A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder

This first double-blind (active) placebo-controlled study (n=30) of repeated ketamine (6x, 35mg/70kg) infusions found it to be effective as a treatment for PTSD (67% clinical response), but this response faded (on average) within a month.

Abstract

“Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.

Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.

Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.

Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.”

Authors: Adriana Feder, Sara Costi, Sarah B. Rutter, Abigail B. Collins, Usha Govindarajulu, Manish K. Jha, Sarah R. Horn, Marin Kautz, Morgan Corniquel, Katherine A. Collins, Laura Bevilacqua, Andrew M. Glasgow, Jess Brallier, Robert H. Pietrzak, James W. Murrough & Dennis S. Charney

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Summary

PTSD is a chronic and disabling condition arising after exposure to a severe trauma, characterized by persistent reexperiencing, avoidance, and hyperarousal symptoms. Few pharmacotherapies have demonstrated sufficient efficacy in PTSD.

Ketamine, an antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, is used for anesthesia at doses of 2 mg/kg or higher and for analgesia at subanesthetic doses. It is considered particularly safe because it reliably preserves breathing reflexes.

Few previous studies have examined the effects of ketamine in trauma-exposed individuals, and results from these studies have been mixed. In contrast, a recent case report found that IV ketamine administered with propofol was associated with rapid and marked symptom improvement in a veteran with treatment-resistant PTSD.

We conducted a proof-of-concept study to test the effects of ketamine in patients with chronic PTSD compared to the benzodiazepine midazolam. Ketamine was found to have a rapid antidepressant effect in patients with PTSD.

Methods

Patients with chronic PTSD were enrolled at the Icahn School of Medicine at Mount Sinai, New York, New York, between May 2009 and December 2012. All patients underwent a physical examination and laboratory screening, and a CAPS score of at least 50 was required to receive the second IV infusion.

Procedures

Patients were randomly assigned to receive a single IV infusion of ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045 mg/kg), administered over 40 minutes, 2 weeks apart.

Patients were admitted to Mount Sinai’s Clinical Research Unit and underwent monitoring for 24 hours, 48 hours, 72 hours, and 7 days after ketamine infusion. Patients who scored 50 or higher on the CAPS 2 weeks after the first infusion received a second infusion.

Outcomes

The primary outcome was PTSD symptom severity 24 hours after infusion, and the secondary outcomes were depression, anxiety, and global impression at 24 hours, 48 hours, 72 hours, and 7 days after infusion.

Side effects were measured with the Patient-Rated Inventory of Side Effects, the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the 4-item positive symptoms subscale.

Statistical Analysis

Ketamine was used to treat 41 patients with PTSD symptoms in a proof-of-concept, randomized, double-blind, crossover trial. The primary end point was the change in IES-R score from baseline to 24 hours after ketamine infusion.

Study Participants

Of 57 potential participants, 41 met eligibility criteria and were randomly assigned to receive ketamine or midazolam during the first infusion. 29 participants completed both infusions and ratings following each infusion, and 12 participants completed the study at 2 weeks.

Demographic and Clinical Characteristics

Patients with chronic PTSD were randomly assigned to receive ketamine or midazolam. Fewer than 50% had received psychotropic medication in the past, and only 2 patients required a psychotropic medication taper.

Primary Outcome

The IES-R scores were significantly improved with ketamine compared with midazolam 24 hours after infusion, and symptoms remained reduced in 7 patients randomly assigned to ketamine first compared with only 1 patient randomly assigned to midazolam first.

Ketamine had a similar effect on the 3 PTSD symptom clusters as midazolam, measured by the IES-R subscales. MADRS and QIDS-SR scores did not differ significantly between treatments, and the CAPS score did not change after 1 week.

Comorbid Depressive Symptoms

Treatment assignment, MADRS score 24 hours after infusion, and baseline IES-R score were all significant predictors of IES-R score 24 hours after infusion.

Durability of Drug Effect

Generalized linear mixed modeling analyses of the first period only demonstrated a significant effect of treatment on the IES-R and QIDS-SR scores and a significant effect of time on the scores.

Adverse Events

Ketamine treatment was associated with short-lived dissociative symptoms, peaking at 40 minutes after start of infusion. No significant psychotic or manic symptoms were observed, and one participant dropped out after his second infusion.

Discussion

Ketamine is associated with rapid reduction in core PTSD symptoms in patients with chronic PTSD, and benefit frequently is maintained beyond 24 hours. Ketamine is also associated with the reduction in comorbid depressive symptoms, possibly broadening the therapeutic use of NMDA receptor modulation for the treatment of depressive symptoms in PTSD patients.

We demonstrated that a single dose of IV ketamine is a safe and generally well-tolerated intervention for patients with chronic PTSD, without significant emergence of psychotic or manic symptoms.

The study was conducted on patients with moderate to severe PTSD symptom levels, and used ketamine as the active placebo control. Ketamine demonstrated a superior effect to that of midazolam, despite the fact that midazolam may have a potential acute benefit.

Ketamine, a glutamate NMDA receptor antagonist, has been shown to improve symptoms of post-traumatic stress disorder (PTSD) in patients through activation of the mammalian target of rapamycin signaling pathway and stimulation of brain-derived neurotrophic factor signaling.

The limitations of this study include the fact that several patients did not receive a second infusion, and ketamine was associated with transient but higher rates of dissociative symptoms than midazolam.

Conclusions

A single dose of IV ketamine reduced core PTSD symptoms and reduced comorbid depressive symptoms in patients with chronic PTSD, and was well tolerated without clinically significant persistent dissociative symptoms.