Non-24-hour sleep–wake disorder

"9-24" redirects here. For the day, see September 24.
Non-24-hour sleep–wake disorder
Classification and external resources
Specialty neurology
ICD-10 G47.24
ICD-9-CM 327.34
MeSH D021081

Non-24-hour sleep–wake disorder (non-24), is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in society."[1] Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light/dark cycle in nature.

The sleep pattern can be quite variable. People with a circadian rhythm that is quite near to 24 hours may be able to sleep on a conventional, socially acceptable schedule, that is, at night. Others, with a "daily" cycle upwards of 25 hours or more may need to adopt a sleep pattern that is congruent with their free-running circadian clock, shifting their sleep times daily, thereby often obtaining satisfactory sleep but suffering social and occupational consequences.

The majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of photic input to the circadian clock.[1] These people's brains may have normal "body clocks", but the clocks do not receive input from the eyes about environmental light levels, as that requires a functioning retina, optic nerve and visual processing center.

The disorder also occurs in sighted people for reasons that are not well understood. Their circadian rhythms are not normal, often running to more than 25 hours. Their visual systems may function normally but their brains are incapable of making the large adjustment to a 24-hour schedule.

Though often referred to as non-24, for example by the FDA,[2] the disorder is also known by the following terms:

The disorder in its extreme form is an invisible disability that can be "extremely debilitating in that it is incompatible with most social and professional obligations".[3]

Mechanisms

The internal circadian clock, located in the hypothalamus of the brain, generates a signal that normally is slightly longer (occasionally shorter) than 24 hours, on average 24 hours and 11 minutes.[4] This slight deviation is, in almost everyone, corrected by exposure to environmental time cues, especially the light–dark cycle, which reset the clock and synchronize (entrain) it to the 24-hour day. Morning light exposure resets the clock earlier, and evening exposure resets it later, thereby bracketing the rhythm to an average 24-hour period. If normal people are deprived of external time cues (living in a cave or artificial time-isolated environment with no light), their circadian rhythms will "free-run" with a cycle of a little more (occasionally less) than 24 hours, expressing the intrinsic period of each individual's circadian clock. The circadian rhythms of individuals with non-24 can resemble those of experimental subjects living in a time-isolated environment, even though they are living in normal society.

The circadian clock modulates many physiological rhythms.[5] The most easily observed of these is the propensity for sleep and wake; thus, people with non-24 experience symptoms of insomnia and daytime sleepiness (similar to "jet lag") when their endogenous circadian rhythms drift out of synchrony with the social/solar 24-hour day and they attempt to conform to a conventional schedule. Eventually, their circadian rhythms will drift back into normal alignment, and symptoms temporarily resolve, but then their clocks drift out of alignment again. Thus the overall pattern involves recurring symptoms on a weekly or monthly basis, depending on the length of the internal circadian cycle. For example, an individual with a circadian period of 24.5 hours would drift 30 minutes later each day and would be maximally misaligned every 48 days. If patients set their own schedule for sleep and wake, aligned to their endogenous non-24 period (as is the case for most sighted patients with this disorder), symptoms of insomnia and wake-time sleepiness are much reduced. However, such a schedule is incompatible with most occupations and social relationships.

Characteristics

Sighted

In people with non-24, the body essentially insists that the length of a day (and night) is appreciably longer (or, very rarely, shorter) than 24 hours and refuses to adjust to the external light–dark cycle. This makes it impossible to sleep at normal times and also causes daily shifts in other aspects of the circadian rhythms such as peak time of alertness, body temperature minimum, metabolism and hormone secretion. Non-24-hour sleep–wake disorder causes a person's sleep–wake cycle to move around the clock every day, to a degree dependent on the length of the cycle, eventually returning to "normal" for one or two days before "going off" again. This is known as free-running sleep.

People with the disorder may have an especially hard time adjusting to changes in "regular" sleep–wake cycles, such as vacations, stress, evening activities, time changes like daylight saving time, travel to different time zones, illness, medications (especially stimulants or sedatives), changes in daylight hours in different seasons, and growth spurts, which are typically known to cause fatigue. They also show lower sleep propensity after total sleep deprivation than do normal sleepers.[6]

Non-24 can begin at any age, not uncommonly in childhood. It is sometimes preceded by delayed sleep phase disorder.[3]

Most people with this disorder find that it severely impairs their ability to function in school, in employment and in their social lives. Typically, they are "partially or totally unable to function in scheduled activities on a daily basis, and most cannot work at conventional jobs".[1] Attempts to keep conventional hours by people with the disorder generally result in insomnia (which is not a normal feature of the disorder itself) and excessive sleepiness,[1] to the point of falling into microsleeps, as well as myriad effects associated with acute and chronic sleep deprivation. Sighted people with non-24 who force themselves to live on a normal workday "are not often successful and may develop physical and psychological complaints during waking hours, i.e. sleepiness, fatigue, headache, decreased appetite, or depressed mood. Patients often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."[6]

Blind

It has been estimated that non-24 occurs in more than half of all people who are totally blind.[7][8] The disorder can occur at any age, from birth onwards. 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.

