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.