Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403–18. https://doi.org/10.1038/nrn3976.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Kaptchuk TJ, Hemond CC, Miller FG. Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice. Bmj Published online July. 2020;20:m1668 https://doi.org/10.1136/bmj.m1668.

    Article  Google Scholar 

  3. Colloca L, Barsky AJ. Placebo and nocebo effects. N Engl J Med. 2020;382:554–61.

    CAS  Article  PubMed  Google Scholar 

  4. Amanzio M, Benedetti F, Porro CA, Palermo S, Cauda F Activation likelihood estimation meta‐analysis of brain correlates of placebo analgesia in human experimental pain. Hum Brain Mapp. 2013;34.

  5. Kaptchuk TJ, Miller FG Placebo effects in medicine. N Engl J Med. 2015;373.

  6. Marchant J. Strong placebo response thwarts painkiller trials. Potential pain treatments are struggling to prove their worth over a rising placebo effect seen in US trials. Nature 2015;6:6.

    Google Scholar 

  7. Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: mediators and moderators. Lancet Psychiatry. 2015;2:246–57. https://doi.org/10.1016/S2215-0366(14)00092-3.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287:1840–1847. https://doi.org/10.1001/jama.287.14.1840.

    Article  PubMed  Google Scholar 

  9. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry. 2002;159:728–37. https://doi.org/10.1176/appi.ajp.159.5.728.

    Article  PubMed  Google Scholar 

  10. Kirsch I The Placebo effect in the treatment of depression and anxiety. Front Psychiatry. 2019;10.

  11. Burke MJ, Kaptchuk TJ, Pascual-Leone A Challenges of differential placebo effects in contemporary medicine: the example of brain stimulation. Ann Neurol. 2019;85.

  12. Yesavage JA, Fairchild JK, Mi Z, Biswas K, Davis-Karim A, Phibbs CS et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75.

  13. Razza LB, Moffa AH, Moreno ML, Carvalho AF, Padberg F, Fregni F, et al. A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:105–13.

    Article  PubMed  Google Scholar 

  14. Eickhoff SB, Bzdok D, Laird AR, Kurth F, Fox PT. Activation Likelihood Estimation meta-analysis revisited. Neuroimage. 2012;59:2349–61. https://doi.org/10.1016/j.neuroimage.2011.09.017

    Article  PubMed  Google Scholar 

  15. Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA. Meta-analysis of the functional neuroanatomy of single-word reading: method and validation. NeuroImage. 2002;16:765–80. https://doi.org/10.1006/nimg.2002.1131

    Article  PubMed  Google Scholar 

  16. Marcus DS, Harwell J, Olsen T, Hodge M, Glasser M, Prior F et al. Informatics and Data mining tools and strategies for the human connectome project. Front Neuroinformatics. 2011;5. https://doi.org/10.3389/fninf.2011.00004

  17. Enck P, Horing B, Broelz E, Weimer K. Knowledge gaps in placebo research: with special reference to neurobiology. Int Rev Neurobiol. 2018;139:85–106. https://doi.org/10.1016/bs.irn.2018.07.018

    Article  PubMed  Google Scholar 

  18. Ashar YK, Chang LJ, Wager TD. Brain mechanisms of the placebo effect: an affective appraisal account. Annu Rev Clin Psychol. 2017;13:73–98. https://doi.org/10.1146/annurev-clinpsy-021815-093015

    Article  PubMed  Google Scholar 

  19. Peciña M, Bohnert ASB, Sikora M, Avery ET, Langenecker SA, Mickey BJ, et al. Association Between placebo-activated neural systems and antidepressant responses: neurochemistry of placebo effects in major depression. JAMA Psychiatry. 2015;72:1087 https://doi.org/10.1001/jamapsychiatry.2015.1335

    Article  Google Scholar 

  20. Burke MJ, Fried PJ, Pascual-Leone A. Transcranial magnetic stimulation: neurophysiological and clinical applications. Handbook of clinical neurology. Elsevier; 2019. p. 73–92.

    Google Scholar 

  21. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol J Int Fed Clin Neurophysiol. 2009;120:2008–39. https://doi.org/10.1016/j.clinph.2009.08.016

    Article  Google Scholar 

  22. Brunoni AR, Chaimani A, Moffa AH, Razza LB, Gattaz WF, Daskalakis ZJ, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74:143–52. https://doi.org/10.1001/jamapsychiatry.2016.3644

    Article  PubMed  Google Scholar 

  23. Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012;72:595–603. https://doi.org/10.1016/j.biopsych.2012.04.028

    Article  PubMed  PubMed Central  Google Scholar 

  24. Siddiqi SH, Taylor SF, Cooke D, Pascual-Leone A, George MS, Fox MD. Distinct symptom-specific treatment targets for circuit-based neuromodulation. Am J Psychiatry. 2020;177:435–46. https://doi.org/10.1176/appi.ajp.2019.19090915

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60. https://doi.org/10.1016/j.neuron.2005.02.014

    CAS  Article  PubMed  Google Scholar 

  26. Weigand A, Horn A, Caballero R, Cooke D, Stern AP, Taylor SF, et al. Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites. Biol Psychiatry. 2018;84:28–37.

