NEUROANATOMY AND PHARMACOTHERAPY OF OCD AND MAJOR DEPRES

本申请推荐Sanjaya Saxena医学博士获得以患者为导向的研究事业发展奖。总体目标是为他提供必要的概念背景和研究技能，以便他进行以患者为导向的强迫症(OCD)和严重抑郁障碍(MDD)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、功能神经成像、定量图像分析、生物统计学、研究设计和研究伦理方面的培训。在他之前在强迫症和MDD的脑功能成像以及难治性OCD的药物治疗方面工作的基础上，他在获奖期间的研究将包括两项主要研究，在本文中提出，涉及OCD和MDD治疗的功能神经解剖学、药物治疗和不同时间段的反应，总共研究42名受试者：1)同时治疗强迫症和MDD的大脑代谢变化：本研究将使用[18F]-氟代脱氧葡萄糖正电子发射断层扫描(FDG-PET)，以描绘在接受帕罗西汀治疗的患者中，同时发生的强迫症和MDD症状的特定大脑系统调节机制。沿着同一大脑内平行的额叶-皮质下回路发生的不同代谢变化将在四周后测量，并在治疗12周后再次测量，并将与特定症状的变化相关联。了解额叶-皮质下回路对强迫症和MDD的调节，以及这些回路上药理作用的不同时间进程，可能会在未来改进对这两种常见疾病的治疗。2)难治性强迫症对帕罗西汀和利培酮疗效的脑代谢预测指标：这项研究有以下具体目的：a)用FDG-PET确定可预测帕罗西汀与帕罗西汀加利培酮疗效的脑代谢模式；b)确定症状或其他临床变量，如自知力或妄想程度，可预测对辅助性利培酮的疗效；以及c)检查辅助利培酮对帕罗西汀无效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，萨克塞纳博士将做好充分准备，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成像和药理学研究，长期目标是改进这些疾病的治疗。

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.