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.

项目概要（摘要） 自杀是年轻人（10 至 34 岁）的第二大死因，目前尚无 针对青少年的基于证据的药物抗自杀干预措施。 自杀包括重度抑郁症（使风险增加 30 倍），以及最近从医院出院 更高水平的精神科护理可能会进一步增强与自杀相关的风险。 氯胺酮在成人治疗抵抗人群中具有抗自杀作用，即使在对其进行控制后也是如此。 尽管在儿科精神病学中没有证据基础，但氯胺酮的抗抑郁作用越来越受到重视。 儿童精神病学家在标签外使用，除了药物之外，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随机临床试验。 患有难治性抑郁症 (TRD) 的青少年显示出快速（1 天）的抗抑郁功效 单剂量氯胺酮的良好耐受性我们有病例报告和试验数据表明耐受性和 TRD 青少年重复给药范例的抗自杀承诺在这里，我们提出了一个两阶段的方案。 测试氯胺酮对高自杀风险青少年的快速抗自杀功效的研究（操作上） 定义为在入组前 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）第一阶段是两周平行、双盲。 比较氯胺酮和咪达唑仑的阶段，第二个是为期 4 个月的开放阶段，其中咪达唑仑- 仍有自杀倾向或抑郁的指定参与者可以接受开放式氯胺酮。所有参与者都将接受氯胺酮。 根据德克萨斯州儿童用药算法的改编进行药物管理，为期 8 周 认知行为治疗 (CBT) 的所有治疗将在开放阶段每周进行一次随访，以确保疗效和安全性。 鉴于对治疗预测生物标志物的需求，与 FDA 协商制定了试验设计。 响应，青少年将使用我们的新型连接组参与基于任务和休息的功能磁共振成像神经成像。 基于预测模型，它使用任务来“调整”跨 RDoC 领域的大脑网络，我们将 确定治疗前连接组表型或“指纹”，以预测治疗反应。 提出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模式，然后进行 4 个月以上的标准护理治疗。 (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级进行测量） 与咪达唑仑进行比较，并确定预测的连接组表型 (3) 描述自杀想法、抑郁症状和使用的轨迹。 4 个月内氯胺酮应答者和非应答者的心理健康资源。 除了提供基础知识外，这里还将推进科学知识并影响临床实践 针对有严重自杀风险的青少年进行后续试验设计所需的数据。