Clinical Management of Bipolar Disorder 7/15/01
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Clinical Management of Bipolar Disorder
Paul E. Keck, Jr, MD
Author affiliations and disclosures are at the end of this activity.
Introduction
Bipolar disorder is a common, severe, and recurrent psychiatric illness
and a major public health problem. In the United States, the lifetime
prevalence rates of bipolar I and II disorders may be as high as 1% to
2%.[1] Bipolar disorder is characterized by mood, behavioral, cognitive,
and perceptual symptoms and a propensity for recurrence in more than 90%
of patients.[2,3] In 1990, bipolar disorder was the sixth leading cause
of disability worldwide, and it was projected to remain a global health
problem well into this century.[4] When untreated, this illness poses
high risks of morbidity and mortality; morbidity is often not confined
to discrete mood episodes. Full recovery of premorbid functioning may
lag behind symptomatic and syndromal recovery by many months.[5-7]
In addition, multiple mood episodes can lead to progressive
deterioration of functioning between episodes and adversely affect
subsequent treatment response to specific agents (PE Keck, MD,
unpublished data, 2001).[8] The cumulative effects of bipolar disorder
can wreak havoc on psychosocial and vocational functioning and quality
of life.[9-11] Bipolar disorder also carries a significant risk of
mortality. At least 25% of patients are estimated to have attempted
suicide. Patients with mixed episodes (co-occurring mania and
depression) appear to have substantially higher suicidal ideation than
patients with classic or pure manic episodes.[12,13]
Genetic underpinnings play a role in the majority of cases of bipolar
illness.[14] For example, concordance rates in monozygotic twins range
from 65% to 75% whereas rates for dizygotic twins are 14%.[15] The risk
for mood disorders in first-degree relatives of probands with bipolar
disorder is much higher than in the general population.[15] In clinical
practice, evidence of a family history of mood disorder in a
first-degree relative, especially of bipolar I or II disorder, can be
useful in pointing to a diagnosis of bipolar illness in a patient
presenting with new onset depressive symptoms or psychosis.[16]
Clinical Features and Diagnosis
Four types of bipolar disorder are defined in the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR)[17]: bipolar I disorder, bipolar II disorder, cyclothymic
disorder, and bipolar disorder not otherwise specified (NOS). The
criteria for manic, hypomanic, mixed and depressive episodes are
summarized in DSM-IV-TR. Other symptoms of manic, mixed and depressive
episodes, which are not listed in DSM-IV-TR, include anxiety, hostility,
impulsivity, violence, poor insight, confusion, memory impairment, and
sensory hyperacuity.[18]
Criteria for Diagnosis
At least 1 manic or mixed episode is required to make a diagnosis of
bipolar I disorder. In addition, the manic or mixed episode cannot be
better accounted for by schizoaffective disorder nor be superimposed on
schizophrenia, schizophreniform disorder, delusional disorder, or
psychotic disorder NOS. Finally, the mood episode cannot be due to a
general medical condition or a substance-induced disorder.
The criteria for bipolar II disorder require the occurrence of at least
1 major depressive episode and at least 1 hypomanic episode, but without
the occurrence of a manic or mixed episode.
The presence of numerous periods of hypomanic and depressive symptoms
during a 2-year period (1 year for children and adolescents) are
required for the diagnosis of cyclothymic disorder. Furthermore,
hypomanic and depressive symptoms cannot have been in remission for more
than 2 months at a time and no major depressive, manic, or mixed
episodes can have been present during the first 2 years of the
disturbance.
The bipolar disorder NOS diagnosis includes disorders with bipolar
features that do not meet the criteria for any specific bipolar
disorder. For example, patients with hypomanic episodes lasting less
than 4 days or patients with ultra-rapid cycling who experience frequent
alternations (within hours or days) between manic, mixed or depressive
symptoms that do not meet criteria for a manic or depressive episode
would be described by this diagnosis.
Until recently, there have been few efficient diagnostic screening tools
for bipolar disorder. The Mood Disorders Questionnaire (MDQ) has been
field-tested in 198 patients with mood disorders in psychiatric
treatment (Figure).[19] In this initial validation trial, 70% of
patients with bipolar disorder were correctly identified using a
threshold of 7 or more endorsed items; 90% who did not have bipolar
disorder were correctly screened out. This instrument may have broad
applicability in psychiatric and primary care settings.
