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Sleep Medicine Jul 2023Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT receptors in clinical development for the treatment of schizophrenia.... (Randomized Controlled Trial)
Randomized Controlled Trial
A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy.
BACKGROUND
Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy.
METHODS
In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment).
RESULTS
Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group.
CONCLUSIONS
Acute and sustained treatment with ulotaront reduced nighttime REM duration and daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy.
REGISTRATION
ClinicalTrials.gov identifier: NCT05015673.
Topics: Humans; Cataplexy; Cross-Over Studies; Narcolepsy; Pyrans; Adult
PubMed: 37209427
DOI: 10.1016/j.sleep.2023.04.019 -
Behavioral and Brain Functions : BBF Dec 2018Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. This disease affects... (Review)
Review
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. This disease affects significantly the overall patient functioning, interfering with social, work, and affective life. Some symptoms of narcolepsy depend on emotional stimuli; for instance, cataplectic attacks can be triggered by emotional inputs such as laughing, joking, a pleasant surprise, and also anger. Neurophysiological and neurochemical findings suggest the involvement of emotional brain circuits in the physiopathology of cataplexy, which seems to depending on the dysfunctional interplay between the hypothalamus and the amygdala associated with an alteration of hypocretin levels. Furthermore, behavioral studies suggest an impairment of emotions processing in narcolepsy-cataplexy (NC), like a probable coping strategy to avoid or reduce the frequency of cataplexy attacks. Consistently, NC patients seem to use coping strategies even during their sleep, avoiding unpleasant mental sleep activity through lucid dreaming. Interestingly, NC patients, even during sleep, have a different emotional experience than healthy subjects, with more vivid, bizarre, and frightening dreams. Notwithstanding this evidence, the relationship between emotion and narcolepsy is poorly investigated. This review aims to provide a synthesis of behavioral, neurophysiological, and neurochemical evidence to discuss the complex relationship between NC and emotional experience and to direct future research.
Topics: Cataplexy; Emotions; Humans; Narcolepsy; Polysomnography; Sleep, REM
PubMed: 30587203
DOI: 10.1186/s12993-018-0151-x -
Revista Brasileira de Psiquiatria (Sao... May 2005Sleepiness is a physiological function, and can be defined as increased propension to fall asleep. However, excessive sleepiness (ES) or hypersomnia refer to an abnormal... (Review)
Review
Sleepiness is a physiological function, and can be defined as increased propension to fall asleep. However, excessive sleepiness (ES) or hypersomnia refer to an abnormal increase in the probability to fall asleep, to take involuntary naps, or to have sleep atacks, when sleep is not desired. The main causes of excessive sleepiness is chronic sleep deprivation, sleep apnea syndrome, narcolepsy, movement disorders during sleep, circadian sleep disorders, use of drugs and medications, or idiopathic hypersomnia. Social, familial, work, and cognitive impairment are among the consequences of hypersomnia. Moreover, it has also been reported increased risk of accidents. The treatment of excessive sleepiness includes treating the primary cause, whenever identified. Sleep hygiene for sleep deprivation, positive pressure (CPAP) for sleep apnea, dopaminergic agents and exercises for sleep-related movement disorders, phototherapy and/or melatonin for circadian disorders, and use of stimulants are the treatment modalities of first choice.
Topics: Disorders of Excessive Somnolence; Humans
PubMed: 16082450
DOI: 10.1590/s1516-44462005000500004 -
European Respiratory Review : An... Jun 2022Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnoea (OSA), defined as the inability to stay awake during the day. Its clinical descriptors... (Review)
Review
Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnoea (OSA), defined as the inability to stay awake during the day. Its clinical descriptors remain elusive, and the pathogenesis is complex, with disorders such as insufficient sleep and depression commonly associated. Subjective EDS can be evaluated using the Epworth Sleepiness Scale, in which the patient reports the probability of dozing in certain situations; however, its reliability has been challenged. Objective tests such as the multiple sleep latency test or the maintenance of wakefulness test are not commonly used in patients with OSA, since they require nocturnal polysomnography, daytime testing and are expensive. Drugs for EDS are available in the United States but were discontinued in Europe some time ago. For European respiratory physicians, treatment of EDS with medication is new and they may lack experience in pharmacological treatment of EDS, while novel wake-promoting drugs have been recently developed and approved for clinical use in OSA patients in the USA and Europe. This review will discuss 1) the potential prognostic significance of EDS in OSA patients at diagnosis, 2) the prevalence and predictors of residual EDS in treated OSA patients, and 3) the evolution of therapy for EDS specifically for Europe.
Topics: Disorders of Excessive Somnolence; Humans; Reproducibility of Results; Sleep Apnea, Obstructive; Sleepiness; Wakefulness
PubMed: 35613742
DOI: 10.1183/16000617.0230-2021 -
Journal of Occupational Health 2011Factors modifying the effect of environmental noise on sleep include sex, age, susceptibility, personality and the health status, including past and present history of... (Review)
Review
UNLABELLED
Factors modifying the effect of environmental noise on sleep include sex, age, susceptibility, personality and the health status, including past and present history of disease.
OBJECTIVE
The effects of noise on sleep and habituation of sleep to noise were summarized.
RESULTS AND CONCLUSIONS
1) The effect of noise on sleep is associated with physical changes, such as changes in heart rate, blood flow volume, breathing and the immune and neurocirculatory systems. During sleep, specific changes in these indicators are noted during different sleep stages. There are individual and sex differences, and it is important to understand the effects of noise on sleep considering several related factors. 2) Habituation to noise is also an important phenomenon that must be addressed while considering the effects of noise on sleep. Habituation is dependent on the type and sound level of the noise. In occupational fields, shift work and job stress should be considered to determine the association between noise and sleep, which is important to retaining a good quality of working life.
