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

自杀回路治疗：通过快速、个性化的 MRI 引导加速 TMS 参与新靶点

• 批准号: 10646517
• 负责人: Joan A Camprodon
• 金额: $ 116.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646517
• 关键词: Acceleration; Acute; Address; Anterior; Antidepressive Agents; Area; Biological; Biological Markers; Brain; Cause of Death; Cellular Phone; Clinical; Development; Devices; Digital biomarker; Family; Feeling suicidal; Functional disorder; Future; Hospitalization; Incidence; Individual; Inferior; Investments; Lobule; Magnetic Resonance Imaging; Measures; Mental Depression; Mental Health Services; Modeling; Parietal; Patients; Phase; Physiologic pulse; Positioning Attribute; Prefrontal Cortex; Protocols documentation; Psychiatric therapeutic procedure; Psychiatry; Randomized; Research; Resources; Safety; Suicide; Suicide attempt; Suicide prevention; Therapeutic; Transcranial magnetic stimulation; Treatment Efficacy; behavior measurement; cingulate cortex; clinical efficacy; completed suicide; confirmatory trial; depressive symptoms; effective therapy; electric field; executive function; innovation; neuroregulation; novel; novel marker; predictive marker; reducing suicide; response; response biomarker; suicidal; suicidal behavior; suicidal patient; suicide rate; treatment strategy

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.

项目摘要和摘要 自杀是全球死亡的主要原因，对个人及其家人造成了悲惨的后果。 尽管获得心理健康服务的机会增加并使用精神病治疗，但自杀率还是 上个世纪保持不变。更糟糕的是，从1999年到2019年，自杀率增加了33％ 迫切需要快速，安全有效的抗杀菌疗法。 我们的小组表征了电路生物标志物，该标志物可以预测并解释 ect。在ECT之前，前扣带回皮层之间过度抗相关的功能连通性（FC） （ACC）和右下顶叶（IPL）预测更大的后抗杀菌反应（预测指标 生物标志物），ECT期间ACC-ipl反相关FC的更大降低与更大的相关 消化功效（反应生物标志物或治疗靶标）。这一发现使我们假设一本小说 生物标志物信息的治疗策略旨在参与此治疗目标：右侧的TMS可能是 用于局部减少ACC-EPR反相关FC，从而减少自杀思想和行为（STB）。 TMS的最新创新已经确定，间歇性theta爆发刺激（ITB）是一种有效的 持续不到3分钟的TMS协议在应用于 传统的38分钟10Hz TMS协议：DLPFC ITB为传统的前额叶前额叶皮层（DLPFC） 由FDA在2018年清除。鉴于ITB的简洁性，已建立了加速协议（AITB） 在一天之内，交付了一场FDA清除6周的ITB课程的等效脉冲，然后 连续5天重复一次。当应用于DLPFC时，AITBS似乎是安全且快速有效的 沮丧。我们的初步证据表明，在自杀的右ipl上，个性化的MRI引导AITB 患者是可行的，安全的，导致STB迅速减少，并降低了ACC-ipl抗相关性。 当前的提案旨在为患者最脆弱的患者开发快速的抗杀虫剂疗法 期间：住院期间和入院后。 R61阶段将在抑郁中随机将患者随机 中度至重度STB的发作可在右侧接收1天（10个会话）的活动或假AITB。 我们将衡量FC的变化，STB的临床降低以及安全性/耐受性。如果我们遇到先验 标准，以下R33阶段将在患有急性STB的精神病病房中随机将患者随机住院 获得5天（50届会话）AITB的完整过程，我们将测量FC，急性减少STB和 在分期后1个月内此密集协议的安全性/耐受性。如果成功，这个项目将 为自杀的高度个性化和生物标志物的快速治疗做出贡献 使用非侵入性装置神经调节的患者，并为A建立生物学和临床证据 未来的大型多中心确认试验解决了精神病学中最关键的问题之一。