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Cited by 519Treatment of Major DepressionElectroconvulsive Therapy StudiesTryptophan and brain disorders

Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism

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Williams, Nolan R., Heifets, Boris D., Blasey, Christine, Sudheimer, Keith, Pannu, Jaspreet, Pankow, Heather, Hawkins, Jessica, Birnbaum, Justin +3 more·2018·American Journal of Psychiatry
DOI 10.1176/appi.ajp.2018.18020138PMC PMC6395554
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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.

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  • Naloxone did not block dissociative experiences linked to ketamine administration in double-blind crossover work.

    “recent double-blind crossover work demonstrated naloxone did not block the dissociative experiences linked to administration of the dissociogenic drug ketamine [122].”

    From Treatment of dissociative identity disorder: leveraging neurobiology to optimize success (2024) · cites this paper as [122]

    The Introduction and Methods > Design describe a randomized, double-blind crossover study using naltrexone, not naloxone, before ketamine. The Results > Dissociation and Discussion report that naltrexone did not significantly reduce ketamine-induced dissociation. Although the Abstract > Results uses “naloxone” in two places, its conclusion also identifies the antagonist as naltrexone. (LLM, conf=0.88)

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  • In patients with treatment-resistant depression (n=12), the opioid receptor antagonist naltrexone at 50 mg attenuated the antidepressant effects of ketamine at 0.5 mg/kg intravenously over 40 minutes one to three days after treatment, as measured by the Hamilton Depression Rating Scale 6-item and 17-item.

    “the opioid receptor antagonist naltrexone (50 mg) attenuated the antidepressant effects of ketamine (0.5 mg/kg i.v. over 40 minutes) one to three days post-treatment as measured by the Hamilton Depression Rating Scale 6 item and 17 item.”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Williams et al., 2018

  • It has been proposed that ketamine's anti-suicidal and antidepressant effects may depend on activation of the opioid system, since pre-treatment with naltrexone attenuated these effects in depressed patients.

    “It has been proposed that ketamine’s anti-suicidal and antidepressant effects may depend on activation of the opioid system, since pre-treatment with naltrexone (an opioid receptor antagonist) attenuated these effects in depressed patients.128,129”

    From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [129]

  • Animal and human evidence indicates the opioid system is required-though not enough by itself-for ketamine's antidepressant action.

    “For instance, preclinical and clinical studies suggest that the opioid system is necessary (although not sufficient) for ketamine’s antidepressant effects, raising possible concerns about addiction and abuse potential [117, 118].”

    From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [118]

  • Both opioid receptor signaling and glutamate transmission appear essential, though not independently sufficient, to induce ketamine's antidepressant action.

    “Both systems appear essential, though not independently sufficient, to induce ketamine’s AD action [81,82,83].”

    From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [83]

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Research works printed but not linked: 2

  1. [47]Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. Am J Psychiatry. 2016; 173(5): 491– 8. 26684923
  2. [73]Pacheco DdF Lima Romero TR, Gama Duarte ID. Central antinociception induced by ketamine is mediated by endogenous opioids and mu- and delta-opioid receptors. Brain Research. 2014; 1562: 69– 75. 24675031

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Authors
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.
Affiliations
  • Palo Alto University (US)
  • From the Department of Psychiatry and Behavioral Sciences and the Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, Calif.; the Department of Psychology, Palo Alto University, Palo Alto, Calif.; and the VA Palo Alto Health Care System, Palo Alto, Calif.
Corresponding author
  • Williams, Nolan R.
  • Schatzberg, Alan F.
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2018-12-01
Volume
175
Issue
12
Pages
1205-1215
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.2018.18020138
PMC
PMC6395554
OpenAlex
W2889166554
Cited by
519
References
121
Citations by year
2026: 56 · 2025: 62 · 2024: 59 · 2023: 54 · 2022: 59 · 2021: 68 · 2020: 86 · 2019: 65 · 2018: 9
FWCI
36.79
Type
journal article
Language
en
Open access
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR001085)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
ketamine, naltrexone, opioid antagonism, antidepressant effects, dissociative effects, treatment-resistant depression, NMDA receptor antagonism
MeSH terms
Adult, Antidepressive Agents, Double-Blind Method, Drug Administration Schedule, Female, Humans, Ketamine, Male, Naltrexone, Narcotic Antagonists, Psychiatric Status Rating Scales, Cross-Over Studies, Depressive Disorder, Treatment-Resistant

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