Objective: Assess the effect of drug and nondrug interventions for treating acute symptoms associated with bipolar disorder (BD) and preventing relapse.
Data sources: Ovid MEDLINE® and PsycINFO®, the Cochrane Central Register of Controlled Trials, and Ovid Embase® bibliographic databases; hand searches of references of relevant systematic reviews through May 2017.
Review methods: Eligible studies included randomized controlled trials and prospective cohorts with comparator arms enrolling adults with bipolar disorder (BD) of any type with 3 weeks followup for acute mania, 3 months for depression, and 6 months for maintenance treatments. We excluded acute mania and depression studies with greater than 50 percent attrition.
Results: We synthesized evidence from 157 unique studies, 108 studies for 28 drugs, 49 studies for nondrug interventions. All drug study findings with at least low-strength evidence were based almost exclusively on adults with bipolar I disorder (BD-I). Asenapine, cariprazine, quetiapine, and olanzapine improved acute mania symptoms compared to placebo (low-strength evidence). However, improvements were of modest clinical significance, with values that were less than the minimally important difference, but still large enough that a reasonable proportion of participants likely received a benefit. Unpooled evidence indicated an overall beneficial effect of risperidone and ziprasidone on acute mania symptoms compared to placebo (low-strength evidence). Participants using atypical antipsychotics, except quetiapine, reported more extrapyramidal symptoms compared to placebo, and those using olanzapine reported more clinically significant weight gain. Lithium improved acute mania in the short term and prolonged time to relapse in the long term compared to placebo (low-strength evidence). No difference was found between olanzapine and divalproex/valproate for acute mania (low-strength evidence). For drugs not approved for BD, paliperidone improved acute mania compared to placebo (low-strength evidence), while topiramate and allopurinol showed no benefit (low-strength evidence). Further, lithium improved acute mania better than topiramate (low-strength evidence), although withdrawals for adverse events were lower for topiramate. Only lithium reached a minimally important difference for acute mania and maintenance treatment. All other drug comparisons to placebo or active controls for acute mania, depression, and maintenance had insufficient evidence. For psychosocial interventions, cognitive behavioral training (CBT) was no better for depression or mania symptoms than psychoeducation or other active psychosocial comparators (low-strength evidence). Systematic/collaborative care had no effect on relapse compared to inactive comparators (low-strength evidence).
Conclusions: We found no high- or moderate-strength evidence for any intervention to effectively treat any phase of any type of BD versus placebo or an active comparator. All antipsychotics approved by the Food and Drug Administration, except aripiprazole, had low-strength evidence for benefit for acute mania in adults with BD-I. Lithium improved short-term for acute mania and resulted in longer time to relapse in the long term versus placebo in adults with BD-I. Aside from low-strength evidence showing CBT and systematic/collaborative care having no benefit for a few outcomes, evidence was insufficient for nondrug interventions. Information on harms was limited across all studies. Future research examining BD treatments will require innovative ways to increase study completion rates.