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

利用氯胺酮作为实验医学探针表征共病创伤后应激障碍和重度抑郁症

• 批准号: 10589027
• 负责人: Cristina Sophia Albott
• 金额: $ 20.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589027
• 关键词: Aftercare; Amygdaloid structure; Bilateral; Biological; Biological Factors; Chronic stress; Clinical; Clinical Research; Cognition; Data; Depressed mood; Development; Disease; Disease model; Executive Dysfunction; Extinction; Functional disorder; Goals; Grant; Health; Hippocampus; Human; Impaired cognition; Impairment; Individual; Infusion procedures; Intervention; K-Series Research Career Programs; Ketamine; Knowledge; Learning; Major Depressive Disorder; Measures; Medicine; Memory; Mental Depression; Mentors; Methods; Modeling; Neuroanatomy; Neurobiology; Neuronal Plasticity; Participant; Pathologic; Patient Self-Report; Pattern; Performance; Placebos; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Public Health; Randomized; Recovery; Research; Research Personnel; Saline; Series; Statistical Methods; Stress; Symptoms; System; Training; Training Support; Trauma; Treatment outcome; Veterans; biomarker identification; clinical predictors; cognitive function; cohort; comorbidity; design; disability; experience; functional disability; health care service utilization; high risk population; improved; improved outcome; innovation; neural circuit; neurobiological mechanism; neuroimaging; novel; predicting response; rehearsal; response; rumination; skills; suicidal risk; synaptic function; trauma exposure

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.

项目摘要/摘要 创伤后应激障碍和严重抑郁障碍(PTSD+MDD)共病最多 创伤常见的病理反应，是主要的公共卫生负担。不幸的是， 关于这种共病背后的神经生物学机制的知识极其有限。如果没有 这样的理解和治疗对这一常见星座的结果将仍然很差。 这项K23职业发展奖旨在为PI提供必要的培训，使其成为 独立调查员进行方案研究，描述潜在的机制 创伤后应激障碍+MDD。为此，应聘者提出了以下培训目标：(1)获得专业知识 在评估执行功能障碍时，(2)获得必要的神经成像知识和技能，以 进行基于神经生物学的PTSD+MDD模型的独立研究，以及(3)获得先进的 统计方法方面的培训。已经组建了一个由导师组成的专家团队来支持这些培训目标。 拟议项目的总体研究目标是使用实验医学概念化 重复输注氯胺酮作为探针，以(1)表征支撑PTSD+MDD的神经生物学因素， (2)证明调节皮质边缘功能连接可带来临床改善；(3) 验证创伤后应激障碍+MDD的连贯模型，为未来的研究、治疗和概念化提供信息。 中心假设是皮质边缘连接障碍与临床症状有关， PTSD+MDD患者的冥想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、反思冥想和认知。本研究的具体目的是：(1) 检查基线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 输注氯胺酮或生理盐水后临床症状和认知的变化；(3)检查 在更大的创伤暴露受试者和健康对照队列中的认知、沉思和神经回路。 本项目的创新方面包括：(1)方法：使用氯胺酮作为实验药物 探索PTSD+MDD相关模型下的生物底物特征；(2)设计： 应用治疗前和治疗后神经影像评估确定预测疗效的生物标志物 经验性验证的PTSD+MDD治疗；(3)概念：提出一种新的PTSD+MDD模型， 建立在神经解剖学和认知功能系统的基础上，这些系统与 创伤后应激障碍+MDD。这项拟议的研究具有重要意义，因为它提出了PTSD+MDD的连贯模型 有可能促进我们对创伤病理反应个体的理解。