This R21/R33 application in response to RFA-MH-15-300 seeks to demonstrate target engagement and clinical viability for a novel combination therapy for Posttraumatic Stress Disorder. PTSD is associated with poor quality of life and comorbidity with both physical and mental illness. While exposure-based psychological treatments have proven efficacious, up to 40% retain PTSD diagnoses following treatment. Thus, new protocols to boost treatment efficacy can have a significant public health impact. Recent basic research suggests that consolidation of fear extinction learning memories is at least partly dopamine-mediated and that boosting dopamine signaling in the consolidation window can decrease fear responding during subsequent exposure to fear cues. The overall goal of the proposed project is to demonstrate the viability of boosting dopamine signaling in the post-learning consolidation window as a novel means of boosting therapy outcomes among adult women with PTSD related to assaultive violence (physical or sexual assault). In the R21 target engagement phase, we will test the impact of endogenous and exogenous manipulations of dopamine neurotransmission on 1) acute functional organization of dopaminergic resting-state networks, and 2) the consolidation of generic (i.e., laboratory-induced) fear extinction learning using concurrent neuroimaging, psychophysiological, and self-report assessments among women with PTSD (Aim 1). In the R33 clinical phase, we seek to replicate and extend target engagement to the clinical context of fear extinction learning for ideographic trauma memories and emotional responding to trauma cues among women with PTSD using concurrent neuroimaging, psychophysiological, and self-report assessments (Aim 2). Successful demonstration of target engagement (Aim 1) and efficacy for the clinical target of trauma memories and emotional responding to trauma cues (Aim 2) would provide critical scientific support of the viability of combining exposure-based therapy with pharmacological agents that boost dopamine signaling as a means to improve treatment outcomes for PTSD.
This application aims to test among adult women with PTSD whether boosting dopamine signaling improves generic and trauma-specific fear extinction learning. Successful pursuit of these goals would advance our ability to treat this chronic and vulnerable population.