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Insight Into Reduction of Wakefulness by Suvorexant in Patients With Insomnia: Analysis of Wake Bouts
Abstract
Objectives:
To examine the duration and frequency of wake bouts underlying the wakefulness-after-sleep-onset (WASO) reduction with suvorexant.
Methods:
We analyzed polysomnogram recordings from clinical trials involving 1518 insomnia patients receiving suvorexant (40/30mg, 20/15mg) or placebo to determine: 1) the number of, and time spent in, long or short wake bouts, 2) the association between sleep quality and bout characteristics. We also compared wake and sleep bout characteristics of suvorexant in insomnia patients versus zolpidem in healthy subjects undergoing experimentally-induced transient insomnia.
Results:
Relative to placebo, suvorexant decreased the number and time spent in long wake bouts (>2 minutes) and increased the number and time spent in short wake bouts (≤2 minutes). The time spent in long wake bouts during Night-1 decreased by 32-54 minutes, while the time spent in short wake bouts increased by 2-6 minutes. On average, a patient returned to sleep from his/her longest awakening more than twice as fast on suvorexant than placebo. The reduced time spent in long wake bouts resulted in odds ratios of self-reported good/excellent sleep quality ranging from 1.59-2.19 versus placebo. The small increase in time spent in short wake bouts had no effect on odds ratios. Findings were more pronounced for the higher (40/30mg) doses of suvorexant. The wake and sleep bout characteristics of suvorexant differed from zolpidem which equally decreased the number of wake and sleep bouts of all durations during the early part of the night.
Conclusion:
Suvorexant reduces WASO by reducing long wake bouts. This reduction has a positive effect on sleep quality.
... Specifically, loss of orexin signaling in animal models and in people with narcolepsy results in fewer long wake bouts and more short wake bouts [21], which is in agreement with the role of the orexin system in stabilizing wake time [22][23][24][25]. In line with this, the DORA suvorexant (40/30 mg and 20/15 mg) reduced the time spent in longer wake bouts (defined as wake bouts > 2 min), while increasing the number and time spent in shorter wake bouts (defined as ≤ 2 min) in patients with insomnia disorder [26]. Whether this wake bout modulation of suvorexant is replicated with daridorexant has not yet been investigated. ...
... Previous groups, including Svetnik et al. [26], have proposed threshold derivations that distinguish between short and long wake bouts. This analysis includes a new proposal for calculating a derivation that is based on the current patient population. ...
... For the time spent in short and long wake bouts, and the distribution of short and long wake bouts throughout the sleep period, additional analyses using the threshold proposed by Svetnik et al. (≤ 2 min for short and > 2 min for long wake bouts) were performed, to allow comparisons with existing literature [26]. The odds of subjects having long wake bouts were not analyzed using this threshold, because almost all patients had wake bouts > 2 min. ...
Background:
Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning.
Methods:
Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study. We analyzed polysomnography data for daridorexant 25 and 50 mg, zolpidem 10 mg, and placebo groups. Polysomnography was conducted at baseline, then on Days 1/2, 15/16, and 28/29 in the phase II study, and Months 1 and 3 in the phase III study. The number, duration, and distribution of wake bouts (≥ 0.5 min) were assessed.
Results:
Data from 1111 patients (phase II study: daridorexant 50 mg [n = 61], zolpidem 10 mg [n = 60], placebo [n = 60]; phase III study: daridorexant 25 mg [n = 310], daridorexant 50 mg [n = 310], placebo [n = 310]) were analyzed. Long wake bouts were defined as > 6 min. Compared with placebo, daridorexant 50 mg reduced overall wake time (p < 0.05; all time points, both studies), the odds of experiencing long wake bouts (p < 0.001; Months 1 and 3, phase III study), and the cumulative duration of long wake bouts (p < 0.01; all time points, both studies). Reductions in long wake bouts were sustained through the second half of the night and correlated with improvements in daytime functioning. An increase in the cumulative duration of short wake bouts was observed with daridorexant 50 mg (p < 0.01 vs placebo, Months 1 and 3, phase III study); this was uncorrelated with daytime functioning.
Conclusion:
Daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo, corresponding with improved daytime functioning.
Clinical trials:
Clinicaltrials.gov NCT02839200 (registered July 20, 2016), NCT03545191 (registered June 4, 2018).
... 151 According to a recent suvorexant trial in both young and older patients with insomnia, dosing for three months of 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo, as shown by the Insomnia Severity Index. 152 A good therapeutic efficacy was also demonstrated with objective sleep measures, such as polysomnography (PSG)-derived indexes, with improvement of sleep latency, sleep efficiency, and sleep maintenance, both after the first night of administration and after 4 weeks, with a dose dependent effect, 153,154 in a 50-to-100 mg study. 155 Relative to placebo, suvorexant was found to decrease substantially the time spent in long wake bouts (> 2 minutes) and to increase slightly the time spent in short wake bouts (≤ 2 minutes) in patients with insomnia. ...
... 155 Relative to placebo, suvorexant was found to decrease substantially the time spent in long wake bouts (> 2 minutes) and to increase slightly the time spent in short wake bouts (≤ 2 minutes) in patients with insomnia. 154 This fits well with preclinical evidence that in mice, progressive loss of the orexin neurons dramatically reduced the ability to maintain long wake bouts, but it also favored brief wake bouts, increasing the risk of awakening at sleep onset and reducing the likelihood of falling back asleep. 156 An EEG spectral analysis study showed that suvorexant, at clinically effective doses, had limited effects on EEG power spectral density compared to placebo in healthy subjects and patients with insomnia, suggesting that suvorexant induces both subjective and objective sleep quality improvement, without major changes in cortico-thalamic neurophysiology. ...
After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.
... We dosed mice at dark onset, the beginning of their active phase, but effects may have been different if given at light onset when the sedating effects of a DORA would not conflict with the circadian waking drive. A similar phenomena occurs in people treated with suvorexant who spend about 60% less time in long (>2 min) wake bouts [40]. This inability to maintain long wake bouts results in more transitions into sleep, but it does not reduce the frequency of short awakenings. ...
... In general, we believe that cataplexy should be quite rare as typical clinical doses of DORAs do not produce severe blockade of orexin signaling, and if a patient were to take a high dose, severe sleepiness would likely surmount any tendency towards cataplexy. Still, in clinical trials of suvorexant, about 1% of participants had hypnagogic hallucinations or sleep paralysis, indicating the potential for mixed, REM sleep-like states [40,58]. Further, people with insomnia sometimes find themselves awake despite taking a medication, and high arousal in combination with a high dose of a DORA might be sufficient to trigger cataplexy, especially if coupled with a positive emotional stimulus at night such as sex or social interactions that could trigger cataplexy. ...
