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Objective/background: The short-term efficacy and safety of daridorexant, a dual orexin receptor antagonist, has been demonstrated in Japanese patients with insomnia disorder. The objective of this study was to evaluate, in a non-overlapping patient population to the short-term study, the long-term safety and efficacy of daridorexant in Japanese patients with insomnia disorder., Patients/methods: In this Phase 3 open-label study conducted in Japan, 154 patients with insomnia disorder were randomized to daridorexant 50 mg (n = 102) or 25 mg (n = 52) for 52 weeks. The primary objective was to assess the safety and tolerability of daridorexant for up to 1 year. Secondary exploratory objectives were to evaluate the long-term efficacy of daridorexant on subjective sleep parameters (total sleep time, latency to sleep onset and wake after sleep onset) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire)., Results: The incidence of treatment-emergent adverse events (TEAEs) was 74 % and 58 % in the 50 mg and 25 mg groups respectively. No serious drug-related TEAEs were reported. Both doses improved next-morning sleepiness (Visual Analog Scale) throughout the study. Five adjudicated adverse events of special interest were reported; excessive daytime sleepiness (n = 1, 25 mg; n = 2, 50 mg), sleep paralysis (n = 1, 50 mg) and nightmare (n = 1, 25 mg). Improvements in sleep and daytime functioning were maintained from Week 2 (first assessment) through to Week 52 in both dose groups., Conclusions: Up to 52-weeks, daridorexant was well tolerated with sustained improvement in sleep onset, sleep maintenance and daytime functioning, supporting its long-term use in Japanese patients with insomnia disorder., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, and writing assistance were provided by Nxera Pharma Japan Co., Ltd. All authors reports financial support was provided by Mochida Pharmaceutical Co Ltd. Naohisa Uchimura reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Naohisa Uchimura reports a relationship with MSD KK that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with MSD KK that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Tsumura & Co that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with EA Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Eisai Co Ltd that includes: funding grants, paid expert testimony, and speaking and lecture fees. Masahiro Suzuki reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants, paid expert testimony, and speaking and lecture fees. Masahiro Suzuki reports a relationship with Meiji Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Shionogi and Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Kao Corporation that includes: paid expert testimony and speaking and lecture fees. Masahiro Suzuki reports a relationship with Kyowa Pharmaceutical Industry Co Ltd that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Viatris Inc that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Yoshitomi Pharmaceutical Corporation that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Jazz Pharmaceuticals Inc that includes: paid expert testimony. Kenichi Kuriyama reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Kenichi Kuriyama reports a relationship with Eisai Co Ltd that includes: consulting or advisory, funding grants, and speaking and lecture fees. Kenichi Kuriyama reports a relationship with MSD KK that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Meiji Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Yoshitomi Pharmaceuical Corporation that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Aculys Pharma, LLC. that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Nobelpharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Nxera Pharma Japan Co Ltd that includes: consulting or advisory. Osamu Togo reports a relationship with Nxera Pharma Japan Co. Ltd that includes: employment. Makoto Uchiyama reports a relationship with Nxera Pharma Japan Co. Ltd that includes: consulting or advisory. Makoto Uchiyama reports a relationship with LIXIL Corporation that includes: consulting or advisory. Makoto Uchiyama reports a relationship with Taisho Pharmaceutical Co Ltd that includes: consulting or advisory., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This Phase 3 double-blind, placebo-controlled study evaluated the efficacy and safety of daridorexant in Japanese patients with insomnia disorder., Patients/methods: 490 patients with insomnia disorder from 95 sites in Japan were randomized to daridorexant 50 mg (n = 163), 25 mg (n = 163) or placebo (n = 164) for 4 weeks, followed by a 7-day placebo run-out and a 30-day safety follow-up. The primary efficacy endpoints, in hierarchical order, were change from baseline at Week 4 in subjective total sleep time (sTST) and subjective latency to sleep onset (sLSO), for