The Pharmacologic Treatment of Bipolar Disorder
Over the past half century, substantial clinical trial data have accumulated to guide clinical management of bipolar disorder, and 13 medications have gained US Food and Drug Administration approval for the treatment of mania or bipolar depression or the maintenance treatment of bipolar disorder. While the number of studies has grown and many controversies related to pharmacologic treatment of bipolar disorder are not yet resolved, the task of transforming the accumulated evidence into useful guidance for clinical practice becomes more manageable and less error prone by limiting consideration to the highest quality studies. Therefore, this article emphasizes points of relative clarity by highlighting findings supported by double-blind, placebo-controlled clinical trials with samples of at least 100 subjects. A MEDLINE search was conducted and augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings for randomized controlled trials published in English between 1950 and April 2010 with at least 100 subjects. Keywords used in the search included randomized controlled trial, mania, hypomania, depression, relapse prevention, placebo, antidepressant, switch, and maintenance treatment of bipolar disorder. A paradigm for implementing evidence-based treatment is offered along with consideration of patterns emerging across clinical trials.
J Clin Psychiatry 2011;72(5):704-715
© Copyright 2011 Physicians Postgraduate Press, Inc.
Submitted: August 24, 2010; accepted March 29, 2011 (doi:10.4088/JCP.10m06523).
Corresponding author: Gary S. Sachs, MD, Massachusetts General Hospital, Clinical Psychopharmacology Unit, WACC 815, 50 Staniford St, Boston, MA 02114 ([email protected]).
The past half century has seen meaningful growth in the number and quality of studies pertaining to the management of bipolar disorders. The quality of data presented at NCDEU and other academic meetings has advanced from case series and pilot studies to fully powered pivotal trials and recent large-scale effectiveness studies such as those carried out by the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) group, the Stanley Foundation, the Bipolar Affective disorder: Lithium/ANti-Convulsant Evaluation (BALANCE) group, and the Bipolar Trials Network. The list of evidence-based treatments now includes 13 US Food and Drug Administration (FDA)-approved medications for bipolar disorder.
The yields of drug development efforts directed at meeting the immense needs of patients and families impacted by the common but poorly understood conditions now referred to as bipolar disorders are far from satisfying, but do comprise a more scientifically valid basis for clinical decision making than was available through the end of the 20th century. As the admittedly dim light of efficacy and effectiveness data gradually illuminates the clinical landscape, even limited visibility offers opportunities to improve patient care. While acknowledging the continued controversy and uncertainties, this review seeks to emphasize well-established points and areas of general agreement that can provide direction for managing the care of patients with bipolar disorder.
CONTEXT FOR PHARMACOLOGIC TREATMENT OF BIPOLAR DISORDER
Bipolar disorders are chronic multidimensional conditions afflicting about 3% to 6% of the population.1-3 Although the illness is often familial, the causes of bipolar disorders remain elusive, and no pathognomonic markers have been identified. Diagnosis is made on the basis of purely clinical criteria. The complexity of symptomatology associated with bipolar disorder often leads to confusion and frustration, which undermine confidence in treatment decisions. A basic fund of knowledge related to bipolar disorder and DSM-IV nosology is presented below to facilitate the process of clinical assessment, which is the foundation for management of bipolar illness. After discussion of these issues, an approach is offered to guide the integration of clinical knowledge and evidence from clinical trials.
Typically in bipolar disorder the onset of affective episodes occurs during adolescence or the early adult years.4,5 Uncertainty frequently plagues the diagnosis, and despite the often dramatic psychopathology observed or reported by patients with bipolar disorders, the rates of false-positive and false-negative diagnosis are high. Field trials suggest that the diagnostic criteria for current acute mania in DSM-IV are highly reliable. However, assessment of current hypomania is much less reliable, and it is difficult to determine the reliability of assessments for prior manic or hypomanic episodes, especially when a patient is currently depressed.
The subsequent course of illness is highly variable. Most individuals experience an irregular course in which acute abnormal mood states alternate with periods of full or partial remission lasting weeks to years. While abnormal mood elevation is the cardinal diagnostic feature of bipolar disorders, most patients find depression to be more frequent, and more disabling, than hypomania or mania. Furthermore, abnormal mood states are seldom the only expression of the complex pathophysiology underlying bipolar disorders. In addition to the full syndromal episodes, patients with bipolar disorders often experience functional impairment due to interepisode subsyndromal affective symptomatology,2,6 comorbid nonaffective psychopathology7-16 (eg, anxiety disorders, substance misuse, cognitive impairment), and general medical conditions17-22 (eg, obesity, migraine headache, inflammatory disorders).
Bipolar disorder ranks as the sixth leading cause of disability worldwide and is associated with increased mortality23-25 relative to the general population. Suicide accounts for a small fraction of the excess mortality associated with bipolar disorder. Mortality ratios comparing patients with bipolar disorder to the general population reveal elevated death rates due to a number of general medical conditions including heart disease, stroke, and infections.26,27 The shortened life span of patients with severe mental illnesses like bipolar disorder represents a major health care disparity.
A PARADIGM FOR INTEGRATION OF MEASUREMENT AND MANAGEMENT
The complexity and variability associated with bipolar disorder lead to an understandable desire for a systematic approach to treatment. Stakeholder feedback obtained by the National Institute of Mental Health (NIMH) prior to the start of the STEP-BD made clear that algorithmic care is unattractive to patients and family members as well as clinicians. There is, however, a desire to move clinical practice beyond the guidance of population-based results to personalized care. In response, STEP-BD included a disease management program based on a collaborative chronic care model in which clinicians were encouraged to use their experience and judgment in light of the best available evidence28 (Figure 1). This model is not the only or necessarily the best model of care. It is presented here because it has been implemented across multiple treatment centers, and, although it is not prescriptive, its use resulted in high rates of treatment concordant with recognized treatment guidelines and in encouraging outcomes.29
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The STEP-BD Collaborative Care model involves 5 main principles30 (Table 1). The model starts with the assumption that the patient meets formal diagnostic criteria for bipolar disorder, agrees to at least 1 treatment objective, and confronts a critical clinical decision point. These decision points are most commonly related to management of acute episodes (depression, hypomania, mania, or mixed), but may be relapse prevention, return to employment, control of rapid cycling, desire to conceive a child, or management of a treatment-limiting adverse effect.
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In this model, clinicians formulate a personalized menu of reasonable choices based on consideration of both the best available evidence pertaining to the current decision point and the clinician’s knowledge of the patient as an individual. Evidence-based practice recognizes an implicit duty to at least offer proven treatments first.31 Clinicians can meet this duty by maintaining a working knowledge of the proven treatments defined in Table 2 as “category A” treatments and by being aware of the key individual characteristics of their patients that pertain to choice of treatment. At a minimum this will include a patient’s history of prior treatment response, adverse effect tolerance, pertinent general medical conditions, and personal preferences. Essential to collaborative care is the concept of having a plan with shared decision making and communication with other professionals and those the patient designates as supports. Including the patient as an active agent in his or her own care requires an engaged, well-informed patient and negotiation skills. Given the opportunity, patients and their care providers are often motivated to make a well-informed selection from the menu of reasonable choices and participate in a variety of self-management strategies. The outcome of each intervention is then evaluated on the basis of routine measures. The measures for assessing the benefit of an intervention may consist of formal scales or judgments made in reference to a patient’s personal goals.
