Is the antidepressant efficacy of ketamine and esketamine mediated via opioid mechanisms?
European Psychiatry – January 01, 2026
Source: OpenAlex
Summary
Ketamine's antidepressant effects in treatment-resistant depression (TRD) may be influenced by the opioid system, but not in a straightforward way. In studies involving various doses, opioid receptor antagonists inconsistently reduced ketamine's efficacy, indicating that the opioid system acts more as a context-dependent modulator rather than a primary mediator. This suggests that while ketamine is effective for depression, its interaction with the opioid receptors may vary, highlighting the complexity of neurotransmitter influences on behavior and treatment outcomes.
Abstract
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.