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: 10689070
• 负责人: Michael H Bloch
• 金额: $ 64.32万
• 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/10689070
• 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; Collaborations; Communities; Complex; Consultations; Cross-Over Trials; Data; Depressed mood; Development; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Event; Feeling suicidal; Fingerprint; 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; Persons; Pharmaceutical Preparations; Pharmacological Treatment; 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; Suicide prevention; Symptoms; Task Performances; Testing; Texas; Vacuum; Validation; Youth; adolescent suicide; antidepressant effect; autism spectrum disorder; 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; neuroimaging; neurotoxicity; novel; pharmacologic; predicting response; predictive marker; rapid test; reducing suicide; responders and non-responders; safety and feasibility; safety outcomes; sound; standard of care; suicidal; suicidal adolescent; suicidal risk; suicide rate; 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）