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When interventions are carried out to a definitive endpoint (declaring that a treatment is effective, ineffective, or intolerable), it is possible to make progress toward optimizing an individual’s treatment plan. Indecisive outcomes, however, may result when tolerable interventions are curtailed without adequate dose or duration or are simply rejected as unacceptable. Integrating measurement into the management facilitates personalized evidence-based treatment decisions.
Several lines of evidence support the rationale of retaining well-tolerated, efficacious treatments and replacing treatments that are ineffective and/or poorly tolerated.32-34 Keeping records of these outcomes facilitates optimization of an individual’s treatment plan through iterative revision of the menu of reasonable choices. No currently available biomarker or group of biomarkers offers a better means of guiding treatment decisions.
Importantly, several studies indicate that a patient’s record of response to treatment has impressive predictive value. For subjects (N = 3,369) enrolled in 10 placebo-controlled pivotal trials for bipolar depression, Calabrese et al35 examined the value of “early response” (defined as improvement in the depression scale score of at least 20% from baseline after 2 weeks of treatment) for predicting the probability of response and remission at the end of each study (7-10 weeks of treatment).
The most compelling finding in this analysis was the high negative predictive value associated with not meeting the criteria for early improvement. Across all of the 10 active treatment groups as well as the placebo groups, subjects with less than 20% improvement after 2 weeks of treatment had only a 10%-20% chance of meeting remission criteria at the end of the study.35 The consistency of this pattern observed across large placebo-controlled studies for bipolar depression suggests that a determination of the need for dose adjustment or a declaration of the treatment as ineffective could be made with acceptable confidence as rapidly as every 2 weeks.
EVIDENCE: DECISION MAKING GUIDANCE AND BENCHMARK METRICS
Implicit in the general consensus that the principles of evidence-based medicine provide the best guidance for clinical practice is the idea of offering proven treatments before unproven treatments.31 Utilizing this principle necessitates a working knowledge of medical evidence and consideration of appropriate metrics. Consumers of medical evidence can assess the clinical meaning of published studies by evaluating the quality of the evidence, by gauging the effect size of various interventions, and by establishing benchmarks applicable to routine clinical practice. Simple metrics are offered below to integrate these processes into meaningful guidance for clinical decision making and metrics for evaluating outcomes in routine practice.
For the purposes of this review, we conducted a MEDLINE search augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings to identify randomized studies of mania, hypomania, depression, or maintenance treatment of bipolar disorder with at least 100 subjects. Although areas remain for which few or no high-quality data are available, the knowledge base pertaining to clinical care of patients with bipolar disorder has grown substantially over the past 2 decades. The daunting task of transforming the accumulated evidence into useful guidance becomes more manageable and less error prone by limiting consideration to the highest quality studies. Results from studies with sufficient methodological rigor to allow valid causal inference, referred to here as category A evidence, represent the highest standard for evidence-based medicine (Table 2). Category A evidence is derived from randomized double-blind placebo-controlled studies with sample sizes adequate to detect differences that are statistically significant and clinically relevant. Formal power calculations to determine sample size adequacy can be complicated. A simple rule of thumb, however, is often sufficient to help clinicians judge the adequacy of sample size in mood disorder treatment studies. Clinical trials with fewer than 100 subjects are unlikely to meet criteria for category A evidence.
This simple benchmark establishes a lower bound on the range of studies we include as having high-quality evidence.
EVIDENCE REVIEW: MANIA
Cade’s 1949 publication36 on the calming effects of lithium was a landmark event setting the stage for an era of progress in psychopharmacology. This case series was followed by persuasive, albeit small, placebo-controlled crossover studies. The first parallel-group placebo-controlled trial for demonstrating the acute antimanic efficacy of lithium did not appear in the literature until 1994.37
As seen in Table 3, category A studies for acute mania now demonstrate the efficacy of 8 dopamine-blocking agents (olanzapine,46,47 ziprasidone,53,54 risperidone,49-52 haloperidol,49 quetiapine,55-60 aripiprazole,61-63 paliperidone,66 and asenapine64,65) and 3 non-dopamine-blocking agents (lithium,37-39 valproate,37,40 and carbamazepine42,43).
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Due to the less stringent standards of the mid-20th century, chlorpromazine has FDA approval for mania but lacks a placebo-controlled trial establishing its antimanic efficacy. In a comparison of lithium to chlorpromazine (n = 255), Prien et al38 found both to be effective for mania, but chlorpromazine (mean dose = 1,000 mg) was more effective in severely ill and agitated patients, while lithium (mean dose = 1,800 mg) was associated with fewer adverse effects.
The available data indicate that 3 weeks of monotherapy treatment with any of these FDA-approved agents is significantly more beneficial than placebo treatment, but seldom sufficient to achieve a complete remission of manic symptoms. After 3 weeks of treatment under the controlled conditions of a randomized controlled trial (RCT), the mean mania rating scale score for subjects receiving any one of the proven antimanic agents still exceeds the minimum symptom score required for study entry at baseline.37,39,46,47,51-54,57,58,61-67 This finding highlights the need for sustained treatment and provides a rationale for combination treatment.
While there are undoubtedly individual differences in response to antimanic agents, the preponderance of accumulated evidence does not indicate important differences in overall efficacy. Nearly all direct comparisons between active agents yield no statistically significant differences in overall antimanic efficacy (lithium vs chlorpromazine,38 haloperidol vs risperidone,49 olanzapine vs divalproex,68 olanzapine vs haloperidol,69 aripiprazole vs haloperidol,70 quetiapine vs lithium,39 quetiapine vs hapoleridol67). Two exceptions to this pattern are noteworthy. Tohen et al71 found olanzapine to have a small, but statistically significant efficacy advantage over divalproex. This advantage was, however, at least partially offset by disadvantages in tolerability. Conversely, the comparison of aripiprazole and haloperidol reported by Vieta et al70 found no difference in efficacy, but a significant advantage for aripiprazole in overall effectiveness due to its greater tolerability.
Number needed to treat (NNT) analyses of the positive category A studies show that for a mania RCT to yield 1 additional responsive subject above the placebo response rate, it is necessary to treat 3 to 6 subjects with a proven antimanic agent. The desire to compare results across studies by comparing effect size is understandable, but making comparisons of the NNT across studies is of questionable validity. An NNT analysis does correct results for placebo response, but does not overcome the methodological limitations that prevent drawing conclusions based on comparisons of treatment other than those available within a single randomized study. Comparing outcomes across placebo-controlled monotherapy mania studies is confounded by differences in study samples as well as study procedures. For instance, the antimanic efficacy of risperidone appears twice as robust in study results based on a sample accessioned in India52 compared to results obtained in a separate study that used nearly the same treatment protocol but enrolled its sample exclusively at sites in the United States.51
Category A studies suggest that adding a dopamine-blocking antimanic agent confers about the same increment of extra benefit over placebo whether used as monotherapy or administered as an adjunct to valproate or lithium.72,73 Valproate was also superior to placebo as an adjunct to antipsychotic treatment.74
The available data are as yet insufficient to conclusively prove that 2 agents are superior to monotherapy, because the advantage of adding a second active agent has been demonstrated only in samples that restricted enrollment to subjects with inadequate response to prior treatment. Nonetheless, combination treatment is a reasonable approach for more severely ill patients, since the preponderance of evidence from these studies shows lower dropout rates among subjects receiving 2 active treatments than those receiving placebo and 1 active treatment.75,76
In addition, placebo-controlled adjunct studies have established the efficacy of adding valproate to dopamine-blocking agents74 and the efficacy of adding risperidone, haloperidol, olanzapine,49 or quetiapine55 to the non-dopamine-blocking agents lithium and valproate.
