Defining the bipolar spectrum and treating bipolar II disorder

The treatment of bipolar II disorder may be complicated by the lack of a universal definition of the bipolar spectrum and by the limited number of studies focusing on bipolar II disorder pharmacotherapy. The appropriate first-line treatment for bipolar II disorder is still being studied, but according to the limited research, antidepressants, mood stabilizers, anticonvulsants, and atypical antipsychotics have been safe and effective in the acute and maintenance treatment of bipolar II depression and/or hypomania or mania. A consensus should be reached on the definition of the bipolar spectrum, and further research is needed to determine the best first-line treatment for bipolar II disorder.     

Lithium and anticonvulsants in bipolar depression

For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder.     

Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm

A review of the methodology and results of 9 controlled studies on the acute treatment of bipolar depression and the risk of switches into (hypo)mania is presented. There are indications but no proof for efficacy of mood stabilizers such as lithium, carbamazepine and valproate. Only lamotrigine has been shown to be effective, with a relative low risk of switching. Several antidepressants appear effective as well, but again there is no (placebo-controlled) proof of their efficacy. The only exception is tranylcypromine which has been found to be more effective than imipramine. The switch ratio into (hypo)mania by tricyclic antidepressants seems to be higher than by several other antidepressants, especially the selective serotonin reuptake inhibitors. In the acute treatment of bipolar depression, it is recommended to start with a mood stabilizer, and to add an antidepressant after 4-6 weeks in case of nonresponse. In severer cases, one might consider to start earlier with the combination of a mood stabilizer and an antidepressant, and in refractory patients, there is a place for tranylcypromine. In the maintenance treatment, there are indications that the combined treatment of a mood stabilizer (mostly lithium) and an antidepressant (TCA) is associated with an increased risk of switches into (hypo)mania, when compared to a mood stabilizer alone. Therefore, it is recommended to try whether a monotherapy with a mood stabilizer is effective, before combining it with an antidepressant.     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD. Depression and Anxiety 4:190–198, 1996/1997. © 1997 Wiley-Liss, Inc.     

Treatment-resistant bipolar disorder

Over the last few years, the number of potential pharmacotherapies for bipolar disorder has greatly expanded. Yet the database for virtually all these newer treatments consists of case reports and case series. Among these newer treatments, recently released anticonvulsants are most promising. Lamotrigine has already shown efficacy for treating bipolar depression, while gabapentin's efficacy has yet to be documented in a controlled study. Alone among its medication class, topiramate, another anticonvulsant, is associated with weight loss. Novel antipsychotics are effective in treating acute mania. With the exception of clozapine, their efficacy as true mood stabilizers is still unknown. Utilizing combinations of mood stabilizers is common and appropriate but demands knowledge of potential pharmacokinetic interactions. Other approaches for treatment resistant bipolar disorder include high-dose thyroid hormones, calcium channel blockers, electroconvulsive therapy, and omega-3 fatty acids. Finally, the efficacy of adjunctive psychosocial strategies is a topic of active investigation.     

Bupropion as add-on strategy in difficult-to-treat bipolar depressive patients

Bupropion, a selective norepinephrine and dopamine reuptake inhibitor, has been suggested for the treatment of bipolar depression, not only because of its efficacy, but also because of a probably lower risk of inducing switches to hypomania or mania. Most studies on bupropion treatment in bipolar patients have been performed in moderately ill out-patients. In contrast, we report on a sample of difficult-to-treat, predominantly severely ill, co-morbid, psychotic or therapy-refractory bipolar depressive in-patients. In this open and prospective study, 13 patients were treated with bupropion as an add-on strategy mainly to other antidepressants and to various mood stabilizers. Our data support the idea that bupropion is a first-line antidepressant in the treatment of severe bipolar depression. Eight of 13 patients showed a >50% reduction of Montgomery-Asberg Depression Scale ratings within 4 weeks. Co-medication with drugs commonly used in treatment-resistant bipolar disorder including venlafaxine, clozapine, lithium, topiramate and sodium valproate was safe in our small sample. While adhering to the suggestion of Goren and Levin not to exceed a daily dose of 450 mg of bupropion when treating bipolar depressed patients, we did not observe any switch from depression to hypomania or mania.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants?

