What is already known on this topic

Recently, clinical guidelines about treatment of mania have been published by important scientific societies.1 Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania; however, antipsychotics should not be continued unless the benefits of reducing relapse outweigh the risks such as weight gain and metabolic syndrome.2 So far, there is no high-quality evidence for such beneficial duration of the therapy. The study by Yatham and colleagues aimed to determine the efficacy of different durations (24 and 52 weeks) of atypical antipsychotic adjunctive therapy to mood stabiliser versus discontinuing the atypical antipsychotic at study entry, in the prevention of any mood relapse in patients with bipolar I disorder and recent mania.

Methods of the study

One hundred and seventy-eight patients from academic centres in Canada and Brazil with bipolar I disorder and aged ≥17 years, who recently remitted from an acute manic or mixed episode with a combination of mood stabiliser (lithium or valproate) and atypical antipsychotic (risperidone or olanzapine) were randomised to one of the three following groups: (1) discontinue risperidone or olanzapine over 2 weeks beginning on the day of randomisation and receive placebo substitution for the remaining 50 weeks; (2) receive risperidone or olanzapine for 24 weeks, followed by tapering and discontinuation of the antipsychotic over the next 2 weeks and placebo substitution for the remaining 26 weeks; and (3) continue risperidone or olanzapine for 52 weeks. All patients continued the same mood stabiliser (lithium or valproate) they were taking at study entry for the 52-week duration of the study. The primary outcome measure was the time to any mood episode, defined as: (1) Young Mania Rating Scale score of 15 or greater, (2) Hamilton Rating Scale for Depression (HAM-D) 21-item score of 15 or greater or HAM-D suicide item score of 3 or greater, (3) Clinical Global Impression Severity score of 3 or greater, (4) hospitalisation for treatment of mood symptoms; or (5) suicide or suicide attempt. Secondary outcome measures were time to a manic episode, time to a depressive episode and time to premature discontinuation from the study for any clinical reason. Randomisation was stratified by drug combination and by centre. Treating clinicians and all research personnel (except trial statistician and pharmacist) were blinded to treatment arm allocation.

What this paper adds

• Patients with bipolar I disorder who recently remitted from a manic episode with adjunctive risperidone or olanzapine therapy are less likely to have a recurrence if these medications are continued for 24 weeks versus discontinuing soon after remission of mania (HR 0.53, 95% CI 0.33 to 0.86).

• Continuing risperidone beyond 24 weeks provides no benefit, although it remains unclear whether continued olanzapine use beyond 24 weeks reduces the risk of recurrence (time to any mood episode: continuation of risperidone for 52 vs 24 weeks, HR 1.85, 95% CI 1.00 to 3.41; continuation of olanzapine for 52 vs 24 weeks, HR 0.48, 95% CI 0.17 to 1.32).

Limitations

• The final sample size of 178 patients was much smaller than the sample size of 540 patients that was originally planned, which reduces the statistical power and makes it difficult to provide more definitive conclusions as to whether the discordant findings truly reflect a reduced risk of relapse with continued olanzapine use over 52 weeks and an increased risk with continued risperidone use beyond 24 weeks.

What next in research

• Studies with larger sample size are needed to yield more precise assessments of the effects of treatments and to compare different individual drugs or treatment duration.

• Other atypical antipsychotics should be investigated. For instance, drugs with less metabolic burden liability such as aripiprazole and asenapine should be examined.3–5

Do these results change your practices and why?

Yes. Psychiatrists hesitate to stop adjunctive antipsychotics even after a long period of remission mainly due to concerns about an increased risk of relapse.6 The present findings provide the rationale behind continuing antipsychotic adjunctive therapy for 6 months following clinical remission, but the decision about whether to continue the antipsychotic for a longer period should be taken on a case-by-case basis.