Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression

This is the first open-label study (2018) to assess the effects of repeated ketamine infusions in the treatment of comorbid PTSD and treatment-resistant depression (TRD) (n=15). Participants received six IV ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period. Ketamine significantly reduced measures of symptoms change for both disorders (MADRS & PTSD Checklist for DSM-V) and the remission rate for PTSD and TRD were 80% and 93.3%, respectively.

Abstract

“Objective: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans.

Methods: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion.

Results: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d‘ ²] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d‘ ² = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration.

Conclusion: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD.

Authors: C. Sophia Albott, Kelvin O. Lim, Miriam K. Forbes, Christopher Erbes, Susanna J. Tye, John G. Grabowski, Paul Thuras, Tegan Batres-y-Carr, Joseph Wels & Paulo R. Shiroma

Summary

A sample of veterans received repeated ketamine infusions for treatment-resistant depression.

Individuals who failed to respond to multiple antidepressant treatments experienced a rapid antidepressant response after ketamine administration, but the response was transient and only 24.1% of participants maintained improvement 14 days post-infusion.

While single-dose ketamine infusions are effective for treating TRD, open-label case series have demonstrated repeated ketamine infusions are more effective, with a longer period of antidepressant response. However, no studies have examined repeated ketamine infusions for treating comorbid PTSD and TRD.

Participants

The study was conducted at the Minneapolis VA Health Care System from May 2015 to June 2016 and assessed change in CAPS-5 score, proportion of individuals in remission from PTSD, proportion of individuals meeting depression response criteria, and proportion of individuals relapsing for either PTSD or depression during the follow-up period.

Statistical Analysis

Descriptive statistics were calculated for sociodemographic variables, primary and secondary outcomes, and side effect measures. Changes in outcome measures were examined using repeated-measures analyses of variance and Cohen d (d′) on a z-score distribution.

Study Participants

Twenty-four individuals provided signed informed consent and underwent screening procedures. Nineteen participants met eligibility criteria, and 15 participants received all 6 infusions and had complete outcome data.

Efficacy

The mean within-subject change in PTSD symptoms significantly decreased over the course of treatment from baseline to 24 hours after the sixth ketamine infusion, and the mean within-subject change in depression symptoms significantly decreased over the course of treatment.

The 6-infusion regimen achieved larger effect sizes compared with previous studies of antidepressant agents for PTSD, and the treatment effect for depression symptoms was significantly greater than that for PTSD symptoms.

The magnitude of effect of ketamine on PTSD symptoms varies depending on the PTSD symptom cluster, and ketamine’s role in rapidly stimulating synaptic plasticity may have enhanced extinction learning via these mechanisms, thereby extending the period of remission for PTSD symptom clusters.