Opioid Receptor Antagonism Attenuates Antidepressant Effects of Ketamine

Abstract

Background:

In addition to N-methyl D-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of the study was to determine if opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant and/or dissociative effects.

Methods:

In a proposed double-blind, cross-over study of 30 adults with treatment-resistant depression, we performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: 50mg naltrexone preceding 0.5mg/kg ketamine or placebo preceding 0.5mg/kg ketamine.

Results:

In the interim analysis, 7 of 12 adults with treatment-resistant depression met responder criteria during the ketamine + placebo condition, defined as a ≥50% reduction on the 17-item Hamilton Depression Scale score at Day 1. The subjects’ reductions in Hamilton Depression Rating Scale 6 and 17-item ratings in the ketamine + naloxone condition were significantly lower than the ratings in the ketamine + placebo condition at post-infusion Days 1 and 3. Secondary analysis of all participants completing both placebo and naloxone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.

Discussion:

Ketamine’s acute antidepressant effect appears to require opioid system activation. Dissociative effects of ketamine in humans are not mediated by the opioid system, nor do they appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.