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.

Introduction

Posttraumatic stress disorder (PTSD) is a debilitating illness with limited pharmacotherapy options. Patients are often treated with monoaminergic antidepressants and off-label combinations of other pharmacotherapies, most of which have inadequate evidence for efficacy in PTSD treatment. Moreover, meta-analytic studies show only small differences between pharmacotherapy and placebo, particularly in Veterans suffering from PTSD.

Ketamine, an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, is a rapid-acting antidepressant with a novel mechanism of action. In a primarily civilian sample, a pioneering proof-of-concept study (n = 41) showed rapid reduction in PTSD and depression symptoms 24 h post a single standard ketamine dose (0.5 mg/kg intravenously over 40 min) compared to midazolam. The standard ketamine dose administered 3 times per week for 2 weeks also was recently reported to significantly reduce PTSD symptoms compared to midazolam in a randomized controlled pilot study (n = 30). In addition, an uncontrolled, open label study (n = 15) in subjects with comorbid PTSD and major depressive disorder (MDD) reported reductions in both PTSD and MDD symptoms following treatment with 6 standard ketamine intravenous infusions over a 2-week period. But another open-label study (n = 10) in individuals with comorbid PTSD and MDD found no significant effects on PTSD symptoms 24 h following single standard ketamine infusion. Moreover, a randomized controlled clinical trial (n = 40) found no significant effects of a single standard infusion of ketamine compared to midazolam in 4 groups of individuals with comorbid PTSD and/or chronic pain. Together, previous studies suggest the potential utility of ketamine in treating PTSD symptoms. However, the evidence is mixed and, to date, only the standard dose (0.5 mg/kg) ketamine has been tested. These findings underscore the need for larger, and more definitive, placebo-controlled trials to determine the efficacy of ketamine in treating PTSD symptoms.

This study investigated the efficacy of ketamine in a double-blind, randomized, 3-arm, controlled clinical trial in Veterans and active duty service members with PTSD symptoms. Though previous studies had used midazolam as an “active” control comparison [10, 11], benzodiazepines may actually worsen PTSD outcomes and thus, we used placebo as the control condition. Our design used 0.5 mg/kg as the “standard” dose of ketamine, but we also explored the use of a low dose of ketamine (0.2 mg/kg), knowing that it could serve as an “active control” if it was not efficacious itself. Considering that the effects of ketamine are short-lived following a single infusion, secondary hypotheses tested the efficacy and durability of repeated ketamine dosing. At the time the study was designed, the evidence suggested that the rapid acting antidepressant ketamine administered twice per week is comparable to 3 times per week. Hence, participants received study drug twice weekly for a total of 8 infusions. Considering that the dissociative symptoms of ketamine are dose dependent, we anticipated that the low dose ketamine will enhance the functional blinding. Although our primary hypotheses focused on PTSD symptoms, we also evaluated the efficacy of ketamine against the depressive symptoms that are highly comorbid in the study population. Finally, we evaluated possible dissociative and psychotomimetic effects of ketamine as well as other adverse events to determine the safety of repeated ketamine dosing in patients with PTSD whose illness itself may be characterized by dissociative pathology.

We hypothesized that a standard dose of ketamine would exert a rapid reduction in PTSD symptoms, and that repeated dosing would: (1) maintain this therapeutic benefit through the end of treatment; and (2) during the 4-week follow-up period.