Published in JAMA Psychiatry April 16, 2014
The first evidence from a randomized clinical trial that the anesthetic agent ketamine may provide rapid symptom reduction in patients with chronic posttraumatic stress disorder (PTSD) when delivered intravenously has been published.
An N-methyl-D-asparate (NMDA) glutamate receptor, ketamine has made headlines in recent years because several trials conducted by investigators at the Icahn School of Medicine at Mount Sinai in New York City have shown that it delivers a rapid antidepressant effect when delivered intravenously and, most recently, intranasally in spray form.
In this latest proof-of-concept study, researchers led by Adriana Feder, MD, found that intravenous (IV) infusion of ketamine hydrochloride (0.5 mg/kg) was associated with significant and rapid reduction of PTSD symptom severity compared with an active control agent.
“These findings may lead to novel approaches in the treatment of chronic PTSD ? a condition that affects a broad spectrum of adults in the United States and beyond, including victims of sexual assault, war veterans, those who have witnessed catastrophic events such as the September 11 terror attacks, and others,” Dr. Feder, associate professor of psychiatry, Icahn School of Medicine at Mount Sinai, said in a release.
“However, this should be viewed as a proof-of-concept study. Additionally, longer-term clinical trials with ketamine will be required to determine if it will be a clinically useful treatment for PTSD,” she added.
Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of PTSD, which is chronic and disabling, the investigators note.
They add that there is a growing body of evidence showing that glutamate plays a major role in mediating stress response, the formation of traumatic memories, and PTSD pathophysiology.
An agent that has been used for anesthesia at 2 mg/kg and analgesia at subanesthetic doses, ketamine has a good safety track record and is superior to other anesthetic agents because it reliably preserves breathing reflexes.
The researchers note there have been no randomized clinical trials examining the effect of ketamine in chronic PTSD. The few that have been conducted were either retrospective or nonrandomized.
Building on previous research showing that ketamine is effective in treatment-resistant depression, the investigators conducted a proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, another anesthetic agent that has pharmacokinetic parameters and nonspecific behavioral effects that are similar to ketamine.
“In recent years, we and others have shown that ketamine could often counter the symptoms of depression in treatment-resistant cases. In the present study, we hypothesized that ketamine would be associated with significantly greater reduction in core PTSD symptom levels 24 hours after a single IV infusion, and that it would also improve comorbid depressive symptoms in patients diagnosed with PTSD,” principal investigator Dennis Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, said in a statement.
The study included 41 patients between the ages of 18 and 55 years with a primary diagnosis of PTSD and a score of at least 50 on the Clinician-Administered PTSD Scale (CAPS). Study participants were free of concomitant psychotropic medications for 2 weeks prior to randomization and for the duration of the study.
The study’s primary outcome was change in PTSD symptom severity 24 hours after infusion, using the Impact of Event Scale–Revised (IES-R). Secondary outcome measures included the Montgomery- Åsberg Depression Rating Scale (MADRS), the Quick Inventor of Depressive Symptomatology, Self-Report (QIDS-SR), and the Clinical Global Impression–Severity (CGI-S) and –Improvement (CGI-I) scales administered at 24 hours, 48 hours, 72 hours, and 7 days after infusion.
In addition, adverse events were monitored with the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.
Rapid Symptom Reduction
For each procedure day, patients were assigned to receive a single IV infusion of ketamine hydrochloride or midazolam administered during a period of 40 minutes.
The order of infusions was randomly assigned, and administrations occurred 2 weeks apart.
Ratings were administered at preinfusion baseline and 24 hours (day 1) after infusion (before patients were discharged from the hospital), 48 hours (day 2) after infusion, 72 hours (day 3) after infusion, and 7 days (day 7) after infusion.
Study results revealed that ketamine infusions were associated with a “significant and rapid reduction in PTSD symptom severity compared with midazolam 24 hours after infusion” (mean difference in IES-R score, 12.7; 95% confidence interval, 2.5 – 22.8; P = .02).
The investigators also report that there was a greater reduction of PTSD symptoms following treatment with ketamine in both crossover and first-period analyses that remained significant after adjusting for baseline and 24-hour depressive symptom severity.
The researchers also found that ketamine was associated with a reduction in comorbid depressive symptom severity and improvement in overall clinical presentation.
In addition, they report that the drug was “generally well tolerated without clinically significant persistent dissociative symptoms.”
“Our results provide the first evidence that a single dose of IV ketamine was associated with rapid reduction of core PTSD symptoms and reduction in comorbid depressive symptoms…,” the authors write.
They add that the results need to be replicated in other trials and that this research should “examine the efficacy and safety of ketamine beyond a single infusion for patients with chronic PTSD, explore the use of ketamine anesthesia to prevent the emergence of PTSD symptoms in surgical patients with a history of trauma, investigate the mechanisms of ketamine action, and identify pretreatment predictors of response to this intervention.”
This study was funded by the Department of the Army – US Navy Medical Research Acquisition Activity. Dr. Charney and Dr. Feder have been named as inventors on a patent application covering the use of ketamine for the treatment of PTSD.