absence of complicating factors, such as increased ICP or
focal neurologic ndings, ECT may be safe if the psychopathology
warrants this treatment. Several other cases of successful and neurologically uncomplicated administration of ECT to patients with meningiomas have been described.40, 41, 50, 85 Recently, the rst case of an ECT
patient with increased ICP associated with a brain tumor, known in
advance, was reported.57 The investigators used dexamethasone, furosemide, and -blockade before treatment to decrease both brain edema
and the increase in ICP associated with ECT. The patient enjoyed a good
therapeutic response without neurologic deterioration.
187
A prudent summary of the brain tumor and ECT literature is that

presence of any tumor probably presents an increased risk for neurologic
complications caused by ECT. In the absence of focal neurologic ndings,
brain edema, mass effect, or papilledema, the risks probably are relatively small. In the presence of such ndings, however, the increased
risk is probably quite high, and ECT should be considered only in the
context of profoundly urgent psychopathology. In any case of known
intracranial tumor in which ECT is being considered, consultation with
a neurosurgeon or neurologist to advise on risk assessment and riskreduction strategies (e.g., dexamethasone and furosemide) is indicated.
Miscellaneous
More than 12 cases of patients with multiple sclerosis receiving full
courses of ECT for psychopathologic states have been reported, with the
suggestion that gadolinium-enhancing lesions before ECT may presage
a particularly high risk for neurologic deterioration during treatment.48, 80
Isolated case reports and small series also describe safe and effective use
of ECT in a diversity of other neurologic conditions, such as cerebral
palsy,71 hydrocephalus with shunt,45 and spinocerebellar ataxia.23
PULMONARY DISORDERS
The two most common pulmonary disorders encountered in ECT
practice are asthma and chronic obstructive pulmonary disease. A paucity of data exist about the relative efcacy and safety of ECT in patients
with these conditions. Although there seems to be no a priori reason
to believe that ECT would be less effective in such patients, some
considerations regarding safety should be discussed. The rst is the
risk for bronchospasm. Taylor90 described a psychotically depressed,
asthmatic man who developed two episodes of short-lived bronchospasm during his otherwise effective and uncomplicated course of ECT.
The American Psychiatric Association (APA) Committee on ECT4 recommends that patients with asthma and chronic obstructive pulmonary
disease receive prescribed bronchodilators before each treatment and
that special attention be given to oxygenation of such patients. A second
safety concern is the risk for prolonged seizures or status epilepticus in
patients taking theophylline during ECT. Peters et al58 and Devanand et
al13 each described a patient who went into status epilepticus with
ECT while taking theophylline, and Abrams2 has described three more.
Rasmussen and Zorumski70 described a series of seven patients given
theophylline during ECT with nontoxic, therapeutic blood levels, none
of whom developed status epilepticus. It is recommended that theophylline be discontinued before ECT. If that is medically contraindicated,
then careful attention should be given to maintaining the lowest therapeutic blood level, concomitant caffeine augmentation should not be
188
RASMUSSEN et al
given, and ready access to rapidly acting anticonvulsant medication

(e.g., intravenous diazepam) should be ensured.
MISCELLANEOUS MEDICAL DISORDERS
A variety of other medical considerations occur in ECT practice. In
pregnancy, the most common adverse events are premature labor, uterine contractions, and vaginal bleeding.4, 51, 95 During the third trimester,
raising gastric pH before the procedure with a nonparticulate antacid
can minimize the risk for aspiration pneumonitis. Adequately oxygenating but not hyperventilating the patient before, during, and immediately
after the procedure can minimize the risk for fetal hypoxia.4, 51, 95 The
reader is especially referred to the APA Committee on ECT report,4
which has thorough recommendations regarding the use of ECT in
pregnant women.
Patients with diabetes mellitus should have their blood glucose
levels monitored closely during their ECT course. Glucose levels just
before ECT may demonstrate signicant hypoglycemia in diabetics who
are fasting and not taking insulin. If this occurs, glucose can be given
intravenously during the procedure. Electrolyte abnormalities, such as
hyperkalemia and hyponatremia, can lead to severe complications, including cardiac dysrhythmias and seizures, respectively. Signicant reux in those patients with hiatal hernias, gastroparesis, obesity, and
pregnancy may require measures to prevent aspiration pneumonia. Histamine-2 antagonists or antacids may decrease gastric acid, but for
patients at severe risk for aspiration, intubation may be necessary. Urinary retention from anticholinergic agents given during ECT can predispose to urinary tract infections and even bladder rupture if not monitored. With the use of skeletal muscle paralysis, the risk for bone
fractures is minimal with modern ECT; however, patients with severe
osteoporosis or recent fractures may need higher than usual muscle
relaxant dosing.4 Testing the adequacy of paralysis with a peripheral
nerve stimulator is recommended in these circumstances. For the patient
with unstable cervical spine disease, pretreatment consultation with an
orthopedic or neurologic surgeon is recommended to assess the risk for
injury, with the neck manipulation needed to ventilate the patient during
the treatment. With the increase in intraocular pressure associated with
ECT, precipitating glaucoma is concerning; however, no published cases
of this complication exist. Administering antiglaucoma medications, except anticholinesterases, before ECT is recommended for individuals
with documented glaucoma requiring treatment.4, 77
SUMMARY
ECT is often a necessary treatment for severe psychiatric disorders
in patients with medical or neurologic comorbidity. Although the avail-
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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Keith G. Rasmussen, MD
Department of Psychiatry and Psychology
Mayo Clinic
200 First Street SW
Rochester, MN 55905
e-mail: rasmussen.keith@mayo.edu
0193953X/02 $15.00 .00
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
From the Department of Psychiatry, University of Pittsburgh and Western Psychiatric

Institute, Pittsburgh (AD); the Treatment Research Center, University of Pennsylvania
and Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania
(RW); and the Portland Veterans Administration Medical Center, Oregon Health
Sciences University, Portland, Oregon (MF)

195
196
DiMARTINI et al
existed; therefore, blood transfusions were an important contributor to

