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

项目总结和摘要 自杀是世界范围内的主要死亡原因，给个人及其家庭带来悲惨后果。 尽管获得精神卫生服务和精神病治疗的机会增加，但自杀率仍在上升。 在过去的世纪中保持不变。更糟糕的是，从1999年到2019年，美国的自杀率增加了33%。 快速，安全和有效的抗自杀治疗是迫切需要的。 我们的研究小组已经确定了一种回路生物标志物的特征，该生物标志物可以预测和解释 等方面ECT前，前扣带皮层与前扣带皮层之间的过度相关功能连接（FC） (ACC)右侧顶下小叶（IPL）预测ECT后更大的抗自杀反应（预测因子 生物标志物），ECT期间ACC-IPL与FC相关的更大减少与更大的 抗自杀功效（响应生物标志物或治疗靶标）。这一发现让我们假设一部小说 生物标志物知情的治疗策略，旨在实现这一治疗目标：TMS超过右IPL可能是 用于局部减少ACC-IPL与FC相关的FC，从而减少自杀想法和行为（STB）。 TMS中的最新创新已经确定，间歇性Theta爆发刺激（iTBS），一种有效的 持续时间不到3分钟的TMS方案，当应用于 背外侧前额叶皮层（DLPFC）作为传统的38分钟10 Hz TMS协议：DLPFC iTBS是 2018年被FDA批准。鉴于iTBS的简洁性，已经建立了加速协议（aiTBS），以 在一天内提供与FDA批准的6周iTBS疗程相同数量的脉冲，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， 萧条我们的初步证据表明，个体化MRI引导的aiTBS优于自杀性患者的右侧IPL。 患者是可行的，安全的，导致STB的快速降低，并降低ACC-IPL的相关性。 目前的提案旨在为最脆弱的患者开发快速抗自杀疗法。 期间：住院期间和出院后。R61阶段将随机分配抑郁症患者， 中度至重度STB发作，接受1天（10次）右侧IPL的活性或假aiTBS治疗。 我们将测量FC的变化、STB的临床降低和安全性/耐受性。如果我们满足我们的先验去 标准，随后的R33阶段将随机分配在精神科住院的急性STB患者， 接受为期5天（50节）的aiTBS完整课程，我们将测量FC，STB急剧减少， 出院后1个月内的安全性和耐受性。如果成功，该项目将 有助于开发高度个性化和生物标志物知情的自杀快速治疗方法， 患者使用非侵入性设备神经调节，并建立生物学和临床证据， 未来的大型多中心验证性试验，以解决精神病学中最关键的问题之一。

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.