Single-arm meta-analysis of drug response in placebo-controlled versus active-controlled antipsychotic drug trials in schizophrenia

Shimeng Dong; Johannes Schneider-Thoma; Spyridon Siafis; Natalie Peter; Stefan Leucht

doi:10.1016/j.euroneuro.2024.04.007

Single-arm meta-analysis of drug response in placebo-controlled versus active-controlled antipsychotic drug trials in schizophrenia

Eur Neuropsychopharmacol. 2024 Apr 20:84:21-26. doi: 10.1016/j.euroneuro.2024.04.007. Online ahead of print.

Authors

Shimeng Dong¹, Johannes Schneider-Thoma¹, Spyridon Siafis¹, Natalie Peter¹, Stefan Leucht²

Affiliations

¹ Technical University of Munich, Germany, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Germany.
² Technical University of Munich, Germany, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Germany. Electronic address: Stefan.Leucht@tum.de.

PMID: 38643697
DOI: 10.1016/j.euroneuro.2024.04.007

Abstract

Antipsychotic drug efficacy may vary in placebo-controlled and active-controlled trials. The study aims to investigate the performance of antipsychotics in these two different study designs using single-arm meta-analysis. We included randomized controlled trials (RCTs) comparing second-generation antipsychotics with placebo or other antipsychotics from our previous systematic reviews and updated the results with the search on Cochrane Schizophrenia Group register until March 06, 2022. The outcomes were the differences in the change of overall, positive and negative symptoms of schizophrenia, and the difference in study discontinuation between placebo-controlled and head-to-head trials. Random-effects single-arm meta-analysis and subgroup test were conducted to examine the differences in each outcome. A total of 208 RCTs (n = 42,159) were included in the analysis. Of these, 85 trials with 17,056 participants were placebo-controlled, while the remaining were head-to-head trials. Antipsychotics in head-to-head trials demonstrated a significantly greater improvement in overall symptoms (MC -23.58; 95 % CI -25.33, -21.83) compared to antipsychotics in placebo-controlled trials (MC -16.74; 95 % CI -17.80, -15.69; p < 0.0001). Similar findings were observed for positive symptoms, negative symptoms, study discontinuation and sensitivity analyses. Notably, when assessing antipsychotics individually, the same antipsychotic consistently demonstrated superior performance in head-to-head trials compared to placebo-controlled trials. In conclusion, antipsychotics in head-to-head trials presented a considerable efficacy superiority compared to those in placebo-controlled trials. Moreover, the efficacy of the same antipsychotics varied depending on the study design. Future trials should carefully consider the methodology and employ strategies to mitigate the potential for overestimation or underestimation of treatment efficacy.

Keywords: Antipsychotics; Placebo-controlled trial; Schizophrenia.

Publication types

Review