Neural mechanisms of expectancy-based placebo effects in antidepressant clinical trials

Sigal Zilcha-Mano, Zhishun Wang, Bradley S. Peterson, Melanie M. Wall, Ying Chen, Tor D. Wager, Patrick J. Brown, Steven P. Roose, Bret R. Rutherford

Research output: Contribution to journalArticlepeer-review


Background: Patient expectancy of therapeutic improvement is a primary mediator of placebo effects in antidepressant clinical trials, but its mechanisms are poorly understood. This study employed a novel antidepressant trial design, with integrated functional magnetic resonance imaging (fMRI), to manipulate patient outcome expectancy and examine its neural mediators. Method: Twenty-three depressed outpatients, in a randomized controlled trial were assigned to either Open (high outcome expectancy) or Placebo-controlled (low outcome expectancy) treatment with citalopram for eight weeks. fMRI scans were acquired before and after the expectancy manipulation (before medication treatment), while participants performed a masked emotional face task. Focusing on an amygdala region-of-interest (ROI), we tested a model where reduction in amygdala activation mediated outcome expectancy effects on the slope of change in depressive symptoms. Results: Following the manipulation, significant differences between conditions were found in neural activation changes in the amygdala, as well as in superior temporal gyrus, insula, and thalamus. Findings support the proposed mediation model according to which activation in the left amygdala ROI decreased significantly in the Open as opposed to the Placebo-controlled group following randomization (p = 0.009) for sad vs. neutral face contrast. The reduced left amygdala activation, in turn, was a significant predictor of decreased depressive symptoms during the trial (p = 0.007), and the mediation model was significant. Conclusions: Results from this study, the first designed to identify the neural mechanisms of expectancy augmentation in an antidepressant randomized control trial, suggest that therapeutic modulation of amygdala activity may be an important pathway by which patient outcome expectancy influences depressive symptoms. identifier: NCT01919216; Trial name: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms, URL:

Original languageEnglish
Pages (from-to)19-25
Number of pages7
JournalJournal of Psychiatric Research
StatePublished - Sep 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Ltd


  • Antidepressants
  • Clinical trials
  • Outcome expectancy
  • Pharmacotherapy
  • Placebo effect

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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