HCV infection rates. Now that the screening of transfused blood for HCV
is routine, most new cases are associated with injection drug use.13 The
National Institutes of Drug Abuse and the Centers for Disease Control
and Prevention report that IV drug use is responsible for at least 60% of
new cases of HCV in the United States.1, 2 An estimated 50% to 80% of
intravenous (IV) drug users are HCV positive; 75% to 85% develop
chronic infections; and of these, 10% to 20% progress to cirrhosis.3 Because data about IV drug use among transplant patients are not systematically gathered in the United States, the exact numbers of LT patients
who potentially acquired hepatotropic viruses through IV drug use are
not known. The authors have identied that as many as 40% to 60% of
patients with HCV treated in a hepatology clinic had histories of prior
IV drug use.22 In one of the authors studies, 29% of patients undergoing
LT for ALD (n 90) had a history of IV drug use, and all of the patients
with IV drug use were infected with HCV.15 Results from another study,
in which wait-listed alcoholic LT candidates were compared to alcoholics
without evidence of liver disease, showed that 60% of patients with ALD
were HCV infected, 21% of whom had a history of IV drug use. In that
study, only 3.3% of the alcoholics without ALD were HCV infected.43
These statistics show that a signicant overlap does exist in patients with
alcoholism and those with IV drug use histories in the LT population. In
addition, a recent survey of 87 US LT programs estimated that methadone
maintained opioid-dependent patients who were predominantly HCV
infected accounted for only 0.5% of all LTs performed since 1988.28 Thus,
LT programs are now faced with increasing numbers of patients with
signicant histories of substance use.
While much research still needs to be done, a substantial amount of
information has been generated about patients undergoing LT for ALD,
including patient characteristics, outcomes, and risk factors for relapse.
The direction that these studies have taken has relied on the prior
ndings from research in addictions in non-LT populations. For example,
the factors believed relevant to relapse have been chosen for study in
patients undergoing LT because of their predictive ability in the non-LT,
addicted population. In addition, very little has been written about
addiction-treatment strategies specically for LT patients. In this area as
well, treatment has been modeled after that in the non-LT, addicted
population. This article reviews the current knowledge of alcohol and
substance use disorders in LT patients and strategies for treatment and
clinical management of these patients. Although this article focuses on
the LT population, many of the issues are applicable to any type of
organ transplantation.
PHYSICAL VERSUS PSYCHIATRIC DIAGNOSES:
THE IMPORTANCE OF IDENTIFYING THE PRESENCE
OF AN ADDICTION
It is often assumed that individuals referred for LT evaluation
because of ALD carry the diagnosis of an alcohol addiction related to
LIVER TRANSPLANTATION
197
the cause of their liver disease; however, substance abuse diagnoses

should be established by a professional experienced in addictions. A
recent survey of 69 US LT programs found that 83% of centers have a
psychiatrist or addiction medicine specialist routinely see each patient
with ALD during the evaluation phase.20 Despite this, in the LT literature, psychiatric diagnoses are not routinely reported, perhaps because
the nonpsychiatric physicians and clinicians who most often author
these reports are unfamiliar with these diagnoses. Using standardized
criteria, the current authors found that only 71% of patients undergoing
LT for ALD met the DSM-IV criteria for alcohol dependence.16 This
discrepancy was rst reported in a study by Beresford,8 who showed
wide variability in the rates of diagnosis of alcohol abuse as opposed to
alcohol dependence that depended on the strictness with which one
adhered to the DSM criteria. Although patients may consume enough
alcohol to acquire end-stage ALD, not all meet criteria for an alcohol
addiction.18 In many patients, the diagnosis of ALD is further confounded
by the existence of comorbid liver diseases, such as viral hepatitis.
Although IV drug use is a common route of infection for viral
hepatitis, not all infected patients contracted it from IV drug use. Similar
to ALD, patients with viral hepatitis who come for an LT evaluation
should be screened by a clinician experienced in evaluating addictions
for a history of past or present substance use. The use of standardized
diagnostic criteria (i.e., DSM-IV or ICD10 criteria) to diagnose substance
abuse or dependence is necessary. In an optimal situation, all LT candidates should be screened for current or past alcohol or substance use
disorders using such criteria. It is important to establish these diagnoses
because patients in remission from substance use disorders are always
at some risk for relapse.
MONITORING ALCOHOL USE BEFORE
AND AFTER LIVER TRANSPLANTATION
Few data regarding alcohol or drug use before LT are available.
This may be because of a powerful disincentive for patients on an LT
waiting list to admit to alcohol or drug use for fear that they will be
removed from the list for their disclosure.41 Nonetheless, clinical experience and research studies have shown that alcohol and drug use does
occur among patients awaiting LT. Therefore, the authors advocate that
LT programs strive for an atmosphere in which patients can feel safe
when asking for addiction treatment if they return to drinking while
awaiting LT. Although sufcient data describing the medical consequences of such episodes of substance use are lacking, it is prudent to
assume that any drug or alcohol use in the face of end-stage liver disease
can be extremely harmful.
Although substance and alcohol use after LT are important clinical
concerns, these issues have rarely been the focus of follow-up surgical
appointments. Depending on the structure of the team and the frequency
198
DiMARTINI et al
of follow-up, patients typically are seen by surgeons plus either LT

clinical coordinators or a combination of the surgical team, hepatologists,
or internists. Some LT teams also have psychiatric clinicians as an
integral part of outpatient follow-up clinical care. Their major role is
to monitor alcohol and substance use, psychiatric symptoms, and the
interaction between them. The psychiatric clinician also can provide
valuable insight into the interpretation of changes in liver enzyme proles, thereby preventing unnecessary liver biopsies or changes in immunosuppression treatment. The authors believe that having a psychiatry
component integrated into the LT team is essential for early identication
of substance use problems and integrating an addiction-treatment plan
into the patients total post-LT care. The Cleveland Clinic Foundation
has formed a chemical-dependency LT team to assess, treat, and monitor
LT patients with addictive disorders.35 This program is a model for
integration of such services.
In a recent prospective study, DiMartini et al18 compared monitoring
methods to identify post-LT alcohol use. Patients were interviewed by
two different methods: (1) an LT psychiatrist during routine clinic appointments and (2) a research assistant who was not a part of the LT
team, either by mail or face to face. Collateral interviews also were
performed with a friend or family member who either lived with the
patient or saw them frequently. In addition, blood alcohol levels for
current alcohol use and carbohydrate-decient transferrin (CDT) levels
for chronic drinking were evaluated for their effectiveness as biochemical
markers. All of these methods were compared to identify the best means
of capturing drinking episodes. Biochemical markers were not helpful
in most cases. All biochemical markers are subject to the timing, quantity,
and frequency with which alcohol is consumed. Thus, depending on the
individual, his or her pattern of use, and the timing of blood sampling,
the marker may or may not capture alcohol use. Nevertheless, blood
alcohol levels occasionally did identify patients who were covertly
drinking; therefore, it is encouraged that levels be included in routine
laboratory tests. Toxicology screening for drug use also has been helpful
in both the pre- and post-LT phases to monitor and identify substance
use.22 CDT levels are not an accurate marker when used in patients with
liver disease, because they frequently are elevated in advanced liver
disease.19 Thus, in both the pre- and post-LT phases, CDT levels are not
recommended for identifying alcohol use.19, 26
Most important, the authors have found that, in most cases, patients
were open to discussing their drinking habits.18 Maintaining an open,
nonjudgmental dialogue with LT recipients seems to be the most effective way to identify alcohol use in the post-LT period. Reviewing liver
enzyme and biopsy results and a candid discussion of the damage
caused by alcohol by provides an opportunity to explore the patients
denial of the consequences of their alcohol use. Even in the most difcult
cases, patients wish to maintain their health and are willing to listen to
advice and recommendations on addiction treatment. In the authors
experience, the LT team has established a powerful emotional bond with
the recipients. Many patients who have resumed drinking were relieved
199
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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DiMARTINI et al
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
201
diagnosis of alcohol dependence, whereas 100% of the repetitive drinkers

