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BIPOLAR DISORDER: A SYNDROME IN EVOLUTION
—
Jeffrey A. Lieberman, MD,* and Charles B. Nemeroff, MD, PhD†
ABSTRACT
Diagnosing and treating bipolar disorder
offers an array of challenges to the clinician. It is
a multidimensional syndrome that can have
numerous clinical presentations with a variety of
symptom domains in the same individual. It can
be difficult to diagnose and evidence shows that
it can often be misdiagnosed. With that challenge, it is important to review the various aspects
of bipolar disorder and the approaches to treatment, old and new. A review of the latest scientific data can guide us to make informed clinical
decisions to make a difference in the quality of
care for our bipolar patients.
B
(Adv Stud Med. 2004;4(10D):S881-S891)
ipolar disorder, possibly more than any of
the other syndromes in psychiatry, is in
the process of evolution and re-evaluation. Although the disorder was previously thought to afflict approximately 1% of
the population, more recent epidemiologic studies
indicate that it is much more prevalent; some studies
*Thad and Alice Eure Distinguished Professor of
Psychiatry, Pharmacology, and Radiology, Vice Chairman
for Research and Scientific Affairs, Department of Psychiatry,
Director, Mental Health and Neurosciences Clinical
Research Center, University of North Carolina at Chapel Hill
School of Medicine, Chapel Hill, North Carolina.
†Reunette W. Harris Professor and Chairman,
Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia.
Address correspondence to: Jeffrey A. Lieberman, MD,
Department of Psychiatry, University of North Carolina, 7025
Neuroscience Hospital, CB 7160, Chapel Hill, NC 27599.
E-mail: jlieberman@unc.edu.
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suggest that 5% or more of the population may suffer
from the disorder. This marked increase in prevalence
estimates is primarily because of the inclusion of individuals who have milder but still clinically relevant and
often disabling forms of the disorder. Furthermore,
there is increasing recognition and emphasis on the
treatment of the depressed phase of the disorder. The
depressed phase of the illness is manifested more frequently, carries high morbidity and mortality, and is
often difficult to treat effectively.
In addition to the evolution in conceptualization
and diagnosis of the disorder, treatment options are
expanding rapidly. Until recently, lithium and valproate were the only agents the Food and Drug
Administration (FDA) approved for the treatment of
the disorder. With increasing recognition of the clinical importance of the disorder, research into the clinical management of the many expressions of the bipolar
syndrome has increased dramatically. This, in turn, has
resulted in a greatly improved understanding of the
neurobiology of the disorder and an increased number
of new agents available for effective intervention. As
these treatments evolve, we are increasingly able to target treatments specific to an individual and illness
phase, thus maximizing treatment effectiveness while
minimizing the side-effect burden.
PREVALENCE OF THE DISORDER
Until recently, it was generally thought that
approximately 1% of the population suffered from
bipolar disorder. However, these estimates were based
primarily on patients with bipolar I syndrome. It is
becoming increasingly clear that a larger percentage of
the population suffer from the varying forms of the
disorder.1 The increase in rates found in many of the
more recent studies can be attributed to the increased
diagnosis of bipolar type II patients and the inclusion
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of “softer” clinical manifestations of the disorder.2,3
Although 4 days is the minimum requirement for the
diagnosis of a hypomanic episode in the Diagnostic
and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV), patients frequently experience
episodes lasting 1 to 3 days.4 Antidepressant-induced
mania, sometimes referred to as “bipolar III,” may
also indicate the presence of an underlying bipolar
disorder.
