02. Ketamine Mechanism

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For our next Quick Take, let’s take up the question, how does ketamine work in terms of its antidepressant effect? Up until now, the leading hypothesis as to that mechanism was that they had an antagonistic effect on the NMDA receptor. But since ketamine is also known to have effects on other neurotransmitters, the question was still somewhat open. A Stanford University team conducted what amounts to a simple trial, even though doing it was surely quite complex, looking at the opioid system and if it’s possible that the opioid system is playing a role in ketamine’s antidepressant effect. If we block the opioid system with naltrexone, then we should see no antidepressant effect from the ketamine. 

Sure enough, that’s exactly how this study played out. Patients were randomized to get naltrexone or placebo before they got their standard ketamine treatment with 0.5 mg/kg. In the people who got pretreatment naltrexone, there was almost no effect of the ketamine. Interestingly, the depression scores for the no-naltrexone group—the ones that actually got ketamine unblocked—were still significantly different from the naltrexone group even 2 weeks after, although at that point, both groups were trending up toward their pretreatment depression scores again. 

The conclusion here, as the authors say, favor the interpretation that ketamine produces its acute antidepressant response primarily through actions at the opioid receptors. That’s almost a left turn in terms of what the mechanism of action is. I think it increases our caution that, before we get carried away with enthusiasm for ketamine, we need to make sure we’re not creating a new way to hook patients on opiates or opiate-like compounds, compounds that have an opiate-like effect. This study, I think, just adds to the basis for maintaining caution about this emerging potential treatment.

Abstract

Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism

Nolan R Williams, Boris D Heifets, Christine Blasey, Keith Sudheimer, Jaspreet Pannu, Heather Pankow, Jessica Hawkins, Justin Birnbaum, David M Lyons, Carolyn I Rodriguez, Alan F Schatzberg

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.

Reference

Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., & Schatzberg, A. F. (2018). Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. American Journal of Psychiatry, 175(12), 1205-1215