( 10 episodes) met criteria for alcohol dependence before LT. Again,
this emphasizes the importance of the pre-LT psychiatric diagnosis.
Predictors for post-LT drinking have not been found consistently, perhaps because of the limitations of pre-LT variables predicting post-LT
events. For example, some variables, such as increased pre-LT duration
of sobriety, may be accrued more related to the context of severe illness
or hepatic encephalopathy and may not truly represent the patients
ability to remain sober after LT.
PATIENTS WITH SUBSTANCE USE AND RELAPSE
There are few published outcome studies regarding outcome of LT
in patients with histories of signicant drug use. Coffman et al12 examined the outcome of 99 patients who had undergone LT for ALD.
Patients who had habitually used other substances in addition to alcohol
demonstrated similar alcohol-relapse rates as did those without a prior
drug use history. The investigators speculated that this outcome was
related to the fact that these patients had stopped their use of drugs
other than alcohol up to 25 years before LT. In a retrospective survey,
Newton32 compared post-LT alcohol relapse between two groups of LT
recipients with ALD. Ninety-eight patients had a history of alcohol use
alone, and 24 patients used alcohol and other substances. Post-LT relapse
was reported for 29.6% of patients in the alcohol-use-alone group. In
contrast, 17% of patients who had used alcohol plus other substances
before LT relapsed with use of alcohol after LT, although this difference
was not statistically signicant.
Even less is reported about patients with substance use histories
who relapse to substance use after LT. Because of the highly controversial
nature of LT in opioid-dependent patients receiving methadone maintenance treatment (MMT), researchers have recently focused efforts on the
post-LT outcomes of these patients. Two studies, specically of MMT LT
recipients, shed light on the issue of potential post-LT substance relapse.
Hails et al25 reported a positive outcome for ve patients on MMT who
received LTs. None of these patients had problems with noncompliance
or relapse in the post-LT follow-up period. In a larger survey of 87 LT
programs in the United States, Koch reported that 56% of these programs
accepted patients on MMT.28 These programs had performed LT on
approximately 180 patients on MMT at the time of the survey. Relapse
to use of illicit opiates was reported in less than 10% of patients; approximately 26% of patients had difculties with noncompliance with immunosuppressive medications.
THE PORTLAND VETERANS AFFAIRS MEDICAL
CENTER EXPERIENCE
The LT program at the Portland Veterans Administration Medical
Center (VAMC) and Oregon Health Sciences University (OHSU) is one
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DiMARTINI et al
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
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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DiMARTINI et al
which the patient pledges to remain abstinent lifelong contradicts a

fundamental premise of the 12-step programs. AA advises that recovering people to take it one day at a time. Thus, the tenets of AA serve
to remind recovering alcoholics that they remain vulnerable to taking
the next drink at all times and that they should consistently work on
their recovery. One could imagine that a patient adhering to the AA
program might not agree to sign a contingency contract. If one considers
the analogy to a suicide contract, the dilemma with the intent of the
contract becomes clear. For example, a suicidal patient who refuses to
sign a contingency contract for safety would make a clinician or physician extremely concerned. In contrast, for a patient with an addiction, a
refusal to sign a lifelong abstinence contract may represent their realistic
appraisal of the ever-present risk for relapse, not a refusal to remain
vigilant to relapse or work on maintaining abstinence.
Weinrieb et al42 made the rst attempt at a randomized, controlled
study of alcoholism treatment in LT patients. A wide range of alcoholism-treatment approaches, including relapse-prevention therapy and
contingency contracting, were considered for the design of the study,
but because most of these patients seemed to lack motivation to accept
alcoholism treatment, they chose to study motivational enhancement
therapy (MET). The largest randomized, controlled trial for alcoholism
treatment to date was Project MATCH.34 Emerging data from that study
suggested that MET was as effective as cognitive-behavioral therapy or
12-step facilitation therapy. They chose MET because they believed that
motivation for treatment should be the major focus and because MET is
the briefest of the three options. They added a naltrexone-versus-placebo
arm because naltrexone was thought to reduce alcohol craving, an important factor in relapse to alcohol drinking.38 MET occurred after LT to
avoid treating patients suffering from hepatic encephalopathy in the preLT phase.
They discovered that this population of patients is more complex
than previously realized. Of 60 LT recipients screened for the study, only
5 were randomized to the protocol, and none completed more than 4
months of the 6-month treatment period. All 5 were taking an average
of 12 medications per day and dropped out early because of the demands of post-LT medical care and the fear of naltrexone-induced hepatotoxicity. Four of the 5 denied any craving for alcohol, and all denied
drinking in the rst post-LT year. Unfortunately, they were unable to
complete this study because many patients were too ill, were ineligible
for the study, or simply did not believe that alcoholism was a problem
for them.42 Traditional methods of alcohol rehabilitation need to be
tailored to meet the unique needs of the LT patient in the immediate
and longer-term post-LT phase. As a result of this study, Weinrieb et al43
undertook a detailed analysis of their project and designed another
study to examine the rehabilitation needs of LT patients in greater detail.
Directly resulting from his prior work, Weinrieb40 designed the
current study comparing MET to treatment as usual in the community.
In this randomized, prospective study, participants receive either treat-
205
ment as usual (usually community-based alcoholism treatment) or seven

individual sessions of MET with case management that is integrated
into the medical care in the LT clinic. Treatment is delivered in the preLT phase because many patients remain on a waiting list for 2 or more
years before they receive an LT, and most are stable enough to tolerate
the treatment. MET can be provided in an LT clinic setting by social
workers, nurses, or counselors. MET seems to be very acceptable to pilot
patients in preliminary trials. Despite the effectiveness and safety record
for naltrexone in the treatment of alcoholism,9 its use was avoided
because patients did not seem to need an anticraving agent and because
they were afraid to take any risks with hepatotoxicity. Case management
was added to the MET to address additional behavioral health needs that
interfered with patients overall functioning, such as quitting smoking,
nancial and family stress, medication compliance, diet, exercise, and
transportation. Patients are followed every 3 months until LT and again
at 1 month, 6 months, and 1 year after LT. Psychiatric symptoms, quality
of life, drinking, drug use, and smoking status are assessed in addition
to measures of health, well-being, and cost-effectiveness. At the time of
this writing, 25 subjects had entered the study. Most have competed the
therapy phase, and 2 have undergone LT. The projected enrollment goal
is 200 subjects by July 2004.
While medications that may reduce the craving for alcohol and
potentially diminish the risk for relapse (e.g., acamprosate, ondansetron,
and naltrexone) have been studied in the general alcoholic population,
no other reports of use of these medications in LT patients exist. Clinical
experience suggests that even patients who are struggling with relapse
post-LT are reluctant to use naltrexone because of its potential, albeit
small, risk for hepatotoxicity. Naltrexone can be a direct hepatotoxin
at dosages higher than the recommended ( 300 mg/d) and is not
recommended for patients with active hepatitis or liver failure. Disulram has been used in non-LT populations to provide a negative reinforcement to drinking alcohol. Disulram blocks the oxidation of alcohol
at the acetaldehyde stage and can create severe nausea, vomiting, and
hemodynamic instability. Its use in LT recipients could place a patient
at risk for severe harm and is not recommended.
Drug Use Disorders
Despite epidemiologic trends reecting an irrefutable link between
drug use and LT after end-stage liver disease, there is little in the eld
of drug addiction treatment research in LT patients. In fact, the authors
know of no other studies of addiction treatment in severely medically
ill people. There is a rapidly emerging need for scientically derived
information in two populations of patients with end-stage liver disease:
(1) those with drug use-associated HCV infection (DUA-HCV) and (2)
HCV-infected MMT opiate addicts. In a recent survey of US LT programs, 87 of 97 programs (90%) responded to questions about MMT and
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DiMARTINI et al
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
207
signicantly different from those undergoing LT for other causes. The

