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.

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.”

Authors: David A. Luckenbaugh, Mark J. Niciu, Dawn F. Ionescu, Neal M. Nolan, Erica M. Richards, Nancy E. Brutsche, Sara Guevara, Carlos A. Zarate

Summary

Data were analyzed from 108 treatment-resistant inpatients receiving a single subanesthetic ketamine infusion. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis, manic symptoms, and vital sign changes.

Pearson correlations showed that increased CADSS score at 40 min was significantly correlated with percent improvement in HDRS at 230 min and Day 7 with ketamine.

Introduction

Ketamine has been shown to reduce depressive symptoms in patients with major depression and bipolar disorder within hours, but is associated with transient dissociation and psychotomimetic side effects.

Ketamine has antidepressant efficacy in major depression, but is associated with psychotomimetic and dissociative side effects. We hypothesized that increased sympathomimetic and hypoglutamatergic effects would correlate with changes in depression on ketamine.

Methods

We analyzed data from 108 treatment-resistant depression patients in three studies, including two double-blind studies and one open-label study. All subjects had at least a moderate severity episode of major depression and a history of at least one failed antidepressant drug trial.

2.1. Ketamine administration

Subjects received a single subanesthetic dose of ketamine by intravenous infusion over 40 min. Blood pressure and pulse were measured every 5 min for the first 40 min, and at various time points post-infusion.

2.2. Data analysis

Linear mixed models were used to examine changes in blood pressure and pulse over the first 40 min and clinical ratings over the first 230 min of the ketamine crossover studies.

Ketamine significantly decreased HDRS ratings from 40 to 230 min, and CADSS, YMRS, and BPRS positive symptoms were significantly increased on ketamine versus placebo from 5 to 40 min. Changes in systolic and diastolic blood pressure and pulse were not significantly related to depression changes.

At 40 min, CADSS, BPRS positive symptoms, and total BPRS were positively correlated with each other, but not with YMRS. There were no significant correlations between vital sign changes and depression or dissociation.

Discussion

Ketamine increased pulse, blood pressure, psychotomimetic and dissociative side effects in depressed patients and correlated with change in depression on the day of infusion and seven days post-infusion.

Different underlying mechanisms may explain why dissociation predicts ketamine’s antidepressant effect, but blood pressure, pulse, and psychotomimetic effects do not. Increases in blood pressure and psychotomimetic effects may be due to increases in dopamine, but in humans, these effects are controversial.

Ketamine may enhance glutamate release by inhibiting GABAergic cortical interneurons, leading to increased long-term potentiation-like synaptic glutamate release and greater AMPA-to-NMDA postsynaptic receptor throughput.

A prior report found no correlation between maximum CADSS and HDRS response following ketamine infusion. Also, more intense psychotomimetic symptoms correlated with improved mood ratings on the MADRS 7 days post-ketamine infusion.

Although the combination of unipolar and bipolar diagnostic groups and the use of open-label and randomized, placebo-controlled studies have limitations, ketamine’s dissociative adverse effects significantly correlated with antidepressant response, but only explained a fraction of the variance in response.

Fig. 1.

Infusion day clinical ratings from 108 treatment-resistant patients with major depression who received a single subanesthetic dose for treatment-resistant major depression.