Category A placebo-controlled clinical trials comparing gabapentin, lamotrigine, topiramate, oxcarbazepine, and licarbazepine to placebo have to date produced only negative results or failed studies (references 41, 44, 45, 48, and 77 and G.S.S., GlaxoSmithKline data on file, 2000). These results do not support a class effect for anticonvulsants as antimanic agents.
EVIDENCE REVIEW: DEPRESSION
A variety of scientific, ethical, and practical design issues have long hampered efforts to address basic clinical questions related to bipolar depression, and consequently most studies examined adjunctive treatment.78-80 Early studies suggesting benefit of monoamine oxidase inhibitors (MAOIs) are limited by small sample size and classification of outcomes based solely on change in depression scale scores.81,82 Thus, reported response rates were not corrected for subjects who experienced treatment-emergent switch to hypomania or mania. Recent parallel-group double-blind studies of bipolar depression have improved methodology, and results for monotherapy including lithium, atypical antipsychotics, and standard antidepressants are becoming available.
The evidence review process identified 11 medication (monotherapy or combination) treatments for which category A studies have been conducted (Table 4). Positive category A evidence clearly supports the 2 FDA-approved treatments, quetiapine85-89 and the combination of olanzapine and fluoxetine (OFC).80 The same 3-arm study that established the efficacy of OFC also found olanzapine monotherapy had significantly better efficacy than placebo for bipolar depression. In that study, the combination of olanzapine and fluoxetine was statistically superior to olanzapine monotherapy as well as superior to placebo.80 Two positive category A studies support the use of lamotrigine for acute bipolar depression.83,94 Lamotrigine does not, however, have FDA approval and has had 4 additional negative or failed studies.95
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To date, only 1 category A study is available with data comparing lithium to placebo as a treatment for acute bipolar depression. This study must be considered a negative study rather than a failed trial for lithium, because the study found no difference between lithium and placebo, while also finding statistically significant advantage for quetiapine over placebo.86
Whenever multiple proven treatments exist, the question arises of which treatment might be best for an individual patient. While matching treatments to individual patients remains an unfulfilled dream, in this instance there may be some clinically interesting pharmacogenetic light at the end of the proverbial tunnel. Perlis et al96 found a differential pattern of response based on genotypes of subjects randomly assigned to treatment with OFC (n = 88) or lamotrigine (n = 85). A set of 19 candidate genes were genotyped. Response to OFC was significantly associated with single nucleotide polymorphisms (SNPs) within the dopamine D3 receptor and histamine H1 receptor (HRH1) genes. Response to lamotrigine was significantly associated with SNPs within the dopamine D2 receptor, HRH1, dopamine β-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes. These findings are consistent with the notion that dopaminergic influences play an important role in bipolar I depression.
Several dopamine-blocking antimanic agents (bifeprunox,92 aripiprazole,90 and ziprasidone91) have produced negative or failed results in bipolar depression studies. This may reflect real differences in the action of these drugs in comparison to quetiapine and olanzapine, but may also result from simple deficiencies in the design and execution of the clinical trials. In addition to disadvantages related to inadequate knowledge of the therapeutic doses of these medications for bipolar depression, some of the trials were quite likely hampered by enrollment of inappropriate subjects and/or low quality ratings on study outcome measures.97,98
The role of standard antidepressants in bipolar depression remains controversial. Baldessarini et al99 reported that despite the ongoing concern about prescribing unopposed antidepressant medication to bipolar patients, antidepressant medication is still the initial treatment for 50% of newly diagnosed patients with bipolar disorder in the United States. Unfortunately, there are few data to support the benefit of this common practice.
A meta-analysis of small double-blind studies is often cited as evidence supporting the adjunctive use of standard antidepressants as a class for the treatment of bipolar depression.100 The utility of this meta-analysis as a guide to treatment is unclear for several reasons. First, the class of drugs referred to as antidepressants is heterogeneous in structure and mechanism (selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, MAOI, etc). Second, data from studies of MAOI-type antidepressants constitute a large proportion of the positive data and, as noted above, tend to overestimate the benefit of treatment because subjects were considered antidepressant responders even if they switched to mania during the course of treatment. Third, no individual standard antidepressant has shown efficacy in a category A study as monotherapy nor as an adjunct to lithium or valproate. Furthermore, the results of recent efficacy and clinical effectiveness studies have not produced results that encourage use of standard antidepressants for bipolar depression.
In a double-blind study comparing placebo to standard antidepressants (bupropion or paroxetine) as adjuncts to mood stabilizers for bipolar depression, STEP-BD found no advantage for standard antidepressants over placebo.93 Separately, STEP-BD used the same infrastructure and outcome measures to conduct a quasi-experimental analysis comparing outcome for STEP-BD subjects who did not participate in the randomized trial, but were prescribed antidepressant medications while participating in the study. This open comparison of the outcome for depressed bipolar patients treated with or without standard antidepressant medications also showed no advantage for adjunctive antidepressant medication.101,102 It is important to note, since study results are often viewed as subject to the limitation of accession bias, that results from the sample receiving open treatment were remarkably similar to results obtained from subjects who consented to participate in the double-blind study. In both studies, the proportion of patients who achieved a durable recovery (defined as 8 consecutive weeks of euthymia) was less than 25%.
Another large effectiveness study conducted by the Stanley Foundation Bipolar Network reported similar discouraging results for standard antidepressants. Altshuler et al103 found that only about 15% of bipolar depressed patients for whom an antidepressant was prescribed in open treatment met criteria for treatment response.
Very limited data are available to guide the treatment of depression in patients with bipolar II disorder. Suppes et al104 reported that the benefit of quetiapine was significantly superior to placebo in the subset of more than 180 bipolar II subjects randomized in 2 bipolar depression studies. In a study with a smaller bipolar II sample, however, Suppes et al88 found that the antidepressant benefit of quetiapine extended release reached statistical significance in bipolar I but not bipolar II subjects.
Amsterdam33,105-108 has published several papers with small samples suggesting that patients with bipolar II might safely be treated with standard antidepressants. The small studies require follow-up in fully powered controlled trials, but do offer some support for the idea that there may be subsets of bipolar II patients who benefit from standard antidepressant medication, even as monotherapy.
TREATMENT-EMERGENT AFFECT SWITCH
Prior to the advent of modern antimanic and antidepressant medications, Emil Kraepelin recognized that patients with manic-depressive illness frequently make direct transitions from one affective state to another of opposite polarity, without an intervening period of recovery.109 The possibility that pharmacologic agents capable of treating mania or depression might lead to treatment-induced mania or depression has long been a serious concern for the field.110-116
Unfortunately, we lack methods to confidently determine whether any given transition between pathological mood states is iatrogenic or due to the natural course of an individual’s illness. Therefore, referring to treatment-emergent depression, hypomania, mania, or mixed episodes is more accurate than using terms such as antidepressant-induced mania or neuroleptic-induced depression.
