Dose-Related Effects of Ketamine for Antidepressant-Resistant Symptoms of Posttraumatic Stress Disorder in Veterans and Active Duty Military: A Double-blind, Randomized, Placebo-Controlled Multi-Center Clinical Trial

BackgroundThis study tested the efficacy of repeated intravenous ketamine doses to reduce antidepressant-resistant symptoms of posttraumatic stress disorder (PTSD). MethodsVeterans 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 (0.2mg/kg; n=53) or standard dose (0.5mg/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 [A]sberg Depression Rating Scale (MADRS). ResultsThere were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard dose ketamine significantly reduced symptoms after the first infusion, while the low dose showed significant symptom reduction after the last infusion and at the 4-week follow-up. The standard ketamine dose also significantly ameliorated depression measured by the MADRS. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 hours and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. ConclusionsThis clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the low dose reduced PTSD symptoms and the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifierNCT02655692