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Abstract APA 2013 Meeting Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site, Randomized, Parallel-Arm, Midazolam-Controlled, Clinical

l Trial James W. Murrough, Dan V. Iosifescu, Lee C. Chang, Rayan K. Al Jurdi, Charles M. Green, Syed Iqbal, Sarah Pillemer, Andrew M. Perez, Alexandra Foulkes, Asim Shah, Dennis S. Charney, Sanjay J. Mathew Background: A single intravenous (IV) infusion of ketamine a high-affinity glutamate N-methyl-d-aspartate (NMDA) receptor antagonist had large and rapid antidepressant effects with 24 hours of administration in several small studies in depressed patients, including those with previous medication-resistance. Given ketamines acute dissociative properties, the use of placebo conditions devoid of psychoactive properties raised the possibility that inadequate blinding biased outcomes. The current study was designed to address these gaps in the literature by testing the rapid (24 hour) antidepressant effects of ketamine in treatment-resistant major depression (TRD) using a randomized, parallel-arm design with an active placebo control condition the benzodiazepine midazolam. Methods: 72 psychotropic medication-free patients with TRD received a single 40minute IV infusion of either ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045 mg/kg) in a 2:1 randomization scheme. The primary outcome was change in MADRS score from baseline to 24 hours post-infusion and proportion of participants meeting response criteria at 24 hours. Secondary outcomes included the (1) durability of antidepressant benefit over the subsequent 7-day interval and (2) safety and tolerability of the interventions. Results: A treatment x time interaction demonstrated differential change for the two groups over the first 24 hour period (F(1,70) = 9.62, p < 0.003). Ketamine demonstrated a 16.5 point decrease (t(46) = -10.31, p < 0.0001) on the MADRS while midazolam showed an 8.8 point decrease (t(24) = -4.63, p < 0.0001). At 24 hours postinfusion, the response rate in the ketamine arm was 63.8%, compared to 28.0% in the midazolam arm (p=0.006). Controlling for site differences, ketamine increased the odds of responding by a factor of 2.16 (95% CI 1.31-4.09). At Day 7, the response rate in the ketamine arm was 45.7%, compared to 18.2% in the midazolam arm (p < 0.034). After controlling for site differences, ketamine increased the odds of responding by a factor of 1.97 (95% CI 1.01-4.34). Both study drugs were well-tolerated. Discussion: In the largest clinical trial testing the efficacy of IV ketamine in mood disorders conducted to date, ketamine was associated with a rapid and large antidepressant effect at 24 hours, significantly superior to midazolam, and this superior efficacy was maintained seven days post-infusion. Ketamine appears to possess rapid antidepressant effects independent of its transient psychoactive effects a conclusion validated by the novel use of midazolam as an active control condition in this study.