Despite several trials that have reported rates of treatment-emergent affect switch (TEAS), the extent to which standard antidepressant medications are associated with treatment-emergent hypomania or mania remains highly controversial. Rather than rehashing this unsatisfying debate, a summary of the data can provide some practical guidance for clinical practice.
None of the medications with category A evidence of efficacy for bipolar depression has been associated with treatment-emergent hypomania/mania. STEP-BD found no evidence of TEAS associated with adjunctive use of bupropion or paroxetine compared to adjunctive placebo.93 The Stanley Foundation Bipolar Network found that venlafaxine was associated with significantly higher rates of TEAS than bupropion or sertraline.117 Furthermore, the same study found that among subjects randomly assigned to these 3 antidepressants, overall TEAS rates were significantly higher among bipolar I subjects compared to bipolar II subjects.118 Defining TEAS as a Young Mania Rating Scale score > 13, they observed a TEAS rate of 12% (of 134) of bipolar I subjects versus 2% (of 48) of bipolar II subjects. Defining TEAS as a Clinical Global Impressions (CGI) mania score of ≥ 3 (mildly ill) produced observed rates of 22% in bipolar I subjects and 8% of bipolar II subjects.
These findings suggest that there may be important differences between agents classified as “antidepressants” in regard to the propensity to induce affective switch. On the other hand, the putative destabilizing effect of standard antidepressants may be a reflection of a relatively small vulnerable subgroup. When standard antidepressants are administered as adjuncts to an antimanic mood stabilizing agent, 80% to 90% of subjects do not experience TEAS.
A recent review by Frye et al119 identified risk factors associated with TEAS: tricyclic antidepressant use, prior history of treatment-emergent mania, hyperthymic temperament, comorbid alcoholism, female gender, comorbid anxiety disorder, prepubertal onset, and bipolar I subtype (vs bipolar II). The effect sizes of most, if not all, of these factors are likely to be modest and have little predictive power for individual care. Perhaps the least controversial recommendation that can be applied in clinical practice is to avoid repeating exposure to any class of medication that has been associated with a personal history of TEAS.
EVIDENCE REVIEW: MAINTENANCE, OR PREVENTION OF RECURRENCE
Although lithium was granted FDA approval as a prophylactic treatment for bipolar disorder in 1974, the first adequately powered parallel-group double-blind placebo-controlled RCT was not published until 2000.120 This industry-sponsored study was designed as a pivotal trial to evaluate the prophylactic utility of divalproex versus placebo and included a lithium arm to establish assay sensitivity. Although widely considered a failed trial because differences on the a priori primary outcome measure did not reach statistical significance and no benefit of lithium was detected, the study did produce several important findings. Divalproex was not significantly better than placebo on the a priori primary outcome variable, time to any mood episode. Divalproex was, however, superior to placebo on some important secondary outcome variables including lower rates of discontinuation for a recurrent mood episode and discontinuation due to a depressive episode. Divalproex was also superior to lithium for protection against depressive symptoms and on Global Assessment Scale scores. More importantly, post hoc analyses suggested that the study failed because a substantial number of subjects were randomized who were not ill at the time of enrollment and therefore not necessarily responders to acute treatment with divalproex.
In light of this problem, subsequent successful maintenance treatment studies have employed designs in which the randomized sample is enriched with responders to open acute treatment with the study drug. Furthermore, in studies with enriched design, subjects randomly assigned to placebo are actually discontinuing treatment with the study drug that had been associated with sufficient improvement to qualify them for the double-blind phase of treatment. Meta-analyses of maintenance studies show that previously stable patients suffer high relapse rates following discontinuation of medication, especially when discontinuation is rapid.121-130 These studies, which typically show survival curves with steep slopes for the placebo group in the first months after randomization, can more accurately be considered treatment-disruption studies. Recognition of this design issue has important ramifications for understanding clinical trial results.
In an NIMH-sponsored study designed to compare the benefit of prophylactic treatment with lithium at low (0.4-0.6 mmol/L) versus standard levels (0.8-1.0 mmol/L), Gelenberg et al131 found a significant advantage for treatment at standard levels. The risk of relapse was 2.6 times higher in those randomly assigned to the lower range treatment. A reanalysis of these data suggested that the higher relapse rate associated with lithium treatment at the low level was really driven by the high relapse rate experienced by subjects who had an abrupt 50% reduction in their dose of lithium as a consequence of randomization to switch from the standard range to the low range. Furthermore, subjects who stayed at the standard range had no advantage over subjects who started and remained at the low range. Thus, an abrupt reduction of even 50% may adversely impact the course of illness in stable patients.
Although most of the relapse prevention data come from studies of agents with acute antimanic activity, similar results are reported following treatment of acute bipolar depression.94 In a small double-blind study, Ghaemi et al132 found trends that reached borderline statistical significance indicating worsening course following discontinuation of effective antidepressant medications.
In a 3-arm prophylaxis study that randomized 117 bipolar I subjects but did not include placebo, Prien et al84 reported that lithium and lithium plus imipramine were superior to imipramine alone in preventing recurrences of mania and found no significant differences between the 3 conditions for prevention of depression.
As seen in Table 5, category A studies support the use of lithium,94,133,134 lamotrigine,94,133,134 olanzapine,34,135,136 aripiprazole,137 quetiapine,138 ziprasidone,139 and the long-acting injectable form of risperidone140 for preventing recurrence of acute episodes. These successful category A studies, however, all randomized patients who had experienced a remission of acute phase symptoms during treatment with the study medication prior to randomization. This methodological issue has important clinical implications. The data from these successful maintenance studies cannot support the practice of switching from acute phase treatments to a new maintenance treatment after resolution of an acute episode. Instead, the data provide persuasive argument against treatment disruption and support continued treatment with agents that were a part of a successful acute phase regimen.
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The BALANCE study141 was a large simple trial designed to compare long-term outcomes of treatment with lithium, valproate, and the combination of lithium and valproate in subjects who were not acutely ill, but warranted maintenance treatment. Consenting bipolar subjects all started 4 to 8 weeks of open treatment with the combination of lithium and valproate. Subjects (n = 330) were then randomly assigned to continuing combination treatment, lithium monotherapy (by tapering off valproate) (plasma concentration, 0.4-1.0 mmol/L), or valproate monotherapy (by tapering off lithium) (750-1250 mg). The primary outcome was time to intervention (either medication or hospitalization), and patients could be randomized without necessarily being euthymic. Although the hazard ratio for combination therapy versus lithium monotherapy was 0.82 (95% CI = 0.58-1.17, P = .27), the difference was not statistically significant. The study did, however, find a significant advantage for combination treatment compared to valproate monotherapy (hazard ratio = 0.59, 95% CI = 0.42-0.83, P = .0023). This finding may not be generalizable due to the low valproate dosage used, but it at least informs practitioners that low-dose valproate maintenance treatment is of little merit.