Figure 1. The Mood Disorder Questionnaire. From Hirschfeld RM, et al. Am
J Psychiatry. 2000;157:1873-1875.[19] Reproduced with permission.
Signs and Symptoms
A number of phenomenologic studies have characterized the prevalence of
the mood, behavioral, cognitive and perceptual disturbances of mania, as
described by Goodwin and Jamison.[20] From these studies, it is clear
that mania as a state of sustained euphoria and grandiosity describes
only a minority of patients. Most patients with mania experience
irritability (80%), depressed mood (72%), and mood lability (69%) as
often as euphoria (71%).[20] The predominance of specific mood states
appears to be determined by the severity of mania and co-occurring
psychiatric illnesses, such as alcohol and substance use disorders.[21]
Although depressed mood is characteristic of bipolar as well as unipolar
depression, many depressed patients report feeling emotionally blunted.
Studies of the behavioral manifestations of mania found that the most
common symptoms were pressured speech (98%), logorrhea (89%),
psychomotor agitation (87%), decrease need for sleep (81%),
hypersexuality (57%), and extravagant behavior (55%).[20]
Less prevalent symptoms included violence (49%), religiosity (39%),
pronounced regression (28%), and catatonia (22%). Although patients with
bipolar depression often have symptoms indistinguishable from major
depressive disorder, some studies suggest that atypical features of
hypersomnia, hyperphagia, and leaden paralysis might be more prevalent
in bipolar depression.[22]
Cognitive symptoms of varying severity are common in mania and
depression. Grandiosity (78%), racing thoughts (71%), and
distractibility (68%) are common nonpsychotic cognitive disturbances in
mania.[20] Impaired insight and lack of recognition of signs and
symptoms of the illness are particularly insidious symptoms because they
prevent or retard treatment seeking and compliance. Inattention,
indecisiveness, and psychomotor retardation are common cognitive
symptoms of bipolar depression.
Perceptual disturbances or psychotic symptoms occur commonly during
manic episodes. In phenomenologic studies, at least two thirds of
patients with bipolar disorder reported experiencing psychosis during a
mood episode.[20] According to recent data from the Stanley Foundation
Bipolar Network, more than 90% of patients reported experiencing
psychotic symptoms (PE Keck, MD, unpublished data, 2001). All forms of
psychosis, including mood-congruent and mood-incongruent delusions,
Schneider's first-rank symptoms, hallucinations, and formal thought
disorder can occur during manic or mixed episodes.[23] The prevalence of
psychosis in bipolar depression is less clear but may occur in up to a
third of patients.[24] This broad range of symptom domains are the
targets for pharmacologic and psychotherapeutic interventions in bipolar
disorder.
Treatment
The core features of bipolar disorder -- its recurrent and cyclic nature
-- make it a challenging illness to manage. Pharmacologic treatment is
further complicated by the risk of inducing opposite or polar changes in
mood state. Acute manic and mixed episodes of sufficient severity can
constitute medical emergencies requiring hospitalization to ensure
safety and enhance rapid recovery. Bipolar depression is associated with
the same substantial risks of morbidity and mortality as major
depressive disorder. Pharmacologic agents with mood-stabilizing
properties form the foundation of treatment of this illness, but
psychotherapy is often warranted. Mood-stabilizing medications are
effective in ameliorating symptoms of bipolar disorder, but cannot,
based on current knowledge, restore normal homeostasis to the underlying
biologic mechanisms of the illness.
Acute Mood Episodes -- Manic and Mixed
Medications for the treatment of acute mania are proliferating
rapidly.[25,26] Currently, 3 medications, lithium, divalproex sodium,
and olanzapine, have indications from the US Food and Drug
Administration (FDA) for the treatment of manic (and mixed) episodes of
bipolar disorder. Only lithium has an indication for the prevention of
manic and depressive episodes.
