A new window may be opening on the treatment of chronic PTSD (post-traumatic stress disorder). Results of a newly published clinical trial suggest that repeated infusions of the drug ketamine over a 2-week period can significantly reduce symptom severity in many patients, while also helping to reduce depression symptoms that often accompany PTSD.

 

The randomized trial, led by Adriana Feder, M.D. of the Icahn School of Medicine at Mount Sinai, was small, involving 30 chronic PTSD patients with moderate to severe symptoms, half of whom received 6 infusions of ketamine over 2 weeks while half received 6 infusions of the psychoactive placebo control drug midazolam over the same period. Both drugs have been used for many years as anesthetics, although in the trial both were given at a sub-anesthetic doses. The trial was fully blinded, with neither patients nor the doctors or clinical raters assessing them knowing who was receiving the two medicines.

 

Dr. Feder is a 2015 BBRF Independent Investigator and 2002 Young Investigator. Co-senior authors on the paper reporting the trial, which appeared in the American Journal of Psychiatry, were Dennis S. Charney, M.D., an Emeritus member of BBRF’s Scientific Council and 2019 winner of BBRF’s Colvin Prize for Outstanding Research in Mood Disorders; and James W. Murrough, M.D., a 2009 BBRF Young Investigator. The team also included Laura Bevilacqua, M.D., a 2017 BBRF Young Investigator.

 

Ketamine has attracted much interest because of its rapid antidepressant effects in patients with treatment-resistant depression. Shown to reduce symptoms in as little as a couple of hours, its effects typically do not last longer than one week.

 

A chemical derivative of ketamine called esketamine was approved by the FDA in 2019 for use in refractory depression. Tests are under way to gauge whether it can safely be given repeatedly over long periods of time—on a “maintenance” basis—to sustain remission or major symptom reduction in depressed patients.

 

The newly reported trial involving patients with chronic PTSD aimed in part to test whether repeated ketamine infusions are safe and effective in reducing symptoms. Chronic PTSD refers to symptoms extending well beyond an immediate or acute response to trauma—debilitating symptoms continuing 3 months or more after the traumatic exposure.

 

In the ketamine trial, the average duration of PTSD symptoms for the 30 enrolled patients was 15 years. Three-fourths of participants were women, with an average age of about 40. Thirteen of the 30 had been traumatized by a sexual assault; 8 had endured physical assault or abuse; 2 had been traumatized during combat; 7 had witnessed violent events.

 

The persistence of PTSD in the participants reflects the difficulty in treating PTSD with psychotherapy and existing medicines. Both have demonstrated efficacy, but some patients are unable to tolerate “exposure therapy,” which requires re-exposure under controlled conditions to triggers for fear responses. Similarly, while many patients respond partially to the two SSRI antidepressants that are FDA-approved for the disorder, only 20%-30% achieve remission.

 

The Mount Sinai team had previously tested ketamine in a proof-of-concept trial that involved a single infusion. That trial, led by Dr. Charney, showed significant PTSD symptom reduction 24 hours following the infusion. The current study is the first randomized study to test the efficacy of a course of repeated infusions in individuals with PTSD. The participants were assessed before treatments began, as well as 24 hours and 2 weeks after the first infusion. Those responding to ketamine were followed until their symptoms returned. A “response” was defined as a reduction in PTSD symptoms of 30% or more following the 2-week course of infusions.

 

While some patients in both the ketamine and midazolam groups responded to treatment, many more in the ketamine group were responders—10 of 15 (67%) vs. 3 of 15 (20%) in the midazolam group. (In this trial, midazolam was employed as a psychoactive placebo control; a tranquillizer, midazolam can temporarily mitigate anxiety symptoms in some patients).

 

The bottom line was that improvement in the ketamine group, beginning 24 hours after the first infusion, was “significantly greater” at 2 weeks than that observed in the midazolam group. Response to ketamine lasted, on average, 27.5 days after the 2-week course of infusions, although in one participant it lasted at least 102 days. This extended benefit, the researchers propose, may be due to the repetition of ketamine infusions, as compared with the potential benefit of just one infusion. While dissociation (a floating or out-of-body feeling) was reported by some in the ketamine group during infusions, this side effect did not persist beyond the 2-hour observation period that followed each infusion, and usually resolved shortly after the end of the infusion. There were no other serious side effects.

 

The other major finding of the trial was that ketamine responders showed “marked improvements” in three of four PTSD symptom areas: intrusive thoughts, avoidance, and negative alterations in cognition or mood. This was in addition to significant reductions in comorbid depressive symptoms.

 

The “large-magnitude improvements” in PTSD symptoms and comorbid depressive symptoms and illness severity, as well as indications of the safety of multiple ketamine doses given over 2 weeks, led Dr. Feder and colleagues to urge that additional trials follow this one. They might test whether esketamine has similar benefits in chronic PTSD; and whether psychotherapy, added to a course of ketamine or esketamine, might reduce the likelihood of relapse once the infusions end.