A Scoping Review of Orexin Antagonists in Post-Traumatic Stress Disorder: Modulating Sleep, Stress, and Fear Circuits

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by hyperarousal, intrusive memories, and impaired fear extinction, often accompanied by persistent sleep disturbances. The orexin (hypocretin) system, which regulates arousal, stress reactivity, and REM sleep, has emerged as a promising therapeutic target in PTSD. This review summarizes preclinical and limited clinical evidence examining the effects of orexin receptor antagonists, especially suvorexant, on PTSD-relevant behaviors and neurobiology.

This narrative review evaluates data from 11 preclinical and clinical studies that investigated the effects of dual (DORA) or selective orexin receptor antagonists on PTSD-like phenotypes. Animal studies involved established stress models, including single prolonged stress (SPS), predator scent stress, fear conditioning/extinction paradigms, and stress-alternatives models. Behavioral outcomes included freezing behavior, anxiety-like behavior, fear extinction retention, and REM sleep modulation. Some studies investigated molecular markers, such as orexin-A levels, corticosterone, CRF-R1, serotonin, mitochondrial fission/fusion proteins, and mTOR signaling. One double-blind clinical trial of suvorexant was also included. IRB approval was not required for this review.

Across studies, orexin antagonism consistently reduced PTSD-like behaviors. Suvorexant improved REM sleep and accelerated fear extinction in mice, even following circadian disruption. Orexin receptor-1 antagonists (e.g., SB334867) facilitated fear extinction and decreased freezing behavior via basolateral amygdala mechanisms. In stress-exposed rodents, suvorexant reversed hyperarousal, avoidance, and anxiety-like behaviors, attenuated elevated orexin-A and CRF-R1 levels in the amygdala, and restored HPA axis function. Mitochondrial dysfunction and mTOR activation, observed in rodent models of PTSD, were normalized with suvorexant treatment, suggesting cellular resilience. One clinical trial of suvorexant in trauma-related insomnia found REM enhancement and nightmare remission in most patients, although a strong placebo response limited group-level findings. Notably, reduced orexin signaling was associated with resilience in multiple models.

The reviewed evidence supports orexin receptor antagonism-particularly via dual antagonists like suvorexant-as a promising therapeutic approach for PTSD, with benefits across numerous domains: fear extinction, sleep regulation, hyperarousal, and cellular stress resilience. These findings suggest that orexinergic overactivation contributes to PTSD pathophysiology and that DORAs may offer an advantage over traditional sedatives by enhancing REM sleep and modulating stress signaling. Limitations include a predominance of preclinical data and heterogeneity in experimental models. Nonetheless, these studies provide a mechanistic foundation for larger clinical trials, particularly in patients with treatment-resistant PTSD or prominent sleep disturbance. Future research should explore receptor-specific roles, optimal timing of intervention, and biomarkers predictive of treatment response.