Question 1 of 10

    Non-24 Hour Sleep-Wake Disorder (Sleep Wake Dis Non 24 Hour)

    Non-24 hour sleep-wake disorder comprises deviation from the normal 24-hour circadian rhythm by one-to-two hour delays. The exact cause remains unknown, but the majority of patients are blind, indicating an absence of light stimulus as a possible defect. The diagnosis is made by clinical findings such as insomnia and sleeping difficulties, while polysomnography and actigraphy are definite diagnostic methods. Melatonin is the cornerstone of therapy.

    Presentation

    Although many individuals make a significant effort to preserve the 24-hour circadian rhythm, the progressive appearance of sleep delays and changes in waking times, the main signs of N24SWD, are most frequently reported, mimicking insomnia [4] [8]. Specifically, sleep onset and waking times are prolonged to a 25-hour (or sometimes even to 27 hours) cycle [1] [6], manifesting as progressive delays in initiation of sleep followed by oversleeping into daytime [6]. After some time, the lack of sleep and rest over a period of days results in extreme fatigue that necessitates a very long recovery sleep of 14-24 hours [6]. Finally, an asymptomatic phase lasting for days or weeks ensues. Once the disease has appeared, patients alternate between asymptomatic and symptomatic phases and both the severity and frequency of the disorder is shown to be dependent on their internal rhythm in relation to the outside world [6].