daridorexant 50 mg vs placebo. sTST and sLSO were also evaluated (secondary endpoints) for daridorexant 25 mg vs placebo. Safety endpoints included adverse events and next-morning sleepiness (Visual Analog Scale, VAS)., Results: Daridorexant 50 mg significantly increased sTST and decreased sLSO versus placebo at Week 4 (least-squares mean difference [LSMD]: sTST 20.3 min [95 % CI 11.4, 29.2] p < 0.001; sLSO -10.7 min [-15.8, -5.5] p < 0.001). Daridorexant 25 mg also significantly improved both endpoints versus placebo (LSMD: sTST 9.2 min [0.3, 18.1] p = 0.042; sLSO -7.2 min [-12.3, -2.0] p = 0.006). Overall incidence of adverse events was similar across groups (50 mg: 22 %; 25 mg: 18 %; placebo 23 %); somnolence, the most common event, increased with increasing dose (50 mg: 6.8 %; 25 mg: 3.7 %; placebo 1.8 %). However, daridorexant did not increase VAS next-morning sleepiness. No rebound or withdrawal-related symptoms were observed after treatment discontinuation., Conclusions: In Japanese patients with insomnia disorder, daridorexant (25 and 50 mg) was well tolerated and significantly improved subjective sleep outcomes, with no evidence of residual effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, and writing assistance were provided by Nxera Pharma Japan Co., Ltd. All authors report financial support was provided by Mochida Pharmaceutical Co Ltd. Naohisa Uchimura reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Naohisa Uchimura reports a relationship with MSD KK that includes: speaking and lecture fees. Mitsutaka Taniguchi reports a relationship with Eisai Co Ltd that includes: consulting or advisory and speaking and lecture fees. Mitsutaka Taniguchi reports a relationship with Taisho Pharmaceutical Holdings Co Ltd that includes: consulting or advisory and speaking and lecture fees. Mitsutaka Taniguchi reports a relationship with Aculys Pharma, LLC. That includes: consulting or advisory and speaking and lecture fees. Mitsutaka Taniguchi reports a relationship with MSD KK that includes: consulting or advisory and speaking and lecture fees. Yasunori Oka reports a relationship with Astellas Pharma Inc that includes: speaking and lecture fees. Yasunori Oka reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Yasunori Oka reports a relationship with MSD KK that includes: speaking and lecture fees. Yasunori Oka reports a relationship with Nobelpharma Co Ltd that includes: speaking and lecture fees. Osamu Togo reports a relationship with Nxera Pharma Japan Co., Ltd that includes: employment. Makoto Uchiyama reports a relationship with Nxera Pharma Japan Co., Ltd that includes: consulting or advisory. Makoto Uchiyama reports a relationship with LIXIL Corporation that includes: consulting or advisory. Makoto Uchiyama reports a relationship with Taisho Pharmaceutical Co Ltd that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Daridorexant, a novel dual orexin receptor antagonist, was approved by the FDA in 2022 for the treatment of insomnia in adults. The aim of this study is to delve into the adverse events (AEs) of daridorexant by analyzing data from the FAERS database, to assess its safety and effectiveness in clinical applications., Methods: This study selected data from the FAERS database from the first quarter of 2022 to the third quarter of 2023. Various data analysis methods were used, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), to assess AEs related to daridorexant., Results: The study analyzed a total of 2,624,030 AE reports, of which 1318 were related to daridorexant. It identified 59 preferred terms (PTs) involving 23 system organ classes (SOCs). Signal mining identified new potential AEs related to daridorexant, including sleep-related psychiatric symptoms (nightmare, abnormal dreams, sleep terror, etc.), emotional and perceptual abnormalities (hallucination, depression, agitation), physiological and behavioral responses (palpitations, dry mouth, energy increased, etc.), suicide risk (suicidal ideation, intentional overdose), and other special concern AEs (tachyphrenia, sleep-related eating disorder, hypersensitivity)., Conclusion: Although some new potential AEs have been identified, these findings need further verification in broader datasets and long-term studies due to limitations in data sources and analysis methods. Future research should comprehensively assess the safety and effectiveness of daridorexant, providing more accurate guidance for medical professionals in the treatment of insomnia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults., Methods: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance., Results: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years., Conclusions: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia., Trial Registration Numbers and Dates of Registration: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017., (© 2024. The Author(s).)