Orexin receptor antagonists are clinically useful for treating insomnia, but thorough blockade of orexin signaling could cause narcolepsy-like symptoms. Specifically, while sleepiness is a desirable effect, an orexin antagonist could also produce cataplexy, sudden episodes of muscle weakness often triggered by strong, positive emotions. In this study, we examined the effects of dual orexin receptor antagonists (DORA's), lemborexant (E2006) and almorexant, on sleep/wake behavior and cataplexy during the dark period in wild-type (WT) mice and prepro-orexin knockout (OXKO) mice. In WT mice, lemborexant at 10 and 30 mg/kg quickly induced NREM sleep in a dose-dependent fashion. In contrast, lemborexant did not alter sleep/wake behavior in OXKO mice. Under the baseline condition, cataplexy was rare in lemborexant-treated WT mice, but when mice were given chocolate as a rewarding stimulus, lemborexant dose-dependently increased cataplexy. Almorexant produced similar results. Collectively, these results demonstrate that DORA's potently increase NREM and REM sleep in mice via blockade of orexin signaling, and higher doses can cause cataplexy when co-administered with a likely rewarding stimulus.
... In contrast to OX1R antagonist 1SORA1, selective antagonism of OX2R had pronounced effect in promoting NREM sleep (Supplementary Figure S1, J-L; Table 1). These data are consistent with previous reports showing that dual OXR antagonist or OX2R selective antagonist increases the amount of NREM sleep [19,20,31,[39][40][41][42][43]. ...
... Importantly, these findings have strong implications for various sleep-related conditions such as insomnia characterized by bouts of wakefulness after sleep onset (WASO) [47]. Indeed, Suvorexant and Almorexant are effective to decrease bouts of wakefulness in patients with insomnia characterized by WASO [30,43] and the data presented here suggest that this may be a result of its effects on specific sleep features such as increasing NREM sleep and the intrusion of NREM sleep into wakefulness. ...
Study Objectives
The present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in transgenic mice.
Methods
We used Hcrt-IRES-Cre knock-in mice and AAV vectors expressing channelrhodopsin-2 (ChR2) to render Hcrt neurons sensitive to blue light stimulation. We optogenetically stimulated Hcrt neurons and measured latencies to wakefulness in the presence or absence of OX1/2R antagonists and Zolpidem. We also examined endogenous Hcrt neuronal activity with fiber photometry. Changes in memory after optogenetic sleep disruption were evaluated by the novel object recognition test (NOR) and compared for groups treated with vehicle, OX1/2R antagonists, or Zolpidem. We also analyzed EEG power spectra of wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep following the injections of vehicle, OX1/2R antagonists, and Zolpidem in young adult mice.
Results
Acute optogenetic stimulation of Hcrt neurons at different frequencies resulted in wakefulness. Treatment with dual OX1/2R antagonists (DORAs) DORA12 and MK6096, as well as selective OX2R antagonist MK1064 and Zolpidem, but not selective OX1R antagonist 1SORA1, significantly reduced the bout length of optogenetic stimulation-evoked wakefulness episode. Fiber photometry recordings of GCaMP6f signals showed that Hcrt neurons are active during wakefulness, even in the presence of OXR antagonists. Treatment with dual OX1/2R antagonists improved memory function despite optogenetic sleep fragmentation caused impaired memory function in a NOR test.
Conclusions
Our results show DORAs and selective OX2R antagonists stabilize sleep and improve sleep-dependent cognitive processes even when challenged by optogenetic stimulation mimicking highly arousing stimuli.
... 11 Suvorexant, the first selective dual ORA, suppresses excessive wakefulness by inhibiting orexin receptors that control wakefulness, thus leading to more physiological sleep. 12 In contrast to BRAs, suvorexant facilitates both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, thereby preserving sleep-stage-specific quantitative electroencephalogram spectral profiles and affording somnolence indistinguishable from that of natural sleep. 13 Given the established association between dreaming and REM sleep, which is characterized by longer, vivid, narrative, and bizarre dream experiences in contrast to NREM sleep, [14][15][16] continuing the BRA alongside suvorexant or substituting suvorexant for the BRA. ...
Aim
Suvorexant is an orexin receptor antagonist (ORA) for the treatment of insomnia. The antagonistic action of suvorexant on orexin receptors is associated with an increase in rapid eye movement (REM) sleep, which can potentially lead to nightmares depending on the patient's condition. However, the precise risk factors for nightmares among patients taking ORAs, such as suvorexant, have yet to be identified. In this retrospective study, we aimed to identify the risk factors for the development of nightmares in patients treated with suvorexant.
Methods
The risk factors were determined by comparing parameters between the nightmare group and the nonnightmare group. This study included 440 patients who received suvorexant at the University of Miyazaki Hospital from April 2014 to January 2021.
Results
We found that 9.1% (n = 40) of the patients experienced suvorexant‐induced nightmares. There was a significant difference in the median age, which was lower in the nightmare group than in the nonnightmare group (p < 0.01). Furthermore, both multiple logistic regression analysis and Cox proportional hazards regression analysis revealed increased odds ratios for nightmares for individuals aged 20–39 years.
Conclusions
This study revealed that elderly patients taking suvorexant had fewer nightmares than nonelderly patients did.
... When comparing the placebo to the suvorexant group, the suvorexant group returned to sleep from their longest awakening twice as fast as the placebo patient. 55 30 men underwent cognitive and physical function tests as well as polysomnography following treatment with suvorexant 20 mg, brotizolam (a GABAa agonist) 0.25 mg, or placebo 15 minutes prior to sleep. Subjects were forced awake at the 90-minute mark following the onset of sleep. ...
Purpose of Review
The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant’s role in targeting insomnia with other comorbidities.
Recent Findings
Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant’s effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer’s disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment.
Summary
Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.
... In contrast, dual orexin-receptor antagonists (DORAs) promote sleep, are used to treat insomnia, and several of them have already been approved or are under development with promising results (e.g., suvorexant, lemborexant, daridorexant) [45][46][47][48]. Patients with insomnia taking one of these drugs returned to sleep from their longest awakening more than twice faster than those on placebo [49]. Moreover, the number of, and time spent in, long wake bouts were reduced in the treated group, suggesting that DORAs may reduce wake time after sleep onset by decreasing long wake bouts. ...
... Given the mechanistic role of orexin in maintaining wakefulness [44,45], the marked increase in orexin activity across the menopausal transition may serve as a key factor mediating insomnia in midlife women. Moreover, orexin has known thermoregulatory effects [46], which may underlie any impact of orexin antagonists on VMS. ...
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 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 minutes 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, 16.8-19.4) and 18.3 (95% CI, 17.2-19.5) in the suvorexant and placebo groups, respectively (p=0.81). 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=0.04]. Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p<0.01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparison. 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.
... In contrast, dual orexin-receptor antagonists (DORAs) promote sleep, are used to treat insomnia, and several of them have already been approved or are under development with promising results (e.g., suvorexant, lemborexant, daridorexant) [45][46][47][48]. Patients with insomnia taking one of these drugs returned to sleep from their longest awakening more than twice faster than those on placebo [49]. Moreover, the number of, and time spent in, long wake bouts were reduced in the treated group, suggesting that DORAs may reduce wake time after sleep onset by decreasing long wake bouts. ...
Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.
