Posttraumatic stress disorder (PTSD) is a common consequence of combat that is manifested in part by trauma-related hyperarousal and reactivity, seen in increased startle responses and impaired sleep that result from central and autonomic nervous system alterations. In fact, disturbed sleep is the most prevalent symptom endorsed by PTSD patients and is potentially debilitating in many domains of functioning (1, 2). As a relatively non-stigmatizing symptom, it is no surprise that disturbed sleep is often the reason that motivates Veterans with PTSD to seek treatment (3, 4). However, most drugs that target sleep result in unwanted side effects, such as next day somnolence, which can impact functioning in both military and civilian life. Furthermore, aside from several SSRI's that are only moderately effective in improving PTSD, little progress has been made toward advancing pharmacological treatments for PTSD and in Veterans. Preclinical evidence suggests that the orexin neuropeptide system may be a shared mechanism accounting for both sleep disturbance and PTSD. Orexin is a central promoter of wakefulness involved in regulation of sleep, and in fear learning and emotional memory. The dual orexin receptor antagonist, suvorexant, is the first of a new class of medications recently FDA-approved to treat insomnia. In contrast to previous generations of treatments used for patients with PTSD that provide delayed and often inadequate symptom relief, suvorexant holds promise of delivering immediate relief for pressing sleep concerns while also potentially reducing PTSD symptoms by targeting a biological mechanism that may account for both conditions. While its efficacy for insomnia has been strongly supported by clinical trials (5-8), the potential benefit of suvorexant on trauma- related sleep disturbance and on PTSD symptoms has not been examined, nor has it been evaluated for safety and tolerability in Veterans. We propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IV clinical trial to test the efficacy and safety of suvorexant on trauma-related sleep disturbance and PTSD symptoms in Veterans. We will use a flexible dose design of suvorexant with a 2-week titration followed by a 10-week steady-dose phase. We predict that suvorexant, as compared to placebo, will result in a greater decrease in insomnia on the Insomnia Severity Index (ISI) over the 12-week trial. We also predict that suvorexant, as compared to placebo, will result in a greater reduction in non-sleep PTSD symptoms in the Clinician Administered PTSD Scale for DSMV (CAPS-5) over the 12-week trial. Secondarily, we will examine potential objectively measured wrist actigraphy as a biological mechanism of clinical improvement with as well as concomitant effects on PTSD-related nightmares using the Pittsburgh Sleep Quality Index-PTSD addendum (PSQI-A). Pending a significant effect of suvorexant on PTSD, we will perform exploratory analyses to evaluate whether ...