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain β-amyloid (Aβ) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aβ deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX 1 and OX 2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features., (Copyright © 2024 by The Author(s).)

Importance: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium., Objective: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization., Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023., Intervention: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital., Main Outcomes and Measures: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed., Results: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups., Conclusions and Relevance: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT04571944.

Introduction: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID., Methods: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients., Results: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories., Conclusions: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics., (© 2024. The Author(s).)

Background: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice., Methods: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = "unfamiliar"; 1 = "familiar") and how they managed insomnia using a nine-point Likert scale (1 = "I never prescribe/perform it"; 9 = "I often prescribe/perform it"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it., Results: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8-5.4 points and 4.0-4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5-1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48-74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points., Conclusion: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists., (© 2024. The Author(s).)

Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results., Competing Interests: Declaration of competing interest Laura Palagini serves as a scientific advisor to Idorsia Pharmaceuticals. Claudio Liguori serves as a scientific advisor to and has received scientific support from Idorsia Pharmaceuticals. The remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant ( 20 ) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.

Study Objectives: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs., Methods: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms., Results: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group., Conclusion: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

Background and Purpose: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown., Experimental Approach: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg -1 ·day -1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX 2 ) receptor antagonist MK-1064 (40 mg·kg -1 ·day -1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry., Key Results: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX 2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX 2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX 2 receptor signalling., Conclusions and Implications: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX 2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder., Aims: Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal., Methods: Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans., Results: Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence., Outcomes: Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAS and MTS were employees and shareholders of Idorsia Pharmaceuticals Ltd at the time the study was conducted. Idorsia has developed daridorexant as a treatment for insomnia and is selling the drug under the trade name Quviviq®. MT, LD, and MEG have no conflicting interests to declare.

Insomnia is present in up to one third of the adult population worldwide, and it can present independently or with other medical conditions such as mental, metabolic, or cardiovascular diseases, which highlights the importance of treating this multifaceted disorder. Insomnia is associated with an abnormal state of hyperarousal (increased somatic, cognitive, and cortical activation) and orexin has been identified as a key promotor of arousal and vigilance. The current standards of care for the treatment of insomnia recommend non-pharmacological interventions (cognitive behavioural therapy) as first-line treatment and, if behavioural interventions are not effective or available, pharmacotherapy. In contrast to most sleep medications used for decades (benzodiazepines and 'Z-drugs'), the new orexin receptor antagonists do not modulate the activity of γ-aminobutyric acid receptors, the main inhibitory mechanism of the central nervous system. Instead, they temporarily block the orexin pathway, causing a different pattern of effects, e.g., less morning or next-day effects, motor dyscoordination, and cognitive impairment. The pharmacokinetic/pharmacodynamic properties of these drugs are the basis of the different characteristics explained in the package inserts, including the recommended starting dose. Orexin receptor antagonists seem to be devoid of any dependence and tolerance-inducing effects, rendering them a viable option for longer-term treatment. Safety studies did not show exacerbation of existing respiratory problems, but more real-world safety and pharmacovigilance experience is needed. This review provides an overview of the orexin history, the mechanism of action, the relation to insomnia, and key features of available drugs mediating orexin signalling., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objectives: We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months., Methods: Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents., Results: The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, P < .001; 2 mo: -3.20 ± 5.64, P < .001; 3 mo: -3.38 ± 5.61, P < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, P = 0.27), 2 months (0.082 ± 4.62, P  = .89), or 3 months (-0.64 ± 4.80, P  = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, P  = .004), 2 months (-1.05 ± 2.97, P  = .029), and 3 months (-1.24 ± 3.06, P  = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, P < .001)., Conclusions: Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced., Citation: Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. J Clin Sleep Med . 2023;19(10):1753-1758., (© 2023 American Academy of Sleep Medicine.)

Competing Interests: The authors have no conflicts of interest to declare.