fact that few patients return to heavy and deleterious alcohol or substance use attests to the success of programs in selecting patients capable
of caring for themselves and their livers after LT. In the pre-LT phase,
establishing the correct addiction diagnosis is essential so that those at
highest risk can be carefully monitored. Although information is emerging about other risk factors for relapse, the authors caution against
considering patients with these characteristics as being categorically
unt for LT. Each individual is unique, and such factors should guide
clinical decision making rather than being absolute contraindications.
After LT, clinical interviews, preferably by a trained psychiatric physician or clinician, are essential to monitoring alcohol and substance use,
and surveillance early on is required. Much work needs to be done with
respect to substance use and relapse after LT because few studies have
explored these issues. In addition, the special treatment needs of those
who relapse has not been addressed. Treatment research is underway
but has relied on traditional strategies that are not always applicable to
LT recipients. Further areas to improve clinical care include improving
health behaviors, specically, smoking cessation. The authors anticipate
that, in the near future, the ongoing work in this area will provide
information and guidance to physicians and clinicians caring for these
unique patients.
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for treatment among alcohol-dependent liver transplant candidates. 20:105119, 2001
44. Wiesner RH, Lombardero M, Lake J, et al: Liver transplantation for end-stage alcoholic
liver disease: An assessment of outcomes. Liver Transplant Surg 3:231240, 1997
Andrea DiMartini, MD
University of Pittsburgh Medical Center
Western Psychiatric Institute
3811 OHara Street
Pittsburgh, PA 15213
e-mail: dimartiniaf@msx.upmc.edu
0193953X/02 $15.00 .00
HERBAL AND NONHERBAL

SUPPLEMENTS IN MEDICALPSYCHIATRIC PATIENT
POPULATIONS
Catherine C. Crone, MD, and Geoffrey Gabriel, MD
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
Congestive heart failure

Coenzyme Q10
Hawthorn
L-Carnitine
Depression
SAMe
St. Johns wort
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
CRONE & GABRIEL
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
While patients often turn to nutritional supplements at the same

time that they are receiving conventional medical care, surveys have
shown that they do not inform their physicians about this practice.44, 47
Patients frequently view these substances as safe because of their natural
origins and are unaware of the potential risks posed by them; however,
multiple reports of contamination, substitution, and adulteration raise
concerns about their use.35, 51
CONCERNS RELATED TO QUALITY CONTROL
Quality control and regulation of nutritional supplements include:
1. Nutritional supplements are not regulated in the same manner
as prescription or over-the-counter (OTC) agents; therefore, they
do not have to prove therapeutic efcacy and may not be manufactured under quality control standards.
2. Current regulations do not require manufacturers to prove that
their supplement is safe before marketing.
3. Lack of quality control has led to:
A. Marketing of products that do not have the correct amount
of active ingredient noted on the product label. Analyses of
some supplements have found no active ingredients present.
B. Contamination of products with additional compounds that
have led to complications, including anticholinergic toxicity
and cardiac glycoside toxicity.
C. Substitution of one compound for another within a nutritional
supplement. This has led to cases of hepatoxicity and renal
failure. Substitutions are not necessarily noted on the product label.
D. Adulteration of supplements with steroids, benzodiazepines,
hormones, and heavy metals.
SUPPLEMENTS IN MEDICAL-PSYCHIATRIC PATIENT POPULATIONS
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
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CRONE & GABRIEL
to moderate AD or vascular dementia. Cases of subdural hematoma,

intracerebral hemorrhage, and postoperative bleeding associated with
use of gingko extract have been reported, suggesting a need for caution
in patients who are on anticoagulants or those facing surgery.56, 108, 114
ALC, an endogenous substance similar in structure to acetylcholine,
acts as a carrier of acetyl groups into mitochondria and a facilitator of
acetylcholine production, with cholinomimetic effects in addition to
neuroprotective effects.22, 23 While results of recent controlled studies are
mixed, most suggest that ALC produces improvement in attention and
may slow the rate of decline compared with placebo17, 143, 157, 169; however,
Thal et al170 failed to demonstrate a slowed rate of decline in patients
with early onset AD treated with 3 g/d of ALC. ALC may have a role
in combination therapy for AD.
Huperzine A (HupA) is an alkaloid compound isolated from Huperzia serrata, a club moss that has been extensively used in Chinese folk
medicine to treat various conditions, including cognitive impairment.8, 100
HupA, which demonstrates no signicant receptor activity or afnity,
has been shown to be a selective and reversible inhibitor of acetylcholinesterase.24, 182 It also has been shown to lessen neuronal toxicity caused
by glutamate.174 The initial studies of HupA in patients with AD have
demonstrated improvement in various tests of cognitive function.186, 187
Cholinergic side effects, which tend to be mild and transient, have been
reported. Because of benign side-effect prole and reported mechanisms
of action, HupA is an attractive potential therapy for AD that warrants
further investigation.
ANXIETY
The use of complementary and alternative medications in the treatment of anxiety disorders is increasingly common because of concerns
about the adverse effects of traditional psychopharmacologic treatments.
Kava, derived from the root of Piper methysticum, is used as an anxiolytic,
a sedative, and a medicinal to treat a wide variety of illnesses.155 Kava
pyrones may serve as mediators at -aminobutyric acid (GABA) receptors located in the amygdala and hippocampus in addition to possessing
anticonvulsant properties.39, 84 A recent meta-analysis135 suggested that
kava is superior to placebo in the treatment of various anxiety states.
Studies comparing kava and benzodiazepines in the treatment of anxiety
suggested no signicant difference in anxiolytic effects.60 While generally
well tolerated with minimal side effects, kava should be used with
caution in the presence of other CNS depressants. Because of possible
dopamine antagonism, kava should not be used in patients with Parkinsons disease or drug-induced extrapyramidal syndromes.148
Valerian is a widely used hypnotic and anxiolytic that is derived
from the plant Valeriana ofcinalis. It has been suggested that the mechanism of action of valerian involves two groups of compounds: valepotriates and sesquiterpenes. These compounds may interact with central
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
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CRONE & GABRIEL
and the incidence of cardiovascular events.178 This was later discovered