    Skin
    Photosensitivity
    • Skin Photosensitivity It generally follows shortly after loss or removal of a person’s eyes, [7] as the photosensitive ganglion cells in the retina are also removed.[symptoma.com]
    • It generally follows shortly after loss or removal of a person’s eyes, [7] as the photosensitive ganglion cells in the retina are also removed.[en.wikipedia.org]
    • It generally follows shortly after loss or removal of a person’s eyes, [9] as the photosensitive ganglion cells in the retina are also removed.[ipfs.io]
    • These intrinsically photosensitive retinal ganglion cells (ipRGCs) are distinct from the rods and cones responsible for vision, and they are the principal photoreceptors of the circadian system.[ 10 ] The ipRGCs convey light information directly to the[onlinelibrary.wiley.com]
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  • Eyes
  • more...
  • musculoskeletal
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  • gastrointestinal
    Nausea
    • […] cells (ipRGCs) are distinct from the rods and cones responsible for vision, and they are the principal photoreceptors of the circadian system.[ 10 ] The ipRGCs convey light information directly to the [onlinelibrary.wiley.com] more... gastrointestinal Nausea[symptoma.com]
    • Common side effects include somnolence, dizziness, fatigue, nausea, and exacerbated insomnia. 19 Tasimelteon: Tasimelteon is also an MT 1 and MT 2 receptor agonist with higher affinity for the MT 2 receptor. 20 In January 2014, the FDA approved tasimelteon[uspharmacist.com]
    • Agonists Agomelatine (Valdoxan or Thymanax; Servier Pharmaceuticals, Neuilly-sur-Seine, France)[ 40 ] Europe Treatment of major depressive episodes in adults 75 yrs of age b 25 mg/day at bedtime; dose may be doubled if symptoms do not improve after 2 wks Nausea[onlinelibrary.wiley.com]
    Diarrhea
    • The most commonly reported adverse events in the tasimelteon group were nasopharyngitis, arthralgia, headache, diarrhea , and constipation. 23 In summary, this small study showed that for every two patients treated with tasimelteon 20 mg daily for an[symptoma.com]
    • The most commonly reported adverse events in the tasimelteon group were nasopharyngitis, arthralgia, headache, diarrhea, and constipation. 23 In summary, this small study showed that for every two patients treated with tasimelteon 20 mg daily for an additional[uspharmacist.com]
    • Pharmaceuticals, Neuilly-sur-Seine, France)[ 40 ] Europe Treatment of major depressive episodes in adults 75 yrs of age b 25 mg/day at bedtime; dose may be doubled if symptoms do not improve after 2 wks Nausea, dizziness, headache, somnolence, insomnia, migraine, diarrhea[onlinelibrary.wiley.com]
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  • neurologic
    Insomnia
    • For patient education information, see the Mental Health Center and the Sleep Disorders Center , as well as Insomnia , Primary Insomnia , Insomnia Medications , Sleep Disorders in Women , Sleep Disorders and Aging , and Sleeplessness and Circadian Rhythm[emedicine.medscape.com]
    • The sleep disruption leads to excessive sleepiness or insomnia, or both.[hetliozpro.com]
    • […] disease Non-24-hour sleep-wake syndrome Disease definition Non-24-hour sleep-wake disorder (non-24 disorder), also known as hypernychthemeral syndrome, is a circadian rhythm sleep disorder characterized by non-synchronization to a 24-hour day leading to insomnia[orpha.net]
    Headache
    • [businessinsider.com] The most common side effects reported with Hetlioz include headache , drowsiness, and nightmares or unusual dreams.[symptoma.com]
    • The most common adverse reactions in the clinical trials were headache, increased alanine aminotransferase, nightmares or unusual dreams, upper respiratory or urinary tract infection.[prnewswire.com]
    • The most common side effects associated with HETLIOZ include headache, elevated liver enzymes (ALT), nightmares or abnormal dreams, and upper respiratory or urinary tract infection.[hetlioz.com]
    • The most common side effects experienced were headache, elevated liver enzymes, nightmares or unusual dreams, and upper respiratory or urinary tract infections.[businessinsider.com]
    • The most common side effects reported with Hetlioz include headache, drowsiness, and nightmares or unusual dreams.[ema.europa.eu]
    Confusion
    • As your sleep pattern drifts a little later every day, Non-24-Hour Sleep-Wake Rhythm can be confused with other circadian rhythm disorders.[sleepeducation.org]
    • [neurologyadvisor.com] Confusion As your sleep pattern drifts a little later every day, Non-24-Hour Sleep-Wake Rhythm can be confused with other circadian rhythm disorders.[symptoma.com]
    • People begin to develop circadian rhythm sleep disorders, and if left unchecked can lead to issues ranging from exhaustion and confusion to medical problems such as obesity, diabetes, depression, and dementia.[alaskasleep.com]
    • Create an emotional TV ad that shows unhappy, confused people being transformed into perfect beings after they take your drug. 6.[madinamerica.com]
    Difficulty Concentrating
    • You may also experience difficulty concentrating, headaches, and low energy levels while awake.[uofmhealth.org]
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  • Entire body system
    Fatigue
    • Entire body system Fatigue This results in a chronic sleep deficit, with symptoms that can mimic depression, attention deficit hyperactivity disorder, chronic fatigue syndrome, fibromyalgia, or just plain fatigue .[symptoma.com]
    • This results in a chronic sleep deficit, with symptoms that can mimic depression, attention deficit hyperactivity disorder, chronic fatigue syndrome, fibromyalgia, or just plain fatigue.[circadiansleepdisorders.org]
    • Signals from the SCN help us stay awake and counteract the effects of fatigue.[vandapharma.com]
    • Untreated Circadian Rhythm Sleep disorder may cause strained social relationships and even fatigue-related motor vehicle accidents Chronotherapy is a means of treating Circadian Rhythm Sleep disorder by initiating gradual behavioral changes that include[dovemed.com]
    • Their fatigue is similar to that of someone traveling across time zones.[bostonglobe.com]
    Excessive Daytime Sleepiness
    • Many people with ASPS complain of early morning insomnia, insufficient sleep, and excessive daytime sleepiness.[alaskasleep.com]
    • The excessive daytime sleepiness affects quality of life and patients’ ability to follow a normal daily schedule.[ema.europa.eu]
    • [en.wikipedia.org] Excessive Daytime Sleepiness Many people with ASPS complain of early morning insomnia, insufficient sleep, and excessive daytime sleepiness .[symptoma.com]
    • Although found primarily in blind individuals, it can also be seen in individuals with normal sight, and is characterized by alternating periods of insomnia and excessive daytime sleepiness .[medlink.com]
    • I was diagnosed with Non-24 Circadian Rhythm Disorder with Excessive Daytime Sleepiness at the age of 20.[drugs.com]
    Malaise
    Developmental Disabilities
    • disabilities, generally respond well to behavioral intervention Morbidity and mortality The mortality rates associated with circadian rhythms are difficult to assess.[emedicine.medscape.com]
  • more...
  • Workup

