Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine

项目摘要(摘要) 自杀是年轻人(10至34岁)的第二大死因，目前没有 针对青少年的循证药理学反自杀干预。青少年的潜在危险因素 自杀包括严重抑郁障碍(使风险增加30倍)，以及最近从 与自杀有关的更高级别的精神护理。这些风险可能会进一步增强对治疗的抗药性 人口。氯胺酮在成人耐药人群中是抗自杀的，即使在控制了它的 抗抑郁作用。尽管没有儿科精神病学的证据，但氯胺酮正越来越多地被 儿童精神科医生在标签外使用，他们没有基于证据的药物选择 TORDIA推荐。我们最近完成了咪达唑仑对照的随机临床试验 青少年难治性抑郁(TRD)表现出快速(1天)的抗抑郁疗效和 对单剂量氯胺酮的耐受性良好。我们有病例报告和试点数据表明耐受性和 反复给药范例在患有TRD的青少年中的抗自杀承诺。在这里，我们建议分两个阶段 测试氯胺酮对自杀高危青少年的快速抗自杀效果的研究(手术 定义为在登记前120天内有TRD和自杀事件)使用保守重复 给药模式(两周内四次静脉输液)。第一阶段为两周平行双盲试验 比较氯胺酮和咪达唑仑的阶段，第二阶段是为期4个月的开放阶段，咪达唑仑- 仍有自杀倾向或抑郁的指定参与者可以接受开放的氯胺酮。所有参与者都将收到 根据德克萨斯儿童用药算法和8周的改编进行用药管理 认知行为疗法(CBT)。所有这些都将在开放阶段每周进行跟踪，以确保有效性和安全性， 试验设计是在与FDA协商后开发的。考虑到治疗的预测性生物标记物的需求 作为回应，青少年将参与基于任务和休息的fMRI神经成像。使用我们的新型连接件- 基于预测建模，它使用任务在RDoC域中“调整”大脑网络，我们将 确定治疗前的连接体表型，或预测治疗反应的“指纹”。我们 建议的3个具体目标：(1)评估治疗高自杀风险青少年的可行性和安全性 采用保守的重复给药氯胺酮范例，随后进行超过4个月的标准护理治疗。 (2)评估氯胺酮48小时对自杀意念的影响(通过哥伦比亚自杀评分进行测量 量表，近期构思量表)与咪达唑仑比较，并确定连接体表型预测 治疗后构思。(3)描述自杀念头的轨迹、抑郁症状和使用 氯胺酮应答者和非应答者4个月以上的心理健康资源。生成的数据 这里将促进科学知识和影响临床实践，除了提供基础 在有严重自杀风险的青年中进行后续试验设计所需的数据。

Project Summary (Abstract) Suicide is the second leading cause of death in young people (10 to 34 years) and there are currently no evidence-based pharmacologic anti-suicidal interventions for adolescents. Potent risk factors for adolescent suicide include Major Depressive Disorder (which increases the risk 30-fold), and recent discharge from a higher level of psychiatric care relating to suicide. These risks may be further enhanced treatment-resistant populations. Ketamine is anti-suicidal in adult treatment resistant populations, even after controlling for its antidepressant effects. Despite having no evidence base in pediatric psychiatry, ketamine is increasingly being utilized off label by Child Psychiatrists, who have no evidence-based pharmacologic options beyond the TORDIA recommendations. We have recently completed a midazolam-controlled randomized clinical trial in adolescents with treatment resistant depression (TRD) showing rapid (1 day) antidepressant efficacy and sound tolerability of a single ketamine dose. We have case report and pilot data suggesting tolerability and anti-suicidal promise of repeat dosing paradigms in adolescents with TRD. Here we propose a two-phase study to test the rapid anti-suicidal efficacy of ketamine in adolescents at high suicide risk (operationally defined as having TRD and a suicide event within the 120 days prior to enrollment) using a conservative repeat dosing paradigm (four intravenous infusions over two weeks). The first phase is 2-week parallel, double-blind phase comparing ketamine to midazolam, and the second is a 4-month open phase in which midazolam- assigned participants who remain suicidal or depressed can receive open ketamine. All participants will receive medication management according to an adaptation of the Texas Children’s Medication Algorithm and 8 weeks of cognitive behavioral therapy (CBT). All will be followed weekly in the open phase for efficacy and safety, with trial design developed in consultation with the FDA. Given the need for predictive biomarkers of treatment response, adolescents will participate in task and rest-based fMRI neuroimaging. Using our novel connectome- based predictive modeling, which uses tasks to “tweak” brain networks across RDoC domains, we will determine pre-treatment connectome phenotypes, or “fingerprints”, that predict treatment response. We proposed 3 specific aims: (1) To evaluate the feasibility and safety of treating adolescents at high suicide risk with a conservative repeat-dosing ketamine paradigm followed by standard of care treatment over 4 months. (2) To evaluate the 48-hour impact of ketamine on suicidal ideation (measured via Columbia Suicide Rating Scale, recent ideation subscale) compared to midazolam, and to identify connectome phenotypes predictive of ideation post-treatment. (3) To describe the trajectory of suicidal thinking, depressive symptoms, and use of mental health resources in both ketamine responders and non-responders over 4 months. The data generated here will advance scientific knowledge and influence clinical practice, in addition to providing the foundational data needed for subsequent trial design in youth at severe suicide risk.