PROJECT SUMMARY Post-traumatic stress disorder (PTSD) often has complex profiles of co-occurring medical conditions and is associated with high risk of self-harm, including suicidality, which is a leading cause of death, particularly among Veterans. There is a critical lack of advancement in PTSD pharmacotherapy, as illustrated by increased use of off-label medications and polypharmacy (multiple drugs used simultaneously) with limited evidence on their relative risks and benefits. Moreover, PTSD and suicidal and nonsuicidal self-harm often remain undocumented in electronic health records (EHR). There is also poor predictability of disease outcomes since there are frequent changes in pharmacological treatment and multiple modifying co-occurring conditions including depression, bipolar disorder, schizophrenia, substance use disorders, traumatic brain injury, and sleep disorders. Our long-term goal is to improve diagnostics, secondary/tertiary prevention, and treatment outcomes of PTSD and its co-occurring conditions via enhanced EHR utilization. To achieve our objectives, we will analyze EHR and administrative claims data from Veterans Health Administration (VHA) and non-VHA databases, collectively covering >1.8M patients with PTSD. Specifically, we aim to: (1) Identify undetected and uncoded co-occurring mental health phenotypes that impact PTSD outcomes using machine learning and characterize disparities in their documentation; (2) Create robust models, accounting for biases and co-occurring conditions, to identify clinical trajectories of PTSD decompensation/recovery in response to time-varying treatments; and (3) Compare risk of self-harm and hospitalization among PTSD treatments using coded and imputed phenotypes through an international network study. We will compare the effectiveness of PTSD psychotropic monotherapies, polypharmacy, and psychotherapy to guide the choice of treatment for improved patient outcomes. By enhancing and validating a positive-unlabeled machine learning approach developed by our team, we will impute unrecorded/undetected mental health conditions co-occurring with PTSD in both VHA and non-VHA databases, and characterize factors associated with documentation disparities. We will model disease trajectories with enhanced latent class / latent trajectory analysis, focusing on self-harm, substance use disorders, and psychiatric hospitalization in PTSD. Finally, we will perform the largest comparative effectiveness studies to date of PTSD treatments on >100 monotherapy and polypharmacy regimens, in addition to psychotherapy interventions, using causal models and methods for addressing biases. These studies will provide high-quality evidence on the risk of hospitalizations and suicidal acts/self-harm. Successful completion of these investigations will improve the quality of clinical psychiatric decision-making, and guide improved service delivery to the Veteran and non-Veteran populations with PTSD/TBI, and/or high risk of self-harm/suicidality.

PROJECT NARRATIVE Post-traumatic stress disorder (PTSD), and its associated conditions (e.g., traumatic brain injury and suicidality) are often underdiagnosed, and have outcomes that are difficult to predict. Treatment of PTSD often involves frequent treatment changes with multi-drug regimens (polypharmacy) and off-label medications for which the relative risks and benefits are largely unknown. To address these problems, we will develop and apply methods to identify undiagnosed patients, predict disease trajectories, and compare the effectiveness of all common PTSD treatments using health records from millions of patients in Veterans Administration (VA) and non-VA databases.