Efficacy of biomarker-guided rTMS for treatment resistant depression

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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.