Objective: Although antipsychotics are often used in the pharmacological treatment of delirium, recent reports suggest the efficacy of orexin receptor antagonists. This study investigated whether orexin receptor antagonists could be a possible treatment option for delirium., Method: A nonblinded nonrandomized routine clinical treatment was performed. Patients treated in intensive care units (ICU) for cardiovascular disease and receiving psychiatric intervention were studied retrospectively. The scores from the Intensive Care Delirium Screening Checklist (ICDSC) were compared between patients treated with orexin receptor antagonists and those treated with antipsychotics., Results: The mean (standard deviation) ICDSC scores were 4.5 (1.8) at day -1 and 2.6 (2.6) at day 7 for orexin receptor antagonist group (n = 25) and 4.6 (2.4) at day -1 and 4.1 (2.2) at day 7 for antipsychotic group (n = 28). The orexin receptor antagonist group showed significantly lower ICDSC scores than the antipsychotic group (p = 0.021)., Conclusion: While precise efficacy cannot be determined from our retrospective, observational, and uncontrolled pilot study, this analysis encourages a future double-blind randomized placebo-controlled trial of orexin-antagonists for delirium treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest to this research. TN has received honoraria for lectures from Otsuka, Eisai, Sumitomo, MSD, Janssen, Takeda. KT has received honoraria for lectures from Eisai, Janssen. KS has received grant for JSPS KAKENIHI, The SEISHIN Medical Research Foundation and Donation to institution for Nagano Prefectural Mental Wellness Center and honoraria for lectures from Sumitomo. DS has received research grant from Ministry of Health, Labour and Welfare, Ministry of Education, Culture, Sports, Science and Technology and honoraria for lectures from Otsuka, Takeda, Shionogi. SW has research grant from Japan Society for the Promotion of Science, Otuka, Eisai, Pfizer, Daiichi Sankyo, Tsumura, Mochida, Astellas, Shionogi, Takeda, Sumitomo and honoraria for lectures from Otuka, Eli Lilly, MSD, Yoshitomiyakuhin, Daiichi Sankyo, Sumitomo, Eisai, Kyowa, Janssen, Pfizer, Takeda, Viatris, Towa., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epilepsy is a common neurological disorder, affecting patients of all ages, reducing the quality of life, and associated with several comorbidities. Sleep impairment is a frequent condition in patients with epilepsy (PWE), and the relation between sleep and epilepsy has been considered bidirectional, as one can significantly influence the other, and vice versa. The orexin system was described more than 20 years ago and is implicated in several neurobiological functions other than in controlling the sleep-wake cycle. Considering the relation between epilepsy and sleep, and the significant contribution of the orexin system in regulating the sleep-wake cycle, it is conceivable that the orexin system may be affected in PWE. Preclinical studies investigated the impact of the orexin system on epileptogenesis and the effect of orexin antagonism on seizures in animal models. Conversely, clinical studies are few and propose heterogeneous results also considering the different methodological approaches to orexin levels quantification (cerebrospinal-fluid or blood samples). Because orexin system activity can be modulated by sleep, and considering the sleep impairment documented in PWE, the recently approved dual orexin receptor antagonists (DORAs) have been suggested for treating sleep impairment and insomnia in PWE. Accordingly, sleep improvement can be a therapeutic strategy for reducing seizures and better managing epilepsy. The present review analyzes the preclinical and clinical evidence linking the orexin system to epilepsy, and hypothesizes a model in which the antagonism to the orexin system by DORAs can improve epilepsy by both a direct and a sleep-mediated (indirect) effect., (© 2023 International League Against Epilepsy.)

Insomnia disorder is considered as a stress-related disorder associated with hyperarousal, stress and emotion dysregulation and the instability of the 'flip-flop' switch system. The orexinergic system is well known for its key role in sleep and arousal processes but also in the allostatic system regulating stress and emotions and may thus be of major interest for insomnia and its treatment. Accordingly, we discuss the potential role of orexins on sleep processes, brain systems modulating stress and emotions with potential implications for insomnia pathophysiology. We reviewed available data on the effect of dual orexin receptor antagonists (DORAs) on sleep and brain systems modulating stress/emotions with implications for insomnia treatment. We present our findings as a narrative review. Few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of orexinergic system, while some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together these findings may let us hypothesise that an orexins overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia. On the other hand, it is possible that by rebalancing orexins with DORAs we may regulate both sleep and allostatic systems, in turn, contributing to a 'switch off' of hyperarousal in insomnia. Nevertheless, more studies are needed to clarify the role of the orexin system in insomnia and to evaluate the effects of DORAs on sleep, stress and emotions regulating systems., (© 2023 European Sleep Research Society.)

Objective: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-β levels and amyloid plaques in mouse models overexpressing amyloid-β, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-β, tau, and phospho-tau., Methods: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-β, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry., Results: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-β ~10% to 20% compared to placebo starting 5 hours after drug administration., Interpretation: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-β concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40., (© 2023 American Neurological Association.)

