Focus on Bipolar Disorder Treatment:
Treatment of Acute Mania

Methods for managing acute mania have been reviewed in a new publication and at a recent medical meeting.

Terence A. Ketter, M.D., is the editor of the latest volume in the Review of Psychiatry series, volume 24: Advances in Treatment of Bipolar Disorder (American Psychiatric Publishing, Inc., 2005). In it, he and his colleagues discuss recent psychopharmacologic advances in the management of acute mania and review the evidence for both established and new treatments in their chapter entitled "Treatment of Acute Mania in Bipolar Disorder." This chapter provides a comprehensive review of the evidence supporting the use of diverse agents in acute mania, including lithium, divalproex, carbamazepine, newer antipsychotics, and adjunctive benzodiazepines.

The first 3 agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute mania were lithium, chlorpromazine, and divalproex. Five of the newer antipsychotics—olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole—are also approved for acute mania, as is another anticonvulsant, the extended-release capsule formulation of carbamazepine.

In the review of lithium and divalproex, Ketter and coworkers remind the reader that the evidence supports their use as first-line interventions for acute mania. They also review evidence that divalproex and carbamazepine appear to have broader efficacy spectra than lithium and therefore may be useful in patients who have not responded to lithium treatment or who have an illness subtype, such as dysphoric or mixed manic episodes, that is not responsive to lithium treatment.

Turning to the newer antipsychotics, the authors examine study results that led to the FDA approval of olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole for the treatment of acute mania. In addition to the monotherapy indication, olanzapine, risperidone, and quetiapine are also approved as therapy for acute mania adjunctive to lithium or divalproex. Although clozapine has not been approved for the treatment of mania, some evidence suggests that adjunctive clozapine may be effective in patients with treatment-resistant bipolar disorder. However, clozapine’s challenging safety profile limits its use.

Newer anticonvulsants have been studied in bipolar disorder as well, but since medications in this class have such diverse psychotropic profiles, one cannot assume that they all have the same effect on the symptoms of bipolar disorder. For example, lamotrigine has been approved for maintenance treatment and appears to have specific efficacy in the treatment of bipolar depression, whereas limited data suggest that oxcarbazepine may ultimately prove to be effective for acute mania. In contrast, controlled trials have indicated that lamotrigine, gabapentin, and topiramate are not effective as primary interventions for acute mania. Thus, newer anticonvulsants as a class are not generally effective for acute mania, but more studies are needed for drugs such as zonisamide and levetiracetam.

Benzodiazepines may also have some modest utility as adjuncts in the treatment of bipolar mania, according to the authors. These agents are usually allowed on an as-needed, adjunctive basis during controlled studies of bipolar disorder to control insomnia, agitation, and anxiety. In patients who experience those symptoms on an ongoing basis or have a comorbid anxiety disorder, benzodiazepines may also prove to be a useful adjunctive treatment option. Risks of abuse or disinihibition may limit the utility of these drugs in some patients.

Ketter and colleagues conclude their chapter by pointing out that clinical trials provide health care providers with the means to understand the relative usefulness, efficacy, and safety of both standard, approved treatments for acute mania as well as newer, more novel options.

Several new research posters at this year’s annual meeting of the American Psychiatric Association (APA) addressed the treatment of patients with bipolar disorders. Spaulding and colleagues studied the use of anxiolytic and hypnotic agents, such as the benzodiazepines, adjunctive to lamotrigine monotherapy for initial mood stabilization (NR303). The addition of these agents significantly improved stabilization rates in patients with (p = .023) and without (p < .008) symptom excursions (increased symptoms of the opposite polarity from the index episode).


Ramey and coworkers reported on the efficacy and safety of ziprasidone for acute mania (NR317). The 12-week study compared ziprasidone to haloperidol and placebo for the first 3 weeks, at which point placebo-treated patients were switched to ziprasidone for the duration of the study. Ziprasidone-treated patients began responding as early as day 2 of the study, and by the time the placebo phase was over, ziprasidone was already superior to placebo (p < .05). Ziprasidone was also well tolerated, with lower rates of extrapyramidal symptoms and other adverse events compared with haloperidol.

