Do the dissociative side effects of ketamine mediate its antidepressant effects?

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 230min and Days 1 and 7.

Results: Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min 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.

Keywords: Bipolar depression; Blood pressure; Ketamine; Major depressive disorder; Predictors; Psychotomimetic.

Conflict of interest statement

Conflict of interest

Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the U.S. government but will share a percentage of any royalties that may be received by the government. The remaining authors have no conflict of interest to disclose, financial or otherwise.

Published by Elsevier B.V.

Figures

Fig. 1

Infusion day (up to 230 min post-infusion) baseline-corrected clinical ratings from 108 treatment-resistant patients with major depression who received a single subanesthetic dose (0.5 mg/kg for 40 min) for treatment-resistant major depression. A. 17-item Hamilton Depression Rating Scale (HDRS), B. Clinician-Administered Dissociative Scale (CADSS), C. Brief Psychiatric Rating Scale (BPRS) Positive Symptoms Subscale, and D. Young Mania Rating Scale (YMRS); *=p<0.05.

Fig. 2

Intra-ketamine infusion (every 5 min) baseline-corrected vital sign recordings from 108 treatment-resistant patients with major depression who received a single subanesthetic dose (0.5 mg/kg for 40 min) for treatment-resistant major depression. A. Diastolic Blood Pressure, B. Systolic Blood Pressure, and C. Pulse; *=p<0.05.

Fig. 3

Pearson Correlations with Clinician-Administered Dissociative States Scale (CADSS) at 40 min Post-Ketamine Infusion with 17-item Hamilton Depressing Rating Scale (HDRS) scores at A. 230 min Post-Ketamine Infusion; B. Day 1 Post-Ketamine Infusion; and C. Day 7 Post-Ketamine Infusion. The strength of the correlation is presented with significance level set at p<0.05 (bolded).