The correlation between sleep and epilepsy has been argued over the past decades among scientists. Although the similarities and contrasts between sleep and epilepsy had been considered, their intertwined nature was not revealed until the nineteenth century. Sleep is recognized as a recurring state of mind and body through alternating brain electrical activities. It is documented that sleep disorders are associated with epilepsy. The origin, suppression, and spread of seizures are affected by sleep. As such, in patients with epilepsy, sleep disorders are a frequent comorbidity. Meanwhile, orexin, a wake-promoting neuropeptide, provides a bidirectional effect on both sleep and epilepsy. Orexin and its cognate receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), orchestrate their effects by activating various downstream signaling pathways. Although orexin was considered a therapeutic target in insomnia shortly after its discovery, its potential usefulness for psychiatric disorders and epileptic seizures has been suggested in the pre-clinical studies. This review aimed to discuss whether the relationship between sleep, epilepsy, and orexin is clearly reciprocal., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests related to this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear., Objective: To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia., Methods: The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs)., Results: We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = -25.40; 95% confidence interval [95%CI] = -40.02--10.78), followed by suvorexant 20/15mg (SMD = -25.29; 95%CI = -36.42--14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = -23.70; 95%CI = -35.89--11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%., Conclusion: Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia., Competing Interests: The authors have no conflict of interest to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Benzodiazepines are used in the treatmentof anxiety and insomnia. On the other hand, they not only have side effects such as drowsiness, poor concentration, and muscle relaxation but also persistent cognitive decline. Even if we try to reduce the dose of these drugs to improve drug-induced cognitive function, it is difficult to do so due to dependence and worsening insomnia. I report four cases in which cognitive dysfunction was improved by switching from benzodiazepines to orexin receptor antagonists (suvorexant and lemborexant ). Orexin receptor antagonists were effective to improve cognitive impairment. In cognitive dysfunction caused by benzodiazepines, switching to orexin receptor antagonists may be effective., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan., Methods: Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1 st , 2009 and March 31 st , 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions., Results: We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABA A -receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments., Conclusion: Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Twenty-five years have passed since the discovery of the orexin system, during which time we have learned more and more about it. A number of studies have been conducted showing the role of the orexin system in insomnia, as well as its potential use in the treatment of obesity and depression. In this review, we present the role of the orexin system in the development of depressive illness and show the characteristics of seltorexant, a potential drug for the treatment of depression. This review describes the structure and synthesis of the compound as well as its pharmacodynamics and pharmacokinetics. Pre-clinical and clinical studies are also described, including side effects. There is evidence that the use of seltorexant is considered safe, with no clear or major clinically significant side effects, which makes it a promising candidate for the treatment of depression and anxiety disorders.

Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response., (© 2021. The Author(s).)

Depression is a devastating mood disorder affecting more than 300 million people worldwide. Almost 30 % of patients still suffer from treatment resistant depression. Although many reports support the involvement of orexin in the pathophysiology of depression, the precise role of orexin is still unclear. In this study, we evaluated the role of the orexin 1 receptor (Orx 1 R) on depressive behaviors and the alterations in postsynaptic density-95 (PSD-95) protein in the chronic mild stress (CMS) model of depression. Fifty-four male Wistar rats were randomly allocated to 6 groups; Control, CMS, acute SB-334867 (SB), CMS+SB, chronic SB (CSB) and CMS+CSB. Rats were exposed to one or two unpredictable stressors each day for three weeks for the induction of CMS. Intracerebroventricular (icv) injection of SB-334867, a selective Orx 1 R antagonist, was performed either 30 min before behavioral tests (acute) or once daily for 14 days (chronic). Behavioral despair was assessed by immobility time in the forced swim test (FST), sucrose consumption in sucrose preference test (SPT), and the number of crosses in the open field test (OFT) on days 1, 11, and 22 of the experiment. Finally, rats were decapitated, and brain tissue of the hippocampus (HPC) and prefrontal cortex (PFC) were collected, and the relative expression of PSD-95 was evaluated by western blotting. The CMS model rats showed a significant increase in FST immobility time (P = 0.001) and a decrease in locomotion (P = 0.04) and sucrose preference (P = 0.039). Chronic application of SB decreased immobility time to the control values (P = 0.001) and diminished locomotion (P = 0.047) and sucrose preference (P = 0.042) in comparison to the CMS group. Acute SB reversed just the immobility time (P ≤ 0.006). Chronic SB treatment increased the relative PSD-95 expression in PFC (P = 0.001). Hence, chronic antagonism of Orx 1 R alleviates depressive behaviors induced by CMS and improves PSD-95 expression in PFC., Competing Interests: Declaration of Competing interest There is no conflict of interest for any of the contributing authors. The authors alone are responsible for the content and writing of the paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep-wake cycle, the stress response, and motivation and reward processing. Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The development of medications used to treat psychiatric conditions has largely proceeded through serendipity, where a potential drug to treat mental illness is identified by chance. This approach is based on a limited understanding of the underlying pathophysiology of mental illness and brain disorders. Identification of novel neurotransmitter systems has allowed for new molecular-based approaches for drug development that identify specific receptor targets to treat a specific symptom. An example of this approach includes the development of suvorexant, which is a dual orexin receptor antagonist FDA approved in 2014 for the treatment of insomnia. This chapter will discuss challenges in psychiatric drug development; the importance of identifying discrete neurotransmitter systems that target a specific symptom, not a syndrome; the orexin pathway and targets within this pathway that can be used to modulate sleep; and a high-throughput approach to streamlining drug development., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans.