Lithium. Data from randomized, controlled trials conducted in the 1960s
and 1970s found lithium to be significantly more efficacious than
placebo in the reduction of manic symptoms.[27-31] In comparison studies
with typical antipsychotics, lithium showed comparable efficacy in
reducing both manic and psychotic symptoms in most trials.[32-38]
In the largest and most rigorous antipsychotic comparison trial, Prien
and colleagues[36] assessed the efficacy and safety of lithium and
chlorpromazine in 2255 acutely manic patients (including patients with
bipolar and schizoaffective disorders). Response was measured according
to degree of psychomotor agitation displayed at baseline by dividing
patients into "highly active" and "mildly active" groups. In the mildly
active group, there were no significant differences in efficacy between
lithium and chlorpromazine on measures of overall psychopathology and
psychosis. In contrast, in the highly active group, chlorpromazine
produced more rapid reduction in measures of agitation, excitement,
grandiosity, hostility, and psychotic disorganization than lithium
during the first week of treatment. However, by week 3 of the trial,
both drugs were significantly and comparably effective. Prien and
colleagues concluded that chlorpromazine was superior to lithium in the
initial treatment of highly agitated patients.
This finding was consistent with the results of all but 1 other study.
Most studies found lithium to be superior to typical antipsychotics in
treating core manic symptoms. The results of these lithium-antipsychotic
comparator trials appear to have influenced the pharmacologic treatment
of inpatients with acute mania in that combination treatment with an
antipsychotic and a mood stabilizer became commonplace. As discussed
later, data actually supporting the superior efficacy of such
combination therapy has only recently emerged. Subsequent research
identified clinical features associated with lithium response. In
particular, patients with multiple prior mood episodes[8] and with
prominent depressive symptoms during mania[39] had lower acute antimanic
response rates to lithium than patients without these features.
Divalproex and olanzapine expanded the therapeutic range of
mood-stabilizing agents, having equal efficacy in manic and mixed
episodes[39,30] and in patients with rapid cycling.[40,41]
Divalproex. Valproate and its divalproex formulation have been shown to
have efficacy in the treatment of acute mania in 10 controlled
trials.[31,42-50] Two randomized, placebo-controlled, parallel-group
trials led to the FDA approval of divalproex for the treatment of acute
mania in bipolar disorder.[31,43]
In the first placebo-controlled study, Pope and associates[43] assessed
the response of 36 patients with bipolar disorder, manic phase
(DSM-III-R), who were either lithium refractory or lithium intolerant,
randomized to divalproex or placebo over 3 weeks. Divalproex-treated
patients had significantly greater improvement on measures of manic
symptoms, overall psychopathology, and global improvement compared with
patients receiving placebo. In addition, 53% of the divalproex group
were responders (defined as greater than 50% reduction in manic symptoms
from baseline), compared with 10% of placebo group. Divalproex was well
tolerated in this study, and no significant difference in the frequency
of side effects between the 2 groups was found.
In the second randomized, placebo-controlled trial Bowden and
colleagues[31] compared the efficacy of divalproex, lithium, and placebo
in a 3-week study in 176 inpatients who met RDC criteria for manic
disorder. Divalproex was again significantly more efficacious than
placebo on outcome measures. Responder rates for the divalproex (48%)
and lithium (49%) groups were comparable and significantly greater than
for the placebo group (25%). Significantly more patients in the lithium
group discontinued participation in the study due to side effects.
In the 2 placebo-controlled trials described above, response to
divalproex was observed within the first week of treatment, usually
after therapeutic plasma concentrations had been achieved. Based on
these observations, a number of studies have assessed the tolerability
and efficacy of divalproex rapid loading (20 or 30 mg/kg/day).[49-51] In
the only double-blind study, divalproex rapid loading (30 mg/kg/day for
2 days followed by 20 mg/kg/day) was compared with divalproex gradual
titration and lithium gradual titration.[49] This study was not powered
to find a significant difference in efficacy among these groups, and
there were no significant differences in adverse events. These findings
confirmed earlier reports indicating that divalproex rapid loading was
well-tolerated.[50,51]
Divalproex was compared with lithium,[42] haloperidol,[50] and
olanzapine[47,48] in other randomized controlled trials in patients with
acute bipolar mania. In the second lithium trial,[42] both divalproex
and lithium treatment groups displayed significant and comparable
improvement on outcome measures of manic symptoms, overall
psychopathology, and global improvement. As in the study by Bowden and
colleagues,[31] patients with mixed mania in this second lithium
comparator trial were more likely to respond to valproate than lithium.
