In the central disorders of hypersomnolence (CDH) narcolepsy types 1 and 2 (NT1, NT2) and idiopathic hypersomnia (IH), mental health problems are highly prevalent, and quality of life is decreased. The aim was to gain insight into relationships between CDH-related symptoms, mental health, and quality of life (QoL) in CDH, using network analysis. Variables involved CDH symptoms, levels of self-reported sleepiness, fatigue, mood, anxiety, attention, hyperactivity/impulsivity, apathy, and QoL indicators in CDH. Associations with diagnosis, sex, and treatment status were examined. The network analysis was on cross-sectional questionnaire data of N = 314 with CDH (NT1 n = 203; NT2/IH n = 111). A Mixed Graphical Model (MGM) with 16 nodes was estimated. Edges were selected using Regularization with EBIC-LASSO; network stability was determined with bootstrapping. Network comparison tests (NCTs) were performed between sub-groups for diagnosis (NT1 vs. NT2/IH), sex, and treatment status. We found that fatigue and depressive symptoms had the highest conditional associations with QoL variables. QoL outcome 'Energy, attention, and activities' had the most conditional associations with other variables in the network, indicating relative importance. Typical CDH symptoms clustered together, of which sleep inertia had the highest conditional association with QoL 'Coping with CDH'. Subjective sleepiness was not directly related to any variables in the network. NCTs showed no significant differences between diagnoses, sexes, or treatment statuses. This study indicates that, within the examined network, fatigue and depressive symptoms are most associated with QoL in CDH, signalling potential relevance in treatment. The impact of treatment on the symptom network should be further investigated using longitudinal data.

Pharmacological management has been the backbone of treatment for disorders of central hypersomnolence despite challenges in drug administration due to intolerable side effects, development of tolerance, and addiction potential. Recent advances in drug therapies for central hypersomnolence disorders, namely sodium oxybate and orexin agonists, have either changed or increased the potential to significantly improve the quality of life of individuals with narcolepsy and idiopathic hypersomnia. Mechanisms of action, pharmacodynamics and pharmacokinetics of previously and commonly used medications, along with the evidence behind their use, are discussed. In addition, oveporexton, an orexin receptor 2 agonist (OX2R) will be discussed as it marks an important first step in directly counteracting the pathology behind narcolepsy with cataplexy and has completed Phase 2 trials with Phase 3 underway. Early clinical data is promising; however, its long term efficacy and safety data is insufficient to garner US Food & Drug Administration approval, though additional trials are ongoing in narcolepsy with cataplexy, and non-orexin deficient central hypersomnolence disorders as well. Regardless, new drug developments may lead expanded treatment options and may have the potential to decrease or potentially eliminate the need for polypharmacy in the treatment algorithm for narcolepsy and idiopathic hypersomnia.

This study aimed at assessing the inter-procedural reliability (compared to the in-office consultation) and the diagnostic accuracy (compared to the reference standard) of the telemedicine consultation to guide the diagnostic workup of adults and children when complaint of excessive daytime sleepiness, possibly due to narcolepsy, is suspected. A cross-sectional diagnostic study was initiated in 2019 and completed in 2023. Consecutive people of any age referred for excessive daytime sleepiness complaint to the Clinic for Narcolepsy in Bologna were eligible for inclusion. The telemedicine consultation was conducted via tablet for the patient and via equipped personal computer in another room for the physician (interviewer). Interviewers expressed diagnostic orientation indicating narcolepsy as 'probable', 'possible' and 'excluded'. The final diagnosis was established by applying the International Classification of Sleep Disorders criteria. Inter-procedural reliability and diagnostic accuracy measures were calculated. Two hundred and twenty-one participants were included in the reliability study, 198 in the diagnostic accuracy study. The agreement between the two consultation modalities on diagnostic orientation was 'substantial' (Kappa 0.74, 95% CI 0.66-0.82). Agreement on the presence of narcoleptic pentad symptoms was 'substantial' (excessive daytime sleepiness, hypnagogic hallucinations, disrupted nocturnal sleep) or 'almost perfect' (cataplexy, sleep paralysis). In children reliability for excessive daytime sleepiness, cataplexy and hypnagogic hallucinations was lower. Telemedicine and in-office consultation had identical sensitivity (100%, 95% CI 94-100) and similar specificity (43%, 95% CI 35-52, vs. 40%, 95% CI 32-49). Telemedicine consultation is a reliable diagnostic triage procedure when excessive daytime sleepiness possibly due to narcolepsy is suspected, in particular to exclude people who do not suffer from narcolepsy without the risk of false negatives.