    To make the diagnosis of N24SWD and distinguish it from other sleep disorders, it is imperative to obtain a thorough patient history, especially the onset of symptoms and sleep disturbances, so that a preliminary diagnosis can be made. One of the easiest, but very effective methods for determining a circadian rhythm sleep disorder is to keep a sleep and waking log for a prolonged period of time [6]. It is important to keep a timeline of occupational and social activities during this process as well, as delayed sleep-phase syndrome may present with similar symptoms but occurs only during vacations [6]. Current diagnostic criteria for N24SWD include the mentioned signs and symptoms of sleep disturbance for at least six weeks that are confirmed by one of the following methods [6] [4] [3]:

    • Polysomography or actigraphy performed for several consecutive days on a fixed daily schedule.
    • Temperature monitoring for 24h for at least five days to observe its fluctuation.

    Treatment

    Treatment principles aim to improve daytime function and overall quality of sleep by attempting to entrain patients into the 24-hour cycle [7]. Melatonin has been suggested as the mainstay of therapy in many sleep disorders, including N24SWD. Higher doses (3-5 mg) for one month 1-2 hours before sleep are recommended and once a 24-hour cycle has been established, a lower dose of 0.5 mg one hour before preferred sleeping time is used, but even lower doses (20-300 μg) in later stages may be sufficient [7]. Recently, a melatonin receptor agonist, Tasimelteon, has been approved for specific therapy of N24SWD and its main benefit is minimal interaction with other endocrine molecules and receptors [11]. Sleep-promoting medications, light therapy (which is not possible in blind patients), strategic avoidance of light, timed physical activity and prescribed sleep-wake scheduling are alternative treatment modalities for sleep disorders but have shown no effect in N24SWD [10], indicating that melatonin use is the mainstay of treatment.

    Prognosis

    Although the condition is not considered as life-threatening, sleep disorders have shown to be a significant risk factor for the development of obesity, diabetes, breast and colorectal cancer, but also depression [11], which is why their early recognition is detrimental. Unfortunately, N24SWD may be difficult to diagnose due to its disease course that comprises both symptomatic and asymptomatic stages [6]. However, irregular sleeping and waking patterns invariably reduce the ability to function on a daily basis, including social and occupational activities and many patients report symptoms at some point. Also, the continuation of melatonin therapy in blind patients is an important aspect as the symptoms of the disorder return once the melatonin therapy is stopped.

    Complications

    Depression
    • At the age of 40 years, the patient’s sleep–wake cycle began to extend without exacerbation of depressive symptoms.[dovepress.com]
    • Apart from the social stress or depression that living with this disorder may cause, the disorder itself is not considered harmful.[sleepassociation.org]
    • Complications Depression At the age of 40 years, the patient’s sleep–wake cycle began to extend without exacerbation of depressive symptoms.[symptoma.com]
    • This leads to a variety of symptoms such as sleeping at odd hours, fuzzy thinking, depression and learning difficulties.[chronobiology.com]
    • Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E (1999) Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression.[journals.plos.org]
    Sleep Deprivation
    • Causes Sleep Deprivation There are many long-term health effects of sleep deprivation .[symptoma.com]
    • There are many long-term health effects of sleep deprivation.[circadiansleepdisorders.org]
    • This can lead to chronic sleep deprivation, lowered immune response, depression, social isolation, unemployment, financial problems, as well as a potential increase in risk of cancer & diabetes.[reddit.com]
    • Shift work results in a circadian sleep disorder in those people in whom the body clocks cannot shift sufficiently, and the person suffers chronic sleep deprivation.[circadiansleepdisorders.org]
    • Attempts to fight against this internal rhythm and sleep on a normal schedule result in severe and cumulative sleep deprivation.[mottchildren.org]
    Hallucinations
    • The episodes can come on quickly and are often associated with excessive eating, wild sexual urges, hallucinations, disorientation and even flu-like symptoms.[cbsnews.com]
    • [cbsnews.com] "Can Sleep Deprivation Cause Hallucinations " .[symptoma.com]
    • "Can Sleep Deprivation Cause Hallucinations" .[en.wikipedia.org]
    Lymphoma
    • There has also been a report of N24 following chemotherapy for Hodgkin’s lymphoma.[rarediseases.org]
    Aneurysm
    Craniopharyngioma