Purpose of Review: We review recent evidence on the use of orexin receptor antagonists (ORAs) for treating insomnia. We evaluate studies on five dual ORAs and one selective ORA., Recent Findings: Research on suvorexant in recent years gradually focus on comorbid insomnia, while lemborexant and daridorexant were still being validated in primary insomnia. Almorexant is now mainly used as a commercial specific inhibitor of the orexin system in animal studies due to safety issues. Although filorexant has also shown a certain sleep-promoting effect, there are few clinical or experimental studies on sleep-related aspects of filorexant in recent years. As for selective ORAs, orexin receptor 2 antagonist seltorexant still has not yet reached phase 3. High-quality clinical trials in insomnia populations are needed which directly compare authorized ORAs and investigate non-approved ORAs, the use of ORAs in comorbid insomnia, and the orexin signaling system pathophysiology in insomnia., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Insomnia affects 4.4-4.8% of the world's population, but because the effect of hypnotic drugs is limited and may cause harmful side-effects, scientists are turning their attention to developing drugs that act on the orexin system. Daridorexant, a selective dual-orexin receptor antagonist (DORA), has exhibited promising results in both animal and human studies. Its activity was evaluated based on the physiology-based pharmacodynamic and pharmacokinetic model. The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects. In this manuscript we conducted a comprehensive review of daridorexant including pharmacodynamics, animal and human research, pharmacokinetics and safety.

Insomnia disorder is common in adults and children. The estimated prevalence ranges from 9% to 15% in the general population, with higher prevalence in certain subpopulations. Hypnotic medications are those that tend to produce sleep and are frequently used to treat insomnia. Commonly used hypnotics in adults include benzodiazepines (BZDs), BZD receptor agonists, antihistamines, antidepressants, melatonin receptor agonists, orexin receptor antagonists, and antipsychotics. However, hypnotic discontinuation is difficult and often unsuccessful. This article discusses strategies to discontinue hypnotics and evidence supporting their use., Competing Interests: Disclosure J.P. Hintze has no potential conflicts of interest or funding sources. J.D. Edinger conflicts of interest or funding: grant support from Merck, Philips, Respironics, Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Delirium occurs very frequently in cancer patients. Insomnia is a symptom of delirium. Lemborexant is a drug that regulates sleep-wake rhythms without causing extrapyramidal symptoms. Based on its ability to improve sleep, lemborexant is expected to have efficacy for insomnia with delirium. The purpose of this study was to determine the efficacy of lemborexant for insomnia in cancer patients with delirium. A retrospective observational study was conducted between July 2020 and February 2021. Fourteen patients (six females; mean age,69 years) were included. Lemborexant was effective in 11 of 14 (78.6%) patients. Of 14 patients, 10 had hyperactive delirium. Lemborexant might have similar efficacy for insomnia with and without delirium when compared with previous studies. The efficacy rate of lemborexant was 70% for patients with insomnia and hyperactive delirium. This study might lead to dose reductions of antipsychotic medications and fewer extrapyramidal symptoms in cancer patients with delirium.