Like other studies above, BALANCE used a discontinuation paradigm. Notably, the study was enriched only to the extent that randomized subjects were able to tolerate the combination of lithium and valproate rather than necessarily respond to combination treatment. The apparent disagreement between this study and the Bowden et al report37 may simply reflect the difference in entry criteria, dosing, and definition of outcome, but it is also possible that maintaining therapeutic lithium levels protects against recurrence due to valproate discontinuation, while valproate as dosed in BALANCE does not protect against recurrence due to lithium discontinuation.
Individual factors reported as associated with relapse and poor outcome for bipolar disorders include early age at onset, psychosis,142 psychiatric comorbidities,143-145 residual mood symptoms,146,147 history of frequent episodes,143,148,149 and use of antidepressants.111 In women with bipolar disorders, postpartum150 and the menopause transition151 are also periods of increased vulnerability to illness relapse. Consistent with early reports suggesting familial response to lithium,152 Perlis and colleagues153 have reported several genes with modest association to lithium response in both the STEP-BD and University College London cohorts. Large-scale genome-wide association studies have promise to identify predictors of individual response to specific prophylactic treatments.
CONCLUSIONS
Bipolar disorders are common chronic complex conditions. Accumulated clinical trial data now offer a scientific basis for clinical decision making. No clinically useful biomarkers have been identified for predicting treatment response. A systematic iterative approach to treatment in which measurement is integrated into the management plan offers a means to bridge from population-based recommendations to personalized care. The distinction between efficacy and effectiveness research includes at least tacit recognition of potential individual differences in response to treatment and the importance of care delivery systems.
Patients with acute mania vary widely in symptomatology and clinical urgency. Although dopamine-blocking agents appear to be preferable for more severely ill patients, non-dopamine-blocking antimanic agents may be more tolerable. Most often, treatment over a period of 3 to 4 weeks is insufficient to achieve full remission. The data support a class effect for dopamine-blocking agents but not anticonvulsants as treatment for acute mania.
Four treatments have positive category A evidence for the treatment of bipolar depression. There is no evidence that adding standard antidepressant medication destabilizes patients treated with agents that have proven antimanic efficacy.
All agents with proven efficacy for relapse prevention have gained approval based on studies that randomized patients who had already improved in response to study medication. This so-called enriched design is an important limitation on the generalizability of results from relapse prevention studies, but has consistently replicated the finding that abrupt discontinuation of treatment can destabilize bipolar patients.
More research and further refinement in methodology are needed to facilitate the translation of population-based data to personalized treatment.
Drug names: aripiprazole (Abilify), asenapine (Saphris), bupropion (Wellbutrin, Aplenzin, and others), carbamazepine (Carbatrol, Equetro, and others), fluoxetine (Prozac and others), gabapentin (Neurontin and others), haloperidol (Haldol and others), imipramine (Tofranil and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), olanzapine (Zyprexa), oxcarbazepine (Trileptal and others), paliperidone (Invega), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel), risperidone (Risperdal and others), topiramate (Topamax and others), venlafaxine (Effexor and others), ziprasidone (Geodon).
Author affiliations: Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston (all authors); and United BioSource Corporation, Lexington (Dr Sachs), Massachusetts.
Potential conflicts of interest: Dr Sachs is an employee of United BioSource Corporation; has been a consultant for Forest, Merck, Sunovion, and Takeda; has received grant/research support from the National Institute of Mental Health and Repligen; has been on the speakers/advisory boards of AstraZeneca, Pfizer, and Otsuka; and is a stock shareholder in Concordant Rater Systems. Drs Dupuy and Wittmann report no financial or other relationships relevant to the subject of this article.
Funding/support: None reported.
REFERENCES
1. Angst J, Gamma A, Lewinsohn P. The evolving epidemiology of bipolar disorder. World Psychiatry. 2002;1(3):146-148. PubMed
2. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J Affect Disord. 2003;73(1-2):123-131. PubMed doi:10.1016/S0165-0327(02)00332-4
3. Kessler RC, Akiskal HS, Ames M, et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of US workers. Am J Psychiatry. 2006;163(9):1561-1568. PubMed doi:10.1176/appi.ajp.163.9.1561
4. Perlis RH, Miyahara S, Marangell LB, et al; STEP-BD Investigators. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Biol Psychiatry. 2004;55(9):875-881. PubMed doi:10.1016/j.biopsych.2004.01.022
5. Leboyer M, Henry C, Paillere-Martinot ML, et al. Age at onset in bipolar affective disorders: a review. Bipolar Disord. 2005;7(2):111-118. PubMed doi:10.1111/j.1399-5618.2005.00181.x
6. Simon GE. Social and economic burden of mood disorders. Biol Psychiatry. 2003;54(3):208-215. PubMed doi:10.1016/S0006-3223(03)00420-7
7. Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2004;161(12):2222-2229. PubMed doi:10.1176/appi.ajp.161.12.2222
8. Summers M, Papadopoulou K, Bruno S, et al. Bipolar I and bipolar II disorder: cognition and emotion processing. Psychol Med. 2006;36(12):1799-1809. PubMed doi:10.1017/S0033291706008804
9. Chengappa KN, Levine J, Gershon S, et al. Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry. Bipolar Disord. 2000;2(3, pt 1):191-195. PubMed doi:10.1034/j.1399-5618.2000.020306.x
10. Goldberg JF, Garno JL, Leon AC, et al. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry. 1999;60(11):733-740. PubMed doi:10.4088/JCP.v60n1103
11. Brady KT, Lydiard RB. Bipolar affective disorder and substance abuse. J Clin Psychopharmacol. 1992;12(suppl):17S-22S. PubMed
12. Biederman J, Faraone SV, Wozniak J, et al. Parsing the association between bipolar, conduct, and substance use disorders: a familial risk analysis. Biol Psychiatry. 2000;48(11):1037-1044. PubMed doi:10.1016/S0006-3223(00)00906-9
13. Winokur G, Turvey C, Akiskal H, et al. Alcoholism and drug abuse in three groups—bipolar I, unipolars and their acquaintances. J Affect Disord. 1998;50(2-3):81-89. PubMed doi:10.1016/S0165-0327(98)00108-6
14. Venn HR, Gray JM, Montagne B, et al. Perception of facial expressions of emotion in bipolar disorder. Bipolar Disord. 2004;6(4):286-293. PubMed doi:10.1111/j.1399-5618.2004.00121.x
15. Clark L, Kempton MJ, Scarn× A, et al. Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression. Biol Psychiatry. 2005;57(2):183-187. PubMed doi:10.1016/j.biopsych.2004.11.007
16. Robinson LJ, Thompson JM, Gallagher P, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord. 2006;93(1-3):105-115. PubMed doi:10.1016/j.jad.2006.02.016
17. Evans DL, Charney DS, Lewis L, et al. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry. 2005;58(3):175-189. PubMed doi:10.1016/j.biopsych.2005.05.001
18. McIntyre RS, Konarski JZ, Soczynska JK, et al. Medical comorbidity in bipolar disorder: implications for functional outcomes and health service utilization. Psychiatr Serv. 2006;57(8):1140-1144. PubMed doi:10.1176/appi.ps.57.8.1140
19. Newcomer JW. Medical risk in patients with bipolar disorder and schizophrenia. J Clin Psychiatry. 2006;67(suppl 9):25-30, discussion 36-42. PubMed doi:10.4088/JCP.1106e16