Several studies have found a high rate of bipolarity
in patients presenting with depression. Akiskal et al
noted that 30% to 55% of a cohort of patients with
major depression suffered from some form of bipolar
disorder if softer and subthreshold forms of the illness
were included.2 In a prospective study of 108 consecutive patients with anxiety and depressive symptoms in
a family practice setting,5 the rate of bipolar spectrum
disorders including types I, II, III, and cyclothymia
was 25.9%. The bipolar diagnosis was frequently not
recognized at the time of initial treatment. In an
Italian study of depressed outpatients in a private practice setting, the rate of bipolar I was found to be 4%
and the rate of bipolar II was noted to be 45%.6 A
French multicenter study conducted by Hantouche et
al was designed to test the feasibility of validating the
diagnosis of soft bipolar spectrum by practicing clinicians.7 Of the 537 patients with major depressive disorder, the rate of bipolar type II disorder was found to
be 22% at initial evaluation. After training and more
systematic evaluation, the rate was found to nearly
double to 40%. Therefore, increasing clinician awareness and sensitivity to the signs of the disorder resulted in much higher diagnostic rates. In a study by Angst
and Presig, after the onset of illness, bipolar patients
spent approximately 19% of their lives in mood
episodes, and the naturalistic follow-up study by
Goldberg et al found that only 41% of bipolar patients
had a good overall outcome over 4.5 years.8,9
PSYCHOSOCIAL ISSUES
Patients with bipolar disorder are at much higher
risk for interpersonal and psychosocial difficulties.
Many patients with bipolar disorder experience a
broad variety of psychosocial difficulties. Calabrese et
al assessed the functional status of 3059 individuals in
the community with bipolar I or II disorder.10
Approximately 50% of the bipolar sample reported
experiencing serious problems at work compared to
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25% of the controls. Approximately 25% of the bipolar cohort had been arrested, jailed, or convicted of a
crime more serious than driving while intoxicated
compared to only 5% of controls. Individuals with
bipolar disorder also experienced difficulties in social
and family interactions. Women tended to have more
problems with social and family life, whereas men had
more difficulty with legal issues. Altshuler et al found
that the Global Assessment of Functioning scale correlated negatively with the Hamilton Rating Scale for
Depression (HAM-D), even though none of the
patients had HAM-D scores high enough to diagnose
a clinical depression.11 Therefore, even subsyndromal
depressive symptoms resulted in increased overall
functional impairment.
GENETIC FACTORS
Although bipolar disorder is one of the most heritable of the psychiatric disorders, identifying the specific genes involved in the disorder remains difficult.
Bipolar disorder appears to be oligogenic (ie, multiple
susceptibility genes each contribute a small effect to
the expression of the syndrome).12,13 The genes responsible for the disorder are probably common in the general population and it is only when specific
combinations of these genetic elements are present
that the syndrome is manifested. Therefore, separation
of the genetic combinations from normal controls may
be difficult as the genetic contributions overlap.
Furthermore, differing genetic patterns may result in
similar phenotypic expressions of the disorder, making
generalization of results difficult.
Pharmacogenetics, or the determination of genetic
markers in patients responding to a particular medication, is a promising approach to developing individually targeted psychopharmacologic interventions.14 For
example, it has been observed clinically that lithium
responders have distinct clinical characteristics. By
analyzing genetic markers in lithium responders, specific genetic loci have been identified.15 In this manner
a distinct clinical, biologic, and genetic profile of the
responders may be identified.
DSM-IV DIAGNOSTIC CRITERIA
The criteria for a manic episode as outlined in the
DSM-IV16 require the presence of a period of elevated,
expansive, or irritable mood lasting at least 1 week.
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The duration may be briefer if a hospitalization is
required. Three or more associated symptoms must be
present (4 or more if the mood is only irritable),
including inflated self-esteem or grandiosity, decreased
need for sleep, increased verbalization or pressure of
speech, insomnia or hypersomnia, psychomotor agitation or retardation, flight of ideas, distractibility,
increased goal-directed activity, and excessive involvement in pleasurable activities with a high potential for
painful consequences. At least 1 manic episode must
be present for a diagnosis of bipolar I disorder.
A diagnosis of bipolar II disorder requires the presence of at least 1 or more episodes of major depression
and at least 1 hypomanic episode. A hypomanic episode
consists of a distinct period of elevated, expansive, or irritable mood lasting at least 4 days. At least 3 associated
symptoms must be present (4 if the mood is irritable).