Divalproex was compared with haloperidol in an open randomized trial in
bipolar inpatients with psychotic mania.[50] Thirty-six patients
received either divalproex rapid loading (20 mg/kg/day) or haloperidol
(0.2 mg/kg/day) for 6 days. Both drugs exerted comparable efficacy in
reducing manic and psychotic symptoms, and improvement occurred most
rapidly in the first 3 days of treatment. Both medications were well
tolerated. Not surprisingly, extrapyramidal side effects were
significantly more common among haloperidol-treated patients. The
reduction in psychotic symptoms observed with divalproex in this trial
was consistent with similar findings in earlier studies and with
improvement in manic psychosis with lithium.
Two randomized, double-blind trials compared divalproex with
olanzapine.[47,48] The studies differed methodologically primarily in
the initial starting dose of each drug and in sample size. In the first
study, by Tohen and colleagues,[47] olanzapine was begun at 15 mg/day
and divalproex was started at 750 mg/day and titrated to a maximum of
2500 mg/day (serum concentrations of 50-125 mg/L). The olanzapine
starting dose was chosen because of evidence of strong drug-placebo
separation at this dose from the second of the 2 placebo-controlled
trials of olanzapine in acute bipolar mania.[40] The divalproex dose was
chosen based on previous studies. In contrast, olanzapine was begun at
10 mg/day in the second study by Zajecka and colleagues,[48] consistent
with package labeling at that time, and divalproex was administered by
rapid loading (30 mg/kg/day for 2 days, then 20 mg/kg/day).
The Tohen study[47] was large enough (N = 251) to detect potential
differences in efficacy between the agents. The Zajecka study[48] (N =
120) was not powered to detect such differences. The olanzapine-treated
group in the Tohen study displayed significantly greater improvement in
manic symptoms and had a greater proportion of patients who met criteria
for remission at the end of the study period than the divalproex-treated
group.[47] Improvement in depressive symptoms in patients with mixed
episodes was also significantly greater with olanzapine than with
divalproex in this trial. Zajecka and colleagues found no significant
differences in efficacy on any outcome measure between patients
receiving olanzapine or divalproex.[48] Mean serum concentrations of
valproic acid were well within the therapeutic range in both studies,
although the Zajecka[48] trial had a higher mean concentration
consistent with the use of rapid loading. Adverse events in each study
were similar and typical of those associated with each agent.
Somnolence, dry mouth, and increased appetite were more common with
olanzapine and nausea, vomiting, and diarrhea were more common with
divalproex in the Tohen study.[47] In the Zajecka study,[48] somnolence,
weight gain, coryza, and edema were more common with olanzapine. Taken
together, the results of these 2 studies suggest that olanzapine and
divalproex were at least comparable as antimanic agents. The differences
in efficacy between the 2 studies could be due to real treatment
differences, size of the study, or differences in valproic acid
concentrations.
Valproate has been studied as adjunctive therapy with typical
antipsychotics in 1 randomized trial of patients with acute bipolar
mania.[52] In this 3-week study, 136 patients receiving typical
antipsychotics were randomized to receive valproate or placebo. At the
end of the study period, significantly more patients receiving valproate
had a decrease in the use of concomitant antipsychotic medications.
Olanzapine. Olanzapine has been studied in 2 placebo-controlled
monotherapy trials,[40,53] 1 placebo-controlled adjunctive therapy
trial,[54] and comparator trials against lithium[55] and haloperidol[56]
in addition to the divalproex comparison trials described above. In the
first placebo controlled study, by Tohen and colleagues,[53] 139
inpatients with acute bipolar manic or mixed episodes received
olanzapine (10 mg/day with adjustments by 5 mg/day increments to a range
of 5-20 mg/day) or placebo for up to 3 weeks. Olanzapine-treated
patients had significantly greater improvement in outcome measures of
mania, psychosis and global improvement as well as significantly more
responders (49% vs 24%, respectively) compared with patients receiving
placebo. Significant differences in improvement in manic symptoms were
not apparent until the third week of the study. In contrast, the second
trial by Tohen and colleagues[40] used a higher initial olanzapine
starting dose of 15 mg/day, and demonstrated significant differences in
favor of olanzapine over placebo at the time of the first rating,
one-week.[40] As in the first study,[53] olanzapine was also
significantly superior to placebo in reducing symptoms of psychosis and
in the proportion of patients who were responders (65% vs 43%) and who
achieved remission (61% vs 36%).[40] A sufficient number of patients in
this second study[40] had mixed episodes or rapid cycling to conduct
post hoc comparisons of olanzapine response in patients with pure mania
or non-rapid cycling. In this analysis, there were no significant
differences in olanzapine response among these treatment groups
suggesting that, like divalproex, olanzapine has efficacy across a broad
spectrum of presentations.