    Etiology

    In blind people, which comprise the majority of N24SWD cases, the cause seems to be the inability of the retina to convey light stimulus to the higher structures responsible for circadian rhythm, thus impeding the normal daily cycle [2]. Other reports suggest that psychosocial factors [2], brain trauma [9], and mutations in the CK1ε gene as possible etiologies [5], but the complete pathophysiological mechanism remains unknown.

    Causes

    Sleep Deprivation
    • Causes Sleep Deprivation There are many long-term health effects of sleep deprivation .[symptoma.com]
    • There are many long-term health effects of sleep deprivation.[circadiansleepdisorders.org]
    • This can lead to chronic sleep deprivation, lowered immune response, depression, social isolation, unemployment, financial problems, as well as a potential increase in risk of cancer & diabetes.[reddit.com]
    • Shift work results in a circadian sleep disorder in those people in whom the body clocks cannot shift sufficiently, and the person suffers chronic sleep deprivation.[circadiansleepdisorders.org]
    • Attempts to fight against this internal rhythm and sleep on a normal schedule result in severe and cumulative sleep deprivation.[mottchildren.org]

    Epidemiology

    Although the condition is considered to be rare, current prevalence rates in the population are unknown [2]. The most significant risk factor for N24SWD, however, is blindness, as about 50% of all individuals who suffer from total vision loss have a diagnosis of N24SWD [7]. Isolated reports have shown that 28% of cases have some preexisting psychiatric disorder, suggesting that it may be an additional risk factor [1]. The onset of N24SWD is documented across all age groups, including infants, middle-aged adults and elderly [6]. At this moment, a familial pattern of inheritance of the disease has not been recognized. Also, this disorder is more commonly seen in males.

    Sex distribution
    Age distribution

    Pathophysiology

    Under physiological conditions, the biological clock of humans (known as circadian rhythm) is designed to function in 24-hour cycles and is able to do so under tight regulation [2] [6]. One of the principal stimuli that initiate this machinery is natural light, which is conveyed by the retina into structures such as the epiphysis (pineal gland), the sympathetic plexuses of the spinal cord and the suprachiasmatic nucleus located in the hypothalamus, the main site where circadian rhythm is regulated. Depending on the amount of natural light, various concentrations of melatonin are secreted from the pineal gland through the activity of the suprachiasmatic nucleus (SCN) [7]. During daytime, the SCN will inhibit the production of melatonin, while this inhibitory effect is abolished during the night, so that sleep is not interrupted [7]. This regulatory system keeps the circadian clock in check throughout life, but in the setting of blindness and absence of light stimuli, the SCN and pineal gland do not receive adequate stimuli, resulting in a disorganized activity and appearance of disturbed sleep [2]. In addition to light deprivation, mutations of the CK1ε, with its role of phosphorylation of proteins responsible for regulation of the circadian rhythm, has been brought into discussion when attempting to find the exact mechanism of disease [5].

    Prevention

    Despite the fact that the mechanism of disease in blind people has been established, the exact trigger of N24SWD remains unknown and current preventive strategies do not exist.

