Noradrenergic biomarkers in PTSD: precision medicine & mechanisms

背景和研究目的：创伤后应激障碍(PTSD)影响多达15%的服役人员 部署后的成员和退伍军人。目前的治疗方法是不够的：大多数治疗创伤后应激障碍的药物 仅适度降低症状强度，而且通常对退伍军人的效果不如平民。 去甲肾上腺素的主要受体之一的拮抗剂哌唑嗪已显示出显著的疗效。 尤其是患有创伤后应激障碍的退伍军人和军人的过度觉醒症状和创伤噩梦， 但对大约三分之一的人口仍然无效。最近，在一次特别分析中发现， 一种简单的、临床可用的去甲肾上腺素信号强度的测量(站立血 压力)能够预测谁会对哌唑嗪有反应。如果这一结果在前瞻性研究中得到验证，它 将提供一种快速有用的临床工具。此外，来自一项观察性研究的初步数据 退伍军人建议暴露在危及生命的或类似的严重创伤中(有或没有可诊断的 创伤后应激障碍)可能会改变突触后神经元调整其对去甲肾上腺素反应强度的方式。如果这个 观察得到了更多数据的支持，它可能导致新的治疗方法。 研究设计和方法：我们将测试几个新的和新兴的去甲肾上腺素信号转导的生物标志物。 患有创伤后应激障碍的退伍军人，有战斗创伤史但没有创伤后应激障碍的退伍军人，以及有 已经部署，但没有创伤接触史。这些生物标记物将包括收缩压 站立后两分钟；完成一个短暂的脉冲后的平均散瞳速度 光；以及对苯肾上腺素滴眼液反应的最大瞳孔放大。我们还将测量水平 血浆和脑脊液中的去甲肾上腺素。使用这些衡量标准，我们将检验以下假设 暴露在创伤中导致未能下调突触后对去甲肾上腺素的反应 去甲肾上腺素的释放量增加，这是去甲肾上腺素释放增加的组合 缺乏突触后下调，导致创伤后应激障碍症状表达。对于那些拥有当前 对于创伤后应激障碍，我们还将使用抗肾上腺素能药物哌唑嗪，使用改进的交叉试验设计 整合N-of-1试验方法学的概念，以检验基线测量的假设 总体而言，去甲肾上腺素信号能够预测谁会对哌唑嗪有反应，谁不会。 职业目标：研究计划和培训计划旨在为申请者的长期发展做好准备 翻译VA研究生涯，研究去甲肾上腺素能失调在心力衰竭病理生理学中的作用 创伤后应激障碍，并利用这一知识开发改进的治疗方法。特别强调的将是 去甲肾上腺素能失调在睡眠结构和功能改变中的影响及其可能导致的 与创伤后应激障碍白天症状的发展或持续有关--以及干预措施是否 调节去甲肾上腺素能信号成功地使睡眠结构和功能正常化。 研究职业发展计划的主要内容：研究和培训计划将准备 长期从事翻译研究的申请者，提供量化方面的高级培训 人类翻译研究中的生物过程，包括睡眠结构和生物体液的量化 生物标记物，以及开发新的以机制为重点的临床试验设计。这项研究计划将 也为长期研究创伤后应激障碍的病理生理学提供了科学依据。 指导/培训计划：围绕研究计划建立的指导和培训计划， 包括正式的研究生级别的课程、密集的场外培训、当地研讨会和日记 俱乐部，以及经验丰富的导师和顾问团队的持续指导。这个团队包括 翻译创伤后应激障碍研究、去甲肾上腺素和自主神经生物标记物、瞳孔生物标记物、 睡眠的定量评估、以机制为中心的临床试验设计、神经心理学和生物统计学。

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.