Neurobiological Mechanisms of Treatment Response in Geriatric Depression

这是重新提交的K-24职业中期研究者奖在以患者为导向的研究（POR）的申请。该奖项的目的是支持海伦Lavretsky，医学博士的职业发展。致力于了解老年抑郁症治疗反应的潜在神经生物学机制。职业发展计划将允许候选人：（1）发展功能性神经成像方面的专业知识，重点是[F-18]fallypride正电子发射断层扫描（PET），这与她正在进行的哌甲酯治疗老年抑郁症的多巴胺能机制的研究有关;（2）通过拟议的课程和教程，将她的知识和技能扩展到功能性MRI（fMRI）的使用;（3）提高她领导临床研究的能力，使用生物标志物，重点关注患有认知障碍或照顾者压力的情绪障碍的老年患者的治疗反应;（4）提高她的指导技能，以及她招募和指导代表性不足的少数民族和妇女学员的能力。指导计划的目标是开始调查谁想要学习设计和进行以病人为导向的研究晚年情绪障碍。在候选人的监督下，学员将通过进行老年情绪障碍研究，并通过编写科学报告和入门级K奖获得实践经验。该研究计划的重点是[F-18]fallypride PET的试点使用，以研究在哌甲酯（MPH）增强西酞普兰的临床试验背景下增强多巴胺能神经传递的作用，以增强16例老年抑郁症受试者的临床和认知结局。本研究的主要目的是证明与接受西酞普兰+安慰剂的受试者相比，接受MPH+西酞普兰的受试者将经历抑郁严重程度的更大降低和执行认知测试的改善，这将与[（18）F] fallypride纹状体/非纹状体BP的更大百分比变化相关。在该奖项的支持下，本申请中提出的其他工作将集中在老年抑郁症的身心干预的使用和机制上。

This is a resubmission of an application for a K-24 Midcareer Investigator Award in patient-oriented research (POR). The objectives of the award is to support career development of Helen Lavretsky, M.D. dedicated to understanding the underlying neurobiological mechanisms of treatment response in geriatric depression. The Career Development Plan will allow the candidate to: (1) develop an expertise in functional neuroimaging focused on the [F-18]fallypride positron emission tomography (PET) that is relevant to her ongoing investigation of the dopaminergic mechanisms of methylphenidate in geriatric depression; (2) extend her knowledge and skills to the use of functional MRI (fMRI) with the proposed coursework and tutorials; (3) enhance her ability to lead clinical studies with the use of biomarkers focused on treatment response in older patients with mood disorders complicated by cognitive impairment or caregiver stress; (4) improve her mentoring skills and her ability to recruit and mentor underrepresented minority and women trainees. The Mentoring Plan is targeted towards beginning investigators who want to learn to design and conduct patient-oriented research in late-life mood disorders. Under supervision by the candidate, trainees will obtain hands-on experience by conducting research in geriatric mood disorders, and by preparing scientific reports and entry-level K awards. The Research Plan is focused on the pilot use of the [F-18]fallypride PET to investigate the role of enhanced dopaminergic neurotransmission in the context of the clinical trial of methylphenidate (MPH) augmentation of citalopram to enhance clinical and cognitive outcomes in 16 subjects with geriatric depression. The primary aims of this study are to demonstrate that subjects receiving MPH with citalopram will experience greater decrease in the severity of depression and improvement in executive cognitive tests compared to those receiving citalopram+placebo, which will be related to the greater percent change in [(18)F] fallypride striatal/nonstriatal BP. With the support of this award, additional work proposed in this application will focus on the use and the mechanisms of mind-body interventions for geriatric depression.