Optimizing Bipolar Treatment: How Long Should Adjunctive Antipsychotic Therapy Be Continued?

UCSD

Effective pharmacotherapy for major mental disorders has existed for more than 50 years, but many questions remain unanswered due to inadequate trial designs or insufficient numbers of studies to perform a robust meta-analysis. To address these questions, there is a growing recognition that more clinically relevant study designs are needed.

An excellent example of such a study by Yatham and colleagues was published recently in Molecular Psychiatry. In it, the authors describe how they designed a study specifically to answer the question: How long should adjunctive antipsychotic therapy be continued after remission from a manic episode?

There is extensive evidence demonstrating the benefits of adjunctive antipsychotics for acute mania and also during the maintenance phase of bipolar I disorder; however, given the additional weight gain and other adverse effects imposed by adjunctive antipsychotics, the literature is unclear on how long the average bipolar I patient on mood stabilizers should continue antipsychotic treatment following remission of a manic episode.

To study this question, the investigators enrolled 159 bipolar I patients who had remitted from a recent manic episode and had been treated with either risperidone or olanzapine in combination with lithium or valproate. The primary outcome measure was time to mood relapse (mania or depression). In this 52-week, double-blind, placebo-controlled trial, subjects were randomized to one of three treatment arms while remaining on their mood stabilizing medication:

• Discontinuation of antipsychotic at study entry (zero-weeks group, n=52)

• Discontinuation of antipsychotic after 24 weeks (24-weeks group, n=54)

• Continuation of antipsychotic for the full 52 weeks (52-weeks group, n=53)

There were 39 mood relapses in the zero-weeks group (depression=25, mania=14) compared with 29 events in the 24-weeks group (depression=23, mania=6) and 29 in the 52-weeks group (depression=22, mania=7). Moreover, the analysis of the Kaplan–Meier survival curves indicated that the time to any mood episode was significantly longer in the 24- and 52-weeks groups. Hazard ratios (HR) comparing the 24- and 52-weeks groups with the zero-weeks group revealed significantly lower risks of any mood episode for the longer durations of antipsychotic adjunctive therapy:

• HR 0.53 for the 24-weeks group (95% confidence interval: 0.33, 0.86; p=0.01)

• HR 0.63 for the 52-weeks group (95% confidence interval: 0.39, 1.02; p=0.06)

To address the specific question of whether 24 or 52 weeks of adjunctive antipsychotic therapy was superior, the HR for mood relapse was compared between these two time frames. The HR for the 52-weeks group relative to the 24-weeks group was not significantly different: HR 1.18 (95% CI: 0.71, 1.99; p=0.52). In addition, mean weight gain was 3.2 kg in the 52-weeks group, while there was a decrease of 0.2 kg in the zero-weeks group and 0.1 kg in the 24-weeks group.

Based on these findings, the authors concluded that continuation of adjunctive antipsychotic therapy for 24 weeks after remission from a manic episode significantly reduces relapse risk; however, beyond 24 weeks, there may be no added benefit for relapse risk, with ongoing adverse effect burden imposed by the continuation of antipsychotic treatment, particularly weight gain.

Psychiatry is the youngest medical specialty, and we are still in the early stages of establishing evidence-based answers to basic treatment issues. This clinically driven study design provides a useful basis for an initial approach to the question of antipsychotic adjunctive therapy in remitted, recently manic bipolar I patients. Individualized treatment decisions must always be made based on clinical history, but this important study indicates that tapering off antipsychotic treatment after 24 weeks of remission is a reasonable consideration in those who have not yet demonstrated that long-term antipsychotic therapy is necessary.

The study was funded by a grant from the Canadian Institutes of Health Research; Lilly Pharmaceuticals and Janssen Canada provided the olanzapine and risperidone, respectively. ■