# Efficacy of biomarker-guided rTMS for treatment resistant depression

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $1,307,136

## Abstract

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.

## Key facts

- **NIH application ID:** 9908173
- **Project number:** 5R01MH118388-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Faith M Gunning
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,307,136
- **Award type:** 5
- **Project period:** 2019-04-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908173

## Citation

> US National Institutes of Health, RePORTER application 9908173, Efficacy of biomarker-guided rTMS for treatment resistant depression (5R01MH118388-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9908173. Licensed CC0.

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