20. Wang PW, Sachs GS, Zarate CA, et al. Overweight and obesity in bipolar disorders. J Psychiatr Res. 2006;40(8):762-764. PubMed doi:10.1016/j.jpsychires.2006.01.007
21. Arnold LM, Hudson JI, Keck PE, et al. Comorbidity of fibromyalgia and psychiatric disorders. J Clin Psychiatry. 2006;67(8):1219-1225. PubMed doi:10.4088/JCP.v67n0807
22. Hamelsky SW, Lipton RB. Psychiatric comorbidity of migraine. Headache. 2006;46(9):1327-1333. PubMed doi:10.1111/j.1526-4610.2006.00576.x
23. McKenna MT, Michaud CM, Murray CJ, et al. Assessing the burden of disease in the United States using disability-adjusted life years. Am J Prev Med. 2005;28(5):415-423. PubMed doi:10.1016/j.amepre.2005.02.009
24. Ustün TB, Ayuso-Mateos JL, Chatterji S, et al. Global burden of depressive disorders in the year 2000. Br J Psychiatry. 2004;184(5):386-392. PubMed doi:10.1192/bjp.184.5.386
25. Murray CJ, Lopez AD, Jamison DT. The global burden of disease in 1990: summary results, sensitivity analysis and future directions. Bull World Health Organ. 1994;72(3):495-509. PubMed
26. Osby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844-850. PubMed doi:10.1001/archpsyc.58.9.844
27. Angst F, Stassen HH, Clayton PJ, et al. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord. 2002;68(2-3):167-181. PubMed doi:10.1016/S0165-0327(01)00377-9
28. Sachs GS. Strategies for improving treatment of bipolar disorder: integration of measurement and management. Acta Psychiatr Scand Suppl. 2004;110(422):7-17. PubMed doi:10.1111/j.1600-0447.2004.00409.x
29. Dennehy EB, Bauer MS, Perlis RH, et al. Concordance with treatment guidelines for bipolar disorder: data from the Systematic Treatment Enhancement Program for Bipolar Disorder. Psychopharmacol Bull. 2007;40(3):72-84. PubMed
30. Sachs G. Managing Bipolar Affective Disorder. London, UK: Science Press Ltd; 2004.
31. Klerman GL. The psychiatric patient’s right to effective treatment: implications of Osheroff v. Chestnut Lodge. Am J Psychiatry. 1990;147(4):409-418. PubMed
32. Altshuler LL, Post RM, Hellemann G, et al. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. J Clin Psychiatry. 2009;70(4):450-457. PubMed doi:10.4088/JCP.08m04191
33. Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry. 2010;167(7):792-800. PubMed doi:10.1176/appi.ajp.2009.09020284
34. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163(2):247-256. PubMed doi:10.1176/appi.ajp.163.2.247
35. Kemp DE, Ganocy SJ, Brecher M, et al. Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord. 2011;130(1-2):171-179. PubMed doi:10.1016/j.jad.2010.10.026
36. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-352. PubMed
37. Bowden CL, Brugger AM, Swann AC, et al; The Depakote Mania Study Group. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA. 1994;271(12):918-924. PubMed doi:10.1001/jama.271.12.918
38. Prien RF, Caffey EM Jr, Klett CJ; Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Arch Gen Psychiatry. 1972;26(2):146-153. PubMed
39. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005;66(1):111-121. PubMed doi:10.4088/JCP.v66n0116
40. Pope HG Jr, McElroy SL, Keck PE Jr, et al. Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen Psychiatry. 1991;48(1):62-68. PubMed
41. Pande AC, Crockatt JG, Janney CA, et al; Gabapentin Bipolar Disorder Study Group. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord. 2000;2(3, pt 2):249-255. PubMed doi:10.1034/j.1399-5618.2000.20305.x
42. Weisler RH, Kalali AH, Ketter TA; SPD417 Study Group. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65(4):478-484. PubMed doi:10.4088/JCP.v65n0405
43. Weisler RH, Hirschfeld R, Cutler AJ, et al; SPD417 Study Group. Extended-release carbamazepine capsules as monotherapy in bipolar disorder: pooled results from two randomised, double-blind, placebo-controlled trials. CNS Drugs. 2006;20(3):219-231. PubMed doi:10.2165/00023210-200620030-00004
44. Wagner KD, Kowatch RA, Emslie GJ, et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry. 2006;163(7):1179-1186. PubMed doi:10.1176/appi.ajp.163.7.1179
45. Kushner SF, Khan A, Lane R, et al. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 2006;8(1):15-27. PubMed doi:10.1111/j.1399-5618.2006.00276.x
46. Tohen M, Sanger TM, McElroy SL, et al; Olanzapine HGEH Study Group. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry. 1999;156(5):702-709. PubMed
47. Tohen M, Jacobs TG, Grundy SL, et al; The Olanzapine HGGW Study Group. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2000;57(9):841-849. PubMed doi:10.1001/archpsyc.57.9.841
48. Study of licarbazepine in the treatment of manic episodes of bipolar disorder. ClinicalTrials.gov identifier: NCT00099229. http://clinicaltrials.gov/ct2/show/NCT00099229?term=NCT00099229&rank=1. Updated December 12, 2007. Accessed March 31, 2011.
49. Sachs GS, Grossman F, Ghaemi SN, et al. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159(7):1146-1154. PubMed doi:10.1176/appi.ajp.159.7.1146
50. Yatham LN, Grossman F, Augustyns I, et al. Mood stabilisers plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomised controlled trial. Br J Psychiatry. 2003;182(2):141-147. PubMed doi:10.1192/bjp.182.2.141
51. Hirschfeld RM, Keck PE Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161(6):1057-1065. PubMed doi:10.1176/appi.ajp.161.6.1057
52. Khanna S, Vieta E, Lyons B, et al. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry. 2005;187(3):229-234. PubMed doi:10.1192/bjp.187.3.229
53. Keck PE Jr, Versiani M, Potkin S, et al; Ziprasidone in Mania Study Group. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160(4):741-748. PubMed doi:10.1176/appi.ajp.160.4.741
54. Potkin SG, Keck PE Jr, Segal S, et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005;25(4):301-310. PubMed doi:10.1097/01.jcp.0000169068.34322.70
55. Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2004;6(3):213-223. PubMed doi:10.1111/j.1399-5618.2004.00115.x
56. Yatham LN, Paulsson B, Mullen J, et al. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24(6):599-606. PubMed doi:10.1097/01.jcp.0000144887.66319.2f
57. Vieta E, Mullen J, Brecher M, et al. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies. Curr Med Res Opin. 2005;21(6):923-934. PubMed doi:10.1185/030079905X46340
58. Ketter TA, Jones M, Paulsson B. Rates of remission/euthymia with quetiapine monotherapy compared with placebo in patients with acute mania. J Affect Disord. 2007;100(suppl 1):S45-S53. PubMed doi:10.1016/j.jad.2007.02.006
59. Yatham LN, Vieta E, Young AH, et al. A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania. Int Clin Psychopharmacol. 2007;22(4):212-220. PubMed doi:10.1097/YIC.0b013e328080ca57
60. Li H, Ma C, Wang G, et al. Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study. Curr Med Res Opin. 2008;24(1):1-10. PubMed doi:10.1185/030079908X253933
61. Keck PE Jr, Marcus R, Tourkodimitris S, et al; Aripiprazole Study Group. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651-1658. PubMed doi:10.1176/appi.ajp.160.9.1651
62. Sachs G, Sanchez R, Marcus R, et al; Aripiprazole Study Group. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006;20(4):536-546. PubMed doi:10.1177/0269881106059693
63. Keck PE, Orsulak PJ, Cutler AJ, et al; CN138-135 Study Group. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord. 2009;112(1-3):36-49. PubMed doi:10.1016/j.jad.2008.05.014
64. McIntyre RS, Cohen M, Zhao J, et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2010;122(1-2):27-38. PubMed doi:10.1016/j.jad.2009.12.028
65. McIntyre RS, Cohen M, Zhao J, et al. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009;11(7):673-686. PubMed doi:10.1111/j.1399-5618.2009.00748.x
66. Vieta E, Nuamah IF, Lim P, et al. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010;12(3):230-243. PubMed doi:10.1111/j.1399-5618.2010.00815.x
67. McIntyre RS, Brecher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania—a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15(5):573-585.