... bouts was associated with orexin neuronal degeneration compared to wild-type mice. Worse survival of wake bouts in NT1 is also consistent with the clinical effect of orexin antagonist drugs41 , sleep aids used to reduce nocturnal wakefulness to treat insomnia.Clinically, the increase in the number of wake bout that occurs concurrently with the decreased survival of wake bouts likely accounts for the increase in WASO in NT1.Of all the sleep stages, REM sleep shows the greatest instability in NT1, with shorter but more numerous REM sleep bouts and decreased survival of REM sleep bouts in NT1 participants compared to subjectively sleepy controls. These findings highlight the prominent REM sleep dysregulation that emerges in the setting of orexin neuron loss. ...
Study Objectives
We determine if young people with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) have distinct nocturnal sleep stability phenotypes compared to subjectively sleepy controls.
Methods
Participants were 5-21 years old and drug-naïve or drug free: NT1 (n=46), NT2 (n=12), IH (n=18) and subjectively sleepy controls (n=48). We compared the following sleep stability measures from polysomnogram (PSG) recording between each hypersomnolence disorder to subjectively sleepy controls: number of wake and sleep stage bouts, Kaplan Meier survival curves for wake and sleep stages, and median bout durations.
Results
Compared to the subjectively sleepy control group, NT1 participants had more bouts of wake and all sleep stages (p≤0.005) except stage N3. NT1 participants had worse survival of nocturnal wake, stage N2 , and REM bouts (p<0.005). In the first 8 hours of sleep, NT1 participants had longer stage N1 bouts but shorter REM and stage N3 bouts (all p’s <0.013). IH participants had a similar number of bouts but better survival of stage N2 bouts (p=0.001), and shorter stage N3 bouts in the first 8 hours of sleep (p=0.003). In contrast, NT2 participants showed better stage N1 bout survival (p=0.006) and longer stage N1 bouts (p=0.02).
Conclusions
NT1, NT2 and IH have unique sleep physiology compared to subjectively sleepy controls, with only NT1 demonstrating clear nocturnal wake and sleep instability. Overall, sleep stability measures may aid in diagnoses and management of these CNS disorders of hypersomnolence.
... Interestingly, this reduction in WASO was not accompanied by a change in awakenings during the night, 30 a finding consistent with preclinical data indicating suvorexant does not affect the ability of salient cues to cause awakening. 36 Additional characterization of suvorexant's effects on WASO and awakenings found that suvorexant affects consolidation of sleep by decreasing the total time spent in and total number of "long" awakening's (>2 min), and that this effect appeared to increase patient-reported good/excellent sleep quality by 2-fold, 37 consistent with other data indicating long awakenings are more impactful than short awakenings for patients with insomnia. 38 Importantly, suvorexant helped patients return to sleep from their longest awakening more than twice as fast as those on placebo. ...
The development of therapeutics for central nervous system (CNS) disorders has many challenges that result in low probability of success and longer-than-typical development timelines. Suvorexant (Belsomra), the first dual orexin receptor antagonist used for insomnia, was approved by the United States Food and Drug Administration ∼10 years after the initial high-throughput screen was conducted to identify orexin receptor antagonists. What accounted for this success and speed? Here we suggest that this program was unique and set up for success by (1) having a robust and high-throughput pharmacodynamic readout that was translatable across species, including humans, (2) a well-validated target with a defined product profile, resulting in a highly energized team with a can-do attitude, and (3) a highly executable and streamlined clinical strategy. The utility of Belsomra for insomnia, as well as other neurological and psychiatric diseases, continues to be explored, most recently for insomnia associated with Alzheimer’s disease.
... Svetnik et al. [154] Healthy young men (18-45 years old) ...
Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward, emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders, depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists (SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders, whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.
... Sleep can be further characterised by its continuity, i.e. are sleep and wake episodes consolidated or are they interrupted by brief intrusions of the other state. Sleep continuity can be quantified as sleep efficiency (i.e. total sleep time/time in bed), wake after sleep onset, the number of awakenings, EEG arousals or the distribution of the duration of uninterrupted sleep bouts as assessed by survival analysis or other methods (Klerman et al. 2013;Svetnik et al. 2018). ...
Disturbances of the sleep-wake cycle are highly prevalent and diverse. The aetiology of some sleep disorders, such as circadian rhythm sleep-wake disorders, is understood at the conceptual level of the circadian and homeostatic regulation of sleep and in part at a mechanistic level. Other disorders such as insomnia, are more difficult to relate to sleep regulatory mechanisms or sleep physiology. To further our understanding of sleep-wake disorders and the potential of novel therapeutics we discuss recent findings on the neurobiology of sleep regulation and circadian rhythmicity and its relation with the subjective experience of sleep and the quality of wakefulness. Sleep continuity and to some extent REM sleep emerge as determinants of subjective sleep quality and waking performance. The effects of insufficient sleep primarily concern subjective and objective sleepiness as well as vigilant attention whereas performance on higher cognitive functions appears to be better preserved albeit at the cost of increased effort. We discuss age-related, sex and other trait-like differences in sleep physiology and sleep need and compare the effects of existing pharmacological and non-pharmacological sleep and wake promoting treatments. Successful non-pharmacological approaches such as sleep restriction for insomnia and light and melatonin treatment for circadian rhythm sleep disorders target processes such as sleep homeostasis or circadian rhythmicity. Most pharmacological treatments of sleep disorders target specific signalling pathways with no well-established role in either sleep homeostasis or circadian rhythmicity. Pharmacological sleep therapeutics induce changes in sleep structure and the sleep EEG which are specific to the mechanism of action of the drug. Sleep and wake promoting therapeutics often induce residual effects on waking performance and sleep respectively. The need for novel therapeutic approaches continues not at least because of the societal demand to sleep and be awake out of synchrony with the natural light-dark cycle, the high prevalence of sleep-wake disturbances in mental health disorders and in neurodegeneration. Novel approaches, which will provide a more comprehensive description of sleep and allow for large scale sleep and circadian physiology studies in the home environment, hold promise for continued improvement of therapeutics for disturbances of sleep , circadian rhythms and waking performance.
... In fact, suvorexant has been reported to improve sleep quality by reducing long wake bout times. 25 Additionally, since several previous studies showed that suvorexant has less effects on sleep architecture and EEG power spectrum than other hypnotics, 19,20 it would be better if patients during PSG can sleep well with suvorexant use. In the present setting, however, optimizing hypnotic use timing or the type of add-on hypnotics might not be enough to sleep well. ...
Purpose
Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG.
Patients and methods
An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant).
Results
Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling.
Conclusion
Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG.
... We found that while suvorexant was effective in hastening the onset of sleep, it also produced an increase in REM and SW sleep fragmentation and increased β energy in waking EROs when compared with VEH. In one clinical trial of insomnia, suvorexant, particularly at high doses, was found to reduce wakefulness after sleep onset although it increased the number and time spent in short wakefulness bouts during sleep when compared with placebo and baseline conditions [106]. Similar findings were reported in an animal model where a progressive loss of orexin neurons was also found to alter the appearance of wakefulness within sleep [107]. ...
