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Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms

Molecular Psychiatry volume 27, pages 1658–1666 (2022)Cite this article

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Abstract

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = −41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = −8, y = 18, z = −15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = −5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

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Fig. 1: Flowchart outlining selection of placebo effects neuroimaging studies.
Fig. 2: Map of brain activations and deactivations associated with placebo effects.
Fig. 3: Placebo effects and depression treatment.
Fig. 4: Implications of shared therapeutic mechanisms.

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Acknowledgements

This study was supported by funding from the Liu Fu Yu Charity Foundation and Sidney R. Baer, Jr. Foundation.

Author information

Author notes

  1. These authors contributed equally: Matthew J. Burke, Sara M. Romanella.

Authors and Affiliations

  1. Neuropsychiatry Program, Department of Psychiatry and Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Matthew J. Burke

  2. Harquail Centre for Neuromodulation and Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

    Matthew J. Burke & Rachel Greben

  3. Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Matthew J. Burke, Sara M. Romanella, Lucia Mencarelli, Michael D. Fox & Emiliano Santarnecchi

  4. Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, Neurology and Clinical Neurophysiology Section, University of Siena, Siena, Italy

    Sara M. Romanella & Lucia Mencarelli

  5. Center for Brain Circuit Therapeutics, Departments of Neurology, Psychiatry, and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Michael D. Fox

  6. Athinoula A. Martinos Centre for Biomedical Imaging, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Michael D. Fox

  7. Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Ted J. Kaptchuk

  8. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Alvaro Pascual-Leone

  9. Hinda and Arthur Marcus Institute for Aging Research and Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA

    Alvaro Pascual-Leone

  10. Guttmann Brain Health Institut, Guttmann Institut, Universitat Autonoma, Barcelona, Spain

    Alvaro Pascual-Leone

  11. Precision Neuroscience & Neuromodulation Program, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Emiliano Santarnecchi

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Contributions

Concept and Design: MB, ES, APL, TJK, MDF. Data collection and processing: SR, RG, LM. Statistical analysis: SR, LM, ES. Drafting of the manuscript: MB, SR, ES. Critical revision of the manuscript: MDF, APL, TJK.

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Correspondence to Matthew J. Burke or Emiliano Santarnecchi.

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Competing interests

MJB has nothing to disclose. ES has nothing to disclose. SR has nothing to disclose. LM has nothing to disclose. RG has nothing to disclose. APL has nothing to disclose. TK has nothing to disclose. MDF has intellectual property on using connectivity imaging to guide brain stimulation but receives no royalties.

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Burke, M.J., Romanella, S.M., Mencarelli, L. et al. Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms. Mol Psychiatry 27, 1658–1666 (2022). https://doi.org/10.1038/s41380-021-01397-3

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