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Post-Traumatic Stress Disorder: Heterogeneity and Translation

NAMHC Concept Clearance

Presenter

Farris Tuma, Sc.D.
Chief, Traumatic Stress Disorders Research Program
Division of Adult Translational Research and Treatment Development

Goal

NIMH is proposing multiple efforts to address the challenges of heterogeneity and translation in post-traumatic stress conditions. This initiative involves two related but distinct components: to interrogate mechanisms responsible for subtypes of impairment in small scale translational experiments; and to acquire longitudinal and dimensional data on emergence and course of post-traumatic clinical phenomena to enhance early prediction and classification of conditions and identify targets for prevention. These initiatives are responsive to the 2012 White House Executive Order on Improving Access to Mental Health Services for Veterans, Service Members, and Military Families, section 5, calling for research to accelerate discovery of underlying mechanisms and rapidly translate this understanding into actionable tools for prevention, early diagnosis, and better treatment.

Rationale

On any given day in the United States, 7-8 million people are struggling with post-traumatic stress disorder (PTSD). Current estimates suggest that roughly 20% of the over 2 million service-members who have served in Iraq and Afghanistan will be affected by PTSD, traumatic brain injury, or both. Advances in basic science have not been easily translated into mechanisms underlying the heterogeneous changes seen in response to stress in humans, particularly among clinical populations. Historically, the manifestations of mental health problems following traumatic stress exposure have been considered largely under the umbrella of PTSD, with recognition that there was great variability in presentation and high comorbidity with other conditions, including depression, substance abuse, and a variety of other symptoms and behaviors. The heterogeneity within PTSD has complicated our ability to identify the mechanisms and course of dysfunction. Although PTSD is the only disorder with a clear precipitating event, we lack an understanding of the different pathophysiological changes that characterize various subtypes of the PTSD syndrome or that distinguish those who will recover naturally from those who might benefit from interventions targeted toward particular mechanisms. NIMH is proposing the two initiatives to address the challenges of translation and heterogeneity in PTSD:

Mechanisms of Fear, Learning, and Memory
This initiative would encourage translational research through collaboration between basic and clinical researchers targeting fear, learning, and memory processes. The goal would be to apply/interrogate putative mechanisms that underlie changes seen in response to stress to humans, particularly clinical populations. Multi-stage research grants are envisioned, involving collaboration between basic and clinical researchers, to develop proof-of-principle studies (from model animals to humans with well characterized paradigms of specific fear, learning, and memory dysfunctions) prior to progression to pilot clinical studies.

Probing Early Pathophysiology in Post-traumatic Stress Conditions
This initiative would aim to identify specific phenotypes of distress and dysfunction and understand the course and trajectory to optimize “treatments as prevention” based on the related pathophysiological changes observed/expected. The initiative may involve new projects and longitudinal designs to identify and probe early pathophysiological changes and adjustment post exposure in trauma patients seen in emergency rooms and other acute trauma settings. Additionally, this effort may involve secondary analyses of existing biological, experiential, demographic, and cognitive data to supplement new data collection. The overall goal would be reliable, multi-method risk prediction algorithm(s) based on biomarkers and cognitive tests that yield phenotypes of post-traumatic stress conditions for further research, as well as an actionable understanding of the course and trajectory of these conditions to optimize prevention based on markers of pathophysiological changes.

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