Study Objectives
Insomnia is a prominent complaint in patients with alcohol use disorders (AUD). However, despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance associated with a history of AUD are currently limited. Recent clinical trials have demonstrated that suvorexant, a dual Hct/OX receptor antagonist, normalizes sleep in patients with primary insomnia, yet its potential for the treatment of sleep pathology associated with AUD has not been investigated in either pre-clinical or clinical studies.
Methods
This study employed a model whereby ethanol vapor exposure or control conditions were administered for 8 weeks to adult rats. Waking event-related oscillations (EROs) and EEG sleep were evaluated at baseline before exposure and again following 24 hours of withdrawal from the exposure. Subsequently, the ability of vehicle (VEH) and 2 doses (10,30 mg/kg IP) of suvorexant to modify EROs, sleep, and the sleep EEG was investigated.
Results
After 24h following EtOH withdrawal, the ethanol treated group had: Increases in waking ERO theta and beta activity, more fragmented sleep (shorter duration and increased frequency of SW and REM sleep episodes), and increased theta and beta power in REM and SW sleep. Suvorexant induced a dose dependent decrease in the latency to REM and SW sleep onsets but also produced REM and SW sleep fragmentation and increased beta energy in waking EROs when compared to VEH.
Conclusions
Taken together, these studies suggest that suvorexant has overall sleep-promoting effects, but it may exacerbate some aspects of sleep and EEG pathology.
... High-frequency firing in the orexin neurons probably triggers release of orexins from dense core vesicles 31,43 . In addition, as with other neuropeptides that are spontaneously released, some basal level of orexin tone may persist at all times; in support of this idea, orexin receptor antagonists promote sleep in humans even during the night, when orexin neurons might be expected to be inactive 44,45 . ...
Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep–wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches.
... While suvorexant reduced WASO, it did not appear to alter the number of awakenings during the night as assessed by PSG (Herring et al., 2012). An analysis of the microdynamics of suvorexant effects on WASO and awakenings found that, relative to placebo, suvorexant decreased the total number and total time spent in "long" awakenings (> 2 min), while slightly increasing the total number and total time spent in "short" awakenings (≤ 2 min; Svetnik et al., 2018). The reduction in long awakenings increased the odds of patient-reported good/excellent sleep quality twofold, while the increase in short awakenings had no effect on sleep quality, supporting the expectation that long awakenings are more impactful for patients with insomnia than short awakenings (Winser, Mcbean, & Montgomery-Downs, 2013). ...
In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on suvorexant, which is currently the only approved agent in this class. The efficacy of suvorexant was established in Phase 2–3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self‐report and by polysomnography, with generally little effect on underlying sleep architecture. The main side‐effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.
The mesopontine tegmental anesthesia area (MPTA) is a focal brainstem locus which, when exposed to GABAergic agents, induces brain-state transitioning from wakefulness to unconsciousness. Correspondingly, MPTA lesions render animals relatively insensitive to GABAergic anesthetics delivered systemically. Using chemogenetics, we recently identified a neuronal subpopulation within the MPTA whose excitation induces this same pro-anesthetic effect. However, very few of these “effector-neurons” express synaptic γ2-containing GABAA receptor isoforms and none express extrasynaptic δ-subunit containing receptors, suggesting that they are not the direct cellular target of GABAergic agents. Here we used pharmacological tools in rats to define the molecular target(s) of GABAergics in the MPTA. GABA microinjected into the MPTA at nanomolar concentrations, selective for GABAAδ-Rs, proved to be pro-anesthetic as was blocking GABA reuptake. Likewise, low-concentration gaboxadol/THIP, also selective for GABAAδ-Rs, was effective, whereas benzodiazepines and zolpidem, which selectively target GABAAγ2-Rs, were not. The GABAergic anesthetics pentobarbital and propofol proved pro-anesthetic when applied to the MPTA at the low concentrations present in the brain after systemic dosing. Glycinergic agonists which are inhibitory, but infective on GABAAδ-Rs, and other non-GABAergic agonists tested, were at most only marginally effective. We conclude that GABAAδ-Rs are the primary molecular target of GABAergic anesthetics in the MPTA. Immunolabeling revealed that this GABAA-R isoform is expressed exclusively by a distinct subpopulation of MPTA “δ-cells” that reside in close apposition to effector neurons. This suggests that during wakefulness, δ-cells serve as inhibitory interneurons which, when silenced by GABAergic agents, disinhibit (excite) the effector-neurons, triggering transition to unconsciousness.
Study objectives
Post-hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal.
Methods
We studied sleep architecture in adults with chronic insomnia disorder from two randomized Phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg). We analyzed sleep–wake transition probabilities, EEG spectra and sleep spindle properties including density, dispersion, and slow oscillation phase coupling. The Wake EEG Similarity Index (WESI) was determined using a machine learning algorithm analyzing the spectral profile of the EEG.
Results
At Month 3, daridorexant 50 mg decreased Wake–to–Wake transition probabilities (P<0.05) and increased the probability of transitions from Wake–to–N1 (P<0.05), N2 (P<0.05), and REM sleep (P<0.05), as well as from N1-to-N2 (P<0.05) compared to baseline and placebo. Daridorexant 50 mg decreased relative beta power during Wake (P=0.011) and N1 (P<0.001) compared to baseline and placebo. During Wake, relative alpha power decreased (P<0.001) and relative delta power increased (P<0.001) compared to placebo. Daridorexant did not alter EEG spectra bands in N2, N3, and REM stages or in sleep spindle activity. Daridorexant decreased the WESI score during Wake compared to baseline (P=0.004). Effects with 50 mg were consistent between Month 1 and Month 3 and less pronounced with 25 mg.
Conclusion
Daridorexant reduced EEG features associated with hyperarousal as indicated by reduced Wake–to–Wake transition probabilities and enhanced spectral features associated with drowsiness and sleep during Wake and N1.
Study objectives:
Obstructive sleep apnea (OSA) and insomnia frequently co-occur, making diagnosis and treatment challenging. We investigated differences in sleep structure, between patients with OSA, insomnia and comorbid insomnia and sleep apnea (COMISA) to identify characteristics that can be used to improve the diagnosis of COMISA.
Methods:
We obtained polysomnography data of 326 patients from the SOMNIA database. The group included patients with OSA (n=199), insomnia (n=47) and COMISA (n=80). We compared statistics related to sleep structure between the three patient groups.
Results:
Wake after sleep onset (WASO) was significantly shorter for the OSA group (median: 60.0 min.) compared to the COMISA (median: 83.3 min., p<0.01) and the insomnia group (median: 83.5 min., p=0.01). No significant differences were found in the total number of awakenings and the number of short (up to and including 2 minutes) and medium-length awakenings (2.5 up to and including 4.5 minutes). However, the number of long awakenings (5 minutes or longer) and WASO containing only long awakenings was significantly lower for patients with OSA (median: 2 awakenings and 25.5 min.) compared to patients with COMISA (median: 3 awakenings, p<0.01 and 43.3 min., p<0.001) and with insomnia (median: 3 awakenings, p<0.01 and 56.0 min., p<0.001). Total sleep time was significantly longer and sleep efficiency was significantly higher for the OSA group (median: 418.5 min and 84.4%) compared to both the COMISA (median: 391.5 min, p<0.001, and 77.3%, p<0.001) and the insomnia group (median: 381.5 min, p<0.001, and 78.2%, p<0.001). The number of sleep stage transitions during the night for patients with COMISA (median: 194.0) was lower compared to patients with OSA (median: 218.0, p<0.01) and higher compared to patients with insomnia (median: 156.0, p<0.001). Other sleep architectural parameters were not discriminative between the groups.