The associated symptoms are similar to those listed for
manic episode, although only 7 associated symptoms are
listed instead of the 9 listed for manic criteria.
Cyclothymic disorder is characterized by at least 2
years of brief periods of mild depression and hypomania, lasting a few days to a few weeks. One year is
required for children or adolescents. There must be no
period of euthymia lasting more than 2 months.
During the first 2 years of the disorder, the individual
must not have experienced a manic, mixed, or major
depressive episode.
DELAYS TO DIAGNOSIS
Despite the greater attention recently given to the
disorder, problems with delay in diagnosis and misdiagnosis are still very common. Hirschfeld et al surveyed 600 members of the National Depressive and
Manic Depressive Association (now the Depression
and Bipolar Support Alliance [DBSA]) with bipolar
disorder for their experience with the mental health
system.17 More than 33% of the group sought help
within 1 year after symptom onset. However, 69%
indicated that they were misdiagnosed, most frequently with major depressive disorder. Those patients who
were initially misdiagnosed saw an average of 4 physicians before the correct diagnosis was made. The correct diagnosis was not made for more than 10 years in
more than 33% of the sample. The rate of accurate
diagnosis was little better than that noted in a 1994
survey in the same group.18 In that study, 73% of
patients noted that they had been misdiagnosed initially.
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Even when a previous manic or hypomanic episode
occurred, there was still a high rate of misdiagnosis.19
INCREASING DIAGNOSTIC ACCURACY
The varied presentation and expression of the bipolar syndromes make for diagnostic confusion, misinterpretation of symptoms, and delay of treatment.
There are several aspects of symptom expression that
make for problems in accurate diagnosis, including the
intermittent expression of symptoms, frequent absence
of classic manic symptoms, late presentation of mania,
and difficulties in obtaining accurate history among
others (Table 1).
Alternatively, there are several aspects of the presentation of the bipolar patient that should raise the
clinician’s suspicions to the presence of the syndrome,
even in the absence of the clear or full expression of the
disorder (Table 2). For example, anger or irritability,
even in the absence of significant depressive symptoms, may indicate the presence of bipolar disorder.
Benazzi noted that patients with depression expressing
angry affect were more comparable to bipolar patients
as compared to those patients without anger.20 The age
of onset of depression was lower in patients with anger.
Other indicators of the presence of a bipolar syndrome
include positive family histories of mania, antidepressant-induced manic symptoms, increased mood lability,
more motor retardation, a greater frequency of depressive episodes, a more severe course of illness, and a more
Table 1. Causes of Delays in Diagnosis of Bipolar
Disorder
• Intermittent expression of symptoms
• Frequent absence of classic manic symptoms
• Presence of subsyndromal symptoms
• Difficulty obtaining history owing to poor insight or lack of
recall of previous episodes
• Presentation of mania late in the course of illness
• Overlap with other syndromes (eg, borderline personality disorder, impulse disorders, ADHD)
• Variable psychotic phenomena, including mood incongruent
phenomena
• Substance abuse may mimic or obscure symptoms
ADHD = attention-deficit hyperactivity disorder.
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Table 2. Diagnostic Clues to the Bipolar Disorder
Syndrome
• Presence of angry affect or irritability, even in the absence of
other affective symptoms
• Poor response to antidepressants
• Promiscuity or impulsive tendencies
• Aggressive behaviors, especially if impulsive
• Presence of a personality disorder, especially borderline or
narcissistic
• History of childhood ADHD, especially with poor response
to stimulants
• Childhood behavioral problems
• Family history of bipolar disorder
• Childhood onset of depression
• Acute onset and offset of depression
ADHD = attention-deficit hyperactivity disorder.
acute onset and offset of affective symptoms.21,22
Temperamental “character traits” or periods of high
energy, even if brief, may also be clues to the diagnosis.19
Bipolar patients frequently also manifest impulse problems, promiscuity, and aggressive behavior.