In a separate study by Tohen and colleagues,[54] olanzapine was compared
with placebo as add-on therapy in patients already receiving lithium or
divalproex for 2 weeks at therapeutic levels for acute mania. Olanzapine
was superior to placebo in improvement in manic and depressive (mixed)
symptoms and in proportion of responders (68% vs 45%).
Berk and associates[55] compared olanzapine 10 mg/day with lithium 800
mg/day (mean serum lithium concentration, 0.7 mEq/L at steady-state) in
30 inpatients with acute mania over a 4-week trial. There were no
significant differences between the 2 groups in improvement in manic
symptoms and overall psychopathology. Olanzapine-treated patients showed
greater improvement than lithium-treated patients on global severity of
illness at study's end. The sample size of this trial likely was too
small to detect potential differences in efficacy between treatments. In
addition, the lithium dose was at the low end of the therapeutic range
for the treatment of acute mania.
In the most recent randomized, controlled trial by Tohen and
colleagues[56] inpatients with acute bipolar mania received either
haloperidol 3-15 mg/day (n = 219) or olanzapine 5-20 mg/day (n = 234)
for 6 weeks followed by another 6 weeks of double-bind continuation
treatment. After 6 weeks, there were no significant differences in
remission rates between the 2 treatment groups (olanzapine, 52%;
haloperidol, 46%). Among patients who were not in remission at 6 weeks,
significantly more olanzapine-treated patients were in remission by 12
weeks (68% vs 41%). Depressive symptoms improved significantly more on
olanzapine and it was significantly more effective in nonpsychotic
patients. The haloperidol group had significantly more extrapyramidal
side effects and the olanzapine group had significantly more weight
gain. This was the first head-to-head comparison of an atypical
(olanzapine) and a typical antipsychotic (haloperidol) to demonstrate a
greater propensity for an atypical agent to improve not only manic but
depressive symptoms.
Carbamazepine* and oxcarbazepine.* Although at least 14 randomized
controlled trials have assessed the efficacy of carbamazepine in acute
bipolar mania, only 5 of these studies are methodologically
sound.[57-62] Carbamazepine was superior to placebo in reducing mania,
psychosis, anxiety, and hostility in the only placebo-controlled acute
treatment trial.[58] Two studies compared carbamazepine with
lithium.[59,60] Lerer and colleagues[59] found a trend toward greater
improvement on most measures of psychopathology in the lithium-treated
group. Moreover, only 29% of patients receiving carbamazepine were
responders compared with 79% receiving lithium. In the second lithium
comparison trial, by Small and associates,[60] 70% of patients
randomized to lithium or carbamazepine discontinued participation in the
study by 8 weeks due to lack of efficacy. Of the remaining patients, 36%
of the carbamazepine group were responders compared with 37% in the
lithium group.
Carbamazepine was compared with chlorpromazine in 2 randomized,
controlled trials in acute bipolar mania.[61,62] Okuma and
colleagues[62] compared these 2 agents in 60 patients in a 6-week study
and found comparable response rates (66%, carbamazepine; 54%
chlorpromazine). Carbamazepine was significantly better tolerated.
Grossi and colleagues[63] reported similar results in a 3-week study (N
= 37): 55% of patients responded to carbamazepine and 68% to
chlorpromazine. Pooled data from these 5 studies revealed an overall
responder rate of 50% for carbamazepine, 56% for lithium, and 61% for
chlorpromazine (differences not significant).
Oxcarbazepine, an antiepileptic drug related to carbamazepine, has been
studied in 2 active comparator trials against haloperidol and lithium in
patients with acute bipolar mania.[63,64] There were no significant
differences in efficacy among these agents in these 2 trials. However,
the studies lacked sufficient power to detect potential efficacy
differences and neither trial used a placebo control group.
