The Effects of Orexin Antagonism on Fear Extinction in PTSD

PTSD is a common consequence of combat manifested in part by trauma-related arousal and reactivity, seen in increased startle and impaired sleep that result from central and autonomic nervous system alterations. Impaired fear extinction may explain prolonged physiological alterations in PTSD [4-7]. Preclinical evidence suggests that orexin, a wake-promoting neuropeptide, may be a shared mechanism underlying both sleep and fear extinction. While rodent studies have shown that pharmacological manipulations that block orexin in rodents facilitate fear extinction [8-10], no studies have tested this in humans with PTSD. In line with the CSRD Combined Proof of Concept and Clinical Trial Merit Review Award mechanism, we propose a proof-of-concept study leading to a clinical trial. During the initial phase, we will develop and establish feasibility of our task and recruitment in 40 eligible participants with PTSD and insomnia. The task will involve a home-based multi-day remote fear conditioning experimental study, in which Veterans with PTSD and insomnia will receive nightly doses of suvorexant or placebo following extinction training over the subsequent 6 nights. Primary Aims of the proof of concept will be to: 1) establish remote fear conditioning procedures collaboratively with Veteran stakeholders; 2) evaluate enrollment, tolerability, adherence, and retention; 3) demonstrate fear conditioning and extinction learning using remote procedures; and 4) determine task feasibility of our home- based remote fear conditioning task. Go/No go milestones include: 1) the ability to enroll and randomize 40 participants by the end of month 23; 2) most participants (> 80%) will take medication as prescribed over 7 nights; 3) no SAEs during the course of treatment as determined by the data monitoring committee review (DMC); 4) < 10% of post-randomization participants will drop out (<4 participants), resulting in 36 individuals who complete all study procedures by month 23; 5) successful demonstration of measurement of fear conditioning (greater skin conductance (SC) responses to CS+ cues vs CS- cues) and fear extinction (differential SC responses to CS+ and CS- cues that diminish over trials) in the combined sample; 6) feasibility of the remote task demonstrated by <15% data loss due to recording issues (e.g., technical malfunction or UCS non-response in <6 participants). If milestones are met, we will advance to a clinical mechanistic trial to evaluate suvorexant in facilitating fear extinction using a double-blind randomized, placebo-controlled experimental design in Veterans with PTSD and insomnia. A total of 120 male and female Veterans with PTSD and insomnia will be randomized to either the suvorexant or placebo condition (n=60 in each condition). Participants will be trained in multi-day remote procedures involving fear conditioning (Day 1) and extinction 3 days later (Day 4), followed by 10 mg. suvorexant or placebo. A flexible dose titration of suvorexant (10-20 mg.) or matching placebo will be administered over the next 6 nights. Participants will then undergo extinction retention and fear reinstatement tests one week after extinction (Day 11). Primary outcome measures will be differential skin conductance responses to CS+ and CS- cues during extinction retention and reinstatement phases. Primary Aims of the Clinical Trial will be: 1) To examine whether suvorexant facilitates fear extinction, seen as greater extinction retention compared to placebo. 2) To examine whether the facilitative effects of suvorexant are more resistant to reinstatement compared to placebo. Pending an effect of suvorexant on fear extinction retention and reinstatement, we will evaluate whether improvement in insomnia mediates these effects. In-home sleep recording (including both sleep EEG and indices of sleep-disordered breathing) and sleep diary measures will be examined as secondary mediators. Greater improvement in sleep quality will partially account for Project Number: 1I01CX002734-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: SABRA INSLICHT | Institution: VETERANS AFFAIRS MED CTR SAN FRANCISCO, SAN FRANCISCO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 MHBP-F (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11052075