Because many of the traits in bipolar patients may
be adaptive or positive, they may not be viewed as clinically significant. For example, a successful hard-driving executive who has “boundless” energy and
requires little sleep may be seen as well suited to
his/her position rather than an individual requiring
clinical attention. Alternatively, an outgoing and
engaging individual is often viewed as very well adapted socially and may be envied for his/her social skills
and capacities. However, on careful history taking,
there is often evidence of other symptoms typical of
mania or depression.
been associated with early onset, more rapid cycling,
increase in course severity, poor response to treatment,
and poor outcome.23-26 Psychiatric comorbidity has
been noted to be higher in patients with bipolar II
compared to patients with bipolar I in some studies,23
but not in others.27
A high rate of substance abuse has been consistently noted in patients with bipolar disorder and is higher than the rate observed in most other axis I disorders.
In a study by Chengappa et al, 57.8% of patients with
bipolar I were found to abuse drugs and alcohol.28 In
patients with bipolar II, the rate was found to be 39%.
In a retrospective study of 267 outpatients with bipolar disorder, the lifetime rate of alcoholism was noted
to be higher in men (49%) than women (29%).29
Compared to the general population, the increased
risk rate was much higher in women (odds ratio =
7.35) compared to the increase in men (odds ratio =
2.77). The presence of comorbid substance abuse significantly worsens the prognosis. Worsened outcome
among substance abusers may be related to increased
problems with compliance, increased denial, problems
differentiating symptoms in the presence of substance
abuse, and other factors.
The rate of comorbid personality disorders also
tends to be high in bipolar disorder. In a study of
remitted bipolar patients, 28.8% were found to have
comorbid personality disorders, primarily of the cluster B and cluster C subtypes.30 Many of the symptoms
of borderline personality disorder overlap with those
symptoms found in bipolar patients, and a significant
proportion of patients with borderline personality
actually may be suffering from bipolar syndrome. In
one study, 44% of patients diagnosed with borderline
personality disorder were thought to have bipolar disorder.31 If patients with antidepressant-induced switching to mania were included, the rate increased to 69%.
MANIA
COMORBIDITY
Comorbidity is common in bipolar disorder. In a
study of 288 outpatients with bipolar I or II disorder,
65% met criteria for a lifetime history of another disorder.23 Anxiety disorders were reported in 42%,
whereas the rate of comorbid eating disorders was 5%.
A history of substance abuse was found in 42% of the
sample. The rate of comorbidity was similar among
patients with bipolar I and II. Comorbid anxiety has
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Acute mania is the most dramatic phase of the
bipolar syndrome and requires rapid and effective
treatment to avoid multiple untoward consequences.
Bipolar disorder accounts for 1 in 7 psychiatric emergencies.32 In cases of extreme agitation or threatening
behavior, intramuscular (IM) injections of medications may be required. Until recently, the most commonly used combination of agents was IM haloperidol
and lorazepam. Although this combination was effec-
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tive in controlling acute symptoms, significant side
effects such as acute extrapyramidal symptoms, including dystonia, and excess sedation often occurred. IM
atypical antipsychotic formulations are now available.
Ziprasidone is available in an IM formulation and has
been noted to be effective within 15 to 30 minutes
with minimal motor side effects or sedation.33
Olanzapine has also been found to be effective in IM
formulation and has been shown to be equivalent to
haloperidol in effectiveness.34
MIXED EPISODES
Increased attention is appropriately being given to
mixed manic episodes. Mixed episodes were first
described by Kraepelin and are characterized by the presence of depressive and manic symptoms during the
index episode.35 They may represent a more virulent
form of the illness and have been associated with
increased suicidal ideation, refractoriness to treatment,
and a poor response to lithium.36 In a survey of 184 adult
inpatients, 58% of patients with mixed mania were suicidal compared to only 1.3% of patients with pure
mania.37 Suicide attempts before the index episode were
also increased in those patients with mixed episodes
(37% vs 8%). The probability of achieving remission
declined by 49% for each prior suicide attempt.
study of 179 patients hospitalized with a manic
episode, individuals with psychotic features had
greater overall impairment as measured on the Global
Assessment Scale.40 However, the severity of mania
scores did not differ between the psychotic and
nonpsychotic cohorts. Treatments that successfully
treated mania also decreased psychosis severity scores.