to be the result of the effects of omega-3 fatty acids in sh oils. Benets
for atherosclerosis may be related to a number of different mechanisms
(e.g., reduced platelet aggregation), but much of the focus has been on
plasma lipid levels.127, 178, 183 Randomized clinical trials have repeatedly
found reductions of 20% to 50% in serum triglyceride levels, produced
by decrease of hepatic triglyceride synthesis.5, 160, 183 Among those who
have a history of myocardial infarction, OFAs also may provide protection from ventricular arrhythmias, a common cause of death in this
population.156, 178 OFAs seem to reduce the susceptibility to arrhythmias
by prolonging the refractory period in cardiac cells.103, 156
Foods containing soy protein recently have soared in popularity as
reports of health benets have gained attention. Soy protein produces
mild reductions in the lipid proles of hypercholesterolemic patients,
but this effect does not necessarily extend to those with normal cholesterol levels.2, 32, 37, 50, 168 The mechanism of action for these lipid-lowering
effects are unknown but may involve isoavones.37, 50 Because they
posses weak estrogenic effects, isoavones have raised safety concerns
for patients with hormone-sensitive tumors. Preclinical studies have
produced conicting results in breast tissue, so some degree of caution
may be warranted.68, 117
Garlic also has been used to lower serum lipid levels, but clinical
studies have been less denite about clinical benets.12, 113, 162 Stevinsons
meta-analysis162 of randomized trials reported that garlic reduced total
cholesterol in hyperlipidemic subjects, but the effects were mild and no
greater than those reached by dietary changes alone. Reports of a spinal
epidural hematoma in one patient and prolonged postoperative bleeding
developing in another, is a reminder of the effects of garlic on platelet
function.20, 140 This should be considered in patients on anticoagulants,
antiplatelet agents, and those otherwise at risk for bleeding.
BIPOLAR DISORDER
The use of OFAs in the treatment of bipolar disorder has demonstrated both promise and controversy.21, 163, 165 The OFAs, which include
-linolenic acid and its by-products, eicosapentaenoic acid and docosheaxaenoic acid, function as components of various biological membranes and may possess physiologic roles in antikindling and suppression of signal transduction.99, 145, 151
Stoll163 examined the use of OFA supplementation in a cohort of
bipolar patients, most of whom were also on conventional mood stabilizer therapy. While this was a preliminary study, the results suggested
that OFAs might offer greater help for depressive symptoms than manic
symptoms.21, 163 On the other hand, low OFA levels also may serve as
markers for depression or the severity of the illness.46 Together with a
potential risk for increased bleeding with OFAs, hypomania and mania
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
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CRONE & GABRIEL
study of mistletoe extract as an adjuvant therapy for patients with head

and neck cancer showed no improvements in 5-year survival rate or
quality of life.161
CONGESTIVE HEART FAILURE
Levels of coenzyme Q10, an antioxidant and cofactor in the mitochondrial oxidative phosphorylation process, are decreased in the myocytes of patients with congestive heart failure (CHF) regardless of
cause.57, 122 Coenzyme Q10 may aid in correcting the cellular dysregulation and necrosis in CHF secondary to the reperfusion state and free
radical stress.90 Most studies to date suggest that coenzyme Q10 supplementation has a positive effect on cardiac variables, including ejection
fraction and functional status.71 however, many of these studies had
small sample sizes and variable inclusion and exclusion criteria, which
make interpretation problematic. A recent randomized, double-blind
study using coenzyme Q10 supplementation (200 mg/d) in 55 patients
with CHF (New York Heart Association class 3 and 4) failed to demonstrate a signicant change in peak oxygen consumption, ejection fraction,
or exercise duration.93 These ndings were similar to a previous study
of supplementation in 25 patients with idiopathic dilated cardiomyopathy.133 Coenzyme Q10 may have procoagulant effects that could interfere
with anticoagulation.158
DEPRESSION
SAMe is a compound synthesized by the body from L-methionine
and adenosine triphosphate, which participate in numerous physiologic
pathways.9, 190 Through a transmethylation process, SAMe transfers
methyl groups to various compounds including dopamine, norepinephrine, serotonin, and phospholipids. Although SAMe also has a role in
transaminopropylation and trans-sulfuration pathways, research indicates that it is the transmethylation process that contributes predominately to the observed antidepressant effects.14, 150 The effects of SAMe on
cell membrane phospholipids also may contribute to the antidepressant
effects through actions on membrane uidity, various receptors, and ion
channels.159, 190
Numerous controlled studies have demonstrated clinical improvement in depressed patients treated with SAMe.16 Compared with standard treatments for depression including tricyclic antidepressants, SAMe
has shown comparable response with fewer side effects.78 Some investigators also have suggested a role for SAMe in augmentation of standard
antidepressant psychopharmacology.11 While early studies tended to use
a parenteral route of administration, more recent research has used oral
formulations with typical doses in the range of 800 to 1600 mg.16
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
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CRONE & GABRIEL
useful in certain subgroups of patients, including those with non

insulin-dependent diabetes mellitus (NIDDM), late-onset diabetes, mild
hyperglycemia, glucose intolerance, or steroid-induced diabetes.3, 27, 121, 137
While reviews of clinical trials have demonstrated little toxicity, isolated cases of renal dysfunction, dermatologic pathology, and possible
delirium associated with chromium (III) supplements have been
reported.28, 58, 75, 79, 188
Studies have suggested that fenugreek has a hypoglycemic effect in
both animal models and humans with insulin-dependent diabetes mellitus (IDDM) and NIDDM.112, 138, 153 Fenugreek also may reduce levels of
total cholesterol, low-density lipoprotein, and very low density lipoprotein while maintaining high-density lipoprotein levels in IDDM patients.153 4-Hydroxyisoleucine, an amino acid extracted from fenugreek,
has a direct effect on beta islet cells resulting in insulin secretion in
patients with NIDDM.146 While no studies have reported toxicity with
its use, fenugreek should be used with caution in patients taking oral
hypoglycemics or insulin.
Bitter melon apparently produced hypoglycemic effects caused by
the presence of a polypeptide known as plant insulin that has a
rapid onset and short duration of effect.40 While animal models have
demonstrated hypoglycemic effects, research with human subjects is
extremely limited.1, 104, 144 Ginseng also has been found to have hypoglycemic properties in animals, which may be the result of effects on
glucose transport and nitric oxide mediated insulin release.64, 130 A recent
study demonstrated that American ginseng (Panax quinquefolius) has
signicant hypoglycemic effects in both NIDDM patients and control
subjects.179, 180 Ginseng has multiple side effects and should be used with
caution in psychiatric patients because of its anxiogenic effects.7, 65
HUMAN IMMUNODEFICIENCY VIRUS
Combination antiretroviral therapy has become the standard of care
for treating patients with HIV, however, viral mutations hamper longterm success. One means by which the virus can disarm the hosts
immune system is through induction of lymphocyte apoptosis. This is
partly achieved by raising ceramide levels, a cellular messenger for
apoptosis.120 L-Carnitine is an amino acid needed for mitochondrial fatty
acid oxidation that supplies energy to muscular tissues.92 Oral and
intravenous doses of L-carnitine have shown some ability to reduce the
frequency of apoptosis in CD4 and CD8 lymphocytes.120 Open-labeled
trials using small patient populations have reported signicant declines
in apoptosis and ceramide levels.31, 120, 132 Adverse effects have been
minimal, with transient gastrointestinal distress being the most common.
Acetyl-L-carnitine, an ester of L-carnitine, may have a role in treating
nucleoside reverse transcriptaseinduced neuropathy.147
Infection with HIV causes severe oxidative stress, leading to the
221
depletion of intracellular glutathione and cysteine, the primary cellular

