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

• 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
• 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

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、企图和自杀意念（SI）仍然是退伍军人健康迫切关注的问题