Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.
Nature medicine – July 24, 2025
Source: PubMed
Summary
A key insight reveals that ketamine's rapid antidepressant action might rely on the brain's opioid system. Researchers gave 26 adults with major depression either a placebo or naltrexone before ketamine. Findings showed naltrexone reduced ketamine's effect on brain glutamate activity and its positive impact on depressive symptoms. This discovery highlights the opioid system's crucial role in ketamine's mechanism, offering valuable direction for developing new, more effective depression treatments.
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 .