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Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.

Luke A. Jelen, David J Lythgoe, James Stone, Allan H. Young, Mitul A. Mehta

Nature Medicine July 24, 2025 DOI: 10.1038/s41591-025-03800-w (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Double-blind crossover study Randomized Peer reviewed
Sample size 26
Population Adults with major depressive disorder
Interventions Naltrexone Ketamine
Dose 50 mg naltrexone, 0.5 mg per kg ketamine
Topics Ketamine Depression Esketamine
Keywords Depression treatment Opioid system Mechanism of action
Citations 29
Registration NCT04977674
Key points Naltrexone attenuated the ketamine-induced increase in glutamatergic activity in the anterior cingulate cortex and reduced the antidepressant effect on day 1, indicating the opioid system modulates ketamine's acute and sustained effects.

Abstract

We investigated the potential role of the opioid system in modulating glutamatergic effects of ketamine administration in major depressive disorder. Twenty-six adults with major depressive disorder participated in a double-blind crossover study, receiving oral placebo or 50 mg naltrexone before an intravenous infusion of 0.5 mg per kg ketamine. Brain glutamatergic activity in the anterior cingulate cortex was measured using functional magnetic resonance spectroscopy and depressive symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale. Naltrexone attenuated the increase in glutamate + glutamine to total N-acetylaspartate ratio during ketamine infusion compared to placebo (F1,253 = 4.83, P = 0.029) and also attenuated the reduction in Montgomery-Åsberg Depression Rating Scale scores on day 1 (condition-by-time interaction, F1,74 = 5.39, P = 0.023). These findings demonstrate that the opioid system modulates the acute response to ketamine and subsequent antidepressant effects. Interactions between the glutamate and opioid systems may have implications for the development of new depression treatment strategies. ClinicalTrials.gov registration: NCT04977674 .

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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