Eight Antimanic Medications More Effective Than Placebo for Bipolar Disorder I

These antimanic medications may be associated with more homogenous and predictable improvements of manic symptoms.

Eight antimanic medications were associated with more predictable improvements to symptoms of acute mania than placebo, according to results of a systematic review and meta-analysis published in eClinicalMedicine.

Researchers conducted a search of publication databases through April 2022 for randomized controlled trials of antimanic medications compared with placebo in the setting of bipolar I disorder (BD). The primary outcome was the variability in manic symptom improvement and the secondary outcomes were efficacy and acceptability.

A total of 39 trials from 34 publications comprising 12,150 patients with BD experiencing an acute manic episode were included. The patients were mean age 39.9 years and 48.6% were women.

The included antimanic medications were aripiprazole, asenapine, brexpiprazole, cariprazine, eslicarbazepine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, topiramate, valproate, and ziprasidone.

To the best of our knowledge, this study provides the first empirical examination of the variability in improvement of manic symptoms in participants with acute mania.

The medications which had significantly lower variability in symptom improvement compared with placebo an average follow-up of 3.4 weeks at are shown:

  • Risperidone (coefficient of variation ratio [CVR], 0.51; 95% CI, 0.38-0.70; I2=0%);
  • Haloperidol (CVR, 0.54; 95% CI, 0.44-0.67; I2=4%);
  • Olanzapine (CVR, 0.59; 95% CI, 0.44-0.67; I2=47%);
  • Ziprasidone (CVR, 0.61; 95% CI, 0.53-0.71; I2=0%);
  • Lithium (CVR, 0.63; 95% CI, 0.52-0.76; I2=0%);
  • Quetiapine (CVR, 0.65; 95% CI, 0.48-0.87; I2=2%);
  • Aripiprazole (CVR, 0.68; 95% CI, 0.56-0.84; I2=25%); and
  • Cariprazine (CVR, 0.70; 95% CI, 0.49-0.99; I2=28%).

The medications with significant efficacy for improving manic symptoms compared with placebo are shown:

  • Risperidone (standard mean difference [SMD], 0.64; 95% CI, 0.31-0.97; I2=15%);
  • Haloperidol (SMD, 0.57; 95% CI, 0.29-0.85; I2=64%);
  • Cariprazine (SMD, 0.51; 95% CI, 0.24-0.78; I2=0%);
  • Olanzapine (SMD, 0.44; 95% CI, 0.30-0.58; I2=0%);
  • Lithium (SMD, 0.42; 95% CI, 0.29-0.55; I2=0%);
  • Ziprasidone (SMD, 0.42; 95% CI, 0.26-0.58; I2=0%);
  • Quetiapine (SMD, 0.40; 95% CI, 0.25-0.54; I2=0%);
  • Asenapine (SMD, 0.40; 95% CI, 0.13-0.67; I2=0%); and
  • Aripiprazole (SMD, 0.32; 95% CI, 0.14-0.49; I2=33%).

The medications which had the least variability and highest efficacy compared with placebo, in order, were risperidone, haloperidol, olanzapine, ziprasidone, lithium, quetiapine, aripiprazole, and cariprazine.

The 2 medications that were found to be more acceptable than placebo were ziprasidone (risk ratio [RR], 0.83; 95% CI, 0.70-0.98; I2=0%) and olanzapine (RR, 0.63; 95% CI, 0.49-0.80; I2=35%).

The analysis is limited by the data available for brexpiprazole, eslicarbazepine, and paliperidone.

Study authors conclude, “To the best of our knowledge, this study provides the first empirical examination of the variability in improvement of manic symptoms in participants with acute mania. We demonstrated that 8 antimanic drugs were associated with lower variability and better efficacy than placebo, suggesting that these antimanic drugs were associated with more homogenous and predictable antimanic outcomes in patients with acute mania.”


Hsu T-W, Thompson T, Solmi M, et al. Variability and efficacy in treatment effects on manic symptoms with lithium, anticonvulsants, and antipsychotics in acute bipolar mania: a systematic review and meta-analysis. EClinicalMedicine. 2022;54:101690. doi:10.1016/j.eclinm.2022.101690