Insomnia disorder: characterization and evaluation of sleep architecture in adult and elderly individuals

Sleep is important for mental and physical well-being. Patients with chronic insomnia, a disorder characterized by difficulties in initiating or maintaining sleep, along with impaired daytime functioning for at least 3 months, often experience mood disturbances, reduced performance at work, absenteeism, and reduced quality of life. This condition continues to impact both day and night, suggesting a complex interplay between neurobiological and psychological factors. One of the leading hypotheses behind this disorder is that the disease is characterized by a persistent state of psychophysiological hyperarousal. However, research findings have been inconsistent. To shed some light into this and assess whether individuals diagnosed with insomnia show sleep architecture signatures consistent with hyperarousal, we utilized one of the largest insomnia PSG datasets to date, derived from the adult phase 2 and phase 3 clinical programs of daridorexant and two additional external datasets. It is important to note that this thesis focused on PSG-derived objective features. While hyperarousal also includes clinical effects like cognitive, emotional, and behavioral symptoms, these aspects were not the primary focus of this PSG-based analysis. Nevertheless, this research offers a comprehensive analysis of sleep architecture in these individuals addressing one of the biggest limitations of previous studies that relied on small sample sizes. The studies conducted revealed that adult and elderly individuals with insomnia are more likely to experience fragmented sleep and long bouts of waking (> 6 minutes) during the night. Additionally, we observed that sleep spindles, more precisely spindle density are reduced in individuals with insomnia compared to non-insomnia controls. This suggests that insomnia is characterized by a vulnerability of NREM sleep making individuals more likely to experience sleep disruptions. With further examination of the spectral composition of sleep, this analysis highlights significant differences in the electroencephalography signatures of insomnia, especially in the alpha and delta bands during night-time wake periods. Contrary to expectations, the study did not find a significant increase in relative beta power in individuals with insomnia compared to non-insomnia controls, suggesting that the faster brain frequencies such as beta bands are not an inherent characteristic of insomnia, instead it might be specific for some insomnia subtypes, and comorbidities associated with it. To assess whether the same set of sleep features were modulated after pharmacological treatment, namely daridorexant and zolpidem, we investigated their effect on sleep architecture for up to 3 months of continuous treatment. Daridorexant selectively reduced the overall number and the duration of long night-time awakenings, showing a greater effect than zolpidem when compared to placebo, with results remaining significant towards the end of the night. Notably, the tested medications (daridorexant and zolpidem) had only a limited effect in reducing shorter night-time awakenings (≤ 6 minutes). This reduction of time spent in long awakenings correlated with all daytime functioning domains of the IDSIQ questionnaire, showing an association between reducing long wake bouts and improving daytime functioning. Additionally, daridorexant dose-dependently increased the likelihood of transitioning into sleep and modulated spectral features during night-time waking without altering the proportion of sleep stages. This suggests a novel therapeutic approach targeting sleep features associated with hyperarousal such as fragmented sleep, long awakenings, and cortical arousal, without disrupting sleep architecture, making the orexinergic system particularly interesting for chronic insomnia.
In conclusion, this thesis describes novel PSG signatures of insomnia supportive of the hyperarousal model and offers insights into how a new class of treatment like daridorexant can selectively modulate these features, advancing our understanding of the disorder.