Efficacy of biomarker-guided rTMS for treatment resistant depression

严重抑郁障碍(MDD)是导致全球残疾的主要原因，约占MDD的30% 患者对传统的抗抑郁药物治疗有抵抗力。重复经颅磁 刺激(RTMS)左侧背外侧前额叶皮质(DLPFC)是FDA批准的干预措施，经证实 对难治性抑郁症有效，但这些患者中只有30%-40%在一次 当然了。其他研究表明，以背内侧PFC(DmPFC)为靶点的rTMS相对有效， 但是，用于告知靶点选择和预测差异治疗反应的生物标志物并不是 目前可用。诊断的异质性一直是生物标记物发现工作的主要障碍。 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。 由价系统电路中不同的静息状态功能连接(RSFC)模式定义 在个体水平上预测靶向dmPFC的rTMS的不同抗抑郁反应。这 验证性疗效试验将测试一种新的、生物类型指导的治疗选择策略，该策略的动机是 假设单个患者对左侧DLFPC与DmPFC rTMS的应答可能性在 部分是由于以下方面的个体差异：1)他们的症状在多大程度上是由特定功能障碍引起的 下游杏仁核、纹状体和显著网络目标包括配价系统的各个方面；和2) 这些靶点的功能障碍可以通过刺激左侧DLPFC或dmPFC来调节的程度。 受试者(N=405)将随机接受)以dmPFC或Left为靶点的生物类型引导的10 HzrTMS DLPFC；b)到接收以相对位置为目标的rTMS的不一致臂；以及c)到第三个臂接收 FDA批准的，护理标准10 HZ rTMS，目标是左侧DLFPC，无论生物类型。所有的病人都会 在治疗前后对一系列功能磁共振成像、行为和临床评估进行测试， RDoC知情的情绪调节和努力评估措施，这将使我们能够验证 下游脑电路治疗目标和目标接合测试，结合最先进的， 解剖逼真的电场建模和纤维束成像。主要目标是确认其疗效。 一种新的RSFC生物标志物引导的耐药差异治疗选择方法的研究 抑郁症，与目前的护理标准相比，有可能显著提高疗效。

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.