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: 10115222
• 负责人: Jennifer Buenzle Dwyer
• 金额: $ 67万
• 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/10115222
• 关键词: 17 year old; Abstinence; Address; Adolescent; Adult; Aftercare; Algorithms; Animals; Antidepressive Agents; 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; 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; novel; overtreatment; predicting response; predictive marker; 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） 自杀是年轻人的第二大死亡原因（10至34岁），目前没有 青少年的基于证据的药物结肠抗自杀干预措施。青少年有效的风险因素 自杀包括重度抑郁症（增加了30倍的风险），最近出院了 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抗治疗的风险 人群。氯胺酮在抗成人治疗群体中是抗杀菌剂，即使在控制措施之后 抗抑郁作用。尽管没有儿科精神病学的证据基础，但氯胺酮越来越多 使用儿童精神科医生的标签，他们没有循证的药学选择 托迪亚的建议。我们最近完成了一项咪达唑仑控制的随机临床试验 具有耐药性抑郁症（TRD）的青少年表现出快速（1天）抗抑郁药的易感性和 单个氯胺酮剂量的声音耐受性。我们有案例报告和试点数据，建议耐受性和 TRD青少年重复给药范例的反杀伤承诺。在这里，我们提出了两阶段 研究以高自杀风险的青少年氯胺酮快速抗杀菌效率（在操作上 定义为在入学前120天内使用TRD和自杀事件）使用保守重复 给药范式（两周内四次静脉输注）。第一阶段是2周平行的双盲 比较氯胺酮与咪达唑仑的相位，第二个是一个4个月的开放阶段，其中咪达唑仑 - 保留自杀或沮丧的分配参与者可以接受开放的氯胺酮。所有参与者都会收到 根据得克萨斯州儿童药物算法的改编和8周的药物管理 认知行为疗法（CBT）。所有这些都将在开放阶段每周遵循，以提高效率和安全性， 试验设计与FDA协商开发。考虑到需要治疗的预测生物标志物 反应，青少年将参与任务和基于REST的fMRI神经影像学。使用我们的小说Connectome- 基于基于RDOC域“调整”大脑网络的基于的预测建模，我们将 确定预测治疗反应的预处理连接组表型或“指纹”。我们 拟议的3个具体目的：（1）评估以高自杀风险治疗青少年的可行性和安全性 在保守的重复剂量氯胺酮范式下，随后在4个月内进行了护理标准治疗。 （2）评估氯胺酮对自杀思想的48小时影响（通过哥伦比亚自杀评级进行测量 比例，最近的想法量表）与咪达唑仑相比，并确定预测的连接组表型 构想后处理。 （3）描述自杀思维，抑郁症状和使用的轨迹 氯胺酮响应者和非反应者的心理健康资源在4个月内。生成的数据 此外，还将推进科学知识并影响临床实践，除了提供基础 随后在年轻人中以严重自杀风险进行试验设计所需的数据。