    Summary

    Non-24 hour sleep-wake disorder (N24SWD) is one of the types of circadian rhythm sleep disorders that is distinguished by chronic disturbances of sleep and wake times that breach the physiological 24-hour cycle regulated by the brain [7]. Because of the fact that almost 50% of blind individuals are diagnosed with N24SWD, the underlying cause seems to be the absence of light perception that consequently disrupts the transmission of retinal signaling to the pineal gland and suprachiasmatic nucleus [2], while the mechanism of N24SWD in sighted people remains unclear [7]. Some reports show that alterations in genes that are involved in transcription of genes responsible for maintenance of the circadian rhythm, such as Casein Kinase I Epsilon (CK1ε), may also be contributing factors to the pathogenesis [5]. In most cases, the sleep-wake patterns don't follow the 24-hour circadian rhythm, causing significant issues with both initiations of sleep and awakening [6]. Insomnia and extreme fatigue may arise, which often have a major impact on daily life. Because of progressive changes in sleep patterns that eventually become "phased" with normal daily rhythm, both symptomatic and asymptomatic phases are reported in patients [7]. To make the diagnosis, clinical criteria including sleeping and waking difficulties for at least six weeks and continuous delays in the onset of sleep that results in the deviation from the 24-hour sleep-wake pattern are necessary [6]. Sleep logs, polysomnography, and actigraphy are valuable methods to confirm N24SWD and distinguish it from other sleep disorders, whereas continuous measurement of body temperature has also been proven as a valid diagnostic procedure [3]. Various treatment strategies have been implemented, but the first drug for treatment of N24SWD, tasimelteon, was recently approved and recommended in blind individuals suffering from this disorder [10]. Tasimelteon is a melatonin receptor agonist that was tailored for individuals with impaired melatonin secretion as a result of inadequate stimulation by light perception through the retina [11], while other therapeutic strategies, such as phototherapy, sleep-promoting drugs, timed physical activity and several other have not shown significant effects [10].

    Patient Information

    Non-24 hour sleep-wake disorder (N24SWD) is a rare but severely debilitating disease of altered sleep and waking patterns that most predominantly occurs in blind people, but cases in sighted people have been documented as well. In individuals who suffer from total vision loss, the cause is presumed to be a lack of brain stimulation by natural light conveyed by the eyes. Normally, the daily cycle of humans is regulated by various structures in the brain that act on the basis of exposure to light (or darkness) and the term "circadian rhythm" is used to describe the 24-hour biological clock that is maintained by the body. One of the most important substances secreted by a small gland in the brain called epiphysis (or pineal gland) is melatonin, which serves to either facilitate sleep during the night or promote wakefulness during the day and the hypothalamus is the part of the brain that regulates its activity. Melatonin is secreted in response to light perceived by the eyes and the retina, but in blind individuals, light signals are not present, thus leading to disruption of the biological clock and the appearance of altered sleeping patterns. A characteristic feature of N24SWD is that the daily biological cycle is prolonged to 25 (rarely to 27) hours, resulting in progressive changes when it comes to going to sleep and waking up, eventually causing extreme fatigue and insomnia. In this "symptomatic" phase, extreme fatigue will occur and mandate a very long sleep after some period of time (14-24 hours), followed by "asymptomatic" phase, in which little or no changes in sleeping habits will be observed. The onset of the disease has been reported across all ages, whereas gender predilection has not been established. To make the diagnosis of N24SWD, symptoms must persist for at least six weeks and diagnostic procedures such as polysomnography or actigraphy may be used for confirmation. The mainstay of therapy is the administration of melatonin before desired sleeping time, in order to entrain the individual back into the 24-hour cycle and maintain its ability to perform daily social and occupational activities. A melatonin receptor agonist, tasimelteon, has been recently introduced into medical practice and is designed specifically for treatment of N24SWD. The prognosis of patients is good with an early diagnosis and appropriate therapy, but sleep disorders, in general, are known to increase the risk for numerous diseases, including cardiovascular, malignant and diabetes. For this reason, it is imperative to recognize this condition as soon as possible, so that patients may continue their daily activities without significant limitations.

