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

退伍军人自杀、企图和自杀意念(SI)仍然是退伍军人健康的迫切关切 管理(VHA)。最近的报告表明，大约一半的退伍军人自杀事件发生在1 死者最后一次遭遇VHA的一个月，其中四分之一发生在1周内。这提供了一种 时间窗干预的机会，并有必要开发一种快速有效的治疗方法 患有SI的退伍军人。静脉注射氯胺酮是典型的抗自杀药物，它能迅速降低某些患者的SI 病人。然而，有人担心氯胺酮对退伍军人和军事人员的毒性。 这些问题包括氯胺酮的潜在毒性和误用，以及抗自杀作用的短暂持续时间。这个 理想的VHA抗自杀治疗：1)可以口服而不是静脉注射；2)将达到 使用与氯胺酮相同的神经底物进行“靶向交战”；3)风险较小；4) 有更长的作用时间和/或更持久的抗自杀效果。因此，这项研究将测试 新型干预尿苷作为退伍军人SI的快速口服治疗。正如提案中所述， 尿苷填补这一角色的潜力在于其共同的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的原因可能在于 事实上，氯胺酮的作用机制依赖于激活从头合成的嘧啶-以及 尿苷是人体内循环中的内源性嘧啶。为患有以下疾病的退伍军人启动尿苷测试 SI，我们将进行为期四周的双盲安慰剂对照临床试验，每天服用2000毫克尿苷治疗 患有SI的退伍军人。为了使这项研究更有信息量，翻译神经成像被整合到方案中 鉴定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，在治疗1周后重复扫描，以追求神经化学生物特征 SI的快速降低。在为期四周的安慰剂对照阶段结束后，参与者将进入 为期六个月的开放标签阶段的研究。开放标签阶段将实现两个目标：1)评估 尿苷在尿苷响应者中的抗自杀作用的持久性；以及2)确保退伍军人最初 随机服用安慰剂的患者有充分和公平的机会从积极治疗中受益。总而言之，虽然 这项研究还旨在为自杀退伍军人试行一种急需的静脉注射氯胺酮的替代品 参与建立自杀意念和治疗反应的神经化学生物标记物。

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.