Conclusions:
Patients with COMISA show specific characteristics of insomnia, including prolonged awakenings. This variable is distinctive in comparison to patients with OSA. The combination of prolonged awakenings and the presence of sleep disordered breathing leads to increased sleep disturbance compared to patients having only one of the sleep disorders.
This article addresses the clinical presentation, diagnosis, pathophysiology and management of narcolepsy type 1 and 2, with a focus on recent findings. A low level of hypocretin‐1/orexin‐A in the cerebrospinal fluid is sufficient to diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and the irreversible loss of hypocretin neurons is responsible for the main symptoms of the disease: sleepiness, cataplexy, sleep‐related hallucinations and paralysis, and disrupted nocturnal sleep. The process responsible for the destruction of hypocretin neurons is highly suspected to be autoimmune, or dysimmune. Over the last two decades, remarkable progress has been made for the understanding of these mechanisms that were made possible with the development of new techniques. Conversely, narcolepsy type 2 is a less well‐defined disorder, with a variable phenotype and evolution, and few reliable biomarkers discovered so far. There is a dearth of knowledge about this disorder, and its aetiology remains unclear and needs to be further explored. Treatment of narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy and disrupted nocturnal sleep. However, new psychostimulants have been recently developed, and the upcoming arrival of non‐peptide hypocretin receptor‐2 agonists should be a revolution in the management of this rare sleep disease, and maybe also for disorders beyond narcolepsy.
Purpose of review:
Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use.
Recent findings:
There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs.
Summary:
Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.
Excessive sleep in a 24-h period is termed hypersomnia when it constitutes a specific disorder, while the urge to fall asleep because of excessive sleepiness is called hypersomnolence. The hypersomnias have been subdivided in primary or central, and secondary or symptomatic of other disorders. In this article the following topics are covered: objective and subjective diagnostic work-up of the hypersomnias, narcolepsy and narcolepsy spectrum disorder, narcolepsy and hypocretin, narcolepsy and immunopathology, established and new treatment modalities for narcolepsy spectrum disorder, idiopathic hypersomnia, recurrent hypersomnias, central hypersomnia in myotonic dystrophy, excessive sleepiness in obstructive sleep apnea, and sleep attacks.
Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. Rats were administered DORA-22 or the GABA receptor-targeting hypnotic eszopiclone early in the light period, then exposed to six hourly clean cage changes with measurements of NREM sleep onset latency. Both compounds initially promoted sleep (hours 1 and 2), with DORA-22 exhibiting a more rapid hypnotic onset; and exhibited extended efficacy, evident six hours after administration in a sleep latencies test. A common complaint concerning hypnotic use is lingering hypersomnolence, and this is a concern in pharmacotherapy of the elderly. A second study was designed to determine a minimal dose of DORA-22 which would initially promote sleep but exhibit minimal extended hypnotic effect. Animals were administered DORA-22, then exposed for six hours to a single cage previously dirtied by a conspecific, followed by return to home cage. EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.
Aims:
This study aimed to assess the chronotherapeutic efficacy of suvorexant on subjective sleep parameters and metabolic parameters in patients with type 2 diabetes and insomnia.
Methods:
Thirteen patients with type 2 diabetes who met the Pittsburg Sleep Quality index criteria for primary insomnia took suvorexant 20 mg/day (15 mg/day for ≥65 years) for 14±2 weeks. The following parameters were assessed before and after the treatment: sleep diary for sleep duration and quality (i.e., sleep onset latency, waking after sleep onset, and sleep efficiency [sSE]), Insomnia Severity Index, clinical and biochemical data, continuous glucose monitoring (CGM), and validated self-administered questionnaire on food intake.
Results:
Suvorexant significantly improved sSE, abdominal circumference, and sucrose intake (all p<0.05), but did not change HbA1c, CGM parameters, or body weight. Correlation analysis revealed that changes in sSE were associated with those in HbA1c and body weight (r=-0.61 and r=-0.66, respectively; both p<0.05).
Conclusions:
Suvorexant significantly improved sleep quality and obesity-associated parameters in patients with type 2 diabetes in 14 weeks. Improvements in sleep quality were associated with improvements in glycemic control. Sleep disorder treatment using suvorexant may provide metabolic benefits for patients with type 2 diabetes.
Objective
To evaluate the associations between cerebrospinal fluid orexin-A (ORX) levels and markers of nocturnal sleep stability, assessed by polysomnography (PSG).
Methods
Nocturnal PSG data and ORX levels of 300 drug-free subjects (55% men, 29.9±15.5 years, ORX level 155.1±153.7 pg/ml) with hypersomnolence were collected. Several markers of nocturnal sleep stability were analyzed: wake and sleep bouts, sleep/wake transitions. Groups were categorized according to ORX levels, in two categories (deficient≤110; >110), in tertiles (≤26, ]26;254], >254), and compared using logistic regression models. Results were adjusted for age, sex and body mass index.
Results
We found higher number of wake bouts (43 vs 25, p<0.0001), sleep bouts (43 vs 25.5, p<0.0001) and index of sleep bouts/hour of sleep time, but lower index of wake bouts/hour of waketime (41.4 vs 50.6, p<0.0001) in subjects with ORX deficiency. The percentage of wake bouts <30sec was lower (51.3 vs 60.8%, p<0.001) and of wake bouts ≥1min30sec higher (7.7 vs 6.7%, p=0.02) when ORX deficient. The percentage of sleep bouts ≤14min was higher (2-5min: 23.7 vs 16.1%, p<0.0001), and of long sleep bouts lower (>32min30sec: 7.3 vs 18.3%, p<0.0001) when ORX deficient. These findings were confirmed when groups were categorized according to ORX tertiles, with a dose-response effect of ORX levels in post-hoc comparisons, and in adjusted models.
Interpretation
This study shows an association between ORX levels and nocturnal sleep stabilization in patients with hypersomnolence. Sleep and wake bouts are reliable markers of nighttime sleep stability that correlate with CSF ORX levels in a dose-dependent manner.
Objectives:
The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an orexin antagonist, approved for treatment of insomnia was evaluated for effects on both the sleep and pain of fibromyalgia.
Methods:
Women, 21- 65 yrs old, with fibromyalgia and co-morbid insomnia (n=10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg, and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and DSM-V criteria for insomnia. A screening 8-hr PSG was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hr PSGs were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hr by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels.
Results:
Suvorexant vs placebo increased total sleep time (7.2 vs 6.7 hrs, p< .05) and reduced wake after sleep onset (37 vs 67 min, p<.04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (p<.001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am test (13.9 vs 13.1 sec) and pm tests (15.8 vs 14.1 sec, p<.03) following suvorexant the previous night.
Conclusions:
Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus.
Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally impacting mnemonic function, yet many hypnotic drugs (e.g., benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine if the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze, then administered DORA-22 (10, 30, or 100mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a six-hour time period (at timepoints 0 and 3 hours), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption - wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared to vehicle treatment for one dose (30mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg); and time spent in platform location and number of platform crossings (10mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.
Historically, pharmacological therapies have used mechanisms such as γ- aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage-specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 57 is January 06, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
A new paradigm for statistical computing that has been evolving is identified. The paradigm of abstract statistical computing is to use software to model (possibly abstract) statistical concepts. Some examples from recent statistical computing research are discussed to illustrate the paradigm.
Study objectives:
In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening.
Method:
DORA 22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n=34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened.
Results:
All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened.
Conclusions:
In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.
To investigate the differential nature of disturbed sleep in subjects with fibromyalgia (FM) reporting sleep difficulties versus subjects with primary insomnia (PI) and subjects who do not complain of disturbed sleep ("normals").
Subjects (FM: n=132; PI: n=109; normals: n=52) were recruited for different studies. FM and PI subjects were pre-selected to meet sleep-disturbance criteria. Subjects with sleep or circadian disorders were excluded from all groups. Polysomnography (PSG) was conducted at screening, during 2 consecutive nights. For this post hoc analysis of PSGs, length and frequency (duration, number) of wake and sleep bouts were analyzed, together with traditional sleep measures; a "bout"=consecutive 30-second epochs of sleep or wake. Data are mean±SD.
FM and PI subjects had decreased total sleep time (TST) and slow wave sleep (SWS), and increased latency to persistent sleep (LPS) and wake time after sleep onset (WASO) versus normals (P<0.05 for each). FM versus PI subjects had more SWS (48.1±32.4 vs. 27.2±23.6 min; P<0.0001) and shorter LPS (58.2±29.8 vs. 70.7±31.3 min; P=0.0055), but comparable WASO (107.7±32.8 vs. 108.6±31.5 min). Despite comparable WASO, FM subjects had shorter (4.64±2.42 vs. 5.87±3.15 min; P=0.0016) but more frequent wake bouts versus PI subjects (41.6±16.7 vs. 35.7±12.6; P=0.0075). Sleep bout duration was similar for FM (9.32±0.35 min) and PI subjects (10.1±0.37 min); both populations had shorter sleep bout duration versus normals (15.7±0.7 min; P<0.0001 both).
Increased frequency of wake and sleep bouts and decreased wake bout duration, together with decreased LPS and increased SWS, suggests sleep in FM is characterized by an inability to maintain continuous sleep but a greater sleep drive compared with PI.
The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.
Despite the common experience that interrupted sleep has a negative impact on waking function, the features of human sleep-wake architecture that best distinguish sleep continuity versus fragmentation remain elusive. In this regard, there is growing interest in characterizing sleep architecture using models of the temporal dynamics of sleep-wake stage transitions. In humans and other mammals, the state transitions defining sleep and wake bout durations have been described with exponential and power law models, respectively. However, sleep-wake stage distributions are often complex, and distinguishing between exponential and power law processes is not always straightforward. Although mono-exponential distributions are distinct from power law distributions, multi-exponential distributions may in fact resemble power laws by appearing linear on a log-log plot.
To characterize the parameters that may allow these distributions to mimic one another, we systematically fitted multi-exponential-generated distributions with a power law model, and power law-generated distributions with multi-exponential models. We used the Kolmogorov-Smirnov method to investigate goodness of fit for the "incorrect" model over a range of parameters. The "zone of mimicry" of parameters that increased the risk of mistakenly accepting power law fitting resembled empiric time constants obtained in human sleep and wake bout distributions.
Recognizing this uncertainty in model distinction impacts interpretation of transition dynamics (self-organizing versus probabilistic), and the generation of predictive models for clinical classification of normal and pathological sleep architecture.
Although mammals of different species have different sleep patterns, brief sleep–wake transitions commonly are observed across species and appear to occur randomly throughout the sleeping period. The dynamical patterns and functions of these brief awakenings from sleep are not well understood, and they often are viewed as disruptions (random or pathologic) of the sleep process. In this article, we hypothesize that brief awakenings from sleep may reflect aspects of the endogenous sleep control mechanism and thus may exhibit certain robust dynamical patterns across species. We analyze sleep recordings from mice, rats, cats, and humans, and we compare the distributions of sleep and wake episode durations. For all four species, we find that durations of brief wake episodes during the sleep period exhibit a scale-free power-law behavior with an exponent α that remains the same for all species (α ≈ 2.2). In contrast, sleep episode durations for all four species follow exponential distributions with characteristic time scales, which change across species in relation to body mass and metabolic rate. Our findings suggest common dynamical features of brief awakenings and sleep durations across species and may provide insights into the dynamics of the neural circuits controlling sleep.
• power law
• sleep regulation
• sleep fragmentation
To develop and demonstrate the utility of measures of sleep continuity based on survival analysis techniques.
Retrospective.
University sleep laboratory.
Anonymous nocturnal polysomnograms from 10 normal subjects, 10 subjects with mild sleep disordered breathing (SDB) (apnea-hypopnea index [AHI], 15-30/hr), and 10 subjects with moderate/severe SDB (AHI > 30/hr).
N/A.
Hypnograms were analyzed to measure the lengths of episodes of contiguous sleep and processed using several common survival analysis techniques. Using separate survival curves for each group to describe the durations of continuous epochs of sleep (sleep run lengths), statistically significant differences were found between all groups (p < .001) as well as between the normal and mild SDB groups (p < .001), suggesting differences in the stability of sleep. Using survival regression techniques applied separately to each subject, statistically significant differences were found among all three groups (p < .001) and, more importantly, between the normal and mild SDB groups (p < .005). Similarly, estimation of sleep continuity based on the pooled sleep run data for each group also showed statistically significant differences (normal vs mild, p < .001; Normal vs moderate/severe, p < .001). In addition, the latter technique showed that changes in the "stability" of sleep could be demonstrated as runs progressed.
Survival curve analysis of the lengths of runs of contiguous sleep provides a potentially useful method of quantifying sleep continuity. The results suggest that sleep becomes more stable as sleep progresses in normal subjects and those with mild SDB and less stable in subjects with moderate/severe SDB.
Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.
Evaluate the hypnotic efficacy of gaboxadol, a selective extrasynaptic GABAA agonist (SEGA), in a phase advance model of transient insomnia.
A randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h.
Sleep research laboratories.
109 healthy subjects (18-58 y).
Gaboxadol 5 mg, 10 mg, and 15 mg (GBX5, GBX10, GBX15) versus placebo (PBO). Zolpidem 10 mg (ZOL10) was used as an active reference.
