Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder

Abstract

IMPORTANCE Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.OBJECTIVE To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. DESIGN, SETTING, AND PARTICIPANTS Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.INTERVENTIONS Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). MAIN OUTCOMES AND MEASURESThe primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.RESULTS Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. CONCLUSIONS AND RELEVANCEThis study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00749203

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Antidepressant doses of ketamine decreased the default mode connectivity (Scheidegger et al, 2012) and reduced core symptoms of PTSD, including avoidance (Feder et al, 2014). Based on these observations in humans and our findings in mice, we hypothesize that silent synapses underlie the enhanced functional connectivity in mental disease, whereas positive effects of ketamine result from their elimination.…”

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

“…Glutamate is thought to play a key role in the pathogenesis of PTSD (5, 6) for several reasons: glutamate underlies synaptic plasticity and memory formation (7), stress significantly impacts glutamate transmission (8), and the glutamate receptor antagonist ketamine may have efficacy in treating PTSD (9). Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that mediate neuromodulatory effects of glutamate, making them a promising target for drug development (10).…”

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…We recently reported that ketamine was superior to an anesthetic control condition (the benzodiazepine midazolam) at rapidly reducing depressive symptoms 24 h following a single intravenous (IV) infusion in a two-site randomized controlled trial (response rates to ketamine and midazolam were 64 and 28%, respectively; Murrough et al, 2013a). Randomized controlled trials have also found positive therapeutic effects of ketamine in bipolar depression (Zarate et al, 2012) and posttraumatic stress disorder (PTSD; Feder et al, 2014). Despite the potential of ketamine as a mechanistically novel therapeutic option for patients with TRD, important concerns regarding safety and toxicity remain (Green and Cote, 2009;Morgan et al, 2009).…”