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

Ketamine infusion strongly induced feelings of awe in people with depression, and these awe experiences consistently predicted and mediated improvements in depression scores over 1 to 30 days, unlike general dissociative effects, which did not mediate outcomes. In a study of 116 participants with depression, 77 received a ketamine infusion and 39 received saline placebo. Awe was measured 40 minutes after infusion, and depression severity was assessed at five time points afterward. Awe scores were significantly higher in the ketamine group and statistically mediated the relationship between ketamine and depression improvement at all time points, suggesting that the awe-inspiring properties of ketamine may contribute to its antidepressant effects.

Study at a glance

Abstract

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. 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. 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. 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.