Characterization of Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder Utilizing Ketamine as an Experimental Medicine Probe

项目总结/摘要 创伤后应激障碍和重性抑郁障碍共病（PTSD+MDD）是最常见的 对创伤的常见病理反应，是一个重大的公共卫生负担。不幸的是， 关于这种合并症的神经生物学机制的知识非常有限。没有 如果没有这样的理解，这一共同群体的治疗结果将仍然很差。 这个K23职业发展奖旨在为PI提供必要的培训，使其成为一名 独立调查员开展方案研究，说明其背后的机制 PTSD+MDD。为此，候选人提出以下培训目标：（1）获得专业知识 在执行功能障碍的评估，（2）获得必要的知识和技能，在神经影像学， 对PTSD+MDD的神经生物学模型进行独立研究，以及（3）获得先进的 统计方法培训。为支持这些培训目标，已经组建了一个专家导师小组。 拟议项目的总体研究目标是使用实验医学概念化， 重复氯胺酮输注作为探针，以（1）表征支持PTSD+MDD的神经生物学因素， (2)证明皮质边缘功能连接的调节产生临床改善和（3） 验证PTSD+MDD的一致模型，为未来的研究，治疗和概念化提供信息。 核心假设是皮质边缘连接障碍与临床症状相关， PTSD+MDD患者的沉思和认知功能障碍以及氯胺酮输注纠正连接障碍 从而改善临床症状、沉思和认知。本研究的具体目的是：（1） 研究基线PTSD+MDD的临床表现、认知功能和神经回路如何预测临床 对氯胺酮输注的反应，（2）检查皮质边缘回路的变化与 氯胺酮或生理盐水输注后临床症状和认知的变化，以及（3）检查 认知，反刍，和神经回路在一个更大的队列创伤暴露的主题和健康对照。 本课题的创新点包括：（1）方法：以氯胺酮为实验药物 用于表征PTSD+MDD的连贯模型的生物基质的探针;（2）设计： 应用治疗前和治疗后神经影像学评估来确定预测对以下治疗的反应的生物标志物： PTSD+MDD的经验验证治疗;（3）概念：提出一种新的PTSD+MDD模型， 是建立在神经解剖学和认知功能系统的病理生理学牵连， PTSD+MDD。这项研究意义重大，因为它提出了一个PTSD+MDD的连贯模型， 有可能促进我们对创伤后病理反应个体的理解。

PROJECT SUMMARY/ABSTRACT Comorbid posttraumatic stress disorder and major depressive disorder (PTSD+MDD) is the most common pathological response to trauma and represents a major public health burden. Unfortunately, knowledge regarding the neurobiological mechanisms underlying this comorbidity is extremely limited. Without such an understanding, treatment outcomes for this common constellation will remain poor. This K23 Career Development Award aims to provide the PI with the necessary training to become an independent investigator conducting programmatic research delineating the mechanisms underlying PTSD+MDD. Toward this end, the candidate proposes the following training objectives: (1) to acquire expertise in the assessment of executive dysfunction, (2) to gain the requisite knowledge and skills in neuroimaging to conduct independent research of a neurobiologically-based model of PTSD+MDD, and (3) to obtain advanced training in statistical methods. An expert team of mentors has been assembled to support these training goals. The overall research objective of the proposed project is to use an experimental medicine conceptualization of repeated ketamine infusions as a probe to (1) characterize neurobiological factors underpinning PTSD+MDD, (2) demonstrate that modulation of corticolimbic functional connectivity generates clinical improvement and (3) validate a coherent model of PTSD+MDD to inform future research, treatment, and conceptualizations. The central hypothesis is that corticolimbic dysconnectivity is associated with clinical symptoms, rumination and cognitive dysfunction in PTSD+MDD and that ketamine infusions correct dysconnectivity thereby improving clinical symptoms, rumination, and cognition. The specific aims of this research are (1) to examine how baseline PTSD+MDD clinical presentation, cognitive function and neurocircuitry predicts clinical response to ketamine infusions, (2) to examine the association of changes in corticolimbic circuitry with changes in clinical symptoms and cognition following either ketamine or saline infusions, and (3) to examine cognition, rumination, and neurocircuitry in a larger cohort of trauma exposed subjects and healthy controls. Innovative aspects of this project include: (1) Method: Use of ketamine as an experimental medicine probe to characterize biological substrates underlying a coherent model of PTSD+MDD; (2) Design: Application of pre- and post-treatment neuroimaging assessments to identify biomarkers predicting response to an empirically validated treatment for PTSD+MDD; (3) Concept: Proposing a novel model of PTSD+MDD that is built on neuroanatomical and cognitive functioning systems implicated in the pathophysiology of PTSD+MDD. The proposed research is significant because it proposes a coherent model of PTSD+MDD that has the potential to advance our understanding of individuals with pathological responses to trauma.