A Targeted Intervention of a Putative Striatal Subtype of Pharmacoresistant Depression

耐药性抑郁症假定纹状体亚型的靶向干预

• 批准号: 10215873
• 负责人: Laura Michele Hack
• 金额: $ 19.3万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215873
• 关键词: Address; Affect; Agonist; Anhedonia; Antidepressive Agents; Area Analyses; Award; Basic Science; Behavior; Biological Markers; Brain; Categories; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Consultations; Consumption; Corpus striatum structure; DSM-V; Data; Depressed mood; Depressive disorder; Dimensions; Disease remission; Dopamine; Dose; Expenditure; Fatigue; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; General Hospitals; Goals; Hamilton Rating Scale for Depression; Image; Individual; Intervention; K-Series Research Career Programs; Knowledge; Major Depressive Disorder; Massachusetts; Measures; Mental Depression; Mentors; Mentorship; Methods; Mood Disorders; Motivation; National Institute of Mental Health; Neurobiology; Neurosciences; Outcome; Patients; Physicians; Placebos; Positioning Attribute; Prevention; Psychiatry; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Research; Research Design; Resistance; Resources; Rewards; Risk Factors; Scientist; Severities; Signal Transduction; Staging; Strategic Planning; Subgroup; Suicide; Symptoms; Testing; Training; Translating; Universities; Ventral Striatum; Work; World Health Organization; behavior measurement; brain reward regions; career; clinical decision-making; design; disability; experience; financial incentive; functional MRI scan; improved; innovation; interest; neuroimaging; novel; novel marker; patient subsets; pleasure; pramipexol; predictive marker; receptor; recruit; response; reward anticipation; reward processing; secondary analysis; statistics; suicidal risk; therapy development; therapy resistant; treatment group; treatment response; treatment-resistant depression

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.

项目概要 重度抑郁症是全球残疾的主要原因，影响着超过 3 亿人。 难治性抑郁症 (TRD) 造成的死亡人数最多，自杀风险增加一倍， 尤其是长期的痛苦和对资源的更多利用，即无法感受到快乐。 是 TRD 发展的最重要的危险因素之一，因为快感缺乏涉及其中。 大脑奖励回路关键区域功能障碍，这些区域是可行的机械生物标志物 用于测试对当前没有反应的抑郁症患者的新颖干预措施的参与度 在这个 K23 提案中，我将部署一种新颖的目标参与设计来评估。 TRD 快感缺失的生物标志物和替代干预方法 I 靶向 D3 受体激动剂。 普拉克索并评估对感兴趣的奖励回路生物标志物腹侧纹状体（VS）的影响， 以及具有明显快感缺失的 TRD 患者的临床、功能和自杀结局。 将确定奖励任务诱发的 VS 激活是否会在一组 TRD 受试者中发生变化 8 周后普拉克索治疗；其次，评估是否存在快感缺乏的症状、功能和症状。 普拉克索治疗 8 周后，同一组的自杀倾向发生变化；第三，评估是否发生变化； 基线腹侧纹状体激活与 VS 激活和临床结果的变化相关。 K23提案和随附的培训计划将使我能够接受三个关键方面的高级培训 领域：传统和生物标记引导的功能神经影像数据的分析和解释 此外，我还组建了跨学科的临床试验和生物标志物。 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 神经影像学（Leanne Williams 博士，主要导师），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（艾伦·沙茨伯格博士，共同导师），统计 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）和神经影像学指导的重度抑郁症试验（Boadie Dunlop 博士， 此外，作为我培训的一部分，我打算在我的学习期间继续临床工作。 职业发展奖，为难治性患者开设自己的咨询诊所 后者在斯坦福大学情绪障碍中心的保护下促进了情绪障碍 多年的获奖经历使我能够很好地进行临床工作和研究。 提出问题并实施研究设计，将基础科学的关键发现明确转化为 该提案将在斯坦福大学进行，以指导临床决策。 著名的神经科学和精神病学研究中心以及斯坦福大学认知和精神病学中心 神经生物学成像，最先进的神经成像设施。

项目成果

Anesthetic-Induced Intraoperative Dream Associated With Remission of a Psychiatric Disorder: A Case Report.

麻醉引起的术中梦与精神疾病缓解相关：病例报告。

• 发表时间: 2022-08-01
• 作者: Chow, Harrison S;Hack, Laura M;Kawai, Makoto;Heifets, Boris D
• 通讯作者: Heifets, Boris D