Blocking the orexin system following therapeutic exposure promoted between session habituation, but not PTSD symptom reduction.

There is a need to identify strategies to increase the effectiveness of treatments for posttraumatic stress disorder (PTSD). Sleep is often disturbed in PTSD and has been implicated in learning processes that underlie recovery from PTSD, including extinction of conditioned fear. Our prior study suggested that diminished arousal during sleep may enhance benefits of therapeutic exposure for PTSD. The orexin system regulates arousal, and blocking the system diminishes arousal and promotes sleep. We, therefore, examined whether a dual orexin receptor antagonist, suvorexant, administered following evening exposure sessions, would enhance their therapeutic effectiveness for PTSD. In this randomized double-blind placebo-controlled trial, adults with PTSD completed four written narrative exposure (WNE) sessions, two of which took place in the evening, and two the next morning. Participants received either suvorexant or placebo after each evening WNE. We found that suvorexant increased N3 sleep and decreased N2 sleep and rapid-eye-movement latency measured by polysomnography. Between session habituation indexed by subjective distress ratings was greater with suvorexant, but there was no group difference in the reduction of PTSD severity from baseline to 1-week follow-up. No safety concerns emerged. The present findings provide preliminary support for enhancement of an effect of therapeutic exposure for PTSD by suvorexant. Further studies with larger samples are needed to translate the present findings into clinical applications, including studies to develop optimal suvorexant administration and exposure session schedules to achieve persistent benefits to sleep and possibly greater treatment augmentation.

Impacts of sex and the estrous cycle on associations between post-fear conditioning sleep and fear memory recall.

Women are at greater risk than men for developing posttraumatic stress disorder (PTSD) after trauma exposure. Sleep, especially rapid-eye-movement sleep (REMS), has been considered a contributing factor to the development of PTSD symptoms through its effects on the processing of emotional memories. However, it remains unknown if sex and sex hormones play a role in the hypothesized impact of sleep on the development of PTSD. Animal models have methodological advantages over human studies in investigating this research question; however, animal models of sleep in PTSD have been tested only with males. C57BL/6 mice (7 males and 15 females) were exposed to 15 footshocks in a footshock chamber, and 5 min after the last footshock, were returned to their home cages for telemetric electroencephalographic sleep recording. Nine to thirteen days later, mice were returned to the footshock chamber for 10 min without footshocks. Fear recall rates were computed by comparing freezing behaviors in the footshock chamber immediately after the footshocks to those during fear context reexposure. Males had significantly lower recall rates compared to metestrous females (that received footshocks on metestrus). Overall, males slept more than both proestrous females (that received footshocks on proestrus) and metestrous females during the dark period. Regression analyses revealed that average REMS episode durations after footshocks were differentially associated with recall rates across groups, such that the association was positive in males, but negative in proestrous females. Results suggest that both sex and the estrous cycle modulate the associations between REMS continuity and fear memory consolidation.