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When does the placebo effect have an impact on network meta-analysis results?
  1. Adriani Nikolakopoulou1,
  2. Anna Chaimani2,
  3. Toshi A Furukawa3,
  4. Theodoros Papakonstantinou1,
  5. Gerta Rücker1,
  6. Guido Schwarzer1
  1. 1Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  2. 2Centre of Research in Epidemiology and Statistics (CRESS-U1153), Inserm, Université Paris Cité, Paris, France
  3. 3Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
  1. Correspondence to Adriani Nikolakopoulou, University of Freiburg Faculty of Medicine, Freiburg 79110, Baden-Württemberg, Germany; adriani.nikolakopoulou{at}


The placebo effect is the ‘effect of the simulation of treatment that occurs due to a participant’s belief or expectation that a treatment is effective’. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.

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Data are available upon reasonable request. Data and code are available upon reasonable request.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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Data availability statement

Data are available upon reasonable request. Data and code are available upon reasonable request.

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  • Contributors AN perceived the idea and planned the research. AN, AC, TAF, TP, GR and GS contributed to the design of the work. TAF contributed to the acquisition of the data, AN did the analysis, AC, TP, GR and GS provided feedback on the analysis and all authors contributed to the interpretation of the results. AN drafted the manuscript and AC, TAF, TP, GR and GS reviewed and commented on drafts and on the final version of the manuscript. AN will act as guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding This work has been supported by a personal fellowship to AN by the Swiss National Science Foundation (SNSF) Grant No. P400PM_186723.

  • Competing interests TAF reports personal fees from Boehringer Ingelheim, DT Axis, Kyoto University Original, Shionogi and SONY, and a grant from Shionogi, outside the submitted work. In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi Tanabe.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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