This paper gives a critical review of recommendations concerning the drug treatment of acute bipolar depression. The suggestions of different guidelines and consensus papers, especially in US-American and Canadian psychiatry, have a strong tendency against antidepressants in bipolar depression; they prefer mono-therapy with mood stabilizers and, in the case of co-medication with mood stabilizers and antidepressants in severe depression, to withdraw the antidepressant as early as possible. The intention of this restrictive use is to avoid the risk of mania and the risk of rapid cycling induced by antidepressants. However, apparently the risk of suicidal acts, which is as prominent in bipolar depression as in unipolar depression, has been totally neglected. Furthermore, the fact that none of the mood stabilizers have proven their antidepressive efficacy leads not only to the risk of depression-related suicidal behavior but also to the risk of chronicity of depressive symptoms due to undertreatment. Altogether the view expressed in some guidelines and consensus papers appears not well balanced. Furthermore, the fact that apparently the selective serotonin re-uptake inhibitors and possibly some other modern antidepressants have only a low risk of inducing a switch to mania should stimulate a rewriting of the guidelines on drug treatment in acute bipolar depression in a less restrictive way concerning the use of antidepressants. Received: 3 January 2000 / Accepted: 2 February 2000     

Advances in the pharmacologic treatment of bipolar depression.

The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment.     

Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics

Abstract:  Bipolar disorder is a complex condition including depression, mania, and in many cases associated with comorbid anxiety symptoms and substance abuse. Mood stabilizers including lithium and divalproex have been considered standard therapy for the treatment of patients with bipolar disorder, but remission rates remain inadequate. Conventional antipsychotics have demonstrated efficacy for acute mania, but they appear to have little role in the maintenance treatment of bipolar disorder. Despite substantial evidence of efficacy and recent guideline recommendations, atypical antipsychotics remain underused for the treatment of bipolar disorder. Data from double-blind, controlled trials are available for a number of clinically meaningful efficacy measures, including improvement in manic symptoms, onset of action, response rates, remission rates, improvement in comorbid depressive symptoms, and induction/worsening of mania or depression. Atypical antipsychotics are effective both as alternatives to lithium or divalproex as monotherapy, or in combination with these mood stabilizers, in the acute and likely the maintenance treatment of mania. The atypical antipsychotics represent an effective and relatively safe addition to our armamentarium for the treatment of bipolar disorder.     

New treatment paradigms in bipolar disorder: Second-generation antipsychotics and combination treatments

During the past decade, the number of treatments documented as effective in treating various phases of bipolar disorder has skyrocketed. From three treatments approved by the United States Food and Drug Administration for acute mania and one as a maintenance treatment, we now have nine acute treatments and four maintenance treatments (the treatment of bipolar depression is excluded because it is a separate topic requiring its own discussion). Dominating these new treatments are the second-generation antipsychotics (SGAs). The result of these studies is not only a major shift in treatment paradigms for bipolar disorder, but a realization that the antipsychotics are a misnamed class of medications because their efficacy extends far beyond the boundaries of psychosis. Another major shift in our thinking about the treatment of bipolar disorder is the acknowledgment and the beginning of a database documenting medication combinations as the rule rather than the exception in treating acute mania and in maintenance treatment.     

New medication treatment options for bipolar disorders

OBJECTIVE: To assess new treatment options for bipolar disorders. METHOD: Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category. RESULTS: Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine). CONCLUSION: Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.     

Medication treatment of bipolar disorder 2000: a summary of the expert consensus guidelines

