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

Ketamine, an NMDA-receptor antagonist, provides rapid anti-depressant 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, has not been previously applied in ketamine research. 116 participants with depression, n=77 who received a ketamine infusion (0.5mg/kg over 40 minutes) and n=39 patients who received saline placebo, completed a validated measure of awe (the AWE-scale) at 40 minutes post-infusion. AWE-scores were examined as potential mediators of depression outcomes (% improvement in Montgomery-Asberg Depression Rating Scale (MADRS) %) at five post-infusion timepoints (24 hours, and 5, 12, 21, and 30 days). Dissociative effects, measured by the Clinician-Administered Disassociation Symptoms Scale (CADSS) scores, were tested in parallel mediation models for comparison. We found that the psychological experience of awe was strongly endorsed by participants during ketamine infusion (but not saline infusion), and there were significant associations between total AWE-score and MADRS improvement (% change) in the ketamine arm at all five time points. Furthermore, at all five time-points total-AWE score statistically mediated the relationship between ketamine and MADRS. By contrast, CADSS scores did not mediate outcomes at any timepoint. 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 anti-depressant effects.