Do the dissociative side effects of ketamine mediate its antidepressant effects?
This meta-analysis (n=108) examined whether the rapid antidepressant effect of a single subanesthetic ketamine (35mg/70kg) infusion is mediated by its dissociative side-effects or other symptoms related to its psychotomimetic profile. The analysis revealed that its dissociative effect was the only mediator that predicted a robust and sustained antidepressant efficacy.
Authors
- Carlos Zarate
- Daniel Ionescu
- David Luckenbaugh
Published
Abstract
Background
The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.
Methods
Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7.
Results
Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r= −0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.
Limitations
Secondary data analysis, combined diagnostic groups, potential unblinding.
Conclusions
Among the examined mediators of ketamine’s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.
Research Summary of 'Do the dissociative side effects of ketamine mediate its antidepressant effects?'
Introduction
A single subanesthetic infusion of ketamine produces rapid antidepressant effects in major depressive disorder (MDD) and bipolar depression that can last about one to two weeks. However, ketamine commonly causes transient dissociation, psychotomimetic symptoms and sympathomimetic hemodynamic changes (for example, raised blood pressure). Other NMDA receptor antagonists that lack these subjective and physiological side effects have shown antidepressant effects too, but generally with smaller magnitude than ketamine. This pattern leaves uncertain whether ketamine’s dissociative, psychotomimetic or sympathomimetic effects are necessary for, or simply accompany, its antidepressant efficacy. Luckenbaugh and colleagues set out to test whether acute sympathomimetic (vital sign) changes and hypoglutamatergic effects manifested as psychotomimetic or dissociative symptoms are associated with ketamine’s antidepressant response. The investigators hypothesised that greater acute sympathomimetic and hypoglutamatergic effects would correlate with larger reductions in depressive symptoms after a single subanesthetic ketamine infusion.
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Study Details
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- APA Citation
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., Nolan, N. M., Richards, E. M., Brutsche, N. E., Guevara, S., & Zarate, C. A. (2014). Do the dissociative side effects of ketamine mediate its antidepressant effects?. Journal of Affective Disorders, 159, 56-61. https://doi.org/10.1016/j.jad.2014.02.017
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