Topics: Age Factors; Dyssomnias; Environmental Exposure; Habituation, Psychophysiologic; Health Status; Humans; Noise; Personality; Sex Factors; Sleep Stages
PubMed: 21952296
DOI: 10.1539/joh.11-0071-ra -
Neurologia (Barcelona, Spain) 2014It has been shown that sleep-related breathing disorders, especially sleep apnea, are very common in patients who have had a stroke, and that they also reduce the... (Review)
Review
INTRODUCTION
It has been shown that sleep-related breathing disorders, especially sleep apnea, are very common in patients who have had a stroke, and that they also reduce the potential for neurological recovery. Nevertheless, other sleep disorders caused by stroke (excessive daytime sleepiness, insomnia, sleep related movement disorders) can also cause or increase stroke-related disability, and this fact is less commonly known.
DEVELOPMENT
Studies with polysomnography have shown many abnormalities in sleep architecture during the acute phase of stroke; these abnormalities have a negative impact on the patient's quality of life although they tend to improve with time. This also happens with other sleep disorders occurring as the result of a stroke (insomnia, narcolepsy, restless legs syndrome, periodic limb movement disorder and REM sleep behavior disorder), which are nevertheless potentially treatable. In this article, we briefly review the physiopathology and epidemiology of the disorders listed above in order to raise awareness about the importance of these disorders and the effects they elicit in stroke patients.
CONCLUSIONS
Sleep disorders that are not breathing-related have scarcely been studied in stroke patients despite the fact that almost all such disorders may present as a result of a cerebrovascular event.
Topics: Acute Disease; Dyssomnias; Humans; Parasomnias; Polysomnography; Quality of Life; Stroke
PubMed: 23810485
DOI: 10.1016/j.nrl.2013.04.004 -
American Family Physician Aug 2013Sleep disorders are common and affect sleep quality and quantity, leading to increased morbidity. Patients with sleep disorders can be categorized as those who cannot... (Review)
Review
Sleep disorders are common and affect sleep quality and quantity, leading to increased morbidity. Patients with sleep disorders can be categorized as those who cannot sleep, those who will not sleep, those with excessive daytime sleepiness, and those with increased movements during sleep. Insomnia, defined as difficulty initiating or maintaining sleep that results in daytime impairment, is diagnosed using history findings and treated with cognitive behavior therapy, with or without sleep hypnotics. Restless legs syndrome is characterized by an urge to move the legs that worsens with rest, is relieved by movement, and often occurs in the evening or at night. Restless legs syndrome is treated based on the frequency of symptoms. Narcolepsy is characterized by excessive sleepiness, cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis. It is diagnosed using a sleep log or actigraphy, followed by overnight polysomnography and a multiple sleep latency test. Narcolepsy is treated with stimulants, such as modafinil; selective serotonin reuptake inhibitors; or gamma hydroxybutyric acid (sodium oxybate). Patients with snoring and witnessed apneas may have obstructive sleep apnea, which is diagnosed using overnight polysomnography. Continuous positive airway pressure is the most common and effective treatment for obstructive sleep apnea. Rapid eye movement sleep behavior disorder is characterized by increased muscle tone during rapid eye movement sleep, resulting in the patient acting out dreams with possible harmful consequences. It is diagnosed based on history and polysomnography findings, and treated with environmental safety measures and melatonin or clonazepam.
Topics: Actigraphy; Central Nervous System Stimulants; Cognitive Behavioral Therapy; Continuous Positive Airway Pressure; Humans; Hypnotics and Sedatives; Narcolepsy; Polysomnography; Practice Guidelines as Topic; REM Sleep Behavior Disorder; Restless Legs Syndrome; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders
PubMed: 23944726
DOI: No ID Found -
Sleep May 2020The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or...
The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.
Topics: Cataplexy; Disorders of Excessive Somnolence; Humans; Narcolepsy; Neuropeptides; Orexins; Sleep, REM
PubMed: 31919524
DOI: 10.1093/sleep/zsz296 -
Sleep Jun 2022
Topics: Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia
PubMed: 35176157
DOI: 10.1093/sleep/zsac040 -
Chest May 2021Comorbid insomnia and sleep apnea (COMISA) are the most common co-occurring sleep disorders and present many challenges to clinicians. This review provides an overview... (Review)
Review
Comorbid insomnia and sleep apnea (COMISA) are the most common co-occurring sleep disorders and present many challenges to clinicians. This review provides an overview of the clinical challenges in the management of patients with COMISA, with a focus on recent evidence regarding the evaluation and treatment of COMISA. Innovations in the assessment of COMISA have used profile analyses or dimensional approaches to examine symptom clusters or symptom severity that could be particularly useful in the assessment of COMISA. Recent randomized controlled trials have provided important evidence about the safety and effectiveness of a concomitant treatment approach to COMISA using cognitive-behavioral therapy for insomnia (CBT-I) with positive airway pressure (PAP). Furthermore, patient-centered considerations that integrate patient characteristics, treatment preferences, and accessibility to treatment in the context of COMISA are discussed as opportunities to improve patient care. Based on these recent advances and clinical perspectives, a model for using multidisciplinary, patient-centered care is recommended to optimize the clinical management of patients with COMISA.
Topics: Cognitive Behavioral Therapy; Continuous Positive Airway Pressure; Humans; Patient-Centered Care; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders
PubMed: 33309524
DOI: 10.1016/j.chest.2020.12.002