Coryell et al found that psychotic features were associated with a greater amount of time ill during the 5year follow-up period.41 However, the time to initial
recovery and time to first relapse was not different
between the psychotic and nonpsychotic cohorts.
Response to acute lithium treatment was also similar
between the 2 groups. Keck et al did not note any difference between psychotic and nonpsychotic bipolar I
cohorts and did not find any distinguishing demographic, psychosocial, or vocational variables.42 A family
history of bipolar disorder was significantly more common in patients with nonpsychotic forms of the disorder. The presence of psychosis, whether it was mood
congruent, surprisingly did not result in a worse overall
outcome in this study. In a study of 50 patients with
bipolar disorder followed for 8 months after their first
hospitalization for a manic episode, mood-incongruent
psychotic features were found to result in more weeks
with psychosis compared to patients with mood-congruent psychosis.43 The mood-incongruent group had
poorer overall functioning during follow-up.
DEPRESSION
SUICIDE RISK
Although the manic episodes associated with bipolar
disorder tend to be the more dramatic element of the disorder, it is the depressed phase that predominates in most
patients and is often the most difficult to treat. In a 13year prospective study of 146 bipolar I patients, it was
found that patients reported depressed mood 32% of the
time, manic/hypomanic symptoms 9% of the time, and
mixed symptoms 6% of the time.38 In a 15-year followup study, it was found that depressive episodes of illness
in patients with bipolar I lasted significantly longer than
manic episodes.39 Morbidity was higher during the entire
follow-up period in patients who initially presented with
a depressed episode.
PSYCHOTIC FEATURES
Although psychosis is commonly observed in the
bipolar syndrome, it has received much less systematic
study than the affective elements of the disorder. In a
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Suicide rates are high in bipolar disorder and early
onset of the disorder is associated with increased suicide rates.44 It has been estimated that at least 25% to
50% of all patients with bipolar disorder attempt suicide at least once.45 Suicide rates among patients with
bipolar disorder average 0.4% per year, which is more
than 20 times higher than in the general population.46
In a Swedish study of 15 386 hospitalized patients
with bipolar disorder, the standardized mortality ratios
for suicide was 15.0 for males and 22.4 for females.47
This compared to rates in unipolar depression of 20.9
and 27.0, respectively.
Treatment with lithium has been shown to decrease
suicide rates dramatically. In a study of pooled data
from 34 studies of 16 221 patients, the risk for all suicidal acts per 100 person-years was 3.10 without lithium.48 This rate dropped dramatically to 0.210 during
treatment compared to the 0.315 baseline rate for the
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general population. In one study, the risk of suicide
was higher during treatment with divalproex compared to lithium.49 The risk of death was 2.7 times
higher with divalproex.
Some of the risk factors for suicide among patients
with bipolar disorder are acute depression, especially
when there is hopelessness, turmoil, global insomnia,
anhedonia, and anxiety or panic; mixed episodes and
cycling within an episode; substance abuse; aggression/impulsivity; history of suicide attempts (personal
or familial); and early onset of the disorder.
MEASURING OUTCOMES
There are several rating scales that are used for the
assessment of symptom severity in patients with
bipolar disorder. The Young Mania Rating Scale
(YMRS)50 is one of the most widely used in research
for the manic phase of the illness. The YMRS consists
of 11 clinician-rated questions. Rated items include
elevated mood, motor activity, sexual interest, sleep,
irritability, speech rate and amount, languagethought disorder, thought content, disruptive-aggressive behavior, appearance, and insight. Alternately,
the Mania Rating Scale51 has been used in recent
studies.52-54 This is based on an 11-item scale derived
from the Schedule for Affective Disorders and
Schizophrenia, Change Version; total score measures
severity of manic symptoms.
