Clinical and Imaging Biomarker Trial of Uridine for Veterans with Suicidal Ideation

针对有自杀意念的退伍军人的尿苷临床和影像生物标志物试验

基本信息

批准号：
10704015
负责人：
Douglas Gavin Kondo
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704015
关键词：
Acute Address Advocate Aftercare Amino Acids Anabolism Anesthesia procedures Anxiety Biological Markers Brain Brain imaging Brain scan Brain-Derived Neurotrophic Factor Clinical Congresses Controlled Clinical Trials Data Delirium Development Diagnosis Double-Blind Method Education Effectiveness FRAP1 gene Feeling suicidal Genes Genitourinary system Glutamine Goals Human Intervention Intravenous Intravenous infusion procedures Investigation Investigational Drugs Ketamine Literature Lithium Magnetic Resonance Spectroscopy Manic Measurement Measures Mental Health Services Mental disorders Methodology Military Personnel Mission Multienzyme Complexes National Institute of Mental Health Odds Ratio Oral Oral Administration Participant Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phencyclidine Phosphorylation Placebo Control Placebos Post-Traumatic Stress Disorders Probability Prodrugs Property Protocols documentation Protons Psychoses Public Health Publications Pyrimidine Randomized Reporting Research Research Domain Criteria Risk Role Scanning Science Severities Soldier Suicide Suicide attempt Suicide prevention Surveys Symptoms Testing Toxic effect Traumatic Brain Injury United States Department of Veterans Affairs Uridine Veterans Veterans Health Administration Visit abuse liability active method addiction antidepressant effect biomarker identification biosignature clinical biomarkers clinical center combat veteran compliance behavior dysphoria evidence base experience gamma-Aminobutyric Acid gastrointestinal imaging biomarker improved in vivo insight man military veteran neural neurochemistry neuroimaging neurotransmission novel open label pilot test reducing suicide response satisfaction spectroscopic imaging suicidal suicidal behavior suicidal morbidity suicidal risk suicide brain suicide substrates suicide victim therapy development tool translational study treatment response tripolyphosphate

项目摘要

Veteran suicides, attempts and suicidal ideation (SI) remain of urgent concern to the Veterans Health Administration (VHA). Recent reports indicate that approximately half of veteran suicides take place within 1 month of the decedent’s final VHA encounter, with one quarter occurring within 1 week. This provides a temporal window of opportunity to intervene, and necessitates development of a rapid-acting treatment for veterans with SI. Intravenous ketamine is the prototypical anti-suicidal drug, that rapidly reduces SI in some patients. However, there are concerns regarding ketamine’s toxicity in both veterans, and military personnel. These include ketamine’s potential for toxicity and misuse, and the brief duration of anti-suicidal effect. The ideal VHA anti-suicidal treatment: 1) Could be administered orally rather than intravenously; 2) Would achieve “target engagement” with the same neural substrates as ketamine; 3) Would have fewer risks; and 4) Would have a longer duration of action and/or a more durable antisuicidal effect. Therefore this study will test the novel intervention uridine as a rapid-acting oral treatment for veterans with SI. As described in the proposal, uridine’s potential to fill this role lies in the broad overlap in the brain mechanisms and neural effects shared by uridine, ketamine and the anti-suicidal drug lithium. The reason for this surprising commonality may lie in the fact that ketamine’s mechanism-of-action dependent on activation of de novo pyrimidine biosynthesis – and the fact that uridine is the endogenous circulating pyrimidine in man. To initiate testing of uridine for veterans with SI, we will conduct a four-week, double-blind, placebo-controlled clinical trial of uridine 2000 mg daily for veterans with SI. To make the study more informative, translational neuroimaging is integrated into the protocol to identify biomarkers of SI. Veterans will undergo proton-1 magnetic resonance spectroscopy (1H-MRS) imaging at baseline, with scans repeated after 1 week of treatment, in pursuit of a neurochemical biosignature of rapid SI reduction. Upon completion of the four-week placebo-controlled phase, participants will enter the six-month open-label phase of the study. The open-label phase will accomplish two goals: 1) To evaluate the durability of uridine’s anti-suicidal effect in uridine responders; and 2) To ensure that veterans initially randomized to placebo have a full and fair opportunity to benefit from active treatment. In summary, while piloting a much-needed alternative to intravenous ketamine for suicidal veterans, this research also aims to participate in establishing the neurochemical biomarkers of suicidal ideation, and treatment response.

退伍军人自杀、自杀未遂和自杀意念 (SI) 仍然是退伍军人健康的迫切关注问题政府 (VHA) 最近的报告表明，大约一半的退伍军人自杀发生在 1 年内。死者最后一次遇到 VHA 的月份，其中四分之一发生在 1 周内。干预的时间窗口，并且需要开发快速作用的治疗方法静脉注射氯胺酮是典型的抗自杀药物，可迅速减少某些人的 SI。然而，人们担心氯胺酮对退伍军人和军事人员的毒性。其中包括氯胺酮潜在的毒性和滥用，以及抗自杀作用的短暂持续时间。理想的 VHA 抗自杀治疗：1) 可以口服而不是静脉注射；2) 可以实现；与氯胺酮具有相同的神经底物的“目标参与”；3）风险较小；4）具有更长的作用持续时间和/或更持久的抗自杀作用，因此本研究将测试。新型干预尿苷作为 SI 退伍军人的快速起效口服治疗方法如提案中所述，尿苷填补这一角色的潜力在于其大脑机制和神经效应的广泛重叠尿苷、氯胺酮和抗自杀药物锂这种令人惊讶的共性可能在于：事实上，氯胺酮的作用机制依赖于从头嘧啶生物合成的激活——以及尿苷是人体内循环的内源性嘧啶这一事实开始对患有以下疾病的退伍军人进行尿苷检测。 SI，我们将进行一项为期 4 周、双盲、安慰剂对照的临床试验，每天服用 2000 毫克尿苷，用于治疗为了使研究提供更多信息，将转化神经影像纳入协议中。为了识别 SI 的生物标志物，退伍军人将接受质子 1 磁共振波谱 (1H-MRS)。基线成像，治疗 1 周后重复扫描，以寻求神经化学生物特征为期 4 周的安慰剂对照阶段完成后，参与者将进入 SI 快速降低阶段。为期六个月的开放标签研究阶段将实现两个目标：1）评估研究。尿苷对尿苷反应者的抗自杀作用的持久性；以及 2) 确保退伍军人最初总而言之，随机接受安慰剂的患者有充分且公平的机会从积极治疗中受益。这项研究还旨在为有自杀倾向的退伍军人试行一种急需的静脉注射氯胺酮替代品参与建立自杀意念和治疗反应的神经化学生物标志物。