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，企图和自杀思想（SI）仍然是退伍军人健康的迫切关注管理（VHA）。最近的报告表明，大约一半的退伍军人自杀发生在1之内死者最后的VHA遇到的月份，其中四分之一发生在1周内。这提供了暂时的干预机会之窗，并需要开发快速行动治疗与SI的退伍军人。静脉注射氯胺酮是典型的抗杀菌药物，在某些人中迅速降低了SI 患者。但是，人们担心氯胺酮在退伍军人和军事人员中的毒性。这些包括氯胺酮的毒性和滥用潜力，以及抗自杀效应的短暂持续时间。这理想的VHA抗自杀治疗：1）可以口服而不是静脉注射； 2）将实现与氯胺酮相同的神经底物“目标参与”； 3）风险较少； 4）会具有更长的作用持续时间和/或更耐用的抗杀菌作用。因此，这项研究将测试新型干预尿苷作为SI退伍军人的快速作用口服治疗。如提议中所述，乌里丁填补这一角色的潜力在于大脑机制的广泛重叠和由尿苷，氯胺酮和抗杀菌药物锂。这种令人惊讶的共同点的原因可能在于氯胺酮的行动机制取决于从头嘧啶生物合成的激活 - 尿苷是人类中的内源性循环嘧啶。启动对尿苷的测试 SI，我们将进行为期四周的双盲，安慰剂对照的uridine 2000毫克的临床试验与SI的退伍军人。为了使研究更有信息，翻译的神经影像学已整合到协议中识别SI的生物标志物。退伍军人将进行质子-1磁共振光谱（1H-MRS）基线成像，治疗1周后重复进行扫描，以追求神经化学生物签名快速SI还原。四周安慰剂控制阶段完成后，参与者将进入研究的六个月开放标签阶段。开放标签阶段将实现两个目标：1）评估尿苷对尿苷反应者的抗杀菌作用的耐用性； 2）确保退伍军人最初随机分配到安慰剂有一个完整而公平的机会，可以从积极的治疗中受益。总而言之这项研究还涉及自杀退伍军人的静脉注射氯胺酮的备用替代品，还旨在参与建立自杀念头的神经化学生物标志物和治疗反应。