Smoking is recognized as the most avoidable cause for multiplicity of chronic diseases. However, smoking cessation rates remain low, in part due to the limited target engagement of the currently approved medications for smoking cessation. Sleep is a promising focus for increasing smoking cessation rates because smokers' sleep problems are exacerbated during the first week of smoking abstinence and are associated with poor smoking cessation outcomes. Furthermore, the currently approved smoking cessation pharmacological agents varenicline and nicotine replacement treatment exacerbate sleep problems beyond what would be observed as a consequence of natural nicotine withdrawal. Addressing sleep problems with dual orexin receptor antagonists (DORAs) is positioned to remedy the shortcoming of overlooking sleep as a viable smoking cessation intervention target. Based on previous animal literature, DORA agents suvorexant and lemborexant may accomplish this by diminishing withdrawal difficulty and reducing nicotine cravings. The pharmacologic focus is the orexin system, not only because orexin peptides mediate the sleep-wake cycle, but also because DORA agents have a milder adverse event profile over previous treatments for insomnia. A novel adjunct DORA treatment to a currently approved smoking cessation pharmacotherapy holds a potential to reduce morbidity and mortality caused by smoking., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Orexin neuropeptides are implicated in physical dependence on opioids and expression of withdrawal symptoms in drug abuse. The paraventricular nucleus of the midline thalamus (PVT) has a high expression of orexin receptors. The current research studied the effect of orexin-A in the PVT area on the development of behavioral indices produced by morphine withdrawal in rats., Methods: Male Wistar rats weighing 250-300 gr were utilised. To produce drug dependence, morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) was injected at an interval of 24 hrs for 7 days. To assess the involvement of the orexin in withdrawal syndrome, we injected orexin-A (100 μM, 200 nl) into the PVT for 7 days before each morphine injection. On the day after the last injection of morphine, naloxone (2.5 mg/kg, i.p.) was injected to elicit the morphine withdrawal symptoms which were observed and checked for 25 min., Results: The results of the current research showed that the orexin-A in PVT enhances the severity of behavioral symptoms prompted by the injection of naloxone in drug-dependent rats., Conclusions: These observations imply that targeting the orexin receptors in PVT might exhibit a new therapeutic strategy for the future treatment of dependence., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective: Fatigue is a common symptom in patients with insomnia. This analysis evaluated whether treatment of nighttime symptoms of insomnia with a dual orexin receptor antagonist, lemborexant, might also reduce fatigue., Methods: Analyses were conducted of two phase 3 studies of subjects with insomnia disorder. Subjects received placebo, lemborexant 5 mg, or lemborexant 10 mg in the 12-month (6 months placebo-controlled) Study E2006-G000-303 (Study 303: SUNRISE-2) of adults (N = 949; full analysis set [FAS]), and the 1-month, placebo- and active-controlled Study E2006-G000-304 (Study 304; SUNRISE-1) of older adults (females ≥55 years, males ≥65 years) (N = 1006; FAS). Fatigue was assessed using the Fatigue Severity Scale (FSS). Patient-reported sleep onset and maintenance endpoints were analyzed using data from electronic sleep diaries., Results: Lemborexant significantly reduced subject-reported fatigue versus placebo over a 6-month treatment period (FSS total score least-squares mean treatment difference of -2.50 for 5 mg and -2.56 for 10 mg of lemborexant; p < 0.05 for both). This reduction was sustained over 12 months of lemborexant in both the overall population and in subjects with clinically meaningful fatigue (FSS total score ≥36) at baseline. Improvements in fatigue over time positively correlated with improvements in sleep onset and maintenance parameters. Improvements in sleep quality were evident as early as 1 week after lemborexant treatment, whereas longer-term treatment (>1 month) may be needed for improvements in insomnia-related fatigue., Conclusions: In addition to improving sleep onset and sleep maintenance in subjects with insomnia disorder, lemborexant provides further benefit by reducing daytime fatigue., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02952820 and https://clinicaltrials.gov/ct2/show/NCT02783729., Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ; FSS = Fatigue Severity Scale; ICSD-3 = International Classification of Sleep Disorders, Third Edition ; LSM = least squares mean; sSE = subjective sleep efficiency; sSOL = subjective sleep onset latency; sTST = subjective total sleep time; sWASO = subjective sleep after wake onset.

