Efficacy of Drugs for Psychosis and Relapse Prevention in Bipolar Depression, Mania

different types of pills scattered
different types of pills scattered
Investigators conducted a meta-regression analysis to determine whether clinical response to active drugs or placebo has a greater effect in trials examining antipsychotics and mood stabilizers.

A meta-regression analysis published in the Journal of Psychopharmacology examined the relative efficacy of active drugs for randomized controlled trials of various bipolar depression and mania monotherapies. The findings of the analysis suggested that the relative efficacy of drugs in bipolar mania trials was influenced by the clinical response rate to the drugs, but for bipolar depression, the relative efficacy of the drugs was influenced by placebo response rate.

Researchers searched PubMed to identify 53 randomized, placebo-controlled trials from 45 publications. Each trial evaluated a single antipsychotic or mood stabilizer for bipolar depression or mania, with adult patients recruited from inpatient and outpatient populations. For trials to be included in the analysis, their clinical response rates needed to reflect a ≥50% reduction of depressive and manic symptoms.

Meta-regression analyses of bipolar mania used data on patients of 44 treatment (n=6234) and 28 placebo (n=3524) groups with a mode trial length of 3 weeks. The relative efficacy of treatment was, overall, positively correlated with the magnitude of clinical response to active drugs (β=1.83; P =.002). Specific analyses of mood stabilizers revealed that clinical response rates, but not placebo response rates, influenced efficacy. However, clinical response rates to antipsychotics showed a significant inverse correlation for both active drugs and placebo.

Bipolar depression trials were typically 8 weeks long, and analyses included data on patients of 32 treatment (n=4999) and 22 placebo (n=2989) groups.

As expected, the relative efficacy of treatment was negatively influenced by placebo response rate, but surprisingly, analyses revealed no influence on efficacy by clinical response to medication.

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The investigators suggested that future trials examining medications for bipolar depression should attempt to reduce heterogeneity of placebo response rates, which ranged from 11.3% to 55.8% in the trials included in this meta-regression analysis.

The investigators cautioned that meta-regression analyses are limited by their observational nature. They also noted that there is incentive for investigators to rate patients as placebo responders in trials in which a treatment appears to be working effectively, thus influencing placebo response rates in successful studies such as the ones included in this analysis. In addition, because trials were selected using only the Montgomery-Åsberg Depression Rating Scale and the Young Mania Rating Scale, analyses of bipolar mania treatments excluded data on ziprasidone and used only limited data on valproate.


Bartoli F, Clerici M, Di Brita C, et al. Effect of clinical response to active drugs and placebo on antipsychotics and mood stabilizers relative efficacy for bipolar depression and mania: A meta-regression analysis [published online January 17, 2017]. J Psychopharmacol. doi:10.1177/0269881117749851