Typical antipsychotics. Typical antipsychotics have been found to be
effective antimanic agents in many randomized controlled trials.[32-38]
Comparison trials of lithium, divalproex, and olanzapine were summarized
above. There is only 1 randomized, placebo-controlled study of a typical
antipsychotic (chlorpromazine) in the treatment of acute mania.[65]
Klein[65] randomized 13 patients with "manic excitement" to
chlorpromazine (1200 mg/day), imipramine (300 mg/day), or placebo for 7
weeks. Chlorpromazine was significantly better than placebo and
imipramine on global outcome. A comparison trial of haloperidol,
risperidone and placebo is discussed later in this review.
Other atypical antipsychotics.* In the early 1990s, the thymoleptic
properties of the prototypical atypical antipsychotic, clozapine, were
first suggested to be mood-stabilizing, and therefore distinct from the
specific antimanic effects of typical agents.[66] These observations
were based on case series of clozapine treatment in highly
treatment-refractory patients with bipolar disorder and the bipolar
subtype of schizoaffective disorder. Only 1 randomized, controlled
clinical trial of clozapine in acute mania has been published.[67] In
this study, 30 hospitalized patients were randomized to clozapine (mean
dose 166 mg/day) or chlorpromazine (mean dose 310 mg/day) in a 3-week
trial. Although the clozapine group exhibited significantly greater
reductions in manic symptoms after 2 weeks of treatment, there were no
significant differences between the 2 groups at the end of the trial.
Risperidone has been studied in 2 controlled trials in patients with
acute bipolar mania.[68,69] Segal and colleagues[68] compared
risperidone (6 mg/day), haloperidol (10 mg/day), and lithium (800-1200
mg/day; mean serum concentration at week 4, 0.7 mEq/L) in 45
hospitalized patients over 4 weeks. All 3 treatment groups had
significant and comparable reductions in manic symptoms from baseline to
end point. The lack of a placebo control group, small sample size, low
therapeutic lithium level, and use of adjunctive lorazepam (as needed)
throughout the trial limit interpretation of the results of this study.
Sachs and colleagues[69] compared the efficacy of risperidone with
haloperidol and placebo as adjunctive treatment to lithium or divalproex
in the treatment of acute bipolar mania. Patients treated with
risperidone or haloperidol displayed significantly greater improvement
in manic symptoms at weeks 1 and 2 of treatment. By week 3, when the
therapeutic effects of lithium or divalproex had adequate time to become
fully manifest, the differences between the 3 treatment groups were no
longer significant. This was the first study to demonstrate greater
initial efficacy for the combination of an antipsychotic and lithium or
divalproex over lithium or divalproex alone (plus placebo, in this case)
in the treatment of hospitalized patients with acute mania. To date,
there are no placebo-controlled trials of risperidone monotherapy in
patients with acute bipolar mania.
In a secondary analysis of improvement in mood symptoms in patients with
schizoaffective disorder participating in ziprasidone clinical trials,
ziprasidone exerted dose-related antimanic and antidepressant
effects.[70] Based on these observations, ziprasidone was compared with
placebo in a large, multicenter, randomized, controlled trial in
patients with acute bipolar mania.[71] In this 3-week study, 197
patients were randomized in a 2:1 ratio to ziprasidone (80 mg on day 1
and 160 mg/day thereafter) or placebo. Patients receiving ziprasidone
displayed significantly greater improvement in manic symptoms by the
second day of treatment compared with patients receiving placebo.
Ziprasidone was also superior to placebo in the reduction of psychosis,
overall psychopathology, and global functioning. Somnolence and
dizziness were the most frequent side effects associated with
ziprasidone.
No randomized controlled trials of quetiapine in the treatment of any
aspect of bipolar disorder have been presented or published to date. The
findings of open-label studies suggest that quetiapine may have
antimanic effects.[72]
New antiepileptics*. Gabapentin, lamotrigine, and topiramate have been
studied in randomized, controlled trials in patients with acute mania.
In 2 studies, a placebo-controlled crossover monotherapy trial[73] and a
placebo-controlled, parallel-group, adjunctive treatment trial,[74]
gabapentin-treated patients did not display significantly greater
improvement in manic symptoms than patients receiving placebo.