Study Objectives: The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS., Methods: In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race., Results: Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (-8.1 [95% CI, -10.2 to -6.0]) compared to placebo (-5.6 [95% CI, -7.4 to -3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated., Conclusion: These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia., Clinical Trial Information: Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

BACKGROUND: Insomnia is a common disorder associated with a substantial burden of illness, particularly in older adults. OBJECTIVE: To compare the efficacy and safety of lemborexant with specified other insomnia treatments through a systematic literature review and network meta-analysis (NMA). METHODS: Medline and Embase were systematically searched from inception to February 2019 and updated with a targeted search of PubMed for pivotal trials in March 2021. Randomized controlled trials in adults with primary insomnia were included if they reported results following at least 1 week of treatment. Interventions of interest were specified as lemborexant, suvorexant, benzodiazepines, benzodiazepine receptor agonists (also called Z-drugs [zolpidem, eszopiclone, zaleplon, zopiclone]), trazodone, and ramelteon. Efficacy outcomes included wake after sleep onset (WASO), sleep efficiency (SE), latency to persistent sleep (LPS)/sleep onset latency (SOL), total sleep time (TST) and Insomnia Severity Index (ISI). Bayesian NMA were performed at predetermined time intervals approximating 4 weeks, 3 months, and 6 months. Safety outcomes included serious adverse events (SAEs), withdrawals due to adverse events (AEs), and specified AEs (dizziness, somnolence, and falls). Subgroup analysis was conducted in the older population. RESULTS: 45 studies were included in the NMA. At 4 weeks, lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography-TST, LPS, and SE-and was ranked second to suvorexant on WASO. Eszopiclone was highly ranked for subjectively measured SOL and ISI at 4 weeks, 3 months, and 6 months. Lemborexant was rated more highly than suvorexant in subjective measures of WASO, TST, and SOL at 4 weeks (the differences were not statistically significant). No statistically significant interactions between treatment effect and older subpopulations were found, indicating that the treatment effect was similar in older and adult populations. The safety profile of lemborexant was broadly similar to the other treatments for SAEs and withdrawals due to AEs. A limitation is the age of some of the included studies (3 were published in 1990 or earlier). A further limitation is the lack of stratification of recommended doses. If the doses used in the study publications do not reflect doses used in clinical practice, this could potentially bias the results. CONCLUSIONS: Lemborexant was ranked highest of the treatments studied on 3 out of the 4 objectively measured insomnia efficacy outcomes, with a safety profile broadly similar to other insomnia treatments. DISCLOSURES: This work was funded by Eisai Inc., which was involved with all stages of the study and analysis. McElroy, O'Leary, and Adena are consultants with Datalytics Pty Ltd., which was paid by Eisai Inc. for conducting the literature review and analysis. They were not financially compensated for collaborative efforts on publication-related activities. Campbell, Tahami Monfared, and Meier are employed by Eisai Inc. This study was presented as a poster at AMCP Nexus Virtual, October 20-23, 2020 and at the AGS Virtual Annual Scientific Meeting 2021, May 13-15, 2021.

Orexins/hypocretins are hypothalamic neuropeptides that promote and stabilize wakefulness by binding to the orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the sleep disorder narcolepsy in mice, rats, dogs, and humans. The orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas suvorexant has been clinically approved for the treatment of insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why orexin receptor antagonists do not induce overt narcolepsy-like symptoms. Here we show that acute and chronic suvorexant promotes both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep without inducing cataplexy in mice. Interestingly, chronic suvorexant increases OX2R mRNA and decreases orexin mRNA and peptide levels, which remain low long after termination of suvorexant administration. When mice are chronically treated with suvorexant and then re-challenged with the antagonist after a 1-week washout, however, cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous orexin knockout mice, with lower brain orexin levels, show cataplexy and SOREM after acute suvorexant administration. Furthermore, we find that acute suvorexant can induce cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that suvorexant can inhibit orexin synthesis resulting in susceptibility to narcolepsy-like symptoms in mice under certain conditions., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Insomnia afflicts many geriatric patients worldwide and results in both clinical and economic consequences. Prescribing hypnotics to the elderly is particularly challenging due to multitudes of adverse effects and drug interactions. Although benzodiazepines and "Z" drugs such as zolpidem have been popular in the past, they carry a high risk of adverse effects in the elderly, such as devastating falls and injuries as well as potentially an increase in mortality. Newer classes of hypnotics such as dual orexin receptor antagonists are much better tolerated and can be explored as a potential treatment for insomnia in the elderly., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double-blind, placebo-controlled, two-period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase-III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO 2 ) during total sleep time (TST) after last dosing. Night-time respiratory function and sleep were further evaluated based on the apnea-hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant - placebo) for SpO 2 during TST as it was 0.18% (90% confidence interval: -0.21 to 0.57). There was also no difference from placebo for SpO 2 during non-rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night-time respiratory function and improves sleep in patients with moderate COPD., (© 2020 European Sleep Research Society.)

Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)