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.

项目概要和摘要 自杀是全世界死亡的主要原因，给个人及其家庭带来悲惨后果。 尽管获得精神卫生服务和使用精神科治疗的机会有所增加，但自杀率却有所下降 上个世纪没有变化。更糟糕的是，从 1999 年到 2019 年，美国的自杀率增加了 33%。 迫切需要快速、安全和有效的抗自杀疗法。 我们的小组已经表征了一种回路生物标志物，可以预测和解释以下药物的抗自杀作用： 等。在 ECT 之前，前扣带皮层之间过度反相关的功能连接 (FC) (ACC) 和右顶下小叶 (IPL) 预测 ECT 后抗自杀反应更大（预测因子 生物标志物），ECT 期间 ACC-IPL 反相关 FC 的更大程度减少与更大程度的相关 抗自杀功效（反应生物标志物或治疗目标）。这一发现使我们假设一部小说 旨在实现这一治疗目标的基于生物标志物的治疗策略：TMS 优于正确的 IPL 可能是 用于集中减少 ACC-IPL 反相关 FC，从而减少自杀想法和行为 (STB)。 TMS 的最新创新已证实间歇性 Theta 突发刺激 (iTBS) 是一种有效的 持续时间不到 3 分钟的 TMS 方案与抗抑郁药一样有效 背外侧前额皮质 (DLPFC) 作为传统的 38 分钟 10Hz TMS 协议：DLPFC iTBS 于 2018 年获得 FDA 批准。鉴于 iTBS 的简洁性，已建立加速方案 (aiTBS) 一天内提供与 FDA 批准的 6 周 iTBS 疗程相当的脉冲数，并 连续 5 天重复此操作。当应用于 DLPFC 时，aiTBS 似乎安全且快速有效 沮丧。我们的初步证据表明，个体化 MRI 引导的 aiTBS 优于自杀患者的正确 IPL 正如预测的那样，患者的治疗是可行的、安全的，可导致 STB 快速减少并减少 ACC-IPL 反相关性。 目前的提案旨在为最脆弱的患者开发快速的抗自杀疗法 时期：住院期间和出院后。 R61 阶段将对抑郁症患者进行随机分组 中度至重度 STB 发作接受 1 天（10 次）的主动或假 aiTBS 至正确的 IPL。 我们将测量 FC 的变化、STB 的临床减少以及安全性/耐受性。如果我们满足我们的先验要求 根据标准，接下来的 R33 阶段将随机分配在精神病科住院的患有急性 STB 的患者 接受为期5天（50次）的aiTBS全程课程，我们将敏锐地测量FC、STB的减少和 出院后 1 个月期间以及该强化方案的安全性/耐受性。如果成功的话，这个项目将 有助于开发高度个性化和基于生物标志物的自杀快速治疗方法 使用无创装置神经调节的患者，并建立生物学和临床证据 未来的大型多中心验证性试验将解决精神病学中最关键的问题之一。