Prefrontal expectancy and reinforcement-driven antidepressant placebo effects

Placebo responses in depression exemplify how expectancies and appraisals impact mood. Cognitive and neural mechanisms underlying these responses are still poorly understood, partly due to the difficulty of simulating antidepressant effects and manipulating mood experimentally. To address these challenges, we developed an acute antidepressant placebo experiment involving the intravenous administration of a "fast-acting antidepressant" and a trial-by-trial sham fMRI "neurofeedback" manipulation, purporting to reveal mood-relevant neural responses. Twenty volunteers with major depression underwent this experiment while rating their expected and actual mood improvement. Mixed-effects analyses of trial-by-trial ratings revealed that the "drug" infusion cues induced higher expectancies of mood improvement, while both the "drug" infusion cue and the sham neurofeedback induced a reported mood improvement. Neurofeedback of greater magnitude, compared to lower magnitude, recruited the lateral prefrontal cortex (lPFC). Individuals with greater lPFC responses to neurofeedback displayed: (1) greater effect of previous mood improvement on expectancy ratings and (2) greater effect of sham neurofeedback on mood improvement. Behavioral antidepressant placebo effects were additionally moderated by changes in peripheral β-endorphin plasma levels and depressive symptomatology. These data demonstrate the feasibility of trial-by-trial manipulation of antidepressant placebo-associated expectancies and their reinforcement. We provide initial insights into the role of the lPFC in the interplay between placebo-induced expectancies and mood, as well as preliminary evidence for the role of the opioid system in antidepressant placebo effects.