Pharmacological treatment of the maintenance phase of bipolar depression: Efficacy and side effects

To prevent relapse/recurrence of mood episodes in bipolar disorder (BD), medications must demonstrate efficacy in preventing both manic/mixed/ hypomanic and depressive relapses/recurrences. Most maintenance treatment studies of BD have continued using relapse-prevention designs to preserve assay sensitivity despite their limited generalizability. This chapter focuses on all traditional efficacy measures including time to intervention for relapse/recurrence of any mood episodes, manic/mixed episodes, and depressed episodes. For safety, we have focused on short- and long-term side effects, especially ≥7% weight gain. To date, lithium, lamotrigine, and quetiapine have been investigated in both manic and depressive index episodes. Divalproex, olanzapine, aripiprazole, paliperidone, and risperidone long-acting injections have been evaluated in manic/mixed index episodes. Both time-to-event results and cumulative risk for relapse/recurrence showed that only quetiapine demonstrated bimodal efficacy in preventing both depressive and manic/mixed/hypomanic relapses. The other medications were only efficacious for preventing manic/mixed relapses or more effective in preventing manic/mixed relapses than depressive relapses. Short-term side effects varied widely among the aforementioned medications, but newly emergent side effects during long-term treatment were relatively rare. With the exception of ziprasidone, significantly higher rates of ≥7% weight gain were observed with all other antipsychotics. The short- and long-term side effects suggest that relapseprevention studies also inflate the safety and tolerability of active treatments.