There are several rating scales for the measurement
of depression symptom severity. The HAM-D55 in a
21- and 17-item format are the most commonly used.
This is a clinician-rated scale to assess the presence and
magnitude of depressed mood, guilty feelings, suicidality, sleep difficulties, anxiety, and weight loss
among others. The Montgomery-Asberg Depression
Rating Scale56 is also widely used and assesses for treatment changes in the severity of a variety of symptoms,
including depressed mood, sleep, appetite, energy,
concentration, and suicidality.
The Positive and Negative Syndrome Scale57,58 is
one of the most widely used scales for dimensions associated with schizophrenia and other psychotic disorders. There are 30 clinician-rated questions that assess
the extent of positive symptoms, such as delusions,
hallucinations, and thought disorganization; negative
symptoms include items such as blunted affect, emotional withdrawal, poor rapport, and social withdrawal, in addition to general psychopathology.
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SCREENING FOR BIPOLAR DISORDER
To improve the diagnosis of bipolar disorder,
Hirschfeld et al developed the Mood Disorder
Questionnaire (MDQ).59 This screening instrument
includes 13 yes/no questions concerning manic or
hypomanic symptoms. The respondent is also queried
as to the presence of multiple simultaneous symptoms
and the psychosocial problems that they may have
caused. The screen is considered positive if multiple
symptoms are present at the same time and they are of
at least moderate severity. The MDQ has been translated in several languages and is available online
through the DBSA Web site at http://www.dbsalliance.org/questionnaire/screening.asp.
In a nationwide survey of 85 000 adults using the
MDQ, the lifetime prevalence of bipolar disorder I
and II was found to be 3% (4% after nonresponse bias
included).17 The highest prevalence rate was in the
18- to 24-year age group at 9%. The high rate in this
age group is considered to be partially an artifact; however, it highlights the tendency for early onset of the
disorder. Thirty-three percent of the sample reported
experiencing difficulties before age 15 years, and 27%
reported the onset of difficulties between ages 15 years
and 19 years.17 Only 20% of patients with positive
screens indicted that they had previously received a
diagnosis of bipolar disorder by a physician and 33%
had been diagnosed with unipolar disorder.
Life charting has also been shown to be an effective
means of detecting and tracking periods of mood
instability and response to treatment.60,61 Life charting
can help clinicians monitor the episodic course of the
illness and the treatment response to often complicated medication regimens. It may aid patients and families to identify early signs of decompensation and to
gain insight into the course of the disorder. Manuals
and forms for clinicians and patients are available at
http://www.bipolarnews.org/Clinician%20Life%20
Charting.htm.
PSYCHOPHARMACOLOGIC ADVANCES
After the introduction of lithium in the early
1950s, there were few advances in the treatment of
bipolar disorder for several decades. Although lithium
was clearly efficacious, the medication appeared to
work well primarily in a particular subgroup of
patients. A good response to lithium has been associ-
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ated with an episodic course interspersed by euthymic
periods, 4 or less cycles per year, and a family history
of bipolar disorder. Alternatively, a poor lithium
response may be predicted by early onset, rapid cycling
(more than 4 episodes per year), a chronic course,
mixed episodes, and a history of substance abuse.62-64
The anticonvulsant carbamazepine was subsequently also found to be effective in mood stabilization65 and appeared to be efficacious in a different
subpopulation of patients compared to lithium.66
Valproate was also found to be effective in stabilizing
mood and offered a differential treatment response
compared to lithium.64 In a study by Bowden et al,
divalproex and lithium were found to be significantly
more effective compared to placebo in reducing the
symptoms of acute mania.67 The efficacy of divalproex
was determined to be independent of prior responsiveness to lithium.
