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Growing placebo response in TMS treatment for depression: a meta-analysis of 27-year randomized sham-controlled trials

Nature Mental Health volume 1, pages 792–809 (2023)Cite this article

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Abstract

This meta-analysis investigated placebo responses in repetitive transcranial magnetic stimulation treatment for depression, an area with limited systematic analysis. The initial literature search yielded 2,783 relevant records from the past 27 years, leading to the analysis of 52 randomized controlled trials encompassing 54 placebo arms with 2,122 sham participants. Placebo responses were large (d = 1.016) and increasing yearly (Z = 2.18, P = 0.029), irrespective of sham methods, assessment scales or age. Nevertheless, the trial location, number of sites, sample size, sponsor, sex ratio, study quality and medication status had an influence on the active or sham effect and consequently the outcome. Notably, the placebo and active effects increased in parallel (rs = 0.738, P < 0.001), resulting in a time-independent trial outcome. These findings reveal significant placebo responses from 1996 to 2022 but with minimal impact on the trial outcomes, as placebo and active effects demonstrated parallel growth. These results could inform the design of further clinical trials, especially for repetitive transcranial magnetic stimulation in the treatment of depression.

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Fig. 1
Fig. 2: Forest plot showing the placebo response in control groups of TMS studies.
Fig. 3: Regression of effect size (d) and selected variables.

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Data availability

The meta-analysis is registered on the INPLASY database (INPLASY2022120103) and details can be found at https://inplasy.com/inplasy-2022-12-0103/. All data related to this study are available on the Open Science Framework (OSF) data repository89 at https://osf.io/gczab/?view_only=62c182373b6a49bb89c7fb31c4dfee28.

Code availability

The code used in the current study is publicly available at the OSF repository89 (https://osf.io/gczab/?view_only=62c182373b6a49bb89c7fb31c4dfee28).

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Acknowledgments

This study was funded by STI2030-Major Projects (2021ZD0203900), Natural Science Foundation of China (NSFC) grant (32241015, T.-F.Y.; 32071054, Y.T.), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181715, T.-F.Y.), the Science and Technology Commission of Shanghai Municipality (23XD1423000 and 23ZR1480800, T.-F.Y.) and the Shanghai Municipal Commission of Health (2022JC016, T.-F.Y.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yangting Xu, Di Zhao & Ti-Fei Yuan

  2. Xiangya School of Medicine, Central South University, Changsha, China

    Yangting Xu & Yuhan Zhang

  3. Graduate School of Peking Union Medical College, Department of Anesthesiology, Beijing Hospital, Beijing, China

    Yuhan Zhang

  4. Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China

    Yanghua Tian

  5. Department of Psychology and Sleep Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China

    Yanghua Tian

  6. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

    Ti-Fei Yuan

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Contributions

T.-F.Y. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. T.-F.Y., Y.T. and Y.X. were responsible for the concept and design. All authors carried out the acquisition, analysis or interpretation of data. Y.X., Y.Z. and D.Z. drafted the paper. D.Z., T.-F.Y. and Y.T. were responsible for critical revision of the paper for important intellectual content. Y.X. and Y.Z. carried out the statistical analysis. T.-F.Y. obtained the funding and provided administrative, technical or material support. Supervision was by T.-F.Y. and Y.T.

Corresponding authors

Correspondence to Yanghua Tian or Ti-Fei Yuan.

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Nature Mental Health thanks Sujit K. Kar, Tyler Kaster and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Xu, Y., Zhang, Y., Zhao, D. et al. Growing placebo response in TMS treatment for depression: a meta-analysis of 27-year randomized sham-controlled trials. Nat. Mental Health 1, 792–809 (2023). https://doi.org/10.1038/s44220-023-00118-9

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