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

降低青少年自杀风险：静脉注射氯胺酮的安全性、功效和连接组表型

• 批准号: 10263371
• 负责人: Michael H Bloch
• 金额: $ 66.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263371
• 关键词: 17 year old; Abstinence; Address; Adolescent; Adult; Aftercare; Algorithms; Animals; Antidepressive Agents; Atlases; Attention deficit hyperactivity disorder; Behavior; Biological; Biological Markers; Bladder; Brain; Cardiovascular Physiology; Case Study; Cause of Death; Child; Childhood; Clinical; Clinical Trials; Cocaine; Cognitive Therapy; Communities; Complex; Consultations; Cross-Over Trials; Data; Depressed mood; Development; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Equilibrium; Event; Feeling suicidal; Fingerprint; Foundations; Functional Magnetic Resonance Imaging; Health; Health Resources; Hour; Individual Differences; Infusion procedures; Intervention; Intervention Studies; Intravenous; Intravenous infusion procedures; Ketamine; Knowledge; Label; Major Depressive Disorder; Measures; Medical; Medication Management; Mental Depression; Mental Health; Midazolam; Monitor; Montgomery and Asberg depression rating scale; Morals; Outcome; Participant; Patients; Pediatric Research; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Population; Prediction of Response to Therapy; Protocols documentation; Psychiatric therapeutic procedure; Psychiatrist; Psychiatry; Randomized; Randomized Controlled Clinical Trials; Recommendation; Regulation; Research Domain Criteria; Resistance; Resources; Rest; Risk; Risk Factors; Safety; Sampling; Scientific Advances and Accomplishments; Selective Serotonin Reuptake Inhibitor; Suicide; Symptoms; Task Performances; Testing; Texas; Vacuum; Validation; Youth; adolescent suicide; antidepressant effect; autism spectrum disorder; base; clinical practice; cognitive function; connectome; connectome based predictive modeling; depressive symptoms; design; efficacy trial; evidence base; evidence based guidelines; hemodynamics; high-risk adolescents; ideation; improved; inattention; modifiable risk; neuroimaging; neurotoxicity; novel; overtreatment; predicting response; predictive marker; rapid test; responders and non-responders; safety and feasibility; safety outcomes; sound; standard of care; suicidal; suicidal risk; treatment response; treatment-resistant depression; trial design

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.

项目摘要（摘要） 自杀是年轻人（10至34岁）死亡的第二大原因，目前没有 青少年的循证药理学抗自杀干预措施。青少年的潜在危险因素 自杀包括严重抑郁症（这会增加30倍的风险），以及最近从一个 与自杀有关的更高水平的精神病护理。这些风险可能会进一步增强治疗抵抗性 人口。氯胺酮在成人治疗抵抗人群中具有抗自杀作用，即使在控制其 抗抑郁作用尽管在儿科精神病学中没有证据基础，但氯胺酮越来越多地被 儿童精神科医生标签外使用，他们没有基于证据的药理学选择， TORDIA建议。我们最近完成了一项咪达唑仑对照的随机临床试验， 显示快速（1天）抗抑郁疗效的难治性抑郁（TRD）青少年， 单剂量氯胺酮的耐受性良好。我们有病例报告和试验数据表明耐受性， TRD青少年重复给药模式的抗自杀承诺。在这里，我们提出了一个两阶段 一项测试氯胺酮在高自杀风险青少年中快速抗自杀功效的研究（操作上 定义为入组前120天内发生TRD和自杀事件），使用保守重复 给药模式（两周内四次静脉输注）。第一阶段为2周平行双盲 第一阶段是比较氯胺酮和咪达唑仑，第二阶段是4个月的开放期，其中咪达唑仑- 指定的参与者如果仍然有自杀倾向或抑郁，可以接受开放式氯胺酮。所有参加者将获得 根据德克萨斯州儿童药物治疗算法和8周的适应性药物治疗管理 认知行为疗法（CBT）在开放期每周对所有患者进行疗效和安全性随访， 与FDA协商制定的试验设计。考虑到对治疗的预测性生物标志物的需求， 响应，青少年将参加任务和休息为基础的功能磁共振成像神经成像。利用我们的新型连接体- 基于预测建模，它使用任务来“调整”RDoC域之间的大脑网络，我们将 确定治疗前的连接体表型，或“指纹”，预测治疗反应。我们 提出3个具体目标：（1）评估治疗自杀高危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4个月的标准护理治疗。 (2)评价氯胺酮对自杀意念的48小时影响（通过哥伦比亚自杀评分测量 量表、近期构思子量表）与咪达唑仑进行比较，并鉴定预测 治疗后的想法。(3)描述自杀想法、抑郁症状和使用 4个月内氯胺酮应答者和无应答者的精神卫生资源。生成的数据 这里将推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。