Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression
This randomised controlled trial (n=116) investigated the psychological mechanisms of ketamine's antidepressant effects. Participants receiving ketamine reported significantly heightened feelings of awe compared to those receiving a placebo. Awe experiences, as measured by the Awe Experience Scale (AWE-S), mediated depression outcomes (% improvement in MADRS scores) at multiple time points (24 hours and 5, 12, 21, and 30 days) post-infusion, indicating a potential role of awe in ketamine's therapeutic efficacy for depression.
Authors
- Aepfelbacher, J.
- Panny, B.
- Price, R.
Published
Abstract
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.
Research Summary of 'Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression'
Introduction
Depression is a major global health burden and many patients do not respond to first-line treatments. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects but these are typically transient and questions remain about how to prolong or amplify clinical benefit. Prior research has emphasised ketamine's molecular and circuit-level actions, whereas acute psychological effects—often labelled dissociative—have been treated as side effects and measured with instruments such as the Clinician-Administered Dissociative States Scale (CADSS). The authors note that CADSS may not sensitively capture the full range of ketamine's subjective effects and that more specific psychological constructs might help explain clinical outcomes. Aepfelbacher and colleagues therefore tested whether the acute subjective experience of awe, measured with the Awe Experience Scale (AWE-S), occurs during a ketamine infusion and whether it relates to antidepressant response. Using data from a randomised controlled trial of a single 0.5 mg/kg ketamine infusion versus saline, the study asked three primary questions: does ketamine induce awe relative to saline, are AWE-S scores associated with clinician-rated depression improvement up to 30 days postinfusion, and do AWE-S scores statistically mediate ketamine's antidepressant effects? For comparison, the investigators ran parallel analyses using CADSS scores to index general dissociative symptoms.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Aepfelbacher, J., Panny, B., & Price, R. B. (2024). Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression. Biological Psychiatry Global Open Science, 4(4), 100316. https://doi.org/10.1016/j.bpsgos.2024.100316
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