antioxidants.45, 132 One of these, reduced glutathione (GSH), is vital for
the maintenance of immunological reactivity, including T-cell activation,
phagocytosis, and cell-mediated cytotoxicity.45, 132 N-acetylcysteine, the
acetylated precursor of cysteine and GSH, restores intracellular GSH and
cysteine levels during periods of severe oxidative stress.91 This knowledge has led to studies examining whether oral N-acetylcysteine can
reverse depleted antioxidant levels and restore immunologic activity
impaired by HIV. So far, randomized placebo-controlled trials in HIV
patients have yielded mixed results.15, 42, 45, 69 The use of N-acetylcysteine
in healthy individuals is not advised because it has demonstrated prooxidant activity in those not under marked oxidative stress.91
Loss of lean body mass negatively affects survival in patients with
HIV disease. Under normal circumstances, the amino acid glutamine is
formed in skeletal muscle and acts as fuel for lymphocytes, macrophages, renal, and intestinal cells.132 During periods of greater stress, as
in HIV infection, skeletal muscle may not be able to provide enough
glutamine. This leads to breakdown of skeletal muscle and produces the
characteristic wasting seen in some HIV patients.132 Appetite stimulants, parenteral nutrition, and other methods add adipose tissue, not
lean body weight.152 Recombinant growth hormone and testosterone lean
body mass, but the former is very expensive. A double-blind, placebocontrolled trial152 recently showed that an antioxidant-glutamine supplement also produced signicant gains in lean body mass in HIV patients with more than 5% disease-related weight loss. The investigators
indicated that their results supported a need for additional studies into
this less costly intervention.
OSTEOARTHRITIS
Osteoarthritis is a signicant source of chronic pain and the second
leading cause of long-term disability in adults.102 Pathologic joint
changes occur when the destruction of cartilage matrix outpaces synthesis of new matrix. Glucosamine and chondroitin sulfates are both components of cartilage matrix and popular supplements for osteoarthritis.
Glucosamine is thought to stimulate production of new cartilage,
whereas chondroitin inhibits proteolytic enzymes responsible for cartilage destruction.41 While a number of clinical trials reported positive
effects with glucosamine supplementation, critical analyses of these
studies have noted various shortcomings.10, 38, 41, 115, 141 A recent metaanalysis115 also found possible publication bias. Chondroitin sulfate has
been tested in fewer clinical trials but seems to provide greater therapeutic effects.106, 115 Despite aws in available data, ndings were sufciently
strong to lead the National Center for Complementary and Alternative
Medicine to fund a multicenter, multimillion-dollar trial of glucosamine
and chondroitin for knee osteoarthritis. Although glucosamine is gener-
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CRONE & GABRIEL
ally well tolerated, it may cause insulin resistance in some patients.80

This is not a concern with chondroitin, but there is a call for caution
depending on the source of the supplement. Commercially available
chondroitin sulfate is mainly derived from shark cartilage or synthetic
processes; however, some of the supplements come from bovine cartilage, raising concerns about the potential risk for bovine spongiform
encephalopathy, or mad cow disease.80
SUMMARY
Nutritional supplements remain a popular choice for patients seeking relief or prevention from a wide range of physical and mental
disorders. Review of available literature nds support for some therapeutic uses, but aws in study design (e.g., small sample sizes) and
methodology (e.g., inadequate blinding and a lack of placebo control)
limit the possibility of making strong recommendations. Quality-control
issues also raise concerns about the safety of supplement use (see previous list). In addition, potential interactions with prescription drugs are
another consideration (Table 1). By becoming more knowledgeable about
the risks and benets of nutritional supplements, psychiatrists can assist
patients in making informed choices and avoiding unnecessary harm.
Table 1. POTENTIAL ADVERSE SIDE EFFECTS OF NUTRITIONAL SUPPLEMENTS
Supplement
Acetyl-L-carnitine
Chondroitin sulfate
Chromium picolinate
Garlic
Gingko
Ginseng
Glucosamine sulfate
Hawthorn
Huperzine
Kava kava
L-Carnitine
Ma huang
Mistletoe
S-adenosyl-L-methionine
Saiboku-to
St. Johns wort
Shark cartilage
Valerian
Potential Adverse Side Effects

Agitation
GI effects, lower limb edema/extrasystoles
Anemia, thrombocytopenia, hemolysis, delirium, renal
dysfunction, hepatic dysfunction
GI effects, hemorrhage
Headache, dizziness, palpitations, restlessness, weakness,
CNS hemorrhage, seizures (?)
Agitation, hypomania, mania, mastalgia, tachycardia
GI effects, insulin resistance
GI effects, dizziness, insomnia, agitation, palpitations
Blurred vision, GI effects, hyperactivity, anorexia
bradycardia
Extrapyramidal reaction, dizziness, dermatitis, sedation,
GI effects
GI effects, gastritis, seizures
Anxiety, irritability, dizziness, hypertension, seizures,
tachycardia, cerebrovascular accident, myopathies
Hepatitis, hypotension, seizures, coma, fever
Anxiety, headache, hypomania, mania
Inammatory alveolitis, inammatory pneumonitis
Anxiety, insomnia, fatigue, hypomania, mania,
phototoxicity
GI effects, dizziness, hypotension, hypercalcemia,
hyperglycemia, generalized weakness, hepatitis
Insomnia, excitability, decreased alertness
223
Table 2. POTENTIAL DRUGSUPPLEMENT INTERACTIONS

Potential Interaction
Supplement
Hemorrhage
Fenugreek, garlic, gingko,

omega-3 fatty acids
Increased coagulability
Hypoglycemia
Coenzyme Q10, St. Johns wort

Bitter melon, chromium
picolinate, garlic, gingko,
ginseng
Glucosamine sulfate, ma huang
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)
Shark cartilage, kava kava,

valerian
N-Acetylcysteine
S-adenosyl-L-methionine
Hawthorn
N-acetylcysteine
St. Johns wort
Garlic, St. Johns wort
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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169. Thal L, Carta A, Clarke W, et al: A 1-year multicenter placebo-controlled study of

