Ketamine safety and tolerability in clinical trials for treatment-resistant depression

This meta-analysis (2015) of open-label studies (n=97) examined the safety, tolerability, and acceptability of intravenous ketamine (35mg/70kg) infusion for patients with depression. They found that it was safe and well-tolerated with little to no psychotomimetic effects, adverse medical effects, or any increase in long-term substance abuse.

Abstract

“Objective: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.

Method: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.

Results: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.

Conclusions: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.”

Authors: Le-Ben Wan, Cara F. Levitch, Andrew M. Perez, Jess W. Brallier, Dan V. Iosifescu, Lee C. Chang, Alexandra Foulkes, Sanjay J. Mathew, Dennis S. Charney & James W. Murrough

Summary

ABSTRACT

Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression.

Data from 205 IV ketamine infusions were pooled from 3 clinical trials conducted at 2 academic medical centers between 2006 and 2012.

The overall antidepressant response rate was 67%, and the attrition rate was 3.1%. Four of 205 infusions were discontinued due to AEs, and ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms.

Ketamine was safe and well tolerated in this large group of patients.

ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.

James W. Murrough, MD, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

Ketamine is a noncompetitive glutamate receptor antagonist that has demonstrated rapid-N-methyl-d-aspartate (NMDA) onset antidepressant effects in patients with major depressive disorder and bipolar depression.

Ketamine has been used as an anesthetic agent in children and adults for the past 50 years. It is considered to be very safe in patient populations.

A study was conducted to evaluate the short-term safety, tolerability, and acceptability of ketamine in treatment-resistant depression (TRD) patients in a research setting. The study found no persistent adverse mental status events, no residual medical sequelae, and no long-term increased risk of ketamine abuse.

METHOD

Three studies involving ketamine administration for treatment-resistant depression were conducted at the Icahn School of Medicine at Mount Sinai and Baylor College of Medicine between 2006 and 2012, and all participants had a primary diagnosis of chronic or recurrent MDD.

A study anesthesiologist administered racemic ketamine (0.5 mg/kg) over 40 minutes by IV infusion pump with standard telemetry monitoring. Dissociative and psychotomimetic effects were assessed before the start of each infusion, immediately upon completion of each infusion (40 minutes), and after 240 minutes.

The anesthesiologist could treat blood pressure or heart rate increases if they resolved spontaneously, but the infusion was discontinued if they remained above protocol-defined limits.

We attempted to contact all study participants by telephone and e-mail when available to determine whether there were any long-term adverse effects of ketamine exposure and to assess the overall acceptability of ketamine as a treatment for depression.

All statistical analyses were performed with IBM SPSS Statistics software (version 20; IBM Corporation, Armonk, New York). ANOVA, paired t tests, Mann-Whitney U tests, and Pearson correlation analyses were used to assess relationships between variables.

RESULTS

The study included 205 participants who received 0.5 mg/kg over 40 minutes of ketamine. The 24-hour response rate was 67%, and the mean MADRS decreased by 19 11.7 points compared to baseline.

The overall attrition rate due to any cause was 3.1% (4 of 97 subjects). Four subjects were discontinued due to adverse events (2 experienced elevated blood pressure, 2 experienced anxiety, and 1 was placed on cardiac monitoring for 24 hours).

As expected, transient increases in mean blood pressure and pulse were observed during the ketamine infusion. A protocol-defined increase in blood pressure or pulse was experienced by 29.8% of participants and 14.3% received medication intervention for these changes.

Ketamine was associated with a small but significant increase in psychotic symptoms and a mild, significant increase in dissociative symptoms as measured by the CADSS. The mean increase in BPRS+ score was also not significantly different between ketamine responders and nonresponders.

46 out of 84 subjects who took ketamine reported no long-term effects. One subject reported increased anxiety and dysphoria, but no increased cravings or use of ketamine or other illicit substances.

Subjects rated ketamine somewhat acceptable to very acceptable, with 1 subject rating it not at all acceptable.

DISCUSSION

This study showed that low-dose ketamine is safe and well tolerated in depressed patients in the context of a well-controlled medical research setting. There was no evidence of ketamine abuse, increased drug cravings, or substance abuse following study participation.

29.8% of subjects receiving ketamine experienced protocol-defined changes in vital signs, mostly elevations in blood pressure. In all but 2 cases, the elevated blood pressure responded rapidly to the intervention, and the ketamine infusion was discontinued.

We found that ketamine administration was associated with small but statistically significant increases in psychotomimetic and dissociative effects. While the average observed peak score of 4.5 is consistent with symptom severity described as “very mild”, caution is warranted in extrapolating our findings to larger patient groups with more diverse symptom histories.

Our longer-term follow up data showed that there were no persistent dissociative or psychotomimetic effects, and no cases of persistent physical symptoms or increased substance use. However, there have been reports of delayed-onset suicidal ideation and dysphoria following ketamine administration in patients with obsessive-compulsive disorder.

This study has several limitations, including combining patient-level data from studies utilizing different clinical trial designs, potentially biasing results toward shared items, and only assessing short-term administration of ketamine. More research is needed to fully understand the risks and benefits of longer-term use of ketamine to treat TRD.

In conclusion, this study suggests that subanesthetic doses of ketamine administered to unipolar depressed patients in a controlled research setting present a low and acceptable level of risk.