Suicide Circuit Therapeutics: Engaging Novel Targets with Rapid and Individualized MRI-Guided Accelerated TMS

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PROJECT SUMMARY AND ABSTRACT Suicide is a leading cause of death worldwide, with tragic consequences for individuals and their families. Despite the increased access to mental health services and use of psychiatric treatments, suicide rates have remained unchanged over the last century. Worse, from 1999 to 2019 suicide rates increased 33% in the U.S. Rapid, safe and effective antisuicidal therapies are critically needed. Our group has characterized a circuit biomarker that may predict and explain the antisuicidal effects of ECT. Before ECT, excessively anticorrelated functional connectivity (FC) between the anterior cingulate cortex (ACC) and the right inferior parietal lobule (IPL) predicts greater post-ECT antisuicidal response (predictor biomarker), and greater reduction of ACC-IPL anticorrelated FC during ECT is associated with greater antisucidal efficacy (response biomarker or treatment target). This finding led us to hypothesize a novel biomarker-informed treatment strategy aiming to engage this treatment target: TMS over the right IPL could be used to focally reduce ACC-IPL anticorrelated FC and hence reduce suicidal thoughts and behaviors (STB). Recent innovations in TMS have established that intermittent Theta Burst Stimulation (iTBS), an efficient TMS protocol that lasts less than 3 minutes, is as effective an antidepressant when applied over the dorsolateral prefrontal cortex (DLPFC) as the traditional 38 minutes 10Hz TMS protocol: DLPFC iTBS was cleared by the FDA in 2018. Given the brevity of iTBS, accelerated protocols (aiTBS) have been established to deliver the equivalent number of pulses of an FDA-cleared 6-week course of iTBS in a single day, and to repeat this for 5 consecutive days. When applied to the DLPFC, aiTBS seems safe and rapidly effective for depression. Our preliminary evidence shows that individualized MRI-guided aiTBS over the right IPL of suicidal patients is feasible, safe, leads to rapid reduction of STB and reduces ACC-IPL anticorrelation as predicted. The current proposal aims to develop rapid antisuicidal therapies for patients in their most vulnerable periods: during hospitalization and post-discharge. The R61 phase will randomize patients in a depressive episode with moderate to severe STB to receive 1 day (10 sessions) of active or sham aiTBS to the right IPL. We will measure changes in FC, clinical reduction of STB and safety/tolerability. If we meet our a priori go criteria, the following R33 phase will randomize patients hospitalized in a psychiatric unit with acute STB to receive a full course of 5 days (50 sessions) of aiTBS, and we will measure FC, reduction of STB acutely and during 1 month post-discharge and safety/tolerability of this intensive protocol. If successful, this project will contribute to the development of highly individualized and biomarker-informed rapid treatments for suicidal patients using noninvasive device neuromodulation, and establish the biological and clinical evidence for a future large multicenter confirmatory trial to address one of the most critical problems in Psychiatry.