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紧迫问题 管理（VHA）。最近的报告表明，大约一半的退伍军人自杀发生在10分钟内。 死者最后一次VHA接触的一个月，其中四分之一发生在1周内。这提供了 时间窗口的机会进行干预，并有必要开发一种快速有效的治疗方法， 退伍军人与SI静脉注射氯胺酮是典型的抗自杀药物，在某些情况下可迅速降低SI。 患者然而，人们担心氯胺酮对退伍军人和军事人员的毒性。 这些因素包括氯胺酮的潜在毒性和滥用，以及抗自杀作用的短暂持续时间。的 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 与氯胺酮相同的神经基质的“目标接合”; 3）风险更小; 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 新的干预尿苷作为一种快速有效的口服治疗退伍军人与SI。如提案所述， 尿苷的潜力，以填补这一作用在于广泛的重叠，在大脑机制和神经的影响，共享 尿苷氯胺酮和抗自杀药锂这种令人惊讶的共性的原因可能在于 氯胺酮的作用机制依赖于从头嘧啶生物合成的激活， 事实上，尿苷是内源性循环嘧啶在人。开始测试尿苷的退伍军人与 SI，我们将进行一项为期四周的，双盲，安慰剂对照的临床试验，每天尿苷2000 mg， 退伍军人与SI为了使研究更具信息性，将翻译神经影像学整合到方案中 以鉴定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，治疗1周后重复扫描，以追踪神经化学生物特征 快速降低SI。在完成为期四周的安慰剂对照阶段后，参与者将进入 研究的6个月开放标签阶段。开放标签阶段将实现两个目标：1）评估 尿苷应答者中尿苷抗自杀作用的持久性;和2）为了确保退伍军人最初 随机分配至安慰剂组的患者有充分和公平的机会从积极治疗中获益。总之，虽然 这项研究的目的是为自杀的退伍军人提供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志物。

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.