Effectiveness of a Synergistic, Neuroplasticity-Based intervention for Rapid and Durable Suicide Risk Reduction

项目摘要。静脉注射氯胺酮，它显示出快速的抗抑郁和抗自杀特性，被认为是 通过快速增强神经可塑性来逆转症状;但令人惊讶的是，关于其可行性，安全性， 以及在现实世界中降低自杀结果的有效性，异质性样本在迫在眉睫的风险。此外，委员会认为， 临床采用的一个重大障碍是缺乏氯胺酮效果持久性的证据，这引起了人们对以下问题的担忧： 虚幻的恢复和随后的自杀风险反弹。我们认为氯胺酮会迅速减少自杀意念 并迅速增加现实世界样本中的认知灵活性，允许认知中的刚性，负面偏见， 迅速逆转。我们进一步预计，这些神经认知变化将提供一个临床机会窗口， 引入1）标准的以危机为导向的精神病护理; 2）自动认知训练（CT）技术， 巩固认知处理的适应性形式（具体而言，积极和面向生活的自我内隐表征） 而神经可塑性仍然很高。实例化自适应形式的处理（通过标准护理和/或自动化处理） CT）在首次用氯胺酮“启动”大脑后代表了一种潜在的协同治疗方法，可以延长 单次氯胺酮输注的急性效应超过其典型的3-7天窗口，有效地促进保护性抗- 自杀的影响是迅速和持久的。在本研究中，将招募200名医疗单位住院患者（年龄18-65岁）， 一家大型一级创伤医院的精神科咨询/联络服务处转介， 严重自杀企图（SA）。利用医疗单位的医生谁是习惯于利用 在其住院医疗环境中常规输注氯胺酮，住院患者将以平行组设计随机分配， 接受单次氯胺酮“预治疗”-在随后的精神病住院治疗前不久-或不接受- 输液患者将完成外显SI和认知目标参与（内隐自杀自我）的急性测量 关联;目标1）。在完全交叉（2 x 2析因）、平行组设计中，患者将随机接受 在输注后“机会之窗”期间，简短的基于网络应用程序的认知训练方案，旨在隐含 扭转消极的自我表征，灌输有益的自我表征，或相同的虚假变体 训练患者、研究者和结局评定者将对治疗状况保持盲态。全面 将采集两种干预成分的可行性/安全性数据。远程评估和医疗记录将 然后在12个月的自然随访中用于捕获SI和SA，以评估是否：氯胺酮，然后 标准的精神病住院治疗对无输液标准治疗（目标2）和积极认知 训练增强和/或延长氯胺酮作用的持久性，潜在地提供一种非常有效的，低- 成本低、便携、非侵入性、安全和高度传播准备策略（目标3）。这项研究将提供新的 氯胺酮在面临迫在眉睫风险的异质性现实世界患者中影响的可行性、安全性和有效性数据 的自杀，并将代表协同联合收割机氯胺酮与标准和新的（认知 培训）在现实世界中的干预，普遍设置，努力利用和扩大氯胺酮的快速效果。

Project Summary. Intravenous ketamine, which displays rapid antidepressant and anti-suicidality properties, is posited to reverse symptoms by rapidly enhancing neuroplasticity; but surprisingly little is known regarding its feasibility, safety, and effectiveness for reducing suicidal outcomes among real-world, heterogenous samples at imminent risk. Furthermore, a significant barrier to clinical adoption is the lack of evidence for durability of ketamine's effects, raising concerns about illusory recovery and subsequent rebound of suicide risk. We posit that ketamine will rapidly decrease suicidal ideation and rapidly increase cognitive flexibility in a real-world sample, allowing for rigid, negative biases in cognition to be rapidly reversed. We further expect these neurocognitive changes will provide a clinical window of opportunity in which to introduce 1) standard crisis-oriented psychiatric care; and 2) automated cognitive training (CT) techniques, which will consolidate adaptive forms of cognitive processing (specifically, positive and life-oriented implicit representations of self) while neuroplasticity remains high. Instantiating adaptive forms of processing (through standard care and/or automated CT) after first 'priming' the brain with ketamine represents a potentially synergistic treatment approach that could extend the acute effects of a single ketamine infusion beyond its typical 3-7 day window, efficiently fostering protective anti- suicidal effects that are both rapid and enduring. In this study, 200 Medical Unit inpatients (age 18-65) will be enrolled by referral from the psychiatric consultation/liaison service in a large Level 1 trauma hospital, following consult for a medically serious suicide attempt (SA). Leveraging medical unit physicians who are well-accustomed to utilizing ketamine infusion routinely in their inpatient medical settings, inpatients will be randomized in a parallel arm design to receive a single infusion of ketamine “pre-treatment”—shortly prior to subsequent psychiatric inpatient stay—or no- infusion. Patients will complete acute measures of explicit SI and cognitive target engagement (implicit suicide-self associations; Aim 1). In a fully crossed (2 x 2 factorial), parallel arm design, patients will then be randomized to receive a brief web-app-based cognitive training protocol during the post-infusion "window of opportunity," designed to implicitly reverse negative self-representations, instilling beneficial self-representations in their place, or a sham variant of the same training. Patients, investigators, and outcome raters will be blinded to treatment condition. Comprehensive feasibility/safety data will be captured for both intervention components. Remote assessments and the medical record will then be used to capture SI and SAs over a 12-month naturalistic follow-up to assess whether: ketamine followed by standard psychiatric inpatient care has a beneficial impact over no-infusion standard-of-care (Aim 2) and active cognitive training enhances and/or extends the durability of ketamine's effects, potentially providing an exceedingly efficient, low- cost, portable, non-invasive, safe, and highly dissemination-ready strategy (Aim 3). This study will provide novel feasibility, safety, and effectiveness data on ketamine's impact among heterogeneous real-world patients at imminent risk of suicide, and will represent a first attempt to synergistically combine ketamine with both standard and novel (cognitive training) interventions in a real-world, generalizable setting, in an effort to exploit and extend ketamine's rapid effects.