Suicide is a major public health concern among Veterans. Suicide rates for male and female Veterans are approximately 2x higher than in the general population, and approximately 5% of all Veterans report a past suicide attempt. Exploring novel pharmacological approaches to treat suicide risk is important to improve suicide prevention efforts. Among the studied etiological components of suicide, neuropeptidergic dysregulation may play a key role. Neuropeptides are important regulators of complex cognitive and behavioral processes, and a promising target for suicide risk is the hypothalamic orexin system, which has attracted attention since its relatively recent discovery in 1998. Orexins (neuropeptides) are central in the regulation of neurophysiological and behavioral processes that are often disturbed in suicidal patients such as the sleep-wake cycle, appetite, affect, and reward circuitry. Targeting the orexin system as a novel pharmacological approach for suicide risk reduction is highly promising given the evidence of abnormalities in orexinergic activity in depression and the clinical symptom overlap between orexin functions and suicidal features.
Leveraging the Veteran’s Administration Million Veteran Project (world’s largest genetic dataset), our research team has identified predicted upregulation of orexin (hypocretin) receptor 1 (HCRTR1) gene expression as a candidate gene target for suicide prevention. The proposed therapeutic action would be to block HCRTR1.
With this proposal, we aim to begin work on the clinical translation of this exciting finding. Suvorexant, a mixed orexin-1 and orexin-2 receptor antagonist, medically available since 2014, and with a well-known safety profile, will serve as our choice of compound to test for this project. Suvorexant has been studied in psychiatric populations with favorable results in quality of sleep improvements and anxiety and depression severity reductions both behaviorally and biologically.
This study proposes to evaluate the initial safety, feasibility, and tolerability of the orexin mixed antagonist suvorexant in 30 Veterans with Major Depressive Disorder at elevated suicide risk and test for the effect of treatment on a preliminary signal of suicide risk as measured by the suicide-related version of the Implicit Association Test (IAT). This study will use clinical and objective (e.g., task-based) secondary measures of two suicide-risk endophenotypes, impulsivity and aggression. Tertiary outcomes include anxiety and sleep disturbance. We will test effects of 10mg and 20mg dosing over 4 weeks. The benefits of a small-scale, single-arm design clinical trial for early phase work such as this are well known and include cost and time, sample size considerations, and the potential to accelerate drug development. This pilot, open-label proof-of-concept study will provide essential preliminary data to support a future well-powered randomized controlled trial evaluating suvorexant for suicide risk.
