PROJECT SUMMARY/ABSTRACT Suicide is a leading cause of death in adolescents worldwide and a substantial public health problem in the United States. Despite prior efforts, outcomes related to suicide in adolescents are not improving over the years. Standard clinical and research approaches involve prevention efforts, risk assessment, crisis intervention, and psychotherapeutic techniques. Few prior studies have focused on developing brain-based treatments and biomarkers for active suicidal ideation in adolescents with depression. Conceptually, dysregulations in prefrontal cortex gamma-aminobutyric acid (GABA) inhibitory function could lead to reduced control of suicidal thoughts and behaviors in adolescents with depression. Transcranial magnetic stimulation (TMS) treatment protocols delivered to the prefrontal cortex modulate GABA inhibitory function, synaptic plasticity, and clinical symptoms of depression. Accelerated TMS protocols that deliver theta burst stimulation (TBS) dosing induce synaptic plasticity changes rapidly, modulate GABA function, have rapid-acting clinical effects, and overcome the many practical limitations of standard TMS. Prior research with a biomarker of GABA activity called long-interval cortical inhibition (LICI) demonstrates potential for clinical implementation to assess suicide risk and guide treatment interventions with TMS. Electromyography (EMG) measures of LICI are easily collected and have been studied extensively in adolescents. Measures of LICI with electroencephalography (EEG) may provide more precise and sophisticated measures of GABA inhibitory function. However, there are methodologic challenges with the use of EEG for LICI measures and no prior data in adolescents with depression. This study is a randomized, double-blind, sham-controlled trial of sequential bilateral accelerated TBS (aTBS) for suicidal ideation in adolescents with major depressive disorder (MDD). All subjects (in both arms) will concurrently receive standard of care treatment. Three TBS sessions will be administered daily for 10 days (5 days per week) for a total of 30 sessions. During each TBS session, continuous TBS is first delivered to the right dorsolateral prefrontal cortex and then intermittent TBS is delivered to the left dorsolateral prefrontal cortex. The proposed TBS parameters were adopted from prior work in adolescents. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. This study will examine the safety, feasibility, and clinical effects of sequential bilateral aTBS. The primary clinical outcome will be assessed over 10 days of treatment and the following year with the Columbia Suicide Severity Rating Scale severity of ideation subscale. The research team will collect pre- and post- treatment LICI measures with EMG to assess suicide risk and guide treatment with TBS protocols. Concurrent LICI measures with EEG will address an exploratory aim to further develop and refine LICI biomarkers. Existing infrastructure and collaborations will foster the rapid clinical implementation of sequential bilateral aTBS and cortical inhibition biomarkers.

PROJECT NARRATIVE Suicide is a leading cause of death in adolescents worldwide and a major public health problem in the United States. This project focuses on a therapeutic trial of a new treatment called sequential bilateral accelerated theta burst stimulation for depressed adolescents with suicidal thoughts. The investigators will also use electrophysiological brain biomarkers to assess the severity of suicidal thoughts and guide treatment in adolescents.