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Effective Health Care Program

Treatment for Bipolar Disorder in Adults

A Systematic Review

Systematic Review Draft

Open for comment through Nov 21, 2017

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Purpose of Review

Assess the effectiveness of drug and nondrug therapies for treating acute symptoms and preventing relapse in adults with all types of bipolar disorder (BD).

Key Messages

  • Lithium, asenapine, cariprazine, olanzapine, quetiapine, risperidone, and ziprasidone were modestly better than placebo for acute mania in adults with BD type I. Harms, such as extrapyramidal symptoms and weight gain, were variable by drug.
  • Lithium was better than placebo for preventing relapse to acute symptoms for BD type I.
  • Evidence was insufficient for drug treatments for depressive episodes.
  • Cognitive behavioral training and systematic/collaborative care may be no better than other behavioral therapeutic approaches for treating or preventing bipolar symptoms.
  • Attrition hindered the ability to draw strong conclusions.

Structured Abstract


Assess the efficacy and effectiveness of drug and nondrug interventions for treating acute symptoms associated with bipolar disorder (BD) and preventing relapse.

Data sources

Ovid MEDLINE® and PsychInfo, 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 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.


We synthesized evidence from 175 unique studies, 111 studies for 28 drugs, 64 studies for nondrug interventions. Seventy studies with greater than 50 percent attrition were excluded. All drug findings with at least low-strength evidence were based on studies almost exclusively enrolling adults with BD-I. Point estimates showed 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 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). For drugs not approved for BD, paliperidone also 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, although withdrawals for adverse events were lower for topiramate. No drug treatment reached a minimally important difference, although lithium came close. All other drug comparisons to placebo or active controls for acute mania, depression, and maintenance had insufficient evidence. For behavioral interventions, cognitive behavioral training (CBT) was no better for depression or mania symptoms than psychoeducation or other active comparators (low-strength evidence). Systematic/collaborative care had no effect on relapse compared to inactive comparators (low-strength evidence). Evidence was insufficient for all other nondrug interventions.


We found no high- or moderate-strength evidence for any intervention to effectively treat any phase of any type of BD compared to placebo or an active comparator. Low-strength evidence showed improved mania symptoms for all FDA-approved antipsychotics, except aripiprazole, when compared to placebo for adults with BD-I. Low-strength evidence also showed benefit from lithium for acute mania in the short-term and resulted in longer periods of maintenance versus placebo in adults with BD-I. Participants using atypical antipsychotics, except quetiapine, reported more extrapyramidal symptoms compared to placebo, and those using olanzapine reported more clinically significant weight gain. Evidence was insufficient for most nondrug interventions. Low-strength evidence showed no benefit for CBT effectiveness on mood symptoms and efficacy of systematic/collaborative care on relapse. Information on harms was limited across all studies. Future studies of bipolar disorders treatments will require innovative ways to increase study completion rates.