acety-L-carnitine in patients with Alzheimers disease. Neurology 47:705711, 1996
170. Thal L, Calvani M, Amato A, et al: A 1-year controlled trial of acetyl-L-carnitine in
early-onset AD. Neurology 55:805810, 2000
171. Thiele B, Brink I, Ploch M: Modulation of cytokine expression by hypericum extract.
J Geriatr Psychiatry Neurol 7(suppl):6062, 1994
172. Tsubono Y, Nishino Y, Komatsu S, et al: Green tea and the risk of gastric cancer in
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173. Van Dongen M, van Rossum E, Kessels A, et al: The efcacy of gingko for elderly
people with dementia and age-associated memory impairment: New results of a
randomized clinical trial. J Am Geriatr Soc 48:11831194, 2000
174. Ved H, Koenig M, Dave J, et al: Huperzine A: A potential therapeutic agent for
dementia, reduces neuronal cell death caused by glutamate. Neuroreport 8:963968,
1997
175. Villani F, Comazzi R, DeMaria P, et al: Effect of dietary supplementation with
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176. Vincent J: Relationship between glucose tolerance factor and low-molecular-weight
chromium binding substance. J Nutr 124:117118, 1994
177. Vincent J: Mechanisms of chromium action: Low-molecular-weight chromium binding
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178. Von Shacky C: n-3 fatty acid and the prevention of coronary atherosclerosis. Am J
Clin Nutr 2000; 71(suppl):224227, 2000
179. Vuksan V, Sievenpiper J, Koo V, et al: American ginseng (panax quinquefolius L)
reduces postprandial glycemia in nondiabetic subjects and subjects with Type 2
diabetes mellitus. Arch Intern Med 160:10091011, 2000
180. Vuksan V, Stavro M, Sievenpiper J, et al: Similar postprandial glycemic reductions
with escalation of dose and administration time of American ginseng in Type 2
diabetes. Diabetes Care 23:12211226, 2000
181. Wagner J, Wagner M, Hening W: Beyond benzodiazepines: Alternative pharmacologic
agents for the treatment of insomnia. Ann Pharmacother 32:680691, 1998
182. Wang H, Tang X: Anticholinesterase effects of huperzine A, E2020, and tacrine in
rats. Acta Pharmacol Sin 19:2730, 1998
183. Weber P, Raederstorff: Triglyceride-lowering effect of omega-3-LC-polyunsaturated
fatty acids- a review. Nutr Metab Cardiovasc Dis 10:2837, 2000
184. Wettstein A: Cholinesterase inhibitors and Ginkgo extracts: Comparison of published
placebo-controlled efcacy studies of a least six months duration. Phytomedicine
6:393401, 2000
185. Woelk H: Comparison of St. Johns wort and imipramine for treating depression:
Randomised controlled trial. BMJ 321:536539, 2000
186. Xu S, Gao Z, Weng Z, et al: Efcacy of tablet huperzine-A on memory, cognition, and
behavior in Alzheimers disease. Acta Pharmacol Sin 16:391395, 1995
187. Xu S, Cai Z, Qu Z, et al: Huperzine-A in capsules and table ts for treating patients
with Alzheimer disease. Acta Pharmacol Sin 20:486490, 1999
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induced by chromium picolinate. J Am Acad Dermatol, 41:820823, 1999
189. Yu GP, Hsieh CC, Wang LY, et al: Green tea consumption and risk of stomach cancer:
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Catherine C. Crone, MD
Assistant Clinical Professor of Psychiatry
Georgetown University Medical Center
Inova Transplant Center
Falls Church, VA 22031
0193953X/02 $15.00 .00
DESIGNER DRUGS IN THE

GENERAL HOSPITAL
Philip A. Bialer, MD
In many ways, the designation designer drugs is a misnomer

because most medications and drugs that people use have been designed
for specic purposes: to stimulate or inhibit certain receptors, to stimulate or inhibit particular enzymes, and so on. The drugs that are the
focus of this article may be more appropriately thought of as party
drugs or club drugs. These are drugs that are most commonly used
in the context of large events, such as raves or circuit parties.
What are raves and circuit parties? Raves are large dance parties
that began to gain popularity in England in the 1980s and have now
become very popular in the United States and elsewhere. They are most
often attended by youths in their late teens to early 20s and are often
held in varying locations at low cost. Raves are parties that last all night
long, with loud, repetitive electronic music and vigorous dancing; most
attendees partake in a variety of mind-altering drug use.56 As raves
have become more established, alcohol has also become more available,
although it is not frequently used in this setting. A Web site58 that is
devoted to the culture of raves states, A large part of the concept of
raves is built on sensory overloada barrage of audio and very often
visual stimuli are brought together to elevate people into an altered state
of physical or psychological existence.
Circuit parties share many similarities with raves except that they
are most often attended by gay men.47 They initially began as fundraisers
for AIDS organizations but have taken on a life of their own in major
cities worldwide throughout the year. These several-day events are
From the Division of Consultation-Liaison Psychiatry, Department of Psychiatry, Beth

Israel Medical Center; and the Department of Psychiatry, Albert Einstein College of
Medicine, New York, New York

231
232
BIALER
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
DESIGNER DRUGS IN THE GENERAL HOSPITAL
233
ketamine.6, 35, 41 Preadministration of benzodiazepines or haloperidol may

reduce some of the perceptual disturbances, emotional distress, and
cognitive dysfunction.12, 34 One report suggests that preadministration of
lamotrigine may prevent the dissociative phenomena of ketamine by
attenuating cortical glutamate release.2 The analgesic effects of ketamine
also have been studied in the management of postsurgical pain,33 cancer
pain, chronic pain,16 and bromyalgia.24
Most people in the club scene take ketamine for the dissociative,
out-of body experience, which begins approximately 15 minutes after
snorting it. Users report a psychedelic experience with illusions, hallucinations, derealization, depersonalization, alteration of body shape or
consistency, and a sense of eternity as they emerge from the trip over
the next 1 to 2 hours.12, 35 Adverse effects include nausea and vomiting,
tachycardia, elevated blood pressure, and paranoid delusions. Many
chronic users of ketamine often experience ideas of reference and prefer
taking the drug in their own homes.13
Ketamine has a high therapeutic index, and few deaths have been
reported associated with its use alone.22 The most dangerous complication is aspiration while sedated, so protection of the airway and supportive care during intoxication are the mainstay of management. Although
thought to be physically and psychologically addictive, no reports of a
withdrawal syndrome have been reported.15 In 1999, the US Food and
Drug Administration made ketamine a Schedule III substance.
METHAMPHETAMINE
Because most raves and circuit parties are all-night affairs, stimulants, such as methamphetamine, commonly are used. It is known on
the street as meth, speed, crystal meth, ice, glass, crank, chalk, and tweak.
Desoxyn, Amphedroxyn, and Methedrine are names of commercially
produced methamphetamine.
Methamphetamine was rst synthesized in the 1920s, and the rst
commercial preparations appeared in the 1930s as nasal decongestants.3
Many people, however, used methamphetamine for weight loss and to
ght fatigue. The Drug Enforcement Administration began cracking
down on the distribution of methamphetamine in the 1970s, and it was
listed as a Schedule II drug. Its popularity in the club scene increased
greatly in the 1980s. The national lifetime prevalence of methamphetamine use has been reported as 2.3%.10 It is more commonly used in the
western United States and has been reported as the most common
substance of abuse in Honolulu and San Diego.3 A psychiatry consultation service in San Diego reported that, over a 5-year period from 1989
to 1995, 8.7% of their consultations were identied as methamphetamine
users.3 Methamphetamine use seems to be increasing in the Midwest
and East, where injecting is also becoming more common.10
Although methamphetamine can be taken orally, snorted, or injected, in the club scene it is most commonly smoked as crystal meth,
which refers to its appearance as clear, chunky crystals that resemble
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BIALER
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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BIALER
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
237
today. The ability of GHB to enhance the effects of steroids and to

