Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial

Abstract

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry (‘0-weeks' group) or (ii) at 24 weeks after entry (‘24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (‘52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…When a combination therapy of an atypical antipsychotic with lithium/divalproex was used to treat acute mania, continuing the atypical antipsychotic for the first 6 months following response offered clear benefit in reducing risk of mood episode recurrence (level 2),367 but the benefits beyond 6 months remain uncertain. Therefore, clinicians are advised to re‐evaluate risks and benefits after 6 months of sustained response to determine whether maintenance combination therapy with an atypical antipsychotic is justified.…”

“…Biweekly long‐acting injectable risperidone monotherapy (level 1)383 or adjunctive therapy (level 2)384 has demonstrated efficacy in preventing any mood or manic episode, but had no clear efficacy in depressive episode prevention in these trials. Further, there was a trend for superiority of oral risperidone adjunctive therapy at 6 months in preventing any mood episode and in preventing mania but not depression 367. Carbamazepine (level 2) has not been assessed in any large placebo‐controlled trials, but active comparator trials support its efficacy 385.…”

Defining the role of SGAs in the long‐term treatment of bipolar disorder

“…However, despite such promising initial evidence favoring the sustained use of SGAs because they reduce the risk of relapse, their adverse metabolic and neurological consequences are a burgeoning problem that cannot be ignored. Concerns about the consequences of long‐term SGA use have led some authors . to argue that they should not be continued unless the benefits clearly offset the costs.…”

“…In order to identify the optimal period of treatment with SGAs following an acute episode, Yatham et al . compared the time to relapse of patients who discontinued SGAs immediately at zero weeks, at 24 weeks, or at 52 weeks and, again, found that continuing SGAs prolonged time to relapse.…”

“…4 to argue that they should not be continued unless the benefits clearly offset the costs. Thus, rather than continuing SGA adjunctive treatmentas-usual when patients reach remission, it is vital that clinicians and researchers determine the ideal duration and dosage needed to maximize prophylaxis while minimizing side effects (Figure 1).In order to identify the optimal period of treatment with SGAs following an acute episode, Yatham et al 4 compared the time to relapse of patients who discontinued SGAs immediately at zero weeks, at 24 weeks, or at 52 weeks and, again, found that continuing SGAs prolonged time to relapse. However, interestingly, patients who discontinued at 24 weeks had similar relapse rates to those who discontinued at 52 weeks, while gaining significantly less weight.…”