    CAS  Article  PubMed  Google Scholar 

  27. Wu GR, Wang X, Baeken C Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression. Hum Brain Mapp. 2020;41.

  28. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–16. https://doi.org/10.1016/j.biopsych.2007.01.018

    Article  PubMed  Google Scholar 

  29. Valkonen-Korhonen M, Leinola H, Könönen M, Niskanen E, Purhonen M, Pakarinen M et al. Bifrontal active and sham rTMS in treatment-resistant unipolar major depression. Nord J Psychiatry. 2018;72.

  30. McCambridge J, Witton J, Elbourne DR. Systematic review of the Hawthorne effect: new concepts are needed to study research participation effects. J Clin Epidemiol. 2014;67:267–77. https://doi.org/10.1016/j.jclinepi.2013.08.015

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shrout PE, Stadler G, Lane SP, McClure MJ, Jackson GL, Clavél FD, et al. Initial elevation bias in subjective reports. Proc Natl Acad Sci. 2018;115:E15–E23. https://doi.org/10.1073/pnas.1712277115

    CAS  Article  PubMed  Google Scholar 

  32. Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Disco. 2013;12:191–204. https://doi.org/10.1038/nrd3923

    CAS  Article  Google Scholar 

  33. Mestre TA, Lang AE, Okun MS Factors influencing the outcome of deep brain stimulation: placebo, nocebo, lessebo, and lesion effects. Mov Disord. 2016;31.

  34. Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry. 2017;4.

  35. Li C-T, Chen M-H, Juan C-H, Huang HH, Chen LF, Hsieh JC, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014;137:2088–98. https://doi.org/10.1093/brain/awu109

    Article  PubMed  Google Scholar 

  36. Brunoni AR, Lopes M, Kaptchuk TJ, Fregni F Placebo response of non-pharmacological and pharmacological trials in major depression: a systematic review and meta-analysis. Hashimoto K, ed. PLoS ONE. 2009;4:e4824. https://doi.org/10.1371/journal.pone.0004824

  37. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry. 2008;53:621–31. https://doi.org/10.1177/070674370805300909

    Article  PubMed  Google Scholar 

  38. Herrington TM, Cheng JJ, Eskandar EN Mechanisms of deep brain stimulation. J Neurophysiol. 2016;115.

  39. Enck P, Zipfel S. Placebo effects in psychotherapy: a framework. Front Psychiatry. 2019;10:456. https://doi.org/10.3389/fpsyt.2019.00456

    Article  PubMed  PubMed Central  Google Scholar 

  40. Erekson DM, Lambert MJ, Eggett DL The relationship between session frequency and psychotherapy outcome in a naturalistic setting. J Consult Clin Psychol. 83:1097–107.

  41. Leuchter AF, Hunter AM, Tartter M, Cook IA. Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. Br J Psychiatry. 2014;205:443–9. https://doi.org/10.1192/bjp.bp.113.140343

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336:999–1003. https://doi.org/10.1136/bmj.39524.439618.25

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lefaucheur J-P, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol J Int Fed Clin Neurophysiol. 2017;128:56–92. https://doi.org/10.1016/j.clinph.2016.10.087

    Article  Google Scholar 

  44. Schambra H, Bikson M, Wager T, DosSantos M, DaSilva A. It’s all in your head: reinforcing the placebo response with tDCS. Brain Stimul. 2014;7:623–624. https://doi.org/10.1016/j.brs.2014.04.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol Off J Int Fed. Clin Neurophysiol. 2000;111:800–805. https://doi.org/10.1016/s1388-2457(99)00323-5

    CAS  Article  PubMed  Google Scholar 

  46. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15:483–506. https://doi.org/10.1016/j.tics.2011.08.003

    Article  PubMed  Google Scholar 

  47. Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G. Prefrontal cortex modulates placebo analgesia. Pain. 2010;148:368–74. https://doi.org/10.1016/j.pain.2009.09.033

    Article  PubMed  Google Scholar 

  48. Benedetti F, Carlino E, Pollo A Hidden administration of drugs. Clin Pharmacol Ther. 2011;90.

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Matthew J. Burke or Emiliano Santarnecchi.

Ethics declarations

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01397-3

Search

Quick links