68. Zajecka JM, Weisler R, Sachs G, et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 2002;63(12):1148-1155. PubMed doi:10.4088/JCP.v63n1210
69. Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 2003;60(12):1218-1226. PubMed doi:10.1001/archpsyc.60.12.1218
70. Vieta E, Bourin M, Sanchez R, et al; Aripiprazole Study Group. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry. 2005;187(3):235-242. PubMed doi:10.1192/bjp.187.3.235PubMed doi:10.1016/j.euroneuro.2005.02.006
71. Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry. 2002;159(6):1011-1017. PubMed doi:10.1176/appi.ajp.159.6.1011
72. Ketter T, ed. Treatment of acute mania in bipolar disorder. Advances in Treatment of Bipolar Disorder. Washington, DC: American Psychiatric Publishing, Inc; 2005:11-24.
73. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67(4):509-516. PubMed doi:10.4088/JCP.v67n0401
74. Müller-Oerlinghausen B, Retzow A, Henn FA, et al; European Valproate Mania Study Group. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol. 2000;20(2):195-203. PubMed doi:10.1097/00004714-200004000-00012
75. Post RM, Ketter TA, Pazzaglia PJ, et al. Rational polypharmacy in the bipolar affective disorders. Epilepsy Res Suppl. 1996;11:153-180. PubMed
76. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry. 1998;155(1):12-21. PubMed
77. Rosa AR, Fountoulakis K, Siamouli M, et al. Is anticonvulsant treatment of mania a class effect? data from randomized clinical trials [published online ahead of print December 15, 2009]. CNS Neurosci Ther. 2009. PubMed doi:10.1111/j.1755-5949.2009.00089.x
78. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158(6):906-912. PubMed doi:10.1176/appi.ajp.158.6.906
79. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55(9):391-393. PubMed
80. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079-1088. PubMed doi:10.1001/archpsyc.60.11.1079
81. Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148(7):910-916. PubMed
82. Thase ME, Mallinger AG, McKnight D, et al. Treatment of imipramine-resistant recurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry. 1992;149(2):195-198. PubMed
83. van der Loos ML, Mulder PG, Hartong EG, et al; LamLit Study Group. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223-231. PubMed doi:10.4088/JCP.08m04152
84. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry. 1984;41(11):1096-1104. PubMed
85. McElroy SL, Weisler RH, Chang W, et al; EMBOLDEN II (Trial D1447C00134) Investigators. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71(2):163-174. PubMed doi:10.4088/JCP.08m04942gre
86. Young AH, McElroy SL, Bauer M, et al; EMBOLDEN I (Trial 001) Investigators. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71(2):150-162. PubMed doi:10.4088/JCP.08m04995gre
87. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360. PubMed doi:10.1176/appi.ajp.162.7.1351
88. Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010;121(1-2):106-115. PubMed doi:10.1016/j.jad.2009.10.007
89. Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600-609. PubMed doi:10.1097/01.jcp.0000248603.76231.b7
90. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28(1):13-20. PubMed doi:10.1097/jcp.0b013e3181618eb4
91. Sachs GS, Ice K, Chappell P, et al. Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder. J Clin Psychiatry. In press.
92. Multicenter, randomized, double-blind, placebo-controlled, parallel-group study of bifeprunox in the treatment of depression in outpatients with bipolar disorder. ClinicalTrials.gov identifier: NCT00134459. http://clinicaltrials.gov/ct2/results?term=NCT00134459. Updated July 6, 2009. Accessed March 31, 2011.
93. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. PubMed doi:10.1056/NEJMoa064135
94. Calabrese JR, Bowden CL, Sachs G, et al; Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013-1024. PubMed doi:10.4088/JCP.v64n0906
95. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9. PubMed doi:10.1192/bjp.bp.107.048504
96. Perlis RH, Adams DH, Fijal B, et al. Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry. 2010;71(5):599-605. PubMed doi:10.4088/JCP.08m04632gre
97. Sachs GS. Understanding why studies fail: what can you see through a third blind eye? Presented at the 15th Biennial Winter Workshop in Psychoses; November 15-18, 2009; Barcelona, Spain.
98. Sachs GS. Found in translation: concordance across global clinical trials. Presented at the 49th Annual NCDEU Meeting; June 29-July 2, 2009; Hollywood, Florida.
99. Baldessarini R, Henk H, Sklar A, et al. Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv. 2008;59(10):1175-1183. PubMed doi:10.1176/appi.ps.59.10.1175
100. Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161(9):1537-1547. PubMed doi:10.1176/appi.ajp.161.9.1537
101. Sachs GS. STEP-BD Update: what have we learned. Presented at the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania.
102. Goldberg JF, Brooks JO 3rd, Kurita K, et al. Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry. 2009;70(2):155-162. PubMed doi:10.4088/JCP.08m04301
103. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003;160(7):1252-1262. PubMed doi:10.1176/appi.ajp.160.7.1252
104. Suppes T, Hirschfeld RM, Vieta E, et al. Quetiapine for the treatment of bipolar II depression: analysis of data from two randomized, double-blind, placebo-controlled studies. World J Biol Psychiatry. 2008;9(3):198-211. PubMed doi:10.1080/15622970701317265
105. Amsterdam JD, Shults J. Fluoxetine monotherapy of bipolar type II and bipolar NOS major depression: a double-blind, placebo-substitution, continuation study. Int Clin Psychopharmacol. 2005;20(5):257-264. PubMed doi:10.1097/01.yic.0000171519.64080.c9
106. Amsterdam JD, Shults J, Brunswick DJ, et al. Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression—low manic switch rate. Bipolar Disord. 2004;6(1):75-81. PubMed doi:10.1046/j.1399-5618.2003.00083.x
107. Amsterdam JD, Wang CH, Shwarz M, et al. Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: a randomized, parallel group, open-label trial. J Affect Disord. 2009;112(1-3):219-230. PubMed doi:10.1016/j.jad.2008.03.029
108. Amsterdam JD, Wang G, Shults J. Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Acta Psychiatr Scand. 2010;121(3):201-208. PubMed doi:10.1111/j.1600-0447.2009.01462.x
