PROJECT SUMMARY This study will leverage large-scale clinical data from the Department of Veterans Affairs (VA) to identify existing pharmaceutical agents commonly prescribed for a multitude of indications that are incidentally associated with improvements in post-traumatic stress disorder (PTSD) symptoms. Through prior efforts, a data source containing almost 20 years of treatment data on all (over one million) VA users diagnosed with PTSD between October 1999 and February 2018 has been constructed, including a complete historical record of their evidence-based medication and psychotherapy receipt within the VA healthcare system. Importantly, the team has also amassed symptom-level patient-reported PTSD outcome data for hundreds of thousands of these patients. The existing data is a powerful resource with which the research team proposes to explore the following specific aims: (1) identify off-label pharmaceutical agents associated with improvements in PTSD symptoms over time; (2) further evaluate the clinical effectiveness of newly-identified off-label pharmaceutical agents for improvement in PTSD symptoms using rigorous causal methods; and (3) identify common adverse events related to off-label pharmaceutical agents associated with improvements in PTSD symptoms in this complex, psychiatrically and medically ill population The proposed project will identify agents that may merit further rigorous clinical evaluation for psychiatric benefit. New therapeutic targets may be identified that will lead to greater treatment options or specific treatments. Further, identification of off-label medications that improve or have contraindicated effects for psychiatric populations will provide critical guidance to practicing clinicians.