NEUROANATOMY AND PHARMACOTHERAPY OF OCD AND MAJOR DEPRES

本申请推荐Sanjaya Saxena， M.D.获得以患者为导向的指导研究职业发展奖。总体目标是为他提供必要的概念背景和研究技能，使他能够开展以患者为导向的强迫症（OCD）和重度抑郁症（MDD）研究。在主要导师和专家顾问的指导下，他将接受神经解剖学、神经精神药理学、功能神经影像学、定量图像分析、生物统计学、研究设计和研究伦理等方面的培训。基于他之前在OCD和MDD的功能脑成像以及难治性OCD的药物治疗方面的工作，他在获奖期间的研究将包括两个主要的研究，在此提议，关于功能神经解剖学，药物治疗，以及OCD和MDD治疗的差异时间反应过程，研究共42个受试者：1)治疗并发OCD和MDD的脑代谢变化。本研究将使用[18F]-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET），描绘在接受帕罗西汀治疗的患者中，强迫症症状和重度抑郁症症状同时发生的特定脑系统介导，帕罗西汀对这两种疾病都有效。在治疗4周后和12周后，在同一大脑内平行的额叶-皮层下回路上发生的不同代谢变化将被测量，并将与特定症状的变化相关联。了解额叶-皮层下回路对强迫症和重度抑郁症的介导作用，以及这些回路的药理作用的不同时间过程，可能会在未来改善这两种常见疾病的治疗方法。2)难治性强迫症患者对帕罗西汀和利培酮反应的脑代谢预测因素：本研究有以下具体目的：a)用FDG-PET识别可能预测单独使用帕罗西汀与帕罗西汀加利培酮反应的脑代谢模式，b)识别可能预测辅助使用利培酮反应的症状或其他临床变量，如洞察力或妄想水平，以及c)检查辅助使用利培酮对帕罗西汀难治的强迫症患者的疗效。凭借在奖励期间获得的额外技能和经验，Saxena博士将为争取独立研究支持做好充分准备，并开展以患者为导向的OCD和MDD神经影像学和药理学研究，以改善这些疾病的治疗为长期目标。

This application proposes Sanjaya Saxena, M.D. for a Mentored Patient-Oriented Research Career Development Award. The overall goals are to provide him with the conceptual background and research skills necessary for him to conduct patient-oriented research on obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Under the guidance of his Primary Mentor and Expert Consultants, he will be trained in neuroanatomy, neuropsychopharmacology, functional neuroimaging, quantitative image analysis, biostatistics, research design, and research ethics. Building upon his prior work in functional brain imaging in OCD and MDD, as well as in pharmacotherapy for refractory OCD, his research during the Award period will include two main studies, proposed herein, on the functional neuroanatomy, pharmacotherapy, and differential time course of response to treatment of OCD and MDD, studying a total of 42 subjects: 1) Cerebral Metabolic Changes with Treatment of Concurrent OCD and MDD: This study will use [18F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), to delineate the specific brain system mediation of OCD symptoms and MDD symptoms occurring simultaneously, in patients treated with paroxetine, a medication shown to be effective for both disorders. Differential metabolic changes occurring along parallel, frontal-subcortical circuits within the same brain will be measured after four weeks and again, after twelve weeks of treatment, and will be correlated with changes in specific symptoms. Understanding the mediation of OCD and MDD by frontal-subcortical circuits, as well as the differential time course of pharmacological effects on these circuits, may lead to improved treatments for both of these common disorders in the future. 2) Cerebral Metabolic Predictors of Response to Paroxetine and Risperidone in Refractory OCD: This study has the following specific aims: a) to identify cerebral metabolic patterns with FDG-PET that might predict response to paroxetine alone vs. paroxetine plus risperidone, b) to identify symptoms or other clinical variables, such as level of insight or delusionality, which might predict response to adjunctive risperidone, and c) to examine the efficacy of adjunctive risperidone for OCD patients who are refractory to paroxetine. With the additional skills and experience acquired during the Award period, Dr. Saxena will be well-prepared to compete for independent research support, and to conduct patient-oriented, neuroimaging and pharmacological research on OCD and MDD, with the long-term goal of improving treatment for these disorders.