The original Expert Consensus Guidelines on the Treatment of Bipolar Disorder were published in 1996. Since that time, a variety of new treatments for bipolar disorder have been reported; however, evidence for these treatments varies widely, with data especially limited regarding comparisons between treatments and how to sequence them. For this reason, a new survey of expert opinion was undertaken to bridge gaps between the research evidence and key clinical decisions. The results of this new survey, which was completed by 58 experts, are presented in The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000, which was published in April 2000 as a Postgraduate Medicine Special Report. In this article, the authors describe the methodology used in the survey and summarize the clinical recommendations given in the resulting guidelines. The expert panel reached consensus on many key strategies, including acute and preventive treatment of mania (euphoric, mixed, and dysphoric subtypes), depression, rapid cycling, and approaches to managing treatment resistance and comorbid psychiatric conditions. Use of a mood stabilizer is recommended in all phases of treatment. Divalproex (especially for mixed or dysphoric subtypes) and lithium are the primary mood stabilizers for both acute and preventive treatment of mania. If monotherapy with these agents fails, the next recommended intervention is to combine them. This combination of lithium and divalproex can then serve as the foundation to which other medications are added if needed. Carbamazepine is the leading alternative mood stabilizer for mania. The experts rated the other new anticonvulsants as second-line options (i.e., their use is recommended if lithium, divalproex, and carbamazepine fail or are contraindicated). For milder depression, a mood stabilizer, especially lithium, may be used as monotherapy. Divalproex and lamotrigine are other first-line choices. For more severe depression, the experts recommend combining a standard antidepressant with lithium or divalproex. Bupropion, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine are preferred antidepressants. The antidepressants should usually be tapered 2-6 months after remission. Monotherapy with divalproex is recommended for the initial treatment of either depression or mania in rapid-cycling bipolar disorder. Antipsychotics are recommended for use in combination with the above regimens for mania or depression with psychosis, and as potential adjuncts in nonpsychotic episodes. Atypical antipsychotics, especially olanzapine and risperidone, were generally preferred over conventional antipsychotics. The guidelines also include recommendations concerning the use of electroconvulsive therapy (ECT), clozapine, thyroid hormone, stimulants, and various novel agents for patients with treatment-refractory bipolar illness. The experts reached high levels of consensus on key steps in treating bipolar disorder despite obvious gaps in high-quality data. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data; however, their recommendations are generally conservative. Experts give their strongest support to initial strategies and medications for which high-quality research data or longstanding patterns of clinical usage exist. Within the limits of expert opinion and with the understanding that new research data may take precedence, these guidelines provide clear pathways for addressing common clinical questions and can be used to inform clinicians and educate patients about the relative merits of a variety of interventions.     

Can antidepressants cause mania and worsen the course of affective illness?

Several investigators have recently challenged the belief that antidepressants can precipitate mania or rapid cycling between mania and depression. With one exception, there appear to be no placebo-controlled studies of switches into mania in bipolar patients during antidepressant treatment. Patients most likely to switch into mania during antidepressant therapy have probably been excluded from maintenance treatment studies and are probably overrepresented in studies at special research facilities. On balance, the available evidence suggests that some bipolar patients become manic, and a few experience rapid cycling, when they are treated with antidepressants. The prevention of these responses will require further research on risk factors and on the antimanic efficacy of coadministered lithium or other mood stabilizers.     

Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers

Introduction: Bipolar patients with breakthrough major depressive episodes despite ongoing adequately‐dosed mood stabilizer medication were randomized in a double‐blind manner to one of three antidepressants with different mechanisms of action: bupropion, sertraline, or venlafaxine. Preliminary data are presented on the switch rates into hypomania or mania for the antidepressants as a group prior to unblinding the specific individual drug efficacy and tolerability data in this ongoing clinical trial.

Methods: Subjects included 64 bipolar patients who participated at five sites in a 10‐week double‐blind trial for depression and a 1‐year blinded continuation maintenance phase for responders. Nonresponders were re‐randomized such that there were 95 acute treatment phases. In the acute phase, doses were titrated to clinical response, side effects, or maximum dose of bupropion (450 mg/day), sertraline (200 mg/day), or venlafaxine (375 mg/day). Daily ratings on the National Institute of Mental Health‐Life Chart Methodology (NIMH‐LCM) were inspected for the degree of improvement on the Clinical Global Impressions scale as revised for bipolar illness (CGI‐BP) and the occurrence of hypomania or mania.

Results: Thirty‐five (37%) of the 95 acute treatment phases were associated with a much or very much improved rating in depression on the CGI‐BP. Thirteen (14%) of these 95 acute trials of antidepressants as adjuncts to mood stabilizers were associated with switches, seven into hypomania and six into mania. Forty‐two patients elected to go into the continuation phase in 48 instances. Sixteen (33%) of the continuation phase trials were associated with mood switches, 10 into hypomania and six into mania.