There are several new antiepileptic agents that are
increasingly being used in the treatment of acute
mania. Lamotrigine is effective for the prevention of
manic and depressive episodes.68,69 Lamotrigine is particularly effective in the treatment of bipolar depression, but was not effective in the treatment of acute
mania in 3 studies. However, the titration schedule
must be kept slow to minimize the risk of potentially
serious Stevens-Johnson syndrome, especially if used
concurrently with valproate.70 Oxcarbazepine possesses
a chemical structure similar to carbamazepine,71 but its
efficacy in bipolar disorder has not been established.
The side effects are less serious than those side effects
observed with carbamazepine.72 Topiramate also may
be a useful adjunctive agent, but double-blind, placebo-controlled studies failed to demonstrate efficacy in
acute mania.73,74 Topiramate, in contrast to many of the
other mood-stabilizing and antipsychotic drugs, has
the advantage of inducing weight loss in some individuals. It has been used as an adjunctive agent to offset the weight-enhancing effects of medications, such
as olanzapine.75
ATYPICAL ANTIPSYCHOTICS IN BIPOLAR DISORDER
The atypical antipsychotic agents are playing an
increasing role in the acute and long-term treatment of
bipolar disorder. In contrast to the typical antipsychotics that bind to dopamine D2 receptors at greater
than 90%, the atypical agents all possess a greater
affinity for the 5-HT2A receptor than the dopamine
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D2 receptor and occupy the dopamine D2 receptor at
70% or less. Each of the atypical agents also possesses
a unique pharmacologic profile that is associated with
varying clinical actions and side-effect profiles. These
distinctions allow the clinician to tailor treatment to
the specific individual.
Olanzapine was the first of the atypical antipsychotics approved for the treatment of bipolar disorder.
It has been shown to be effective in several studies,
alone and in combination with other mood stabilizers.76,77 Clozapine, the first of the atypical agents available, also has been shown to be effective. Similar to its
role in schizophrenia,78 clozapine has been shown to be
effective in treatment-resistant bipolar disorder.79
However, its side-effect burden, including the risk of
agranulocytosis,80 precludes the use of this agent as
first-line therapy.
Of all of the atypical agents, olanzapine and clozapine are the most likely to induce weight gain, hyperlipidemia, and disturbances in glucose metabolism.81
Therefore, caution should be used in administration of
these agents in patients already at risk for such problems.82 Obesity in the general population is reaching
epidemic proportions and has continued to increase
over the past several decades.83 Patients with bipolar
disorder42 or schizophrenia are already at higher risk
for health problems and chronic medical illnesses
compared to the general population. Medicationinduced obesity and the associated metabolic syndrome increase this risk even further. In addition to
the health risks, obesity may result in higher noncompliance rates.84
In a study by Zajecka et al, olanzapine monotherapy was compared to treatment with divalproex in hospitalized acutely manic patients.85 No differences were
noted in efficacy between the 2 agents. However,
patients treated with olanzapine experienced more
weight gain and somnolence. The weight gain after 3
weeks on olanzapine was 4.0 kg compared to 2.5 kg on
divalproex. There was one death in a patient treated
with olanzapine who developed diabetic ketoacidosis.
