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，具有快速抗抑郁和抗自杀的特性，被认为是 通过迅速增强神经可塑性来逆转症状；但令人惊讶的是，人们对其可行性、安全性、 以及减少现实世界中处于迫在眉睫风险的异质样本中自杀结果的有效性。此外， 临床应用的一个重大障碍是缺乏氯胺酮效果持久性的证据，这引发了人们对 虚幻的康复和随后的自杀风险反弹。我们假设氯胺酮会迅速减少自杀意念 并在真实世界的样本中迅速增加认知灵活性，允许认知中的僵化、负面偏见 迅速逆转。我们进一步预计，这些神经认知变化将为临床提供一个机会之窗 引入1)面向危机的标准精神护理；2)自动化认知训练(CT)技术，这将 巩固认知加工的适应性形式(具体地说，积极的和面向生活的自我内隐表征) 而神经可塑性仍然很高。实例化适应性处理形式(通过标准护理和/或自动化 CT)在第一次用氯胺酮对大脑进行预充剂后，代表了一种潜在的协同治疗方法，可以扩展 单次输注氯胺酮的急性效应超过了其典型的3-7天窗口，有效地培养了保护性抗- 既迅速又持久的自杀效应。在这项研究中，200名医疗单位住院患者(年龄18-65岁)将在 从大型一级创伤医院的精神科咨询/联络服务转诊，在咨询了 医学上严重的自杀未遂(SA)。利用熟悉使用的医疗单位医生 在他们的住院医疗环境中常规输注氯胺酮，住院患者将以平行的手臂设计随机进行 在随后的精神科住院治疗前不久，接受一次氯胺酮“预治疗”--或者不-- 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 协会；目标1)。在完全交叉(2 x 2阶乘)平行臂设计中，患者随后将随机接受 在输液后的“机会之窗”期间基于网络应用的简单认知训练方案，旨在隐含地 颠倒消极的自我表征，在他们的位置上灌输有益的自我表征，或者是同样的虚假变体 训练。患者、研究人员和结果评分者将对治疗条件视而不见。全面 将为两个干预组件捕获可行性/安全性数据。远程评估和医疗记录将 然后用来捕获SI和SAS，在12个月的自然随访中评估是否：氯胺酮 标准的精神科住院护理比不输液的护理标准(目标2)和积极的认知具有有益的影响 训练增强和/或延长了氯胺酮作用的持久性，潜在地提供了一种非常有效、低成本的 成本、便携、非侵入性、安全和高度传播准备的战略(目标3)。这项研究将为我们提供新的 氯胺酮对面临迫在眉睫风险的异类患者影响的可行性、安全性和有效性数据 这将是首次尝试将氯胺酮与标准和新的(认知)相结合 培训)在真实世界、可推广的环境中进行干预，以努力利用和扩大氯胺酮的快速效应。

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.