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

Background: Randomised placebo-controlled trials investigating treatments for bipolar disorder have been hampered by wide variations of active drugs and placebo clinical response rates. It is important to estimate whether the active drug or placebo response has a greater influence in determining the relative efficacy of drugs for psychosis (antipsychotics) and relapse prevention (mood stabilisers) for bipolar depression and mania. Methods: We identified 53 randomised, placebo-controlled trials assessing antipsychotic or mood stabiliser monotherapy (‘active drugs’) for bipolar depression or mania. We carried out random-effects meta-regressions, estimating the influence of active drugs and placebo response rates on treatment relative efficacy. Results: Meta-regressions showed that treatment relative efficacy for bipolar mania was influenced by the magnitude of clinical response to active drugs (p=0.002), but not to placebo (p=0.60). On the other hand, treatment relative efficacy for bipolar depression was influenced by response to placebo (p=0.047), but not to active drugs (p=0.98). Conclusions: Despite several limitations, our unexpected findings showed that antipsychotics / mood stabilisers relative efficacy for bipolar depression seems unrelated to active drugs response rates, depending only on clinical response to placebo. Future research should explore strategies to reduce placebo-related issues in randomised, placebo-controlled trials for bipolar depression.