stimulate the release of human growth hormone also has been studied.
Many inferred that this effect on growth hormone could produce an
increase in muscle mass, although this has never been proven.40 There
has been continued investigation, especially in Europe, of the use of
GHB in the treatment of alcohol dependence, opiate withdrawal, weight
control, and neuroprotection in cerebral ischemia.40 Reports of its abuse,
particularly in the club scene, began surfacing in the 1990s. The Centers
for Disease Control and Prevention reported 57 cases of GHB poisoning
in 1990,8 which led the FDA to ban its over-the-counter sale. In 1995 and
1996, 69 cases of poisoning and one death were reported in New York
and Texas.49 As of January 2000, the Drug Enforcement Administration
has recorded 60 known deaths attributed to GHB use.10 GHB was classied as a Schedule I drug in March 2000.
On the streets, GHB is known by a variety of names: liquid E (for
liquid ecstasy), liquid X, GBH, Georgia home boy, grievous bodily harm, scoop,
soap, salty water, organic Quaalude, easy lay, fantasy, cherry menth, G-rifc,
and sodium oxybate. In addition to being available for purchase in clubs,
kits and recipes are readily available over the Internet for home synthesis.54 Many purchasers are bodybuilders who use GHB for its purported,
but unproven, anabolic effects. -Butyrolactone and 1,4 butanediol are
precursors that can be converted to GHB after ingestion.30.32 They can be
purchased as dietary supplements in health food stores and are also
ingredients in some industrial solvents.10 It is relatively inexpensive,
selling for $5 to $40 per capful, or dose, which is generally 1 to 2
teaspoons. The exact amount of GHB present varies, however, because
of its illicit synthesis.
GHB is a colorless, odorless liquid with a mild salty or soapy taste
that can easily be masked by party drinks. After oral ingestion, GHB is
rapidly absorbed, producing its clinical effects within 20 to 30 minutes.
It is also rapidly metabolized to succinic semialdehyde, with an elimination half-life of 27 minutes.31, 40 Almost all of GHB is excreted through
the lungs as carbon dioxide. Only 2% to 5% is eliminated through the
urine and can be detected only using gas chromatography or mass
spectrometry. This has made it difcult to evaluate people who have
presented in EDs with suspected GHB toxicity or withdrawal, and the
clinician often must depend on information given by friends or signicant others. Its mechanism of action is somewhat unclear. In high concentration, it is a partial -aminobutyric acid B (GABAB) agonist but
does not have any GABAA activity.31, 40 A biphasic dopamine response
occurs with initial suppression and then subsequent release of dopamine.
Increased CNS acetylcholine, serotonin, and GABA have all been reported after administration of GHB.31
In terms of dosing, 10 mg/kg usually produces a euphoric effect,
short-term amnesia, and hypotonia; 20 to 30 mg/kg produces drowsiness and sleep and is the dose used to produce rapid eye movement
sleep in narcoleptics; 50 to 60 mg/kg results in general anesthesia. The
lethal dose has been reported to be 5- to 15-fold the anesthetic dose.
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BIALER
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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BIALER
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.
It is interesting that the individuals described here were not taking

GHB as a part of the club scene but rather were using it at home at high
daily doses for prolonged periods of time. Similar cases have now been
reported. Based on these reports and the authors own experience, the
authors recommendations for treatment of withdrawal from GHB, or
its precursors, include:
1. Admission to an ICU setting
2. Administration of a lorazepam drip titrating to a heart rate of 90
bpm or less and a blood pressure of 140/90 mm Hg or less
3. The addition of valproic acid as soon as the patient can take oral
medications; this may be a particularly helpful medication in
these cases because valproic acid has been shown to have both
GABAA and GABAB agonist activity51, 53
4. When the patient is medically stable, a switch from IV lorazepam
to PO clonazepam
5. Slow tapering-off of the clonazepam
SUMMARY
This article has reviewed the potential complications of acute intoxication and withdrawal from some of the more commonly used club, or
designer, drugs. Although limited, acute use of these drugs is claimed
by users to be benign, in the context of crowded raves and circuit
parties, where multiple drugs may be used, hyperthermia, dehydration,
and life-threatening reactions may occur. In addition, mounting evidence
of the long-term effects of continued use of these drugs is cause for
241
great concern. Finally, awareness of a severe withdrawal syndrome from

GHB and its precursors is particularly important to psychiatrists of the
medically ill, who may be called on to help in the management of these
patients.
ACKNOWLEDGMENTS
The author wishes to thank Gissela Cedeno for her help in the preparation of the
manuscript.
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Philip A. Bialer, MD
Beth Israel Medical Center
First Avenue and 16th Street, Fierman 509
New York, NY 10003
e-mail: pbialer@bethisraelny.org

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2002, Vol.25, Issues 1, Psychiatry in The Medically Ill

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PSYCHIATRY IN THE MEDICALLY ILL

PSYCHIATRY IN THE MEDICALLY ILL

0193953X/02 $15.00 .00

From the Departments of Psychiatry and Internal Medicine, Division of Consultation-Liaison

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

symptoms. The reader is referred elsewhere for a comprehensive review

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

themselves throughout the body. Wherever they end up they develop

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

Figure 2. Noncontrast T1-weighted MR image showing multiple intraparenchymal cysticerci

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

in NCC is associated with benecial effects.29 Further research is needed

Table 1. INCLUSIONARY CRITERIA FOR PANDAS

Association with GABHS

Association with neurologic

of PANDAS. This is based on our knowledge of immune responses.

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

Table 2. DOCUMENTATION OF RECENT GABHS INFECTIONS

Positive GABHS throat culture

A positive throat culture is not sufcient evidence of a

Rise in antistreptococcal titres

ASO titres typically increase 36 wk following

present with the triad of headache, stomachache, and fever.39 Based on

Table 3. COMMON ASSOCIATED SYMPTOMS IN PANDAS

PANDAS pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection.

chorea and PANDAS. In a small study of 27 children with PANDAS, 23

Figure 4. Proposed pathogenesis of PANDAS (pediatric autoimmune neuropsychiatric

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

year of follow-up, treatment gains were maintained. Perlutter et al,

(54%), myalgia or arthralgia (44%), headache (42%), fever or chills (39%),

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

in more than 50% of patients, including increased cerebrospinal uid

subsequent serologic testing is falsely negative even though the patient

PSYCHIATRIC PRESENTATIONS OF NON-HIV INFECTIOUS DISEASES

PSYCHIATRY IN THE MEDICALLY ILL

0193953X/02 $15.00 .00

The electroencephalogram (EEG) is one of the oldest tools in clinical

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

BOSTWICK & PHILBRICK

EEG failed as a diagnostic tool of functional alteration on many

Case 1: Postoperative Delirium Versus

For the psychiatrist working in the medical-surgical setting, the EEG

BOSTWICK & PHILBRICK

the depression, anxiety, psychosis, or conversion disorder that

Variable findings, therefore, unhelpful

In ordering the EEG, medical psychiatrists must keep in mind

BOSTWICK & PHILBRICK

Detecting seizure disorders often requires technical adjustments as

BOSTWICK & PHILBRICK

sufficient time period without artifact or confounding factors present?

PSYCHIATRY IN THE MEDICALLY ILL

0193953X/02 $15.00 .00

THE SIZE OF THE PSYCHIATRIC PROBLEM

From the Department of Psychiatry, University of Oxford, Oxford, United Kingdom

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

consequences of other acute medical problems42 and include the whole

PSYCHIATRIC CONSEQUENCES OF MOTOR VEHICLE ACCIDENTS

Immediate Psychological Reactions

that it can be diminished by sympathetic medical care and by early

PSYCHIATRIC CONSEQUENCES OF MOTOR VEHICLE ACCIDENTS

OTHER PSYCHIATRIC COMPLICATIONS

SOCIAL, FINANCIAL, AND FAMILY CONSEQUENCES

Previous psychological status