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.
Published by Oxford University Press on behalf of the CINP 2025.