Leucht S, et al. - A meta-analysis was presented of all placebo-controlled trials in patients with acute exacerbations of schizophrenia. In addition, the researchers investigated which trial characteristics have changed over the years and which were moderators of drug-placebo efficacy differences. About twice as many patients improved with antipsychotics as with placebo, however, only a minority experienced a good response. By industry sponsorship and increasing placebo response, effect sizes were reduced, not decreasing drug response. Drug development could benefit from smaller samples but better-selected patients.

• The exploration involved multiple electronic databases.
• For this study, the outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects.
• The physicians examined potential moderators of efficacy by meta-regression.

• A total of 167 double-blind randomized controlled trials were included, with 28,102 mainly chronic participants.
• For overall efficacy, the standardized mean difference (SMD) was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38.
• They observed at least a “minimal” response in 51% of the antipsychotic group vs. 30% in the placebo group, and 23% vs. 14% had a “good” response.
• Positive symptoms (SMD 0.45) improved more compared to negative symptoms (SMD 0.35) and depression (SMD 0.27).
• Even in the short term, quality of life (SMD 0.35) and functioning (SMD 0.34) improved.
• In side effects, antipsychotics differed substantially.
• 16 trial characteristics changed over the decades among the response predictors analyzed.
• However, only industry sponsorship and increasing placebo response were significant moderators of effect sizes in a multivariable meta-regression.
• Over time, drug response remained stable.