A Targeted Intervention of a Putative Striatal Subtype of Pharmacoresistant Depression

项目摘要 重度抑郁症是全球残疾的主要原因，影响超过3亿人。个人 难治性抑郁症（TRD）患者死亡率最高，自杀风险增加一倍， 特别是长期的痛苦和更多的资源使用。快感缺失，即无法感受到快乐， 其中最重要的风险因素的发展TRD。因为快感缺失意味着 大脑奖励回路关键区域的功能障碍，这些区域是可行的机械生物标志物 用于测试对目前没有反应的抑郁症患者的新型干预措施的参与， 可用的抗抑郁药在此K23提案中，我将部署一种新颖的目标参与设计来评估 TRD中快感缺失的生物标志物和替代干预方法。I靶向D3受体激动， 普拉克索，并评估对感兴趣的奖赏回路生物标志物，腹侧纹状体（VS）， 以及伴有明显快感缺失的TRD患者的临床、功能和自杀结局。首先我 将确定TRD受试者中奖励任务诱发的VS激活是否因此而改变 第二，评估快感缺乏是否测量，功能， 用普拉克索治疗8周后，同一组中自杀倾向的变化;第三，评估是否 基线腹侧纹状体激活与VS激活的变化和临床结果相关。这 K23提案和附带的培训计划将使我能够在三个关键方面接受高级培训 领域：分析和解释功能神经影像学数据，传统和生物标志物引导 临床试验和多个领域的生物标志物。此外，我还组织了一个跨学科的 导师团队非常适合指导我完成这个项目，由职能部门的领导者组成， 神经成像（Leanne威廉姆斯博士，初级导师），抑郁症的生物标志物（Andrew Krystal博士， 合作者），抑郁症和传统临床试验（Alan Schatzberg博士，合作导师），统计学 和创新的临床试验设计（合作者Philip Lavori博士），奖励处理（Michael博士 Treadway，合作者）和神经成像指导的重度抑郁症试验（Boadie Dunlop博士， 合作者）。此外，作为培训的一部分，我打算在任职期间继续从事临床工作。 职业发展奖，为耐药患者开设自己的咨询诊所 在斯坦福大学的情绪障碍中心的保护下， 年的奖项。开展临床工作与研究将理想地定位我问科学 问题和实施研究设计，明确地将基础科学的关键发现转化为 指导临床决策。这项提议将在斯坦福大学进行， 著名的神经科学和精神病学研究中心，以及斯坦福大学的认知和 神经生物学成像，最先进的神经成像设备。

PROJECT SUMMARY Major depression is the leading cause of disability worldwide, affecting over 300 million people. Individuals with treatment-resistant depression (TRD) experience the greatest toll, with double the risk of suicide, particularly prolonged suffering, and greater use of resources. Anhedonia, the inability to feel pleasure, is among the most important risk factors for the development of TRD. Because anhedonia implicates dysfunction in key regions of the brain’s reward circuits, these regions are viable mechanistic biomarkers for testing engagement of novel interventions for depressed people who do not respond to currently available antidepressants. In this K23 proposal, I will deploy a novel target-engagement design to evaluate a biomarker and alternative intervention approach for anhedonia in TRD. I target D3 receptor agonism with pramipexole and evaluate the effects on a reward circuit biomarker of interest, the ventral striatum (VS), as well as clinical, functional, and suicidality outcomes in TRD patients with prominent anhedonia. First, I will determine whether reward task-evoked VS activation changes in a group of TRD subjects as a result of treatment with pramipexole after 8 weeks; second, evaluate whether anhedonia measures, function, and suicidality change in the same group after 8 weeks of treatment with pramipexole; and third, assess whether baseline ventral striatal activation is associated with change in VS activation and clinical outcomes. This K23 proposal and accompanying training plan would enable me to receive advanced training in three key areas: the analysis and interpretation of functional neuroimaging data, traditional and biomarker-guided clinical trials, and biomarkers across multiple domains. Furthermore, I have assembled an interdisciplinary mentorship team ideally suited to guiding me through this project, consisting of leaders in functional neuroimaging (Dr. Leanne Williams, Primary Mentor), biomarkers in depression (Dr. Andrew Krystal, Collaborator), depressive disorders and traditional clinical trials (Dr. Alan Schatzberg, Co-Mentor), statistics and innovative clinical trial design (Dr. Philip Lavori, Collaborator), reward processing (Dr. Michael Treadway, Collaborator), and neuroimaging-guided trials in major depressive disorder (Dr. Boadie Dunlop, Collaborator). Furthermore, as part of my training, I intend to continue clinical work during the period of my Career Development Award, launching my own consultation clinic for patients with treatment-resistant mood disorders facilitated under the umbrella of the Mood Disorders Center at Stanford during the latter years of the Award. Conducting clinical work together with research will ideally position me to ask scientific questions and implement study designs that explicitly translate key discoveries from basic science into guidance for clinical decision-making. This proposal will be carried out at Stanford University, a world renowned hub of neuroscience and psychiatry research and at Stanford’s Center for Cognitive and Neurobiological Imaging, a state-of-the-art neuroimaging facility.