Conclusions: In this randomized double‐blind prospective study of three second‐generation antidepressants (bupropion, sertraline, and venlafaxine) in bipolar patients whose depression broke through ongoing treatment with mood stabilizers, switches into hypomania or mania occurred in 14% of the acute phases and 33% of the continuation phases. Individual data on each drug will be assessed in the next phase of the study after more subjects are recruited and the blind is broken.     

Quetiapine monotherapy for bipolar depression

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called "unipolar" depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers - antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration.     

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.     

Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations

BACKGROUND: To review the literature on efficacy of third generation anticonvulsants for treatment of bipolar disorder and provide clinical recommendations. METHOD: Open and controlled studies, case reports, and case series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide were located through electronic searches of several databases, by manual search of proceedings of international meetings, and through contacting authors of recent reports. RESULTS: Lamotrigine is the best studied anticonvulsant and has efficacy in acute bipolar depression and in longer term treatment of bipolar depression as well as rapid-cycling bipolar II disorder but not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct in bipolar disorder, but double-blind trials failed to confirm efficacy in acute mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is reported to be effective in acute mania and rapid-cycling bipolar disorder in several open studies, but methodological problems in a double-blind study led to a failed study in acute mania. However, topiramate may lead to weight loss in some patients. Zonisamide deserves further investigation, but tiagabine does not appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an unmet need in treating bipolar depression and rapid-cycling bipolar disorder. Other third generation anticonvulsants with the exception of tiagabine offer promise but require confirmation of their efficacy from double-blind studies.     

Verapamil treatment for women with bipolar disorder.

BACKGROUND: Additional pharmacological treatments are needed for patients with bipolar disorder. We describe our experience with verapamil in an inclusive, sequential series of outpatient women (some pregnant) with bipolar disorder. METHODS: All women who were prescribed verapamil for bipolar disorder (n = 37) were included. We used the criterion of 50% reduction in scores on the Mania Rating Scale or the Hamilton Rating Scale for Depression to define response for women who were treated for an acute episode of bipolar hypomania/mania or depression, respectively. For euthymic women who chose verapamil maintenance treatment, we evaluated whether they met criteria for a recurrent episode during therapy. RESULTS: Treatment for acute episodes was initiated in 28 women. Of women with depression and mania, 39% and 100% responded, respectively. Seven of the nine patients (77%) with mixed states responded: all seven improved to response criterion on the mania scale, and two responded on the depression scales as well. Six of eight patients who received continuation therapy remained well. CONCLUSIONS: These data provide evidence that verapamil is effective for mania. The response rate for mania compares favorably to that for other mood stabilizers. After decades of case reports and underpowered clinical trials, we must definitively study verapamil for efficacy and gender specificity in bipolar disorder.     

Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials

CONTEXT: Recommendations of treatment guidelines concerning the use of second-generation antipsychotic (SGA) agents for acute mania vary substantially across committees or working groups. Meta-analyses addressing the use of SGAs in the treatment of acute mania are lacking. OBJECTIVE: To conduct a meta-analysis of the efficacy and safety of SGAs in the treatment of acute mania. DATA SOURCES: Randomized controlled trials comparing SGAs with placebo, first-generation antipsychotic drugs, or mood stabilizers (MSs) in the treatment of acute mania were searched for in the PsiTri and MEDLINE databases (last search: May 2006). STUDY SELECTION: The abstracts, titles, and index terms of studies were searched using the following key words: aripiprazole, amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zotepine in conjunction with mania, manic, and bipolar. DATA EXTRACTION: Data on efficacy, global dropout, dropout due to adverse events, dropout due to inefficacy, weight gain, rate of somnolence, and extrapyramidal symptoms were extracted and combined in a meta-analysis. DATA SYNTHESIS: A total of 24 studies with 6187 patients were included. The SGAs were significantly more efficacious than placebo. The analysis demonstrated that adding antipsychotic agents to MS treatment was significantly more effective than treatment with MSs alone. The SGAs displayed efficacy comparable with that of MSs. Some SGAs seemed to induce more extrapyramidal symptoms than placebo. The SGAs were also associated with higher rates of somnolence than placebo. CONCLUSION: Currently available data suggest that combining SGAs and MSs is the most efficacious treatment of acute mania.