NEUROANATOMY AND PHARMACOTHERAPY OF OCD AND MAJOR DEPRES

本申请提出Sanjaya Saxena，M.D.以病人为导向的研究职业发展奖。 总体目标是为他提供必要的概念背景和研究技能，以进行强迫症（OCD）和重度抑郁症（MDD）的患者为导向的研究。 在他的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，功能性神经影像学，定量图像分析，生物统计学，研究设计和研究伦理学的培训。 基于他之前在强迫症和抑郁症脑功能成像以及难治性强迫症药物治疗方面的工作，他在获奖期间的研究将包括本文提出的两项主要研究，即功能神经解剖学、药物治疗和对强迫症和抑郁症治疗反应的不同时程，共研究42名受试者：1）并发强迫症和抑郁症治疗的脑代谢变化：本研究将使用[18 F]-氟-脱氧葡萄糖正电子发射断层扫描（FDG-PET）来描述在接受帕罗西汀治疗的患者中同时发生的OCD症状和MDD症状的特定脑系统介导，帕罗西汀是一种对两种疾病均有效的药物。 在治疗四周后和12周后，将测量同一大脑内沿沿着的额叶-皮层下回路发生的不同代谢变化，并将其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抑郁症的介导，以及对这些回路的药理作用的不同时间过程，可能会导致未来改善这两种常见疾病的治疗。 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：本研究的具体目的如下：a）用FDG-PET鉴定脑代谢模式，其可预测对单独帕罗西汀与帕罗西汀加利培酮的反应，B）鉴定症状或其他临床变量，如自知力或妄想水平，其可预测对连续性利培酮的反应，和c）检查连续性利培酮对帕罗西汀难治的强迫症患者的疗效。凭借在获奖期间获得的额外技能和经验，Saxena博士将做好充分准备，以争取独立的研究支持，并对强迫症和MDD进行以患者为导向的神经影像学和药理学研究，长期目标是改善这些疾病的治疗。

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.