Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression

Background: Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research.

Methods: One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery-Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison.

Results: We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery-Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery-Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point.

Conclusions: Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.