Idiopathic hypersomnia (IH) and narcolepsy type 2 (NT2) are central disorders of hypersomnolence characterised by excessive daytime sleepiness and substantial functional burden. Narcolepsy type 1 (NT1), defined by orexin deficiency, serves as an established biologic standard for evaluating therapies targeting the orexin system. Alixorexton (ALKS 2680) is a highly potent, oral, selective orexin 2 receptor (OX2R) agonist in clinical development for IH, NT2 and NT1. In this phase 1b, randomised, double-blind, placebo-controlled, four-way crossover study (ISRCTN98204977), adults aged 18-65 years with IH (n = 8), NT2 (n = 9) or NT1 (n = 10) received single oral doses of alixorexton (IH/NT2: 5, 12, 25 mg; NT1: 1, 3, 8 mg) and placebo across four treatment periods. The primary endpoint was safety and tolerability. Wakefulness was assessed by mean sleep latency on the Maintenance of Wakefulness Test (MWT) over 8 h post-dose and subjective alertness by the Karolinska Sleepiness Scale (KSS). Alixorexton was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate, with no serious TEAEs and no discontinuations due to TEAEs. In IH and NT2, alixorexton demonstrated statistically significant, clinically meaningful, dose-dependent increases in MWT sleep latency versus placebo and improved self-reported alertness. NT1 showed a similarly robust, dose-dependent response at lower doses, consistent with orexin-deficient biology. These findings support OX2R agonism as a therapeutic approach for central disorders of hypersomnolence, including conditions with uncertain orexin dysfunction and informed ongoing phase 2 evaluation in IH and narcolepsy. Trial Registration: A study in healthy subjects to see the effects of the test medicine ALKS 2680 in single- and multi-dose regimen; prospectively registered at ISRCTN on October 17, 2022 (identifier: ISRCTN98204977; URL: https://www.isrctn.com/ISRCTN98204977).

The purpose of this article is to provide an overview of how to evaluate, diagnose, and manage patients with hypersomnia disorders.

Excessive daytime sleepiness has become a significant problem in society. Despite evidence for the effect of sleep need on EEG and calls for better EEG-derived predictors and diagnostics, no study has conducted a review to determine the best practice for using EEG to measure sleepiness. We aimed to provide this. Correlation coefficients were calculated for beta, alpha, theta, and delta wake EEG power across normal and sleep restriction/deprivation conditions, in order to determine which measures are most predictive of sleep need, in what conditions and using which parameters. Our results demonstrate that increases in EEG theta power are associated with increases in subjective sleepiness during both normal and sleep loss conditions. A similar increase was observed for EEG delta power, but only in the conditions of sleep loss. EEG alpha power showed no correlation with subjective sleepiness in either condition. This review also identified novel EEG markers, such as microstates and event-related potentials, and a limited number of studies that examined EEG measures of sleepiness in clinical sleep-disorder cohorts. Our study is the first to thoroughly examine the current EEG markers of sleepiness and the influence of recording conditions on sleepiness assessment using the EEG.

Sleep is emerging as a key health topic in modern society. The prevalence of and focus on sleep-wake disorders is increasing, which has led to a large interest from the pharmaceutical industry to develop new treatments targeting sleep biology (that is, drugs that have the potential to mimic normal sleep-wake physiology). The orexin (also known as hypocretin) system is one of the key targets and regulators of sleep and wakefulness. In this Review, we will discuss the mechanisms by which loss of orexin signalling is involved in narcolepsy type 1 and whether loss and/or disruption of orexin signalling might have a role in other sleep disorders such as narcolepsy type 2, idiopathic hypersomnia and obstructive sleep apnoea. We will also describe current and emerging therapies for sleep disorders involving orexin, such as orexin receptor antagonists for insomnia and orexin receptor agonists for narcolepsy.

Excessive daytime sleepiness (EDS) is a frequent complaint in the general population. Other than being a common symptom associated with various sleep disorders, EDS may be a consequence of chronic sleep deprivation or the primary symptom of central disorders of hypersomnolence (CDH). In addition to narcolepsy type 1 (NT1), the other conditions within the CDH spectrum are less well-defined and share considerable clinical and neurophysiological similarities. Herein, we describe the clinical management of a complex case that highlights several challenges in the diagnostic process of a patient with EDS and a history of obsessive-compulsive disorder (OCD). In the absence of other sleep disorders, secondary structural causes, and orexin deficiency as possible causes for EDS, the patient was initially diagnosed with NT2 based on electrophysiological criteria. However, the clinical course, which showed only a partial response to various stimulant medications for subjective and objective daytime sleepiness, led us to question the diagnosis. A detailed psychiatric and neuropsychological assessment revealed, in addition to the previously identified severe OCD and anxiety, a diagnosis of attention deficit hyperactivity disorder (ADHD), subsequently leading to a revised diagnosis of hypersomnia associated with a psychiatric disorder (HPSY). The literature regarding OCD and sleep disorders remains scarce but the connection between ADHD and hypersomnia, as well as narcolepsy, is well-established. Our case report illustrates that a psychiatric and neuropsychological assessment should be considered mandatory for patients with objective EDS.

Sleep disturbances are among the most prevalent and clinically significant features observed across the psychosis spectrum, ranging from clinical high-risk (CHR) mental states to first-episode psychosis (FEP) and chronic schizophrenia. Far from being merely secondary phenomena, sleep difficulties-including insomnia, circadian rhythm disruption, altered sleep architecture, hypersomnia, and nightmare disorder-are increasingly acknowledged as transdiagnostic risk factors that may contribute to symptom severity, cognitive impairment, functional decline, and heightened suicidal risk. This narrative review consolidates current evidence on the epidemiology and neurobiological foundations of sleep disturbances in the psychosis spectrum and critically evaluates available non-pharmacological and digital interventions aimed at targeting sleep as a modifiable clinical outcome. We posit that sleep represents a critical, potentially modifiable intervention target within psychosis and that integrating sleep-focused care into standard clinical pathways may substantially enhance clinical, functional, and safety outcomes throughout the illness spectrum, pending replication in adequately powered randomized controlled trials.