Fontaine et al estimated that the lives saved from suicide prevention with clozapine were nearly offset by
the estimated rate of life-years lost through obesity.86
Quetiapine has been shown to be effective as an
adjunctive therapy to lithium and divalproex,87
enhancing the clinical effect of both of these agents. In
a study of pooled data from several double-blind
placebo-controlled studies, quetiapine monotherapy
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was shown to be more effective compared to placebo
in patients with bipolar I.88 The average dose of quetiapine was 600 mg/day in this study. Recent studies
have shown quetiapine to be effective as monotherapy89,90 and adjunctive treatment with mood stabilizers91,92 in bipolar mania. Calabrese et al reported that
quetiapine was shown to be an effective and well-tolerated treatment for bipolar depression and was not
associated with treatment-emergent mania.93 Although
there is some weight gain with quetiapine, it is much
more modest compared to clozapine or olanzapine.94
Ziprasidone has also recently been approved by the
FDA for the treatment of acute mania and mixed
episodes. In a 3-week double-blind study, ziprasidone
40 to 80 mg twice daily was more effective in acute
mania and mixed episodes (with or without psychosis)
compared to placebo on a variety of measures.52
Separation from placebo was noted on the Mania
Rating Scale by the second day of the study and was
sustained throughout the length of the study. Patients
on ziprasidone did not experience weight gain or clinically significant electrocardiogram changes. Affective
symptoms were also improved in a cohort of patients
with schizoaffective disorder.95 In a 52-week, openlabel extension of the 3-week study, ziprasidone
demonstrated long-term symptom and global
improvement in patients with bipolar disorder while
displaying a weight- and lipid-neutral profile.96
Similar to the other atypical agents, ziprasidone
acts as an antagonist of serotonin 2A (5-HT2A) and D2
receptors, with greater affinity for 5-HT2A. Effect on
the 5-HT2c, 5-HT1D, and 5-HT1A receptors has been
suggested to explain the capacity of ziprasidone to
ameliorate negative symptoms and improve cognition.97,98 Ziprasidone also inhibits the reuptake of serotonin and norepinephrine, which may underlie
antidepressant properties of the agent.99
With regard to side effects, ziprasidone treatment is
associated with very low rates of weight gain compared
to all the other atypical agents other than aripiprazole.
Allison et al reported that in at least 81 trials, the greatest weight gain was noted with clozapine (4.45 kg) and
olanzapine (4.15 kg).100 Weight gain on risperidone
was intermediate at 4.15 kg and there was negligible
weight gain on ziprasidone at 0.04 kg. The data on
quetiapine were insufficient and aripiprazole was not
included in the analysis.
Risperidone was compared to placebo in a 3-week
double-blind placebo-controlled study in acute bipolar
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mania.101 A flexible dose of 1 to 6 mg/day was used,
with the average dose being 4.1 mg/day. Risperidone
was significantly better compared to placebo as early as
day 3 and continued throughout the study.
Risperidone may result in extrapyramidal symptoms,
usually at higher doses.102 Prolactin increases, menstrual irregularities, and sexual dysfunction may also be
observed with this atypical agent. In a study comparing risperidone (1–6 mg/day) to quetiapine
(200–1200 mg/day), the rate of sexual dysfunction
was 50% in the risperidone cohort compared to 16%
in the quetiapine cohort.103 Prolactin levels were
increased in patients treated with risperidone (mean =
57.7 mg/mL) compared to levels in patients receiving
quetiapine (13.8 ng/mL). Only 11.7% of patients
spontaneously volunteered that sexual dysfunction was
present before administration of the questionnaire in
the study. Because patients may not make a connection between the onset of the sexual problems and the
medications, it is important that these problems be
actively elicited by the clinician.
Aripiprazole, the last atypical agent to be introduced,
also has been demonstrated to be an effective treatment
of acute mania. In a 3-week double-blind study of 262
patients with bipolar disorder manifesting manic or
mixed symptoms, 15 to 30 mg per day of aripiprazole
was found to be superior to placebo.104 The response rate
on medication was 42% compared to 21% for patients
receiving placebo. Aripiprazole has recently received
FDA approval for treatment of acute mania.
CONCLUSIONS
Bipolar disorder is one of the most clinically complex syndromes in psychiatry. It is a multidimensional
syndrome characterized by mood, behavioral, cognitive, and perceptual symptoms and has a propensity
for recurrence in more than 90% of patients.105,106 The
burden of this disorder causes tremendous individual
suffering and societal costs when left untreated or
inadequately treated.
The many varying forms of presentations between
individuals and within the same patient make accurate
diagnosis difficult. The treatment algorithms are also
complex because the many different phases of the disorder need to be treated effectively. Despite the many
complexities, our understanding of the disorder has
been rapidly evolving, as have the range of psychopharmacologic interventions. For many years,
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lithium was the only effective treatment available. We
now have many new anticonvulsants and atypical
agents to help manage this disorder. Targeted use of
these agents allows for rapid and long-term mood stabilization in most patients while minimizing potential
side effects.
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