Background and Study Objective: Posttraumatic stress disorder (PTSD) affects as many as 15% of service members and Veterans following deployment. Current treatments are insufficient: most medications for PTSD decrease symptom intensity only moderately, and often appear to be less effective in Veterans than civilians. Prazosin, an antagonist of one of the major receptors for noradrenaline, has demonstrated significant efficacy for particularly hyperarousal symptoms and trauma nightmares in Veterans and service members with PTSD, but is still not effective for approximately 1/3 of the population. Recently, in a post hoc analysis, it was found that a simple, clinically-accessible measurement of the strength of noradrenergic signaling (standing blood pressure) was able to predict who would respond to prazosin. If this result is validated in a prospective study, it would provide a rapidly useful clinical tool. In addition, preliminary data from an observational study of Veterans suggests that exposure to life-threatening or similarly severe trauma (with or without diagnoseable PTSD) may change the way post-synaptic neurons adjust the strength of their reaction to noradrenaline. If this observation is supported by further data, it could lead to new treatment approaches. Study Design and Methods: We will test several new and emerging biomarkers of noradrenergic signaling in Veterans with PTSD, in Veterans with a history of combat trauma but without PTSD, and in Veterans who have been deployed but without a history of trauma exposure. These biomarkers will include systolic blood pressure two minutes after standing; the average dilation velocity of the pupil following the completion of a brief pulse of light; and the maximal dilation of the pupil in response to phenylephrine eye drops. We will also measure levels of noradrenaline in plasma and in cerebrospinal fluid. Using these measures, we will test the hypothesis that exposure to trauma results in a failure to downregulate the post-synaptic response to noradrenaline when the amount of noradrenaline released increases, and that it is the combination of increased noradrenaline release and a lack of postsynaptic downregulation that leads to PTSD symptom expression. For those with current PTSD, we will also administer the anti-adrenergic drug prazosin, using a modified crossover trial design that integrates concepts from N-of-1 trial methodology, in order to test the hypothesis that baseline measures of overall noradrenaline signaling are able to predict who will respond to prazosin and who will not. Career Goals: The research proposal and training plan are designed to prepare the applicant for a long-term translational VA research career studying the role of noradrenergic dysregulation in the pathophysiology of PTSD, and using this knowledge to develop improved treatments. Particular emphasis will be placed on the impact of noradrenergic dysregulation in the alteration of sleep structure and function, and how this may lead to the development or perpetuation of daytime symptoms of PTSD ? as well as whether interventions that modulate noradrenergic signaling are successful in normalizing sleep structure and function. Key Elements of the Research Career Development Plan: The research and training plan will prepare the applicant for a long-term translational research career by providing advanced training in the quantification of biologic processes in translational studies in humans, including the quantification of sleep structure and biofluid biomarkers, and in the development of novel mechanism-focused clinical trial designs. The research plan will also provide a scientific basis for a long term research program studying the pathophysiology of PTSD. Mentoring/Training Plan: The mentorship and training plan, which is built around the research plan, incorporates formal graduate-level coursework, intensive off-site training periods, local seminars and journal clubs, and ongoing mentorship from a highly experienced team of mentors and consultants. This team includes experts in translational PTSD research, noradrenergic and autonomic biomarkers, pupillary biomarkers, the quantitative assessment of sleep, mechanism-focused clinical trial design, neuropsychology, and biostatistics.
This work is expected to contribute to Veteran's health in three major ways: (1) We are testing a method to predict in advance, based on a simple, non-invasive office test, which Veterans with PTSD are most likely to respond to the medication prazosin. If this is successful, it will contribute to a precision medicine approach to matching Veterans to the treatment most likely to work for them. (2) The same test could also be used in a research context, so that new treatments could be tested specifically in the individuals most likely to respond to them. (3) Our results will also provide new information about what brain changes follow exposure to a severe emotional trauma, and why in some people these changes result in the development of PTSD, while others are resilient. This information is expected to help in the development of new strategies for treating, or even preventing, PTSD. Many of these results may also turn out to be helpful for Veterans with other types of anxiety disorders, or with problems falling or staying asleep.
