μ-Opioid antagonist naltrexone partially abolishes the antidepressant placebo effect and reduces OFC encoding of reinforcement.

Abstract Background Like placebo analgesia, the antidepressant placebo effect appears to involve cortical and subcortical endogenous opioid signaling, yet the mechanism through which opioid release impacts mood remains unclear. The orbitofrontal cortex (OFC) – which integrates various attributes of a stimulus to predict associated outcomes – has been implicated in placebo effects and is rich in μ-opioid receptors. We hypothesized that naltrexone blockade of μ-opioid receptors would blunt OFC-dependent antidepressant placebo effects. Methods Twenty psychotropic-free patients with Major Depressive Disorder (MDD) completed a randomized, double-blind, placebo-controlled, crossover study of one oral dose of 50mg of naltrexone or matching placebo immediately before completing two sessions of the Antidepressant Placebo fMRI Task. This task manipulates placebo-associated expectancies and their reinforcement while assessing expected and actual mood improvement. Results Behaviorally, manipulations of antidepressant placebo expectancies and their reinforcement had positive, interactive effects on participants’ expectancy and mood ratings. The high expectancy condition recruited the dorsolateral and ventrolateral prefrontal cortex (dl/vlPFC), as well as dorsal attention stream regions. Interestingly, increased dl/vlPFC brain responses appeared to attenuate the antidepressant placebo effect. The administration of one oral dose of naltrexone, compared to placebo, partially abolished the interaction of the expectancy and reinforcement manipulation on mood and blocked reinforcement-induced responses in the right central OFC (cOFC). Conclusions Our results show preliminary evidence for the role of μ-opioid cOFC modulation in antidepressant placebo effects by positively biasing the value of placebo based on reinforcement and enhancing subsequent hedonic experiences.