Efficacy of Agents in Treating Mania

Efficacy of Agents in Treating Mania


Guidelines for Treating Manic Episodes

When the American Psychiatric Association (APA) last revised their guidelines for the treatment of patients with bipolar disorder in 2002,1 the recommended first-line treatment for more severe manic or mixed states was a combination of lithium or valproate and an atypical antipsychotic.

Efficacy of Agents in Treating Mania

Roy H. Perlis, MD, MSc
From the Department of Psychiatry, Harvard Medical School, and the Bipolar Clinical and Research Program, Massachusetts General Hospital, Boston

Supported by an educational grant from Eli Lilly and Company.

Guidelines for Treating Manic Episodes

When the American Psychiatric Association (APA) last revised their guidelines for the treatment of patients with bipolar disorder in 2002,1 the recommended first-line treatment for more severe manic or mixed states was a combination of lithium or valproate and an atypical antipsychotic. In patients with less severe manic or mixed episodes, the recommended treatment was monotherapy with lithium, valproate, or an atypical antipsychotic. The guidelines were somewhat vague about the distinction between more and less severely ill patients, although the general understanding was that severely ill patients require hospitalization while patients who were less ill might be managed as outpatients.

For patients who were already being treated but were experiencing breakthrough symptoms, the APA guidelines1 recommended that the primary mood-stabilizing medication be optimized and then an atypical antipsychotic be added, if necessary. Optimizing a mood stabilizer—which usually refers to making sure that the dose is in the therapeutic range or sometimes at the higher end of the therapeutic range—is a common clinical practice, but little evidence explicitly addresses the value of optimization. However, because the practice is so common in the clinical arena, it is a standard recommendation.

Efficacy and Tolerability Data
The APA guidelines1 left key unanswered questions for the clinician, such as how to choose among the various options for treating mania given that there are numerous agents to choose from, both across and within classes. Clinicians also have to decide how to weigh tolerability and safety during acute treatment. Efficacy and safety data in the literature can help with this process. The following review focuses on monotherapy.

Efficacy. When reviewing the efficacy data, a useful approach is to look at meta-analysis results rather than results from individual studies because the clinical trials that have been conducted have been similar in design and outcome measurements. A meta-analysis2 of placebo-controlled monotherapy trials of atypical antipsychotics included patients with acute manic or mixed episodes and placebo-treated subjects. Aripiprazole, risperidone, olanzapine, quetiapine, and ziprasidone were each evaluated in several studies. Three of the placebo-controlled studies also included an active comparator known to have efficacy in treating mania (lithium or haloperidol).

AV 1: Pooled Trial Drug Effects (Random-Effects Model) of Active Monotherapy vs Placebo for Bipolar Mania (00:58)
The important conclusion from this meta-analysis2 is that all of the atypical antipsychotics tested had generally similar monotherapy efficacy, which was also not substantially different from that of lithium or haloperidol (see AV 1). The possibility that efficacy differences exist between the individual treatments cannot be ruled out. However, individual differences are likely to be quite modest, both among the atypical antipsychotics and between the atypicals and lithium and haloperidol.

Typically, in study results, the duration of the trial and the time to onset of action are important for interpreting data. Most of the studies in the meta-analysis2 lasted 3 weeks. Unfortunately, time to onset cannot be compared directly from the data because the individual mania studies used different initial assessment times. Although some antipsychotics separated from placebo at 2 days, many studies did not assess for this separation until day 7.

In the last decade, interest in using the newer anticonvulsants for mania has grown. Unfortunately, a meta-analysis3 found that none of these drugs have shown significant efficacy for treating mania. Adequately powered trials for topiramate, lamotrigine, and gabapentin were negative, and smaller trials did not suggest efficacy for tiagabine and zonisamide. Studies4 have demonstrated that extended-release carbamazepine is superior to placebo for the treatment of acute manic or mixed episodes, but the carbamazepine derivative oxcarbazepine had no benefit in a large study5 in children and adolescents with manic or mixed states.