Polysomnographic (PSG) and self-reported (s) sleep measures
Wakefulness after sleep onset (WASO) decreased (P < 0.05) and total sleep time (TST) increased (P < 0.001) in all treatments versus PBO. Latency to persistent sleep was shorter (P < 0.05) than PBO for all treatments except GBX5. GBX10 and GBX15 increased slow wave activity (SWA; 0.75-4.5 Hz, P < 0.001) and theta activity (4.75-7.75Hz; P < 0.001) and reduced sigma activity (12.25-15.0 Hz; significant for GBX15 only, P < 0.001) compared to PBO in NREM sleep EEG, in a dose-response manner. Zolpidem suppressed power density over a broad low frequency range including delta and theta frequencies (2.25-8.0 Hz, P < 0.05) and also enhanced sigma activity (P < 0.001). Self-reported sWASO and sTST improved for all treatments versus PBO (P < 0.05). Self-reported sleep latency was reduced following GBX10 (P < 0.05) and ZOL10 (P < 0.001). Neither drug treatment was associated with residual effects the morning after treatment.
Gaboxadol and zolpidem improved objective and subjective efficacy measures in this model of transient insomnia. The gaboxadol-induced enhancement of SWA and theta activity and the reduction of sigma activity contrasts with zolpidem's effects on the spectral EEG. These differences may reflect the different mechanisms of action of the two drugs.
Study objectives:
Suvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.
Methods:
Prespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/ elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnographic (PSG; subset of patients) sleep maintenance and onset endpoints.
Results:
Suvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints)/ Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.
Conclusions:
Suvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.
Clinicaltrials.gov trial registration numbers:
NCT01097616, NCT01097629.
Objective: To investigate the effect of pregabalin on wake and sleep bout parameters. Materials and Methods: A post hoc analysis of polysomnography data from a randomized, placebo-controlled, crossover study investigating the effect of pregabalin (150 to 450 mg/d) and placebo on sleep in fibromyalgia (FM). Eligible patients had FM and sleep-maintenance problems, including wake after sleep onset >= 45 minutes and total sleep time (TST) 3.0 to 6.5 hours, but no other sleep/circadian rhythm disorders. Polysomnography was performed for 2 consecutive nights (screening, post-treatment). Wake and sleep bout duration and frequency were derived; a "bout"=consecutive 30-s epochs of sleep or wake. Results: Of 119 patients randomized (103 [87%] female), data were available for 103 treated with pregabalin and 106 with placebo. Pregabalin versus placebo treatment decreased mean +/- SD number of wake/sleep bouts (33.24 +/- 1.33 vs. 36.85 +/- 1.32; difference: -3.61 [95% confidence interval, -6.03, -1.18]; P=0.0039) and increased sleep bout duration (15.25 +/- 0.63 vs. 11.58 +/- 0.62 min; +3.67 min [2.22, 5.12 min]; P < 0.0001). Pregabalin decreased mean duration of wake bouts versus placebo (3.41 +/- 0.55 vs. 3.94 +/- 0.55 min; -0.53 min [-1.06, -0.002 min]; P=0.0493). An exploratory correlation analysis of treatment effects found stage 1 sleep was negatively correlated with wake and sleep bout duration and positively with wake/sleep bout number; slow wave sleep (%total sleep time) was positively correlated with wake and sleep bout duration and negatively with wake/sleep bout number. Conclusions: Pregabalin improved sleep parameters characteristic of disturbed sleep in FM, by preventing awakenings and increasing sleep bout duration. These effects are reflected in, and correlated with, a decrease in "light sleep" (stage 1) and an increase in "deep sleep" (slow wave sleep).
Background:
The orexin receptor antagonist, suvorexant, is approved for treating insomnia at a maximum dose of 20 mg. We evaluated its effects on sleep architecture.
Methods:
The analyses included pooled polysomnography data from two similar randomized, double-blind, placebo-controlled, 3-month trials evaluating two age-adjusted (non-elderly/elderly) dose regimes of 20/15 mg and 40/30 mg in 1482 patients with insomnia. Polysomnography was recorded at baseline and on three nights during the treatment: Night-1, Month-1, and Month-3. Effects on non-REM sleep stages 1 (N1), 2 (N2), 3 (N3)/slow wave sleep (SWS), and REM sleep were evaluated. A power spectral analysis of non-REM sleep was also performed.
Results:
Suvorexant increased the time (in minutes) spent in all sleep stages compared with placebo. When suvorexant and placebo were compared in terms of changes in percentage of total sleep time spent in each stage, there were small decreases of ≤1%, ≤2.2%, and ≤0.8% for N1, N2, and N3/SWS on average, respectively, and an average increase of ≤3.9% in REM. The largest differences from placebo were observed at Night-1 and generally diminished over time. Suvorexant reduced REM latency (number of non-REM 30-s epochs from lights-off to the first REM epoch) compared with placebo; the reduction was greater at Night-1 (~40-50 non-REM epochs) in comparison to later time points (~12-25 non-REM epochs at Month-3). The spectral analysis of non-REM showed a small decrease in power of 3-6% in the gamma and beta bands, and a small increase of 4-8% in the delta band, at Night-1 for suvorexant relative to placebo; these effects were not apparent at the later Month-1 and Month-3 time points.
Conclusion:
Overall sleep architecture appears to be preserved in insomnia patients taking suvorexant. The power spectral profile of suvorexant is generally similar to placebo.
Study objectives:
Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep. To determine the effects of the orexin neurons on the dynamics of sleep/wake behavior, we analyzed sleep/wake architecture in a novel mouse model of acute orexin neuron loss.
Measurements and results:
We analyzed sleep/wake architecture in orexin-tTA ; TetO diphtheria toxin A mice at different stages of orexin neuron degeneration using survival analysis and other methods. Progressive loss of the orexin neurons dramatically reduced survival of long wake bouts, but it also improved survival of brief wake bouts. In addition, with loss of the orexin neurons, mice were more likely to wake during the first 30 sec of nonrapid eye movement sleep and then less likely to return to sleep during the first 60 sec of wakefulness.
Conclusions:
These findings help explain the sleepiness and fragmented sleep that are characteristic of narcolepsy. Orexin neuron loss impairs survival of long wake bouts resulting in poor maintenance of wakefulness, but this neuronal loss also fragments sleep by increasing the risk of awakening at the beginning of sleep and then reducing the likelihood of quickly returning to sleep.
Chronic insomnia is defined by difficulties in falling asleep, maintaining sleep, and early morning awakening, and is coupled with daytime consequences such as fatigue, attention deficits, and mood instability. These symptoms persist over a period of at least 3 months (Diagnostic and Statistical Manual 5 criteria). Chronic insomnia can be a symptom of many medical, neurological, and mental disorders. As a disorder, it incurs substantial health-care and occupational costs, and poses substantial risks for the development of cardiovascular and mental disorders, including cognitive deficits. Family and twin studies confirm that chronic insomnia can have a genetic component (heritability coefficients between 42% and 57%), whereas the investigation of autonomous and central nervous system parameters has identified hyperarousal as a final common pathway of the pathophysiology, implicating an imbalance of sleep-wake regulation consisting of either overactivity of the arousal systems, hypoactivity of the sleep-inducing systems, or both. Insomnia treatments include benzodiazepines, benzodiazepine-receptor agonists, and cognitive behavioural therapy. Treatments currently under investigation include transcranial magnetic or electrical brain stimulation, and novel methods to deliver psychological interventions.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin defi ciency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin defi ciency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifi cally hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specifi c degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, fi rst with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic fi ndings and now awaiting experimental testing are models of the possible immune mechanisms by which a specifi c and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identifi cation of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.
