Overview of hypnotic effects on sleep architecture

BZ and non-BZ hypnotics, which have been used as sleep medications for over half a century, exert hypnotic effects by acting on GABA receptors. Their known effects on PSG include shortened sleep onset latency, reduced slow-wave sleep, increased sleep spindles, and decreased REM sleep [10,11,12]. In Japan and the United States, orexin receptor antagonists have been available for 10 years, and due to their high safety profile and weak dependence potential [13,14,15,16], they are increasingly used as first-line sleep medications, with growing recognition among general practitioners. However, there are few systematic reports on how these agents affect human sleep architecture.

The PSG data analysis results from daridorexant administration to insomnia patients in this study demonstrated dose-dependent improvement in multiple sleep parameters.

Previous PSG studies of orexin receptor antagonists

Clinical trials using PSG with various orexin receptor antagonists [9, 17, 18] have reported sleep effects including shortened latency to persistent sleep and prolonged total sleep time. Furthermore, a systematic review reported that prolonged total sleep time and increased REM sleep time were common findings for DORAs in both healthy subjects and insomnia patients. In this Phase II clinical trial, both parameter values during each treatment period and changes from baseline showed prolonged total sleep time and increased REM sleep time and percentage. However, the effects of DORA on NREM sleep remain inconclusive, with most insomnia studies reporting no significant effects on total NREM sleep, though some show decreased %stage N1 and variable effects on %stage N2 and N3.

Effects of daridorexant on NREM sleep architecture

One notable finding in this study is the effect of daridorexant administration on NREM sleep architecture. Although no significant dose-dependent relationship was observed for total NREM sleep duration, an increase of approximately 40 min was observed from baseline (278.5 ± 44.3 min) to DR 25 mg treatment (319.3 ± 32.4 min). Regarding stage-specific NREM sleep durations, stage N1 showed statistically significant dose-dependent decreases in change from baseline, while stage N2 and stage N3 showed statistically significant increases. The significance of these findings was confirmed using the Jonckheere-Terpstra test, indicating clear changes in sleep architecture between placebo and active treatment. Therefore, daridorexant administration in insomnia reduced light NREM sleep while increasing deeper NREM sleep (stages N2 and N3), suggesting that improvement in NREM sleep architecture can be expected in insomnia patients.

Effects of daridorexant-induced reduction in nocturnal awakenings on sleep architecture

In this study, a dose-dependent relationship was observed between the reduction in the number of persistent nocturnal awakenings and daridorexant dose. A previous post-hoc analysis of daridorexant Phase 2 data showed that long awakenings (≥ 6 min) were significantly reduced with 50 mg compared to placebo [19]. In the sleep quarter analysis, NAW (Fig. 4a) showed greater reductions compared to placebo during the first two quarters of sleep for all three doses, with 50 mg showing continued reduction through the third quarter. Statistically, 50 mg demonstrated a significant effect in reducing awakenings during the first quarter of sleep.

The persistent awakenings (NAW) defined in this study indicate disruption of sleep stage continuity, differing from brief arousal responses. NAW was defined as awakenings lasting at least 1 min (2 consecutive epochs of stage W). These awakenings require subsequent sleep onset beginning with light sleep, suggesting that the number of sustained awakenings indicates fragmentation and superficiality of sleep structure. Therefore, the dose-dependent relationship observed for NAW in this analysis is presumed to be related to daridorexant-induced structural changes in NREM sleep (reduction of light sleep and increase of deeper sleep). Furthermore, awakenings with persistent durations of 5 min or longer are considered memorable [20], and their reduction would be effective for improving insomnia symptoms.

Slow wave sleep (SWS) enhancement effects

In this study, it was presumed that the reduction of persistent awakenings led to deeper sleep, with significant dose-dependent relationships observed not only for N2 increases but also for N3 increases. In the sleep quarter analysis, N3 time (Fig. 4b) showed greater increases compared to placebo during the first quarter of sleep for all three doses. Enhancement of deep sleep by DORA has been reported in basic research using rats and mice [21, 22]. In both young adult rats with sleep fragmentation caused by ethanol vapor exposure and control rats, DORA-12 administration increased delta and theta power in sleep EEG, confirming increased deeper sleep [21]. This study represents the first report showing daridorexant tends to increase SWS sleep during the first quarter of sleep in humans.

REM sleep enhancement effects

According to a review of DORA effects on REM sleep, REM sleep latency shortening was observed in 60–70% of studies, and REM sleep amount increases were observed in over 80% of studies targeting insomnia patients. In this study, significant dose-dependent relationships were observed for REM sleep latency, REM sleep time, and REM sleep percentage in patients with objective insomnia on PSG. Since the baseline REM sleep percentage before medication was 19.6 ± 6.3%, below 20%, the involvement of REM sleep rebound phenomenon [23] in insomnia was presumed to contribute to this REM sleep increase. The sleep quarter analysis (Fig. 4c) showed significant increases compared to placebo during the first quarter of sleep with 25 mg and 50 mg administration, suggesting REM rebound involvement. A particularly interesting finding was that while placebo changes decreased in the final quarter, the active treatment groups showed significant increases. This change suggests that daridorexant further promotes the tendency for REM sleep to increase in the latter half of sleep, and this effect persisting through the final quarter suggests that daridorexant’s sleep effects are maintained through the night.

Promotion of natural sleep architecture

The prolonged TST observed with daridorexant administration in this study included increases not only in REM sleep but also in NREM sleep (stages N2 and N3). Basic research [24, 25] suggests that orexin neurons govern the transition from REM to NREM sleep and that DORAs may restore several abnormalities un sleep micro-architecture as well as macro-architecture. Neural circuits mediated by orexin receptors are involved in the regulation of sleep and wakefulness, and NREM and REM sleep. Daridorexant is expected to promote sleep and restore natural sleep architecture. Detailed examination of its effects on daytime mood, sleep satisfaction, cognitive function, and their relationships with sleep architecture is anticipated in the future.

Limitations

This study has several limitations. First, this is a secondary analysis of Phase II clinical trial data, and the exploratory nature should be acknowledged. Second, the sample size was limited to 47 cases from a Japanese population, which may limit generalizability to other ethnic groups. However, consistent dose-response patterns were observed and statistically validated. Additionally, this study aimed to evaluate dose-response relationships in sleep architecture and REM sleep enhancement in the latter part of the night, rather than to determine the optimal dose through pairwise dose comparisons. The sample size in this trial was limited for detailed between-group comparisons. Future prospective studies in larger populations, including elderly patients, are needed to verify the differential effects and clinical significance of each dose. Third, direct comparisons with other hypnotics were not performed, limiting conclusions regarding relative efficacy. Fourth, subjective outcomes and next-day cognitive function assessments were not conducted, making it impossible to evaluate correlations between PSG improvements and clinical endpoints. Finally, while NAW was introduced as a novel sleep fragmentation index showing promising results, validation in larger populations would strengthen its application as a sleep assessment tool.