Study of Naltrexone-Induced Blockade of Antidepressant Effects
Condition: Depression; Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      The goal of this study is to determine whether antidepressant placebo effects and contextual
      cues broadly, can be blocked by one single dose of the µ-opioid antagonist naltrexone. To
      test this hypothesis, 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.
    

Detailed description: 
      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.
    

Intervention name(s): Naltrexone 50 Mg Oral Tablet; Placebo oral tablet
Intervention type(s): Drug; Drug
Intervention description(s): Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).; Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.
Intervention MeSH terms: Naltrexone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a pharmaco-fMRI study of one single dose of naltrexone or placebo followed by an fMRI session in a crossover design.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science