Three studies examined the efficacy of lamotrigine in the treatment of
acute bipolar mania or hypomania.[73,75,76] The study by Frye and
colleagues,[73] which included the gabapentin-treatment group described
above, randomized patients to lamotrigine, gabapentin or placebo in a
crossover series of 6-week monotherapy trials. There were no significant
differences among the 3 treatment groups in reduction of manic symptoms.
In the trial by Anand and colleagues,[75] outpatients with manic or
hypomanic symptoms that were inadequately responsive or tolerant to
lithium were randomized to lamotrigine or placebo for up to 8 weeks.
Lamotrigine or placebo were either added to ongoing medications or given
as monotherapy. There were no significant differences between the 2
treatment groups in reduction of manic symptoms or response rate. In 1
other small inpatient trial,[76] lamotrigine was comparable to lithium
in reduction of acute manic symptoms. However, this trial lacked a
placebo control group, used low therapeutic lithium levels, and had an
insufficient sample size to detect potential differences in efficacy
between agents.
Topiramate has been studied in 1 randomized, placebo-controlled,
monotherapy trial in inpatients with acute mania. An interim analysis of
this study revealed strong trends for superior efficacy of topiramate
(at approximately 250 mg/day and 500 mg/day) over placebo in reduction
of manic symptoms. However, these differences failed to reach
significance by the conclusion of the study (D. Van Kammen, MD,
unpublished data).
Acute Mood Episodes -- Depressed
The treatment of acute bipolar depression has been largely ignored in
clinical trials during the past 20 years. Lithium is the most
well-studied medication in the treatment of this phase of the illness.
Pooled results from controlled trials found that 36% of patients had
marked improvement in depressive symptoms with lithium and 79% had at
least partial improvement.[77] Three small controlled trials of
carbamazepine in bipolar depression reported relatively low response
rates ranging from 32% to 46%, although most patients in these trials
were refractory to lithium and other agents.[78-80] In a large,
multicenter, randomized, placebo-controlled, 6-week, monotherapy trial,
lamotrigine (50 mg/day and 200 mg/day) was superior to placebo in the
reduction of depressive symptoms in patients with bipolar I
disorder.[81] There was no significant difference in the proportion of
patients switching into mania or hypomania among the treatment groups.
There are no randomized, controlled studies of divalproex, any atypical
antipsychotics, or other new antiepileptics in the acute treatment of
bipolar depression.
Most studies of antidepressants in acute bipolar depression were
conducted before the 1990s and consist of trials of tricyclic
antidepressants and the monoamine oxidase inhibitor,
tranylcypromine.[77] Not surprisingly, these agents were found to be
effective in the treatment of bipolar depression. More recently,
fluoxetine, paroxetine, and bupropion have been reported to
significantly reduce depressive symptoms in bipolar depression when
administered with lithium.[82-84]
Mood switches into mania, hypomania, or mixed states and rapid cycling
are risks associated with antidepressant treatment in bipolar
depression. However, few studies have investigated this phenomenon
systematically. In theory, this risk should be diminished when
antidepressants are administered with mood-stabilizing agents. However,
whether, or how much, coadministration of mood-stabilizing or antimanic
agents prevents this risk is unclear. Nevertheless, most current
guidelines recommend the use of concomitant mood stabilizers when
administering an antidepressant for patients with bipolar I
depression.[85,86]
Maintenance Treatment
The prevention of recurrent mood episodes is one of the most important
goals of long-term treatment of bipolar disorder. Unfortunately,
conducting randomized, controlled trials of maintenance treatment in
patients with bipolar disorder is methodologically complex.[87] Lithium
is the most well-studied medication as maintenance therapy and is the
only medication with an FDA-approved indication, although valproate and
carbamazepine are frequently used for this purpose.
