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

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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.