Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism

Abstract

Objective: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.

Method: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.

Results: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone 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.

Conclusions: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

Trial registration: ClinicalTrials.gov NCT02911597.

Keywords: Depression; Ketamine; Opioid.

Figure 1.

CONSORT Diagram of participants in a Study of Ketamine’s Antidepressant Effect after Naltrexone Pretreatment

Figure 2.. Naltrexone pretreatment blocks ketamine’s antidepressant effect, but not dissociative symptoms.

Time-course of primary outcome measures (mean ± SD) for ketamine-responsive TRD patients (n=7) in two crossed over conditions, ketamine + naltrexone (K+N) and ketamine + placebo (K+P). Treatments delivered on Day 0 following first questionnaire. A. Left, HDRS6 time-course. Analysis of between-group HDRS6 differences on Day 1 shows that K+N group scores were significantly higher than K+P group scores, with the latter group demonstrating expected post-infusion HDRS6 score reduction. Right, Box and whisker plot illustrating the distribution of the Day 0-to-Day 1 score changes for HDRS6 in each treatment condition in ketamine responders. (Horizontal line, median; “+”, mean; box, 25–75^th percentile; whiskers, minimum-maximum score). B. Left, HDRS17 time-course, demonstrating qualitatively similar results as in A. Right, Box and whisker plot for distribution of Day 0-to-Day 1 score changes for HDRS17 in each treatment condition, as in A. C. Time course of the secondary outcome measure, CADSS score, on day of infusion. Peak CADSS scores immediately following infusion (+40 minutes) did not differ between groups.

Figure 3.. Time-course of HDRS6 and HDRS17 in an alternate patient grouping consistently demonstrates naltrexone block of ketamine’s antidepressant effect.

A. Left, HDRS6 time-course (mean ± SD) in all patients who received both infusions in the crossed over design (N=12), including N=5 patients who did not meet the ketamine responsive criterion required for inclusion in our primary outcome analysis. A. Left, HDRS6 time-course. The difference between K+N versus K+P group scores on Day 1 after infusion is maintained with inclusion of ketamine non-responders in the cross-over analysis. Right, Box and whisker plot of the Day 0-to-Day 1 score changes for HDRS6 in each treatment condition for all crossed-over patients. (Horizontal line, median; “+”, mean; box, 25–75^th percentile; whiskers, minimummaximum score). B. Left, HDRS17 time-course, demonstrating qualitatively similar results as in A. Right, Box and whisker plot for distribution of Day 0-to-Day 1 score changes for HDRS17 in each treatment condition, as in A.