Efficacy of biomarker-guided rTMS for treatment resistant depression

重度抑郁症（MDD）是全球残疾的主要原因，约30%的MDD 患者对常规抗抑郁药物治疗有抗性。重复经颅磁 左背外侧前额叶皮质（DLPFC）刺激（rTMS）是FDA批准的干预措施，已被证明 治疗难治性抑郁症的疗效，但只有30-40%的这些患者达到缓解后，单 当然了其他研究表明，靶向背内侧PFC（DMPFC）的rTMS是有效的， 但用于告知靶位点选择和预测差异治疗反应的生物标志物并不 目前可用。诊断异质性一直是生物标志物发现努力的主要障碍。 最近，我们开发并验证了一种诊断四种新的MDD亚型或“生物型”的方法。 由价系统回路中不同的静息状态功能连接（RSFC）模式定义， 预测在个体水平上对靶向DMPFC的rTMS的不同抗抑郁反应。这 一项确证性疗效试验将测试一种新的、生物型指导的治疗选择策略， 假设个体患者对左侧DLFPC与DMPFC rTMS反应的可能性是在以下条件下确定的： 部分由个体差异决定，1）他们的症状在多大程度上是由特定的功能障碍引起的。 下游杏仁核、纹状体和包括价系统方面的显著网络靶标;以及2） 通过刺激左侧DLPFC或DMPFC可以调节这些目标的功能障碍的程度。 受试者（N=405）将随机接受a）靶向DMPFC或左侧的生物型引导的10 Hz rTMS DLPFC; B）至接受靶向相反部位的rTMS的不确认臂;和c）至接受靶向相反部位的rTMS的第三臂 FDA批准的标准治疗10 HZ rTMS靶向左侧DLFPC，不考虑生物型。所有患者将被 在治疗前后进行了一系列功能磁共振成像、行为和临床评估， RDoC告知情绪调节和努力评估的措施，这将使我们能够验证 下游脑回路治疗目标和目标接合测试，结合最新技术， 解剖学上真实的电场建模和纤维束成像。主要目标是确认疗效 一种新的RSFC生物标志物指导的方法，用于治疗耐药的差异治疗选择 抑郁症，与目前的标准治疗相比，具有显著增强疗效的潜力。

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.