PROJECT SUMMARY/ABSTRACT No medication has shown consistent benefit for the multiple clinical problems of individuals who have experienced severe traumatic stress. Behavioral sensitization to stressors and cross- sensitization between stressors and addictive stimuli may underlie the strong associations between PTSD and early-life trauma, substance and alcohol use disorders, and recurrent psychiatric disorders. Low-dose N-methyl-D-aspartate receptor (NMDAR) antagonists affect mechanisms of interactions between trauma and illness-course by blocking cross-sensitization between traumatic and addictive stimuli, improving regulation of arousal, and rapidly reducing depressed mood and suicidal ideation. This Phased Innovation (R61/R33) application proposes a milestone-driven, experimental medicine approach to testing an investigational NMDAR antagonist, lanicemine (AZD6765), in adults with severe PTSD-related symptoms and psychophysiological manifestations of elevated anxious reactivity. We hypothesize that lanicemine, a potent and selective probe of NMDAR function with a favorable safety and tolerability profile, could impact a mechanistic biomarker (anxiety potentiated startle) and ultimately benefit subgroups of patients with severe PTSD symptoms. The proposed R61 clinical trial, conducted at three academic medical centers [Baylor College of Medicine, Yale University School of Medicine, and Icahn School of Medicine at Mount Sinai], examines the safety and efficacy of 2 dosage levels of parenterally-administered lanicemine in a parallel-arm, randomized, double-blind, placebo-controlled trial in adult patients (N=36) with severe PTSD and elevated anxiety potentiated startle (APS). We hypothesize that lanicemine displays a dose-dependent normalization of APS following three infusions over 5 days. If functional target engagement is demonstrated and the drug is safe and tolerable in this patient population, we will proceed to the R33 study. The R33 study examines the best dose of lanicemine in a larger sample of patients (N=90) in a randomized double-blind, placebo-controlled trial of longer duration, and tests whether normalization of APS is associated with clinical benefit. Secondary measures of functional target engagement and target validation include P50 auditory evoked potentials, quantitative gamma-band EEG, and Mismatch Negativity, which are examined with respect to their relationship to changes in APS and clinical measures. The long-term goal of this application is to determine whether there is sufficient biological and clinical rationale to proceed with this pharmacological mechanism for the treatment of this underserved and debilitated patient population.