Project Summary Posttraumatic Stress Disorder (PTSD) is a debilitating and a chronic mental illness. There are currently only two FDA-approved medications for the treatment of PTSD, both of which may take weeks to months to reach full clinical effects. The rates of nonresponse to these selective serotonin reuptake inhibitor antidepressants are high. Therefore, there is a tremendous need to test novel pharmacological approaches to PTSD. Trauma focus psychotherapies on the other hand require a high level of commitment by attending weekly visits for a substantial amount to time. An average course of Prolonged Exposures therapy (PE) or Trauma focus CBT usually lasts about 3 months until completion with high dropout rate and about 50% of completers being classified as non-responders. Recent studies demonstrated the effectiveness of intensive exposure therapy for PTSD which is being delivered within 1-2 weeks period that are as affective as a 3-month full course treatment but have a lower dropout rate. There are evidences to suggest that fear extinction may be further enhanced with the use of ketamine, an N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist mostly used as anesthetic. Interest in ketamine as a possible treatment for PTSD began when it was found to alleviate depressive symptoms. Two recent studies have reported that ketamine reduces PTSD symptoms during the course of drug administration period and up to 7-day post treatment, but all participants convert to PTSD soon after drug discontinuation. Using a biomarker-informed, double blind placebo-controlled design, the present proposal aims to examine the efficacy of ketamine infusion (0.5mg/kg vs 0.2mg/kg in the R61 phase to established dose; selected superior dose will advance to the R33), as compared to an active placebo (midazolam 0.045mg/kg) in enhancing postretrieval extinction of Criterion A original trauma memory. Pharmacological intervention will be combined with an intensive 4-day exposure therapy, utilizing elevated BDNF levels and increased neuroplasticity, to potentially produce a rapid and sustained reduction in PTSD symptomatology. In addition, we propose use of state-of-the-art neuroimaging assessments at baseline and at the end of treatment trial to gain insight into the neurobiology of PTSD and the neural mechanisms dictating treatment response or resistance.