Is the antidepressant efficacy of ketamine and esketamine mediated via opioid mechanisms?

Background Ketamine and esketamine produce rapid and sustained antidepressant effects in persons with treatment-resistant depression (TRD). Although it is posited that these effects are largely attributed to N-methyl-D-aspartate receptor antagonism, the potential involvement of the opioid system remains unclear. This systematic review investigates whether ketamine and esketamine antidepressant efficacy is mediated through the opioid system. Methods We conducted a systematic search of preclinical and clinical studies investigating the potential involvement of the opioid system in the antidepressant effects of ketamine and esketamine. Database searches on PubMed, Cochrane Library, Embase and PsycINFO occurred from inception to September 27, 2025. Results 16 studies were identified: 12 clinical (n = 790) and 4 preclinical studies. Clinical designs included randomized controlled trials, case reports, pre-post studies and observational cohort studies. Preclinical studies utilized animal models of depression. Only one study examined esketamine. Naltrexone (nonselective opioid antagonist) attenuated ketamine’s effects in three studies, while four reported no such effect and one reported mixed evidence. Genetic markers of opioid receptor subtypes (i.e., OPRM1 and OPRD1) were examined in three studies, but results were inconclusive, potentially due to limited evidence. Separately, opioid use was not associated with ketamine response. Few studies directly examined opioid receptor subtypes. Conclusions The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine’s antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.