Carlson and colleagues presented results from pooled data from 2 trials of aripiprazole in patients with acute manic or mixed episodes (NR273). In these 2 placebo-controlled, 3-week studies of 513 patients (aripiprazole N = 254, placebo N = 259), more patients assigned to the aripiprazole group experienced response or remission at day 4 compared with patients in the placebo group (p < .01). This difference remained significant throughout the 3 weeks (p < .05). By week 3, the majority of aripiprazole-treated responders were in remission (87%).

Sajatovic and associates investigated the treatment of bipolar mania in older adults (aged 55 years and older). The data were derived from two 12-week, double-blind randomized controlled trials of quetiapine versus placebo. In this report, results and adverse events in older adults were analyzed separately from those in younger adults. Older adults responded more quickly than younger adults--mean Young Mania Rating Scale (YMRS) scores decreased significantly among older adults by day 4 (p = .003), whereas in younger adults, this significant difference appeared at day 14. Both age groups had several of the same common (> 10%) adverse effects (dry mouth, somnolence, and insomnia), but in older adults, postural hypotension, weight gain, and dizziness were common as well.

Townsend and coworkers addressed a factor that may affect outcome in acutely manic patients: anxiety. Twenty-six patients experiencing an acute manic episode were included. These patients had their mood stabilizer or antipsychotic medications stopped before the baseline visit. The investigators found a significant association between PANSS/BPRS measures of anxiety, tension, and excitement and YMRS scores (p < .05), and a somewhat weaker association between heart rate and YMRS scores (p = .08).

The treatment of mixed mania was also discussed at this year’s APA. In a scientific symposium, Goldberg and colleagues reviewed the role of antidepressants in mixed mania based on data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) (Scientific and Clinical Report Session 5). Data from patients who entered the program while experiencing mania or hypomania with depressive symptoms were examined. Antidepressants taken in conjunction with mood stabilizers or atypical antipsychotics had little to no effect on time to recovery among these patients.

Dr. Ketter stressed the clinical importance of the findings of the above presentations, noting that as indicated by Spaulding and colleagues and by Townsend and associates, anxiety symptoms are common in patients with bipolar disorders and may respond to adjunctive anxiolytic agents. He also noted that the reports of rapid onset of antimanic effects with ziprasidone as reported by Ramey and coworkers and with aripiprazole as noted by Carlson and colleagues are consistent with the notion that atypical antipsychotics as a class tend to provide rapid relief of manic symptoms. Ketter also commented that as indicated by Sajatovic and associates, the treatment of older adults with mania can yield special challenges with respect to adverse effects. Finally, as suggested by Goldberg and associates, although the depressive symptoms seen in mixed episodes are clinically important, the use of antidepressants in such episodes is not recommended due to the risk of further destabilizing mood. Taken together, the above suggest that clinicians have a growing armamentarium of options to provide safer and more effective treatment of acute mania in patients with bipolar disorders.


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Drug names: aripiprazole (Abilify), carbamazepine (Tegretol, Equetro, and others), chlorpromazine (Sonazine, Thorazine, and others), clozapine (Clozaril, FazaClo, and others), divalproex (Depakote), gabapentin (Neurontin and others),  haloperidol (Haldol and others), lamotrigine (Lamictal), levetiracetam (Keppra), lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa), oxcarbazepine (Trileptal), quetiapine (Seroquel), risperidone (Risperdal), topiramate (Topamax), ziprasidone (Geodon), zonisamide (Zonegran).

Disclosure of off-label usage: The author has determined that, to the best of his knowledge, clozapine is not approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant bipolar disorder; gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide are not approved for the treatment of acute mania; and benzodiazepines are not approved for the adjunctive treatment in acute mania. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information.

Supported by an educational grant from GlaxoSmithKline.