109. Kraepelin E. Manic-Depressive Insanity and Paranoia. Edinburgh, UK: E & S Livingstone; 1921.
110. Angst J. Switch from depression to mania—a record study over decades between 1920 and 1982. Psychopathology. 1985;18(2-3):140-154. PubMed doi:10.1159/000284227
111. Ghaemi SN. Treatment of rapid-cycling bipolar disorder: are antidepressants mood destabilizers? Am J Psychiatry. 2008;165(3):300-302. PubMed doi:10.1176/appi.ajp.2007.07121931
112. Goodwin FK. The biology of recurrence: new directions for the pharmacologic bridge. J Clin Psychiatry. 1989;50(suppl):40-44, discussion 45-47. PubMed
113. Wehr T, Goodwin FK. Tricyclics modulate frequency of mood cycles. Chronobiologia. 1979;6(4):377-385. PubMed
114. Wehr TA, Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 1979;36(5):555-559. PubMed
115. Ahlfors UG, Baastrup PC, Dencker SJ, et al. Flupenthixol decanoate in recurrent manic-depressive illness: a comparison with lithium. Acta Psychiatr Scand. 1981;64(3):226-237. PubMed doi:10.1111/j.1600-0447.1981.tb00778.x
116. Zarate CA Jr, Tohen M. Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry. 2004;161(1):169-171. PubMed doi:10.1176/appi.ajp.161.1.169
117. Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006;189(2):124-131. PubMed doi:10.1192/bjp.bp.105.013045
118. Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants. Am J Psychiatry. 2006;163(2):313-315. PubMed doi:10.1176/appi.ajp.163.2.313
119. Frye MA, Helleman G, McElroy SL, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry. 2009;166(2):164-172. PubMed doi:10.1176/appi.ajp.2008.08030322
120. Bowden CL, Calabrese JR, McElroy SL, et al; Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57(5):481-489. PubMed doi:10.1001/archpsyc.57.5.481
121. Baldessarini RJ, Tondo L. Recurrence risk in bipolar manic-depressive disorders after discontinuing lithium maintenance treatment: an overview. Clin Drug Investig. 1998;15(4):337-351. PubMed doi:10.2165/00044011-199815040-00010
122. Baldessarini RJ, Tondo L, Floris G, et al. Reduced morbidity after gradual discontinuation of lithium treatment for bipolar I and II disorders: a replication study. Am J Psychiatry. 1997;154(4):551-553. PubMed
123. Baldessarini RJ, Tondo L, Ghiani C, et al. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010;167(8):934-941. PubMed doi:10.1176/appi.ajp.2010.09060880
124. Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84, discussion 111-116. PubMed
125. Baldessarini RJ, Tondo L, Viguera AC. Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications. Bipolar Disord. 1999;1(1):17-24. PubMed doi:10.1034/j.1399-5618.1999.10106.x
126. Faedda GL, Tondo L, Baldessarini RJ. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry. 2001;158(8):1337-1339. PubMed doi:10.1176/appi.ajp.158.8.1337-a
127. Faedda GL, Tondo L, Baldessarini RJ, et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry. 1993;50(6):448-455. PubMed
128. Suppes T, Baldessarini RJ, Faedda GL, et al. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry. 1991;48(12):1082-1088. PubMed
129. Tondo L, Baldessarini RJ, Floris G, et al. Effectiveness of restarting lithium treatment after its discontinuation in bipolar I and bipolar II disorders. Am J Psychiatry. 1997;154(4):548-550. PubMed
130. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007;164(12):1817-1824, quiz 1923. PubMed doi:10.1176/appi.ajp.2007.06101639
131. Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321(22):1489-1493. PubMed doi:10.1056/NEJM198911303212201
132. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380. PubMed doi:10.4088/JCP.08m04909gre
133. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432-441. PubMed doi:10.4088/JCP.v65n0321
134. Bowden CL, Calabrese JR, Sachs G, et al; Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400. PubMed doi:10.1001/archpsyc.60.4.392
135. Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005;162(7):1281-1290. PubMed doi:10.1176/appi.ajp.162.7.1281
136. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003;160(7):1263-1271. PubMed doi:10.1176/appi.ajp.160.7.1263
137. Keck PE Jr, Calabrese JR, McQuade RD, et al; Aripiprazole Study Group. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67(4):626-637. PubMed doi:10.4088/JCP.v67n0414
138. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109(3):251-263. PubMed doi:10.1016/j.jad.2008.06.001
139. Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2010;71(2):130-137. PubMed doi:10.4088/JCP.09m05482yel
140. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11(8):827-839. PubMed doi:10.1111/j.1399-5618.2009.00761.x
141. Geddes JR, Goodwin GM, Rendell J, et al; BALANCE investigators and collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-395. PubMed doi:10.1016/S0140-6736(09)61828-6
142. Goodwin FK, Jamison KR, Ghaemi SN, eds. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. New York, NY: Oxford University Press; 2007.
143. Otto MW, Simon NM, Wisniewski SR, et al; STEP-BD Investigators. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br J Psychiatry. 2006;189(1):20-25. PubMed doi:10.1192/bjp.bp.104.007773
144. Baldassano CF. Illness course, comorbidity, gender, and suicidality in patients with bipolar disorder. J Clin Psychiatry. 2006;67(suppl 11):8-11. PubMed
145. Judd LL, Schettler PJ, Akiskal HS, et al. Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry. 2008;65(4):386-394. PubMed doi:10.1001/archpsyc.65.4.386
146. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163(2):217-224. PubMed doi:10.1176/appi.ajp.163.2.217
147. Marangell LB, Dennehy EB, Miyahara S, et al. The functional impact of subsyndromal depressive symptoms in bipolar disorder: data from STEP-BD. J Affect Disord. 2009;114(1-3):58-67. PubMed doi:10.1016/j.jad.2008.07.006
148. Levin FR, Hennessy G. Bipolar disorder and substance abuse. Biol Psychiatry. 2004;56(10):738-748. PubMed
149. Nierenberg AA, Miyahara S, Spencer T, et al; STEP-BD Investigators. Clinical and diagnostic implications of lifetime attention-deficit/hyperactivity disorder comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD participants. Biol Psychiatry. 2005;57(11):1467-1473. PubMed doi:10.1016/j.biopsych.2005.01.036
150. Freeman MP, Smith KW, Freeman SA, et al. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry. 2002;63(4):284-287. PubMed doi:10.4088/JCP.v63n0403
151. Robertson Blackmore E, Craddock N, Walters J, et al. Is the perimenopause a time of increased risk of recurrence in women with a history of bipolar affective postpartum psychosis? a case series. Arch Women Ment Health. 2008;11(1):75-78. PubMed doi:10.1007/s00737-008-0215-2
152. Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63(10):942-947. PubMed doi:10.4088/JCP.v63n1013
153. Perlis RH, Smoller JW, Ferreira MA, et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry. 2009;166(6):718-725. PubMed doi:10.1176/appi.ajp.2009.08111633
