Neurobiological Mechanisms of Treatment Response in Geriatric Depression

这是K-24职业生涯中期研究人员奖(POR)的重新提交的申请。该奖项的目的是支持海伦·拉夫雷茨基医学博士的职业发展，她致力于了解老年抑郁症治疗反应的潜在神经生物学机制。职业发展计划将使候选人能够：(1)发展专注于[F-18]FalyPride正电子发射断层扫描(PET)的功能神经成像方面的专长，这与她不断研究哌酸甲酯治疗老年期抑郁症的多巴胺能机制相关；(2)将她的知识和技能扩展到通过拟议的课程和教程使用功能磁共振成像(FMRI)；(3)通过使用侧重于治疗老年情绪障碍伴认知障碍或照顾者压力的生物标志物的能力，增强她领导临床研究的能力；(4)改善她的指导技能以及招募和指导代表不足的少数族裔和女性受训人员的能力。指导计划的目标是那些想要学习设计和进行以患者为导向的晚年情绪障碍研究的初学者。在候选人的指导下，学员将通过进行老年情绪障碍的研究，以及准备科学报告和入门级K奖来获得实践经验。该研究计划的重点是[F-18]FolyPride PET的试点使用，以调查增强的多巴胺能神经传递在西酞普兰(MPH)增强西酞普兰的临床试验背景下的作用，以改善16名老年抑郁症患者的临床和认知结果。这项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，接受西酞普兰治疗的受试者在抑郁严重程度和执行认知测试中将经历更大的减轻和改善，这将与纹状体/非纹状体BP的[(18)F]FolyPride百分比变化更大有关。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心身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.