Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active-duty military: a double-blind, randomized, placebo-controlled multi-centre clinical trial

This double-blind RCT (n=158) assessed 8 repeated doses of intravenous ketamine administered twice weekly at a low dose (0.2 mg/kg; n = 53), standard dose (0.5 mg/kg; n = 51) ketamine or placebo (n=54) in veterans and service members with PTSD. It was found that the standard dose of ketamine reduced MADRS scores significantly more than placebo. However, the trial failed to find a significant dose-related effect of ketamine on PTSD symptoms measured using the CAPS-5.

Abstract

“This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed-effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.”

Authors: Chadi G. Abdallah, John D. Roache, Ralitza Gueorguieva, Lynnette A. Averill, Stacey Young-McCaughan, Paulo R. Shiroma, Prerana Purohit, Antoinette Brundige, William Murff, Kyung-Heup Ahn, Mohamed A. Sherif, Eric J. Baltutis, Mohini Ranganathan, Deepak D’Souza, Brenda Martini, Steven M. Southwick, Rebecca R. Burson, Kevin B. Guthmiller, John P. McCallin, Matthew B. Hoch, Alexander Timchenko, Sergio E. Souza, Charles E. Bryant, Jim Mintz, Brett T. Litz, Douglas E. Williamson, Terence M. Keane, Alan L. Peterson & John H. Krystal

Notes

Update: see here for a correction to Table 1 in the original article.

Ketamine is widely available as an off-label treatment for mental health disorders. While the ability of ketamine to alleviate symptoms of disorders like depression and anxiety has been well-documented, other than positive anecdotal reports, there is currently a lack of clinical evidence demonstrating the therapeutic effects of ketamine for other mental health disorders such as PTSD. Despite this lack of evidence, ketamine is still being used off-label to treat these disorders in regions where it is legally permitted. In order for ketamine-assisted therapy to become a viable and accessible treatment for people everywhere, clinical evidence is needed.

The present study is the largest study to date exploring the effects of ketamine to alleviated the symptoms of PTSD. Prior to this study, only two trials have investigated the effects of ketamine in people with PTSD: Feder et al. (2014) and Feder et al. (2021). Both of these trials yielded positive results in terms of the therapeutic effects of ketamine. Thus, the present study sought to build on these findings by using a larger sample size and exploring the effects of different doses of ketamine as the standard dose of 0.5 mg/kg was solely used in previous studies.

158 veterans and active service members took part in this study. The study was a double-blind, placebo-controlled, randomized three-arm study. Participants were randomised to three groups: standard dose (n=51, 0.5 mg/kg), low dose (n=53, 02. mg/kg) and placebo (n=54, saline). Participants received study drugs twice per week for four weeks yielding a total of eight dosing sessions. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion using the self-report PTSD Checklist for DSM-V (PCL-5) and the Clinician-Administered PTSD Scale for DSM-V (CAPS-5). Researchers simultaneously assessed the antidepressant effects of ketamine in this population using the Montgomery Åsberg Depression Rating Scale (MADRS).

The main findings:

• The trial failed to find a significant dose-related effect of ketamine on symptoms of PTSD over the 4-week study duration. Thus, these findings do not support the use of PTSD in veterans and service members.
• There was no significant difference in response rate (i.e., 25% or more improvement in the PTSD Checklist for DSM-5 (PCL-5) scores) at 24hr post first infusion (Day 1), 24 h post last infusion (Week 4), and at the end of 4 weeks of follow-ups (Week 8).
• Ketamine significantly reduced MADRS scores when compared to placebo at Day 1 and at the end of treatment in the standard dose group. These findings support the use of ketamine as an antidepressant.
• The fact that this study was carried out in veterans and service members may, in part, be responsible for the lack of effect. Previous trials have indicated low treatment response in these populations.

The present study assessed the ability of ketamine to alleviate symptoms of PTSD in veterans and service members. It was found that repeated doses of ketamine did not significantly impact symptoms of depression. However, a significant antidepressant was observed. These findings may partially be explained by the study cohort. The previous studies assessing ketamine for PTSD were carried out in civilian populations, the majority (77%) being female. This stands in contrast to the present study of mainly male veterans and service members.

In the world of psychedelics, many have the tendency to overestimate the therapeutic potential of psychedelics. Touting psychedelics as wonder drugs for all types of mental health disorders can negatively impact the experience of patients and arguably, the chance of psychedelics becoming widely available. Based on the research above, people may seek the off-label use of ketamine to better their mental health only to find the therapy to be ineffective while also being out-of-pocket given the high prices of these treatments. Ultimately, more research is needed to clarify the effects ketamine has on PTSD before any conclusions can be drawn.

Summary

INTRODUCTION

Posttraumatic stress disorder (PTSD) is a debilitating illness with limited pharmacotherapy options. Most treatments have inadequate evidence for efficacy.

Ketamine, an antagonist of NMDA glutamate receptors, is a rapid-acting antidepressant with a novel mechanism of action. It was recently reported to significantly reduce PTSD and depression symptoms.

In a randomized controlled pilot study, ketamine was found to reduce PTSD symptoms compared to midazolam. However, in an uncontrolled, open label study, ketamine was not found to reduce PTSD symptoms compared to midazolam.

This study investigated the efficacy of ketamine in Veterans and active duty service members with PTSD symptoms. The study used a low dose of ketamine (0.2 mg/kg) and tested the safety of repeated ketamine dosing in patients with PTSD whose illness itself may be characterized by dissociative pathology.

