The management of acute mania

Bipolar disorder is a common, severe psychiatric disorder that is characterised by recurrent manic, mixed, and depressive episodes. Cognitive, behavioural, and psychotic symptoms often occur during mood episodes, and suicide rates in bipolar disorder are among the highest of all psychiatric illnesses.¹ Acute bipolar manic and mixed episodes often constitute medical emergencies, requiring admission to hospital to ensure safety and rapid recovery. However, morbidity from mania is not limited to acute episodes as full recovery of functioning often lags months behind remission of symptoms.² Medications form the cornerstone of treatment of mania, and in the past decade randomised controlled trials of new medications for this syndrome have proliferated. These studies have addressed important questions about the short term efficacy and tolerability of new agents, alone and in combination.

The efficacy of agents for the treatment of acute mania has typically been established in three to four week, placebo controlled, randomised, parallel group, monotherapy trials in patients admitted to hospital without clinically significant medical or psychiatric comorbidity who are able to give informed consent. These trials provide important data about the ability of an agent to reduce manic symptoms over a minimal time period sufficient to measure improvement. Lithium, valproate, carbamazepine, and the atypical antipsychotics, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have established efficacy compared with placebo in at least two such trials.³,⁴ This body of evidence represents a substantial expansion of the therapeutic options available for the treatment of acute mania. This is good news for patients and clinicians alike.

But what exactly do these studies tell us? Lithium and valproate in the United States, and lithium and carbamazepine in Europe, have been first line treatments for acute mania for many years.⁵ Interestingly, the first placebo controlled, parallel group trials showing carbamazepine's efficacy in acute mania have been completed only recently. Typical antipsychotics also have been widely used for acute mania for decades, but in the absence of any efficacy data from placebo controlled trials except for one small study of chlorpromazine.⁶ The recently shown efficacy of atypical antipsychotics in acute mania represents a real advance in treatment. Beyond the overall efficacy data themselves reported in these studies, the atypical antipsychotics have the advantages of improved tolerability over typical agents and relatively rapid rates of onset, with evidence of significant reduction of manic symptoms within 2-7 days compared to placebo.⁷

However, limitations to translating these efficacy data to effectiveness in clinical practice are notable.⁸ Exclusion of severely ill patients who cannot provide informed consent, limitations imposed on comorbidity by exclusion criteria, and high dropout rates restrict the generalisability of study results.⁸ In most studies, response rates (usually defined as those patients displaying a 50% or greater reduction in manic symptoms from baseline to end point) range from 40-65%, with differences in response rates for drug and placebo ranging from 20% to 40%. In clinical terms, this means that in positive studies, some 50% of patients have at least 50% improvement.⁹ The glass is half full, or half empty. The goal of treatment in practice is remission of symptoms and restoration of functioning. These trials were generally not designed to assess these critical outcome measures.

It may be too much to expect a single agent, at least among those presently available, to produce rapid and complete symptomatic remission for most patients within relatively brief time frames of 3-4 weeks. This brings us to the use of combination treatment for acute mania. Although giving antipsychotics in combination with lithium, valproate, or carbamazepine in hospitalised manic patients has been common practice in the United States, and to a lesser extent, in Europe, since the 1970s, the superior efficacy of such combinations was shown only recently in clinical trials of adequate power.¹⁰ Nevertheless, combinations of valproate and typical antipsychotics, and of the atypical antipsychotics risperidone, olanzapine, and quetiapine with lithium, valproate, or carbamazepine had greater and more rapid response rates than placebo plus monotherapy comparison groups. Notably, combination treatment was generally well tolerated in these trials. As a group, these studies imply that combination treatment for most patients in hospital for mania represents a substantial acute advantage in treatment over monotherapy.

This is also good news but presents yet another dilemma. Once a patient has the good fortune of responding to combination treatment and leaving the hospital improved, the questions loom of when and if to taper one agent in the combination and strive for monotherapy for maintenance treatment. Only two randomised controlled studies compare combination treatment with maintenance treatment of bipolar disorder with monotherapy.¹¹,¹² Both found combination treatment superior to monotherapy in preventing relapse, although, not surprisingly, at the cost of a greater burden of side effects.

The treatment of acute mania cannot really be considered in isolation from the long term or maintenance treatment of bipolar disorder, and it is at this interface that we lack much needed data. The field is poised for longer term effectiveness studies of combination treatment, enrolling manic patients who are more broadly representative of clinical populations.