Study of Naltrexone-Induced Blockade of Antidepressant Effects

Neuroimaging offers a precise and objective way to characterize the neural and molecular basis of the antidepressant response in humans. Furthermore, the combination of neuroimaging with pharmacological manipulations opens the possibility of investigating drug-induced brain changes associated with behavioral responses. In this study, the investigators aimed to whether antidepressant placebo effects and contextual cues broadly can be blocked by one single dose of the µ-opioid antagonist naltrexone. To assess trial by trial manipulation of antidepressant placebo effects inside of the scanner, the investigators have developed and piloted an fMRI task, specifically designed to record and modulate mood improvement using simulated neurofeedback. In a pilot study using this task, patients with MDD who reported acute mood improvement in response to positive neurofeedback, showed increased blood-oxygen-level-dependent (BOLD) responses in the ACC, and in particular, the rostral ACC (rACC), a reliable marker of treatment response in depression, and analgesic effects. In summary, these preliminary studies demonstrate 1) the contribution of the opioid system to the formation of antidepressant effects in MDD; and 2) increased rACC BOLD responses in patients who reported acute mood improvement induced by positive neurofeedback after a fast-acting antidepressant. Still, the opioid modulation of acute mood improvement and rACC BOLD responses in patients with MDD has not been investigated, which justifies the research proposed in this application. Based on this preliminary evidence, The investigators hypothesize that antidepressant effects in patients with Major Depression rely on opioid modulation of rACC activity, and therefore can be partially or totally blocked using the selective µ-opioid antagonist naltrexone.To test this hypothesis, 20 un-medicated, patients with MDD completed a randomized, double-blind, placebo-controlled, cross-over study of 50mg of the µ-opioid antagonist naltrexone or matching placebo, immediately before a Pharmaco-fMRI scanning session. The study aims to: AIM 1: Evaluate the effect of naltrexone on acute mood improvement and rostral anterior cingulate (rACC) BOLD activity induced by positive neurofeedback after a fast-acting antidepressant. The investigators hypothesize that naltrexone-induced blockade of µ-opioid receptors will reverse the acute mood improvement and increased rACC BOLD activity induced by positive neurofeedback. AIM 2: Determine the extent to which individual differences in the rACC BOLD activity induced by positive neurofeedback after a fast-acting antidepressant predict acute mood improvement. The investigators hypothesize that increased rACC BOLD activity induced by positive neurofeedback will be associated with greater acute mood improvement. AIM 3: Define the role of the rACC BOLD activity induced by positive neurofeedback as a mediator of the effect of group (naltrexone versus placebo) in acute mood improvement.