In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks.
Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.
In addition, 67% vs 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.
Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York City, told Medscape Medical News.
It was also a bit surprising that in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Feder, who is also a co-inventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.
The findings were published online January 5 in the American Journal of Psychiatry.
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Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the US Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.
PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.
“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Feder said.
The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.
For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.
“We were encouraged by our initial promising findings” of the earlier trial, Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”
Thirty patients (ages 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).
The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).
During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).
In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).
Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
Results showed significantly lower total CAPS-5 scores for the ketamine group vs the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).
Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster — arousal and reactivity — did not show a signficant improvement.
In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.
Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).
Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.
“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Feder noted.
There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.
The most frequently reported AE in the ketamine group compared with midazolam after the start of infusions was blurred vision (53% vs 0%), followed by dizziness (33% vs 13%), fatigue (33% vs 87%), headache (27% vs 13%), and nausea or vomiting (20% vs 7%).
The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.
The results “were very satisfying,” added Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”
She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Feder said.
Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.
“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Feder said.
Speaks to Clinical Utility
Commenting for Medscape Medical News, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University School of Medicine, New Haven, Connecticut, called this a “very solid and well-designed” study.
“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.
He agreed with the investigators that PTSD has long been a condition that is difficult to treat.
“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Sanacora said.
Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.
“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication and it very strongly supports the initiation of a large study to address that,” said Sanacora.
He noted that although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.
“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Sanacora concluded. “I think the data are very strong.”
The study was funded by the Brain and Behavior Research Foundation; Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator; Gerald and Glenda Greenwald; and the Ehrenkranz Laboratory for Human Resilience. Feder is a co-inventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.
Am J Psychiatry. Published online January 5, 2021. Abstract