Lithium. Randomized placebo-controlled trials of lithium in the 1960s
and 1970s demonstrated that lithium reduced the relapse rate by 4-fold
over placebo after 1 year of treatment.[88] A subsequent study found
that patients receiving lithium at 0.8-1.0 mEq/L had 2.6 times lower
risk of relapse than patients maintained at concentrations of 0.4-0.6
mEq/L.[89] On the other hand, patients maintained at higher
concentrations in this study experienced significantly more side
effects. In a post hoc analysis of this study, Keller and colleagues[90]
found that patients maintained at lower lithium concentrations were more
likely to experience subsyndromal symptoms and these symptoms were more
likely to worsen at any time than were symptoms in the
higher-concentration group. The occurrence of subsyndromal symptoms
increased the risk of relapse by 4-fold. These findings have important
clinical implications because they indicate that the optimal management
of bipolar disorder requires pharmacologic titration and
psychotherapeutic intervention sufficient to eradicate subsyndromal
symptoms while minimizing side effects. Many patients do not respond
completely to acute or maintenance treatment with a single mood
stabilizer. Combinations of mood stabilizers, mood stabilizers and
antidepressants, or mood stabilizers and atypical antipsychotics are
frequently used in these circumstances, although the relative efficacy
of such combinations has not been studied.
Carbamazepine and divalproex. The efficacy of carbamazepine in the
maintenance treatment of bipolar disorder has been less clearly
demonstrated than in acute mania. Interpretation of the results of the
only placebo-controlled trial is limited by the use of adjunctive
antimanic and antidepressant medications for breakthrough symptoms
during the study.[91] Two comparison trials of lithium vs carbamazepine
were recently reported.[92,93] In the first study, carbamazepine-treated
patients required significantly more adjunctive medications for
recurrent symptoms and experienced more side effects leading to
treatment discontinuation than lithium-treated patients.[92] In the
second trial, relapse rates did not differ signficantly between the 2
treatments.[93] Two studies of oxcarbazepine maintenance treatment were
too small to interpret.[94,95]
The efficacy of divalproex maintenance treatment in preventing relapse
was studied in one large, placebo-controlled, lithium comparison
study.[96] In this trial, there was no significant difference in time to
relapse over 1 year among the 3 treatment groups. However, in analysis
of secondary outcome measures, patients who began the trial on
divalproex and were randomized to continue divalproex were significantly
less likely to relapse than patients who began treatment on divalproex
and were randomized to placebo.
Other Agents. There are no randomized, blinded, controlled studies of
the atypical antipsychotics, gabapentin, or topriamate in the
maintenance treatment of bipolar disorder. In an open-label, randomized,
1-year trial, clozapine was found to be superior to treatment as usual
in patients with treatment refractory bipolar disorder and the bipolar
subtype of schizoaffective disorder.[97] Lamotrigine was compared with
placebo in maintenance relapse prevention in patients with rapid cycling
bipolar I and bipolar II disorder in a 6-month trial. Lamotrigine was
superior to placebo in terms of time to need for adjunctive medication
and duration of time in the trial for bipolar II but not bipolar I
patients.[98] These findings are consistent with the hypothesis that
lamotrigine may have antidepressant but not antimanic effects in bipolar
disorder.
Emerging Research*
Two major groups of medications, atypical antipsychotics and new
antiepileptics, are under active investigation for their thymoleptic
properties and potential use in bipolar disorder. In addition to the
medications in these classes described above, new atypicals on the
horizon include iloperidone and aripiprazole, and new antiepileptics
currently available include zonisamide, tiagabine, and levitiracetam.
Omega-3 fatty acids, inositol, rapid transcranial magnetic stimulation,
and vagal nerve stimulation are investigational innovations requiring
more study.
*This clinical module discusses off-label uses of psychotropic
medications; these medications may not be approved by the FDA for these
uses.
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------------------------------------------------------------------------
Author Affiliations and Disclosures
Paul E. Keck, MD
Professor of Psychiatry and Pharmacology, Vice Chairman for Research,
Department of Psychiatry, University of Cincinnati College of Medicine.
Co-director, Biological Psychiatry Program, University Cincinnati
Medical Center, Cincinnati, Ohio
Clinical Editor
Robert Kennedy
Site Editor/Program Director
Medscape, Inc.
Disclosure
According to ACCME and ACPE accreditation requirements, authors must
disclose all financial associations/special relationships with
proprietary entities/commercial supporters that may have a direct
relationship to the subject matter of the educational activity. They
must also disclose any discussion of unlabeled or investigational uses
of products in the educational activity.
Paul E. Keck, MD, has disclosed that he receives research grant support
from Abbott Laboratories, AstraZeneca, Eli Lilly and Company, Pfizer
Inc., and Merck. He serves as a consultant to Abbott Laboratories,
AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer Inc.,
Pharmacia Corporation, and Janssen Pharmaceutical Products.