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

Abstract

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. CLINICALTRIALS.

Gov identifier: NCT01919216; Trial name: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms, URL: https://ichgcp.net/clinical-trials-registry/NCT01919216.

Keywords: Antidepressants; Clinical trials; Outcome expectancy; Pharmacotherapy; Placebo effect.

Conflict of interest statement

Conflict of interest

Drs. Zilcha-Mano and Rutherford had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Rutherford, Zilcha-Mano, Wager, Peterson, Wang, Wall, Brown, Roose, and Chen have no disclosure or conflict of interest to report. This paper has not been previously presented.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Masked emotional face task.

In this task, participants viewed N=30 sad, fearful, happy, or neutral faces for 33ms followed by a 160ms presentation of a neutral face. Using this masking technique, subjects were only consciously aware of the second, neutral face. Participants then rated the valence and arousal of the neutral face on an affective circumplex grid.

Figure 2.

Within- and Between-group neural activation maps for the sad vs. neutral face contrast. Panels a-b present Scan 1, Scan 2, and their difference (Scan 2 – Scan 1) for the Open and Placebo-controlled groups, respectively. Panel c presents the between-group difference in neural activation change from Scan 1 to Scan 2.

Figure 3.

Within- and Between-group neural activation maps for the sad vs. neutral face contrast. To the left is depicted the amygdala region-of-interest, and the panels moving left to right depict within- and between-group change in neural activation from pre- to post-randomization.