Elsevier

Journal of Affective Disorders

Volume 159, 20 April 2014, Pages 56-61
Journal of Affective Disorders

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

https://doi.org/10.1016/j.jad.2014.02.017Get rights and content

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.

Introduction

A single subanesthetic dose of ketamine has been shown to reduce depressive symptoms within hours in major depression (aan het Rot et al., 2010, Berman et al., 2000, Mathew et al., 2010, Messer et al., 2010, Murrough et al., 2013, Valentine et al., 2011, Zarate et al., 2006) and bipolar disorder (Diazgranados et al., 2010, Zarate et al., 2012) patients. This effect is sustained for approximately 1–2 weeks (Ibrahim et al., 2012). While results are encouraging, most patients experience transient dissociation and psychotomimetic side effects and hemodynamic changes (e.g., increases in blood pressure) that limit its clinical use (Green and Johnson, 1990).

Other noncompetitive (Zarate et al., 2013) and more specific NMDA receptor antagonists (Ibrahim et al., 2012, Preskorn et al., 2008) have antidepressant efficacy in major depression and are relatively devoid of psychotomimetic and dissociative side effects. The effects of these other antagonists, however, are not as robust as ketamine, which may reflect their decreased binding/affinity for the NMDA receptor complex (Aan Het Rot et al., 2012). Thus, it is unclear if the psychotomimetic sequelae, dissociative experiences, and/or hyperdynamic vital sign changes associated with a subanesthetic dose of ketamine are necessary to achieve antidepressant effects. Therefore, the objective of this analysis was to determine whether increased sympathomimetic and hypoglutamatergic effects were related to ketamine׳s antidepressant efficacy. We hypothesized that increased sympathomimetic and hypoglutamatergic (psychotomimetic and dissociative) effects would correlate with changes in depression on ketamine.

Section snippets

Methods

We analyzed data from 108 treatment-resistant depression patients (MDD=74; BD=34) in a current major depressive episode without psychotic features, diagnosed according to the Structured Clinical Interview for Axis I DSM-IV Disorders-Patient Version (First et al., 2002) (see Diazgranados et al., 2010, Ibrahim et al., 2012, Zarate et al., 2012, Zarate et al., 2006 for study details). For two studies, ketamine was administered double-blind (Diazgranados et al., 2010, Zarate et al., 2012, Zarate et

Results

All patients received a single ketamine infusion. Patients randomized to receive riluzole as an add-on treatment (Ibrahim et al., 2012) were excluded from analyses at Days 1 and 7.

The sample had moderate-to-severe depression in the current episode lasting an average of 55.7 (SD=97.2) months (Table 1). The sample was 85% Caucasian (n=92) with half females (n=54) and 21% (n=21) current smokers.

A linear mixed model showed a significant drug by time interaction indicating HDRS ratings were

Discussion

In agreement with previous reports (Driesen et al., 2013, Gibbs, 1970, Krystal et al., 1994), data from 108 depressed MDD or BD participants demonstrated that ketamine increased pulse, blood pressure, psychotomimetic and dissociative side effects. Dissociative side effects, but not psychotomimesis or sympathomimetic effects, correlated with change in depression on the day of infusion and seven days post-infusion. The present correlation suggests dissociative side effects as a clinical biomarker

Role of funding source

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator Award to CAZ, and by the Brain & Behavior Mood Disorders Research Award to CAZ.

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.

Acknowledgments

We would like to thank the 7-SE Unit nursing staff, research assistants, and patients for the invaluable contributions to the protocol.

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