Background
Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal Phase-3 trials.
Methods
Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30mg (non-elderly/elderly) and 20/15mg (non-elderly/elderly) were evaluated. The primary focus was 40/30mg, with fewer patients randomized to 20/15mg. There was an optional 3-month double-blind extension in Trial-1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at Week-1, Month-1, and Month-3 by patient-reported subjective total-sleep-time (sTST) and time-to-sleep-onset (sTSO), and in a subset of patients at Night-1, Month-1, and Month-3 by polysomnographic (PSG) endpoints of Wakefulness-After-persistent-Sleep-Onset (WASO) and Latency-to-onset-of-Persistent-Sleep (LPS). 1021 patients were randomized in Trial-1 and 1019 patients in Trial-2.
Results
Suvorexant 40/30mg was superior to placebo on all subjective and PSG endpoints at Night-1/Week-1, Month-1 and Month-3 in both trials, except for LPS at Month-3 in Trial-2. Suvorexant 20/15mg was superior to placebo on sTST and WASO at Night-1/Week-1, Month-1 and Month-3 in both trials and at most individual timepoints for sTSO and LPS in each trial. Both doses of suvorexant were generally well-tolerated, with <5% of patients discontinuing due to adverse events over 3-months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued.
Conclusions
Suvorexant improved sleep onset and maintenance over 3-months of nightly treatment and was generally safe and well-tolerated.
Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.
We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813.
322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (-18·0 min vs -8·4 min, difference -9·5, -14·6 to -4·5; p=0·0002).
Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance.
Merck & Co Inc.
This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.
The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins.
Objective:
To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia.
Methods:
We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep.
Results:
Suvorexant showed significant (p values <0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated.
Conclusions:
The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia.
Classification of evidence:
This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.
Orexin (hypocretin) receptor antagonists stand as a model for the development of targeted CNS small-molecule therapeutics. The identification of mutations in the gene for the orexin 2 receptor responsible for canine narcolepsy, the demonstration of a hypersomnolence phenotype in hypocretin knockout mice and the disruption in orexin signaling in narcoleptic patients provides clear genetic proof of concept for targeting orexin-induced arousal for the treatment of insomnia. The full characterization of the genes encoding orexin and its two cognate receptors enabled the rapid development of in vitro and ex vivo assays with which to identify lead compound structures and to optimize potency and pharmacokinetic properties. Polysomnographic measures with cross-species translatability capable of measuring the sleep-promoting effects of orexin receptor antagonists from mice to man, and the existence of knockout models not only allow efficacy assessment but also the demonstration of mechanism of action. Focused efforts by a number of groups have identified potent compounds of diverse chemical structure with differential orexin receptor selectivity for either the orexin 1 receptor (OX₁R) or the orexin 2 receptor (OX₂R), or both. This work has yielded tool compounds that, along with genetic models, have been used to specifically define the role these receptors in mediating orexin-induced arousal and vigilance state control. Optimized dual receptor antagonists with favorable pharmacokinetic and safety profiles have now demonstrated efficacy in clinical development and represent a distinct mechanism of action for the treatment of insomnia relative to current standard of care.
A common complaint of older persons is disturbed sleep, typically characterized as an inability to return to sleep after waking. As every sleep episode (i.e., time in bed) includes multiple transitions between wakefulness and sleep (which can be subdivided into rapid eye movement [REM] sleep and non-REM [NREM] sleep), we applied survival analysis to sleep data to determine whether changes in the "hazard" (duration-dependent probability) of awakening from sleep and/or returning to sleep underlie age-related sleep disturbances. The hazard of awakening from sleep-specifically NREM sleep-was much greater in older than in young adults. We found, however, that when an individual had spontaneously awakened, the probability of falling back asleep was not greater in young persons. Independent of bout length, the number of transitions between NREM and REM sleep stages relative to number of transitions to wake was approximately 6 times higher in young than older persons, highlighting the difficulty in maintaining sleep in older persons. Interventions to improve age-related sleep complaints should thus target this change in awakenings.
The neuropeptides orexin A and orexin B, produced in hypothalamic neurons, are critical regulators of sleep/wake states. Deficiency of orexin signaling results in narcoleptic phenotype in humans, dogs, and rodents. Recently, accumulating evidence has indicated that the orexin system regulates sleep and wakefulness through interactions with neuronal systems that are closely related with emotion, reward, and energy homeostasis. In this review, we will discuss the current understanding of the physiology of the orexin system especially focusing on its roles in the regulation of sleep/wakefulness states.
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Research on the effects of sleep-disordered breathing (SDB) on sleep structure has traditionally been based on composite sleep-stage summaries. The primary objective of this investigation was to demonstrate the utility of log-linear and multistate analysis of the sleep hypnogram in evaluating differences in nocturnal sleep structure in subjects with and without SDB.
A community-based sample of middle-aged and older adults with and without SDB matched on age, sex, race, and body mass index was identified from the Sleep Heart Health Study. Sleep was assessed with home polysomnography and categorized into rapid eye movement (REM) and non-REM (NREM) sleep. Log-linear and multistate survival analysis models were used to quantify the frequency and hazard rates of transitioning, respectively, between wakefulness, NREM sleep, and REM sleep.
Whereas composite sleep-stage summaries were similar between the two groups, subjects with SDB had higher frequencies and hazard rates for transitioning between the three states. Specifically, log-linear models showed that subjects with SDB had more wake-to-NREM sleep and NREM sleep-to-wake transitions, compared with subjects without SDB. Multistate survival models revealed that subjects with SDB transitioned more quickly from wake-to-NREM sleep and NREM sleep-to-wake than did subjects without SDB.
The description of sleep continuity with log-linear and multistate analysis of the sleep hypnogram suggests that such methods can identify differences in sleep structure that are not evident with conventional sleep-stage summaries. Detailed characterization of nocturnal sleep evolution with event history methods provides additional means for testing hypotheses on how specific conditions impact sleep continuity and whether sleep disruption is associated with adverse health outcomes.
This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.
To determine whether the increased wake within a bedrest episode in healthy older people is due to an increased number and/or increased duration of awakenings by evaluating the rates of transition between sleep and wake bouts within a bedrest episode.
Analysis of previously reported polysomnographic data from 13 older and 11 younger healthy individuals scheduled to sleep at many different phases of the endogenous circadian cycle during conditions of forced desynchrony (18.7 hours wake: 9.3 hours bedrest) of the circadian and wake-bedrest cycles.
General clinical research center
None.
None.
Older subjects had an approximately 2.7-fold increased rate of awakening from sleep but the same rate of falling back asleep as younger subjects. These differences between young and older individuals were observed at most circadian phases and throughout the bedrest episodes. In addition, the circadian variation in transition rates was greater in younger than older subjects.
These results suggest that the reduced consolidation of sleep within a bedrest episode is due to difficulties remaining asleep, rather than falling asleep once awake, and is a primary change in sleep with aging.