Efficacy of biomarker-guided rTMS for treatment resistant depression

生物标志物引导的 rTMS 对难治性抑郁症的疗效

• 批准号: 10633055
• 负责人: Faith M Gunning
• 金额: $ 130.71万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633055
• 关键词: Accounting; Aftercare; Amygdaloid structure; Anatomy; Anhedonia; Antidepressive Agents; Anxiety; Area; Arousal; Behavior assessment; Biological Markers; Brain; Brain scan; Clinical; Clinical assessments; Corpus striatum structure; Data; Diagnosis; Diagnostic; Dimensions; Disease remission; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Heterogeneity; Individual; Individual Differences; Intervention; Left; Major Depressive Disorder; Maps; Measures; Medical; Mental Depression; Methods; Modeling; Motivation; Patients; Pattern; Pharmacotherapy; Prediction of Response to Therapy; Prefrontal Cortex; Publishing; Randomized; Research Domain Criteria; Resistance; Rest; Scanning; Selection for Treatments; Site; Symptoms; System; Testing; Time; Transcranial magnetic stimulation; Work; anxious; arm; biomarker discovery; biotypes; clinical predictors; comparative efficacy; confirmatory trial; depressive symptoms; disability; disorder subtype; efficacy evaluation; electric field; emotion regulation; improved; indexing; individual patient; machine learning method; novel; pharmacologic; predicting response; predictive marker; repetitive transcranial magnetic stimulation; response; standard of care; tractography; treatment response; treatment-resistant depression

Major depressive disorder (MDD) is a leading cause of global disability, and approximately 30% of MDD patients are resistant to conventional antidepressant pharmacotherapy. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an FDA-cleared intervention with proven efficacy in treatment-resistant depression, but only 30–40% of these patients achieve remission after a single course. Other studies have shown that rTMS targeting the dorsomedial PFC (DMPFC) is comparably effective, but biomarkers for informing target site selection and predicting differential treatment response are not currently available. Diagnostic heterogeneity has been a major obstacle to biomarker discovery efforts. Recently, we developed and validated an approach to diagnosing four novel MDD subtypes or “biotypes” defined by distinct resting state functional connectivity (RSFC) patterns in Valence System circuits and predicting differing antidepressant responses at the individual level to rTMS targeting the DMPFC. This confirmatory efficacy trial will test a novel, biotype-guided treatment selection strategy motivated by the hypothesis that an individual patient's likelihood of responding to left DLFPC vs. DMPFC rTMS is determined in part by individual differences in 1) the degree to which their symptoms are driven by dysfunction in specific downstream amygdala, striatal, and salience network targets comprising aspects of Valence Systems; and 2) the degree to which dysfunction in those targets can be modulated by stimulating the left DLPFC or DMPFC. Subjects (N=405) will be randomized to receive a) biotype-guided 10 Hz rTMS targeting the DMPFC or left DLPFC; b) to a disconfirmation arm receiving rTMS targeting the opposite site; and c) to a third arm receiving FDA-cleared, standard-of-care 10 HZ rTMS targeting the left DLFPC, regardless of biotype. All patients will be tested before and after treatment on a battery of fMRI, behavioral, and clinical assessments, grounded in RDoC-informed measures of emotion regulation and effort valuation, which will enable us to validate downstream brain circuit treatment targets and test for target engagement, in conjunction with state-of-the-art, anatomically realistic electric field modeling and fiber tractography. The primary goal is to confirm the efficacy of a novel RSFC biomarker-guided approach to differential treatment selection in treatment resistant depression, with the potential for significantly enhanced efficacy compared to the current standard-of-care.

重度抑郁症（MDD）是全球残疾的主要原因，约占MDD的30％ 患者对转化的抗抑郁药疗法有抵抗力 左侧背侧前额叶皮层（DLPFC）的刺激（RTMS）是一种FDA清除干预措施 抗治疗抑郁症的疗效，但只有30-40％的患者在一次单一后实现了改建 当然。其他研究表明，针对背部PFC（DMPFC） 但是用于告知目标选择和预测差异治疗反应的生物标志物不是 目前可用的诊断异质性是生物标志物发现工作的主要障碍。 最近，我们开发了一种诊断四种新型MDD亚型或“生物型”的方法 由价值系统电路中的不同静止状态功能连接（RSFC）模式定义 预测针对DMPFC的单个级别的抗抑郁反应 确认功效试验将测试由新颖的生物类型治疗选择策略，该策略由以下 假设有和个人患者对左DLFPC vs. DMPFC RTMS的反应的可能性是 部分差异为1）特异性功能障碍驱动症状的程度。 下游杏仁核，纹状体和显着性网络目标是价值系统的组成； 可以通过刺激左DLPFC或DMPFC来调节目标中的TOWHICH功能障碍。 受试者（n = 405）将被随机接收a）针对DMPFC或左的生物型引导的10 Hz RTM dlpfc; b）接收针对相对位置的RTM的脱节； 靶向左DLFPC的FDA清除，标准的10 Hz RTM，无论所有患者如何。 通过fMRI，行为和临床评估进行治疗前后测试， 情绪调节和努力估值的RDOC信息衡量标准，这将使我们能够验证 下游大脑电路目标并测试目标参与，并结合最新的面临 解剖学上逼真的电场建模和纤维牵引力。 一种新型的RSFC生物标志物指导的方法，用于抗治疗中的差异治疗选择 深度，与当前护理标准相比，具有显着增强功效的潜力。