AV 2: Least-Squares Mean Change From Baseline Among Patients With Bipolar I Disorder
Few head-to-head studies have been conducted with newer agents in the treatment of mania. One randomized, double-blind, placebo-controlled trial6 compared risperidone and olanzapine in the treatment of hospitalized patients with bipolar I disorder in mixed or manic nonpsychotic episodes. No discernible difference in mania improvement was found between risperidone and olanzapine in the 3-week study (see AV 2). Two other head-to-head studies7,8 compared olanzapine and divalproex for the treatment of mania. One of the studies7 suggested a modest difference in efficacy favoring olanzapine. The smaller study,8 which was not powered to show a significant difference, suggested a slight numeric difference in efficacy in favor of olanzapine. When compared with lithium, olanzapine was found to be at least as effective.9 One randomized, double-blind, placebo-controlled trial10 found quetiapine and lithium to be similarly efficacious in subjects with bipolar I disorder who were experiencing a manic episode. Likewise, another randomized, double-blind, placebo-controlled trial11 showed no significant difference in mania improvement between risperidone, lithium, and haloperidol.

AV 3: Side Effects With Atypical Antipsychotics (00:22)
Tolerability. Efficacy is not the only consideration necessary in choosing a treatment for acute mania. Treatment dropout owing to side effects is also an important consideration. A medication is not very clinically useful or effective, despite having efficacy, if it is not well tolerated. Atypical antipsychotics are associated with several particular side effects12,13 that must be considered (see AV 3). However, a meta-analysis of monotherapy trials (N=2455) by Scherk and colleagues14 found that rates of dropout because of side effects with atypical antipsychotics was either similar to or less than the rate observed among placebo-treated patients with acute mania.

Rates of dropout due to adverse events in the meta-analysis14 were similar for not only the atypical antipsychotics but also lithium and divalproex, even though the drugs differ in their specific side effect profiles. One important exception was that dropout because of side effects was lower with atypical antipsychotics than with haloperidol. This result is noteworthy because the APA recommendations1 favoring atypical antipsychotics rather than typical antipsychotics were widely criticized as not being cost-effective and perhaps not being supported by the efficacy data. However, when the tolerability data are considered, likely effectiveness advantages for the atypicals are evident.

All of the atypical antipsychotics available in the United States, except clozapine, have been approved by the U.S. Food and Drug Administration for the treatment of acute mania. Meta-analyses have shown that the efficacy of these medications in treating acutely manic patients with bipolar disorder seems to be similar within the class, greater than that of placebo, and generally similar to that of lithium, divalproex, and haloperidol. Evidence also suggests that atypical antipsychotics are associated with similar numbers of dropouts due to adverse events as placebo and with better tolerability than haloperidol.

Because efficacy across medications for bipolar mania is similar, relying solely on efficacy criteria for acute and maintenance therapy does not allow for a clear choice between medications. Thus, clinicians must consider what tolerability issues are of greater or lesser concern to the individual patient.

Drug Names
aripiprazole (Abilify), carbamazepine (Carbatrol, Tegretol, and others), clozapine (Clozaril, FazaClo, and others), divalproex (Depakote), gabapentin (Neurontin and others), haloperidol (Haldol and others), lamotrigine (Lamictal and others), lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa), oxcarbazepine (Trileptal and others), quetiapine (Seroquel), risperidone (Risperdal), tiagabine (Gabitril), topiramate (Topamax), ziprasidone (Geodon), zonisamide (Zonegran and others).

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American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder [Revision]. Am J Psychiatry 2002;159(suppl 4):1–50
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;67:509–516
Yatham LN, Kusumakar V, Calabrese JR, et al. Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations. J Clin Psychiatry 2002;63:275–283
Weisler RH, Hirschfeld R, Cutler AJ, et al. Extended-release carbamazepine capsules as monotherapy in bipolar disorder: pooled results from two randomised, double-blind, placebo-controlled trials. CNS Drugs 2006;20:219–231
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;163:1179–1186. Correction 2006;163:1843
Perlis RH, Baker RW, Zarate CA, et al. Olanzapine versus risperidone in the treatment of manic or mixed states in bipolar I disorder: a randomized, double-blind trial. J Clin Psychiatry 2006;67:1747–1753
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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;66:111–121
Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol 1998;21:176–180
Weiden PJ, Buckley PF. Reducing the burden of side effects during long-term antipsychotic therapy: the role of “switching” medications. J Clin Psychiatry 2007;68(suppl 6):14–23
Lehman AF, Lieberman JA, Dixon LB, et al, for the American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. 2nd ed. Am J Psychiatry 2004;161(suppl 2):1–56
Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry 2007;64:442–455

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