METHODS Study design

This double-blind, randomized, controlled trial was conducted at three centers and included Veterans and active duty service members with PTSD symptoms. All participants provided written informed consent prior to enrollment.

Participants were randomized to one of three parallel study arms: Placebo, Low dose, or Standard dose of ketamine. Eight 40-min intravenous infusions of the study drug were administered twice weekly, and participants were followed weekly for 4 weeks after the last infusion.

Participants who did not respond to double-blind medication were offered a single administration of open label, standard dose ketamine, but their follow-up data were not included in the durability of effect analyses.

Study criteria

The study enrolled Veterans and service members between the age of 18 and 70 years who met the following criteria: (1) diagnosed with PTSD; (2) had CAPS-5 score of 23 or higher; (3) had a history of nonresponse to at least 1 adequate trial of FDA approved antidepressant; (4) were unmedicated or stable on an antidepressant for at least 4 weeks.

Statistics

The power calculation and analysis plans were previously reported [15], and the results are similar without covarying for severity. The dissociative and psychotomimetic effects were examined using comparable mixed models for CADSS and PANSS, while adding interval (30 min vs. 120 min) and appropriate interactions to the models.

RESULTS

A total of 262 participants were consented and assessed for eligibility. 158 participants were randomized, began treatment, and were included in the study analysis.

Effects of ketamine on primary outcome

The primary analysis found no significant effect of treatment on PCL-5 scores, and there was no treatment-by-time interaction. The secondary analyses found no significant reduction in PCL-5 scores after the first standard dose or at the end of treatment compared to placebo.

Responder analysis

The percentage of responders showing a 25% improvement in PCL-5 at 24 h post-first infusion was higher in the two active groups than in the placebo group, but the difference in proportions was not significant.

Effects of ketamine on secondary outcomes

The CAPS-5 scores showed no significant reductions in either the ketamine low dose or the ketamine standard dose group, compared to placebo. Ketamine had significant dose-related effects on depression symptoms. The mixed model showed a significant treatment-by-time interaction and a time effect, but no treatment main effect. The standard dose was significantly superior to placebo for MADRS reduction, but not for the low dose group.

Durability of the ketamine effects

After the 4-week treatment period, participants in the standard dose, low dose, and placebo groups had no significant improvement on the CAPS-5. They were offered open-label, standard dose ketamine, but there were no differences between placebo and ketamine standard dose.

Ketamine had a time effect on CAPS-5 scores and MADRS, but no treatment or treatment*time effects. At 4 weeks posttreatment, ketamine low dose had non-significant lower CAPS-5 scores compared to placebo, and no differences between other groups.

Adverse effects of ketamine

Ketamine-induced dissociative symptoms were dose-dependent and time-dependent, with a reduction of dissociative symptoms observed over the 8-infusion treatment period.

Ketamine reduced posttraumatic stress disorder (PTSD) and depression symptoms over the treatment period, but did not differ between treatment groups. There was a non-significant effect of ketamine on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), but a significant effect of ketamine on the MADRS.

Ketamine-induced psychotomimetic symptoms improved by 120 min after infusion, with significant treatment*interval interactive effects.

The majority of participants reported at least one adverse event, and 162 were considered at least “possibly” related to treatment. The most common AEs were agitation, anxiety, irritability, and constipation, and nightmare occurrence was comparable across groups.

DISCUSSION

This randomized, controlled trial of twice-weekly ketamine infusions failed to demonstrate significant efficacy on PTSD symptoms in Veterans and active duty military, but did show significant antidepressant effects in patients who had considerable depressive symptoms at baseline.

Ketamine was found to be effective in treating depression symptoms in patients with PTSD, and the low dose group had no rapid antidepressant effect during treatment, but had reduced depressive symptoms at the end of the 4-week follow-up.

The current study did not support the pilot findings by Feder and colleagues [11], which reported significant effects of standard dose ketamine on PTSD symptoms. The differing results may be due to several factors, including the different study populations, sex differences, and treatment duration.

The previous study did not find rapid effects of ketamine on PTSD or depression symptoms at 24 h post first infusion.

Ketamine research is challenging due to the potential for functional unblinding. Midazolam has been used as a putative “active control”, but the potential negative effects of benzodiazepine on PTSD are previously documented. The pre to post improvements in the current study were large, even within the placebo group, and suggest that expectations were not negative in our placebo-treated participants. The effect sizes of both ketamine doses on PCL-5 scores were large and in the predicted range.

The placebo response was high in this study, which required repeated invasive medical interventions and supportive medical milieu.

The current study demonstrated the feasibility and short-term safety of repeated intravenous ketamine in a large cohort of patients with PTSD. The ketamine-induced dissociative and psychotomimetic effects were transient, and the dose used was lower than the standard dose used to treat depression.

The current study failed to support the a priori hypothesis test of ketamine efficacy on PTSD symptoms in Veterans and military personnel, but did provide evidence of benefit due to ketamine.

DISCLAIMER

The views expressed herein are solely those of the authors and do not reflect the official policy or position of Brooke Army Medical Center.

ACKNOWLEDGEMENTS

The authors thank the individuals who participated in this study for their invaluable contribution, and the Emerge Research Program staff, nurses and lab staff of the Biostudies Unit for their invaluable expertise.