Orexin Antagonists Consistently Reduce PTSD-Like Behaviors by Modulating Sleep, Stress, and Fear Circuits

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition marked by hyperarousal, intrusive memories, and impaired fear extinction, frequently coupled with persistent sleep disturbances. Current treatments often fall short in comprehensively addressing both the core symptoms and associated sleep issues. The orexin (hypocretin) system, a key regulator of arousal, stress reactivity, and REM sleep, has emerged as a promising therapeutic target due to its central role in these interconnected processes. Modulating this system offers a novel approach to tackle the multifaceted pathology of PTSD.

This scoping review analyzed data from 11 preclinical and clinical studies investigating the effects of dual (DORA) or selective orexin receptor antagonists on PTSD-like phenotypes. Animal studies utilized established stress models, including single prolonged stress (SPS), predator scent stress, and fear conditioning/extinction paradigms. Behavioral outcomes assessed included freezing behavior, anxiety-like behavior, fear extinction retention, and REM sleep modulation. Some studies also investigated molecular markers such as orexin-A levels, corticosterone, CRF-R1, serotonin, mitochondrial fission/fusion proteins, and mTOR signaling. The review also incorporated findings from one double-blind clinical trial of suvorexant.

Across the evaluated studies, orexin antagonism consistently reduced various PTSD-like behaviors. Specifically, 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 through mechanisms involving the basolateral amygdala. In stress-exposed rodent models, suvorexant effectively reversed hyperarousal, avoidance, and anxiety-like behaviors. It also attenuated elevated orexin-A and CRF-R1 levels observed in the amygdala and restored HPA axis function. Furthermore, mitochondrial dysfunction and mTOR activation, which are characteristic features in rodent models of PTSD, were normalized with orexin antagonism.

The most significant finding was the consistent demonstration that orexin antagonism effectively mitigates the core behavioral and neurobiological hallmarks of PTSD across diverse preclinical models.