A historical review of placebo-controlled, relapse prevention trials in schizophrenia: The loss of clinical equipoise

Schizophr Res. 2021 Mar:229:122-131. doi: 10.1016/j.schres.2020.11.022. Epub 2020 Nov 22.


Recent ethical critiques have proposed that placebo-controlled, relapse prevention trials in schizophrenia are no longer justifiable and are therefore unethical. This review provides an historical perspective on the justifications for these trials and how arguments evolved over several decades. We identified 87 placebo-controlled, relapse prevention trials published over the last seventy years and examined the purpose for each trial. We found that first-generation trials had compelling justifications, yet these arguments changed considerably over time. Second-generation trials offered comparatively weaker-and sometimes no-justifications for their conduct. Without clear and compelling justifications for a given trial, it is not ethical to continue using this study design.

Keywords: Antipsychotic; Ethics; History; Placebo; Schizophrenia.

Publication types

  • Review

MeSH terms

  • Antipsychotic Agents* / therapeutic use
  • Humans
  • Randomized Controlled Trials as Topic
  • Recurrence
  • Research Design
  • Schizophrenia* / drug therapy
  • Secondary Prevention


  • Antipsychotic Agents