The Risks of Adding Antipsychotics to Mood Stabilizer May Outweigh Benefits After 6 Months

Following an acute manic episode, many patients with bipolar disorder are treated with a combination of a mood stabilizer and an atypical antipsychotic to reduce the risk of a manic relapse; however, due to the side effects of antipsychotics, including weight gain and metabolic syndrome, most agree that antipsychotic therapy should be maintained only if the benefits of using the medication can be shown to outweigh the risks.

Martin Dee, UBC

What is the ideal time range for using an atypical antipsychotic as an adjunct to a mood stabilizer? Some studies have reported a period of up to 24 months, though other research has suggested the risk of manic relapse is significantly raised only in the first few months following an acute episode.

Up to now, no clinical studies have explicitly assessed the risks and benefits of adjunctive antipsychotic therapy at different durations within the same trial. But a trial published October 13 in Molecular Psychiatry has provided some of the first data in this regard: six months of adjunctive antipsychotic therapy is helpful in reducing mania relapse, but beyond that there is no benefit.

The analysis was far from a complete picture—olanzapine and risperidone were the only two medications administered, and though the study enrolled 159 patients, there was not enough statistical power to deduce the performance of either individual antipsychotic.

Still, it provides some of the first guidance in managing antipsychotic use for bipolar disorder, said lead study author Lakshmi Yatham, M.D., of the Department of Psychiatry at the University of British Columbia.

“The data suggest that a patient who had a manic episode will have a greater chance of staying well over the next six months with a mood stabilizer and antipsychotic therapy,” Yatham said, noting that the risks of weight gain or other adverse effects during this time remain a concern. However, beyond six months, “continued antipsychotic use may not add any more benefit,” he added.

Yatham and colleagues recruited patients with bipolar I disorder who had recently remitted from a manic episode following treatment with a mood stabilizer (lithium or valproate) and risperidone or olanzapine. Patients were randomly assigned to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at the trial’s start (“0-week group”) or 24 weeks after entry, or continuation of the antipsychotic therapy throughout the 52-week trial.

They found that patients on antipsychotics and mood stabilizers for 24 weeks following remission of their manic episode had about half the risk of relapse as patients who tapered off antipsychotics following remission (the 0-week group) and the same relapse risk as patients taking antipsychotics for the full 52 weeks.

In terms of weight gain, the 24-week group gained only an average of 0.1 kg while the 52-week group gained an average of 3.2 kg; the 0-week group lost 0.2 kg on average.

The findings suggest that when weighing the risks and benefits of risperidone or olanzapine adjunctive therapy, 24 weeks may be the best option, Yatham said.

Although the secondary analyses of data for each individual medication did not give any definitive answers on whether olanzapine or risperidone might be more effective and/or produce fewer side effects, they did show some intriguing trends.

“It’s possible that olanzapine might continue to provide additional relapse reduction after six months, while also providing some reduction in depressive episodes,” Yatham told Psychiatric News. “At the same time, adjunctive olanzapine contributed to a majority of the weight gain in our study, and this should be weighed against unclear long-term benefits.”

Yatham and his group are planning additional trials to examine the long-term effects of other antipsychotics as adjunctive treatments for bipolar disorder since it seems that different atypical antipsychotics will act differently in the long run. He noted a recent study showing that quetiapine might be able to reduce both mania and depression in remitted bipolar patients, but that data did not become available until after their trial started, so they could not include quetiapine among their tested agents.

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