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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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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 1205 - 1215
PubMed: 30153752

History

Received: 5 February 2018
Revision received: 8 April 2018
Revision received: 19 May 2018
Revision received: 29 May 2018
Accepted: 4 June 2018
Published online: 29 August 2018
Published in print: December 01, 2018

Keywords

  1. Ketamine
  2. Opioid
  3. Depression

Authors

Details

Nolan R. Williams, M.D. [email protected]
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.
Boris D. Heifets, M.D., Ph.D.
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.
Christine Blasey, Ph.D.
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.
Keith Sudheimer, Ph.D.
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.
Jaspreet Pannu, B.S.
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.
Heather Pankow, B.S.
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.
Jessica Hawkins, B.S.
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.
Justin Birnbaum, M.D.
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.
David M. Lyons, Ph.D.
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.
Carolyn I. Rodriguez, M.D., Ph.D.
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.
Alan F. Schatzberg, M.D. [email protected]
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.

Notes

Address correspondence to Dr. Williams ([email protected]) and Dr. Schatzberg ([email protected]).
Presented at the 73rd Annual Scientific Convention of the Society of Biological Psychiatry, New York, May 10–12, 2018.

Competing Interests

Dr. Rodriguez has served as a consultant for Allergan, BlackThorn Therapeutics, and Rugen Therapeutics. Dr. Schatzberg has received research support from Janssen, and he has served as a consultant for Alkermes, Avanir, Bracket/Clintara, GLG Consulting, Jazz, McKinsey, Neuronetics, Owl, and Sage; he has equity in Corcept, Dermira, Gilead, Incyte Genetics, Intersect, Madrigal, Merck, Seattle Genetics, Titan, and Xhale. The other authors report no financial relationships with commercial interests.

Funding Information

Stanford Clinical and Translational Science Award to Spectrum: NIH UL1 TR 001085
National Alliance for Research on Schizophrenia and Depression10.13039/100009670: Young Investigator
Pritzker Family Fund:
Avy L. and Robert L. Miller Foundation: Miller Award
Supported by the Stanford Clinical and Translational Science Award to Spectrum (NIH UL1 TR 001085) (Drs. Williams and Schatzberg); the 2016 NARSAD Young Investigator Grant program (Dr. Williams); the Brain and Behavior Research Foundation (Dr. Rodriguez); the Avy L. and Roberta L. Miller Foundation (Dr. Williams); and the Pritzker Family Fund (Dr. Schatzberg).

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