Placebo—To be or not to be? Are there really alternatives to placebo-controlled trials?

Fas Jacob Krol, Michal Hagin, Eduard Vieta, Rephael Harazi, Amit Lotan, Rael D. Strous, Bernard Lerer, Dina Popovic*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalEuropean Neuropsychopharmacology
StatePublished - Mar 2020


  • Controlled clinical trials
  • Non-inferiority trial
  • Placebo
  • Placebo-controlled trial
  • Superiority trial
  • Trial design


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