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Randomized Controlled Trial
. 2025 Aug 1;28(8):pyaf056.
doi: 10.1093/ijnp/pyaf056.

Antidepressant efficacy of ketamine plus naltrexone for major depression comorbid with alcohol use disorder: a randomized controlled trial

Gihyun Yoon  1   2 , Brian Pittman  2 , Elizabeth Ralevski  1   2 , Ismene L Petrakis  1   2 , John H Krystal  1   2
Affiliations
Randomized Controlled Trial

Antidepressant efficacy of ketamine plus naltrexone for major depression comorbid with alcohol use disorder: a randomized controlled trial

Gihyun Yoon et al. Int J Neuropsychopharmacol. .

Abstract

Importance: The comorbidity of major depressive disorder (MDD) and alcohol use disorder (AUD) is often treated inadequately. This study evaluated the impact of adding the opioid receptor blocker, naltrexone, to the NMDA glutamate receptor antagonist, ketamine, for the treatment of MDD comorbid with AUD. In so doing, it also attempted to shed light on the contribution of opioid receptor stimulation to the antidepressant effects of ketamine in this population.

Objective: To compare the efficacy of ketamine plus naltrexone to ketamine plus saline and midazolam plus saline for reducing depression and decreasing alcohol consumption in outpatients with comorbid MDD and AUD.

Design, setting, and participants: A 3-arm, randomized, double-blind, parallel-group study was conducted. Participants were 65 adults with current MDD and AUD, with Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 20 or higher and heavy drinking at least 4 times in the month prior to randomization.

Interventions: Randomized (1:1:1) to receive (1) intravenous (IV) ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) plus intramuscular (IM) naltrexone (380 mg), (2) IV ketamine plus IM saline, or (3) IV midazolam (0.045 mg/kg) plus IM saline.

Main outcomes and measures: Co-primary: MADRS; complete alcohol abstinence. Secondary: alcohol craving, anxiety, quality of life, safety.

Results: Of 65 participants, 58 received at least 1 ketamine/midazolam infusion: 20 in ketamine-naltrexone, 19 in ketamine-saline, 19 in midazolam-saline. All groups improved significantly (>80% depression remission). No group differences were observed in MADRS changes during treatment (primary outcome), although antidepressant effects persisted longer in ketamine groups compared to midazolam. There were no significant group differences in alcohol-related outcomes. Ketamine groups showed greater improvement in anxiety and quality of life (secondary outcomes) than midazolam, with the ketamine-naltrexone group showing greater improvement in anxiety than ketamine-saline. No study-related serious adverse events.

Conclusions and relevance: This study found similar antidepressant and anti-alcohol effects across 3 groups. Compared to midazolam, the ketamine groups showed longer-lasting antidepressant effects and greater improvements in anxiety and quality of life. Comparable outcomes between the 2 ketamine groups suggest opioid receptor antagonism did not alter ketamine's therapeutic effects.

Clinical trial registration: The study was registered at ClinicalTrials.gov (Identifier: NCT02461927).

Keywords: alcohol use disorder; clinical trial; ketamine; major depressive disorder; naltrexone; pharmacotherapy.

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Conflict of interest statement

Dr Krystal has served as a consultant for Aptinyx, Inc.; Biogen, Idec, MA; Bionomics, Limited (Australia); Boehringer Ingelheim International; Clearmind Medicine, Inc.; Cybin IRL (Ireland Limited Company); Enveric Biosciences; Epiodyne, Inc.; EpiVario, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Otsuka America Pharmaceutical, Inc.; Perception Neuroscience, Inc.; Praxis Precision Medicines, Inc.; Spring Care, Inc.; Sunovion Pharmaceuticals, Inc. Dr Krystal has served as a scientific advisory board member for: Biohaven Pharmaceuticals; BioXcel Therapeutics, Inc. (Clinical Advisory Board); Cerevel Therapeutics, LLC; Delix Therapeutics, Inc.; Eisai, Inc.; EpiVario, Inc.; Freedom Biosciences, Inc.; Jazz Pharmaceuticals, Inc.; Neumora Therapeutics, Inc.; Neurocrine Biosciences, Inc.; Novartis Pharmaceuticals Corporation; Praxis Precision Medicines, Inc.; PsychoGenics, Inc.; Tempero Bio, Inc.; Terran Biosciences, Inc. In the past 3 years, Dr Krystal has the following patents with John Krystal, Godfrey Pearlson, Stephanie O’Malley, Marc Potenza, Fabrizio Gasparini, Baltazar Gomez-Mancilla, and Vincent Malaterre: Mavoglurant in treating gambling and gaming disorders. He is an inventor on patents licensed by Yale University to Janssen Pharmaceuticals, Biohaven Pharmaceuticals, Spring Health, Freedom Biosciences, and Novartis Pharmaceuticals. Dr Krystal has stock or stock options from Biohaven Pharmaceuticals, Catego Therapeutics, Clearmind Medicine, Inc., Damona Pharmaceuticals, EpiVario, Inc., Freedom Biosciences, Neumora Therapeutics, Rest Therapeutics, Spring Health, Tempero Bio, Inc., Terran Biosciences, and Tetricus, Inc. Other authors declare no conflict of interest to report.

References

    1. Griswold MG, Fullman N, Hawley C, et al. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2018;392:1015-1035. - PMC - PubMed
    1. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547. - PMC - PubMed
    1. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the epidemiologic catchment area (ECA) study. JAMA. 1990;264:2511-2518. - PubMed
    1. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54:313-321. - PubMed
    1. Rounsaville BJ, Dolinsky ZS, Babor TF, Meyer RE. Psychopathology as a predictor of treatment outcome in alcoholics. Arch Gen Psychiatry. 1987;44:505-513. - PubMed

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