    Other symptoms

    No Autism
    • [webmd.com] It also occurs in some children with developmental disorders, including autism spectrum disorders.[symptoma.com]
    • Other causes include: Developmental brain disorders, including autism spectrum disorder Brain damage from head injury or tumors Symptoms When you have Non-24 you feel sleepy during the day and have trouble falling asleep at night.[webmd.com]
    • It also occurs in some children with developmental disorders, including autism spectrum disorders.[circadiansleepdisorders.org]
    • In pervasive developmental disorders such as autism a relatively high frequency of occurrence of N24 and other circadian rhythm and sleep disorders has been noted.[rarediseases.org]
    • Circadian rhythm disturbances have been reported in children with cancer and may be seen following injury to the hypothalamus or brainstem in those with endocrine dysfunction or following cranial irradiation. [3] In children with autism spectrum disorder[emedicine.medscape.com]
    Adenoma
    • […] have been reported in children with cancer and may be seen following injury to the hypothalamus or brainstem in those with endocrine dysfunction or following cranial irradiation. [3] In children with autism spectrum disorder [emedicine.medscape.com] Adenoma[symptoma.com]
    • […] and the etiology of their circadian disorder is less well understood. [13] At least one case of a sighted person developing non-24 was preceded by head injury; [14] another patient diagnosed with the disorder was later found to have a "large pituitary adenoma[en.wikipedia.org]
    • […] and the etiology of their circadian disorder is less well understood. [19] At least one case of a sighted person developing non-24 was preceded by head injury; [20] another patient diagnosed with the disorder was later found to have a "large pituitary adenoma[ipfs.io]
    Pituitary Adenoma
    • […] found to have a "large pituitary adenoma [ipfs.io] Cervicitis The SCN also sends a nerve signal that follows a complex poly-synaptic pathway via the cervical spinal ganglia to regulate the activity of the pineal gland, which is responsible for the production[symptoma.com]
    • adenoma that involved the optic chiasma ". [1] Thus the problem appears to be neurological.[en.wikipedia.org]
    Cervicitis
    • The SCN also sends a nerve signal that follows a complex poly-synaptic pathway via the cervical spinal ganglia to regulate the activity of the pineal gland, which is responsible for the production of melatonin.[symptoma.com]
    Learning Difficulties
    • This leads to a variety of symptoms such as sleeping at odd hours, fuzzy thinking, depression and learning difficulties.[chronobiology.com]
    • [sleepassociation.org] This leads to a variety of symptoms such as sleeping at odd hours, fuzzy thinking, depression and learning difficulties.[symptoma.com]
    No Family History
    • Younger onset age of BD and family history of suicide were associated with presence of CRSWD in BD patients.[journals.plos.org]
    • history is common in 40% of those with Circadian Rhythm Sleep Disorder It is important to note that having a risk factor does not mean that one will get the condition.[dovemed.com]
    Chemotherapy
    • There has also been a report of N24 following chemotherapy for Hodgkin’s lymphoma.[rarediseases.org]

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    References

    1. Hayakawa T, Uchiyama M, Kamei Y, et al. Clinical analyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases. Sleep. 2005;28(8):945-952.
    2. Uchiyama M, Shibui K, Hayakawa T, et al. Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome. Sleep. 2002; 25(1):83-8.
    3. Shibui K, Okawa M, Uchiyama M, et al. Continuous measurement of temperature in non-24 hour sleep–wake syndrome. Psychiatry Clin Neurosci. 1998;52 (2): 236–7.
    4. Shibui K, Uchiyama M, Iwama H, Ozaki S, Takahashi K, Okawa M. Periodic fatigue symptoms due to desynchronization in a patient with non-24-h sleep–wake syndrome. Psychiatry Clin Neurosci. 1998;52 (5): 477–81.
    5. Takano A, Uchiyama M, Kajimura N, et al. A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology. 2004;29(10):1901–1909.
    6. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
    7. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. Sleep. 2007;30(11):1445–1459.
    8. Zhu L, Zee PC. Circadian Rhythm Sleep Disorders. Neurol clin. 2012;30(4):1167-1191.
    9. Boivin DB, James FO, Santo JB, Caliyurt O, Chalk C. Non-24-hour sleep-wake syndrome following a car accident. Neurology. 2003 Jun 10;60(11):1841-3.
    10. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2015;11(10):1199-1236.
    11. Lavedan C, Forsberg M, Gentile AJ. Tasimelteon: A selective and unique receptor binding profile. Neuropharmacol. 2015;91:142–147.



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