Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults

Sigal Zilcha-Mano, Meredith L. Wallace, Patrick J. Brown, Joel Sneed, Steven P. Roose, Bret R. Rutherford

Research output: Contribution to journalArticlepeer-review


Depressed patients’ expectations of improvement drive placebo effects in antidepressant clinical trials, yet there is considerable heterogeneity in the magnitude of expectancy effects. The present study seeks to identify those individuals who benefit most from expectancy effects using baseline neuroimaging and cognitive measures. Older adult outpatients diagnosed with major depressive disorder (MDD) participated in a prospective, 8-week clinical trial in which expectancy was experimentally manipulated and its effects on depression outcome measured. Based on the literature, we selected a priori 12 cognitive and brain-based variables linked to depression and expectancy, together with demographic variables, and incorporated them into a combined moderator. The combined moderator was developed as a weighted combination of the individual moderators, and was used to identify individuals who benefited most from expectancy effects. The combined moderator was found to predict differential change in depression severity scores between the high- vs. low-expectancy groups with a medium-size effect (Spearman effect size: 0.28). While at the sample level no expectancy effect was found, the combined moderator divided older adults with MDD into those who did and those who did not improve as the result of expectancy manipulation, with those benefiting from the manipulation showing greater processing speed, executive function, and frontostriatal white matter tract integrity. The findings suggest that it is possible to identify a subgroup of older adult individuals with MDD for whom expectancy manipulation results in greater antidepressant treatment response, supporting a precision medicine approach. This subgroup is characterized by distinct cognitive dysfunction and neuroimaging impairments profiles.

Original languageEnglish
Article number475
Pages (from-to)475
JournalTranslational Psychiatry
Issue number1
StatePublished - 15 Sep 2021

Bibliographical note

Funding Information:
We are thankful for the helpful feedback by Dr. Helena Kraemer on the statistical analyses. This study was funded by NIMH R01 MH102293 (to Dr. Rutherford). Work on this paper was supported by The U.S.-Israel Binational Science Foundation (BSF) grant 2017263 (to Dr. Zilcha-Mano).

Funding Information:
Drs. Zilcha-Mano and Rutherford 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. Drs. Zilcha-Mano, Brown, Sneed, Rutherford, and Roose have no disclosures or conflicts of interest to report. Dr. Wallace receives statistical consulting fees from Noctem and grant funding from the National Institute on Aging, both unrelated to this work. This paper has not been previously presented.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry


Dive into the research topics of 'Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults'. Together they form a unique fingerprint.

Cite this