Without light to the retina, the suprachiasmatic nucleus (SCN), located in the hypothalamus, is not cued each day to synchronize the circadian rhythm to the 24-hour social day, resulting in non-24 for many totally blind individuals.[7] Non-24 is rare among visually impaired patients who retain at least some light perception. Researchers have found that even minimal light exposure at night can affect the body clock.[10]

Symptoms

Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include:

Prevalence

There are an estimated 140,000 people with N24 – both sighted and blind – in the European Union, a total prevalence of approximately 3 per 10,000, or 0.03%.[14] It is unknown how many individuals with this disorder do not seek medical attention, so incidence may be higher. The European portal for rare diseases, Orphanet, lists Non-24 as a rare disease by their definition: fewer than 1 affected person for every 2000 population.[15] The US National Organization for Rare Disorders (NORD) lists Non-24 as a rare disease by its definition.

Sighted

As of 2005, there had been fewer than 100 cases of sighted people with non-24 reported in the scientific literature.[16]

Blind

While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect more totally blind individuals than sighted. It has been estimated by researchers that of the 1.3 million blind people in the U.S.,[17] 10% have no light perception at all.[18] Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, suffer from non-24.[8]

Causes

Sighted

Sighted people with non-24 appear to be more rare than blind people with the disorder 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 that involved the optic chiasma".[1] Thus the problem appears to be neurological. Specifically, it is thought to involve abnormal functioning of the suprachiasmatic nucleus (SCN) in the hypothalamus.[21] Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder.[19] "Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy".[3] According to the American Academy of Sleep Medicine (AASM): "Patients with free-running (FRD) rhythms are thought to reflect a failure of entrainment".[22]

There have been several experimental studies of sighted people with the disorder. McArthur et al. reported treating a sighted patient who "appeared to be subsensitive to bright light".[23] In other words, the brain (or the retina) does not react normally to light (people with the disorder may or may not, however, be unusually subjectively sensitive to light; one study found that they were more sensitive than the control group.[6]) In 2002 Uchiyama et al. examined five sighted non-24 patients who showed, during the study, a sleep–wake cycle averaging 25.12 hours.[24] That is appreciably longer than the 24.02-hour average shown by the control subjects in that study, which was near the average innate cycle for healthy adults of all ages: the 24.18 hours found by Charles Czeisler.[4] The literature usually refers to a "one to two hour" delay per 24-hour day (i.e. a 25–26 hour cycle).

Uchiyama et al. had earlier determined that sighted non-24 patients' minimum core body temperature occurs much earlier in the sleep episode than the normal two hours before awakening. They suggest that the long interval between the temperature trough and awakening makes illumination upon awakening virtually ineffective,[25] as per the phase response curve (PRC) for light.

In their clinical review in 2007, Okawa and Uchiyama reported that people with Non-24 have a mean habitual sleep duration of nine to ten hours and that their circadian periods average 24.8 hours.[6]

Blind

As stated above, the majority of patients with Non-24 are totally blind, and the failure of entrainment is explained by the loss of photic input to the circadian clock. Non-24 is rare among visually impaired patients who retain at least some light perception; even minimal light exposure can synchronize the body clock.[10] A few cases have been described in which patients are subjectively blind, but are normally entrained and have an intact response to the suppressing effects of light on melatonin secretion, indicating preserved neural pathways between the retina and hypothalamus.[18][26]

Diagnosis

Sighted

The diagnosis is typically made based on a history of persistently delayed sleep onset that follows a non-24-hour pattern. In their large series, Hayakawa reported the average day length was 24.9 ± 0.4 hours (range 24.4–26.5).[16] There may be evidence of "relative coordination" with the sleep schedule becoming more normal as it coincides with the conventional timing for sleep. Most reported cases have documented a non-24-hour sleep schedule with a sleep diary (see below)[27] or actigraphy.[16] In addition to the sleep diary, the timing of melatonin secretion[23] or core body temperature rhythm[28][29] has been measured in a few patients who were enrolled in research studies, confirming the endogenous generation of the non-24-hour circadian rhythm.

Blind

The disorder can be considered very likely in a totally blind person with periodic insomnia and daytime sleepiness, although other causes for these common symptoms need to be ruled out. In the research setting, the diagnosis can be confirmed, and the length of the free-running circadian cycle can be ascertained, by periodic assessment of circadian marker rhythms, such as the core body temperature rhythm,[30] the timing of melatonin secretion,[8][31] or by analyzing the pattern of the sleep–wake schedule using actigraphy.[32] Most recent research has used serial measurements of melatonin metabolites in urine or melatonin concentrations in saliva. These assays are not currently available for routine clinical use.

Treatment

A sleep diary with nighttime in the middle and the weekend in the middle, to better notice trends

Sighted

Enforcing a 24-hour sleep–wake schedule using alarm clocks or family interventions is often tried but usually unsuccessful. Bright light exposure on awakening to counteract the tendency for circadian rhythms to delay, similar to the treatment for delayed sleep phase disorder,[6] and seasonal affective disorder (SAD) has been found to be effective in some cases,[33][34][35] as has melatonin administration in the subjective late afternoon or evening.[23][36][37][38] Light therapy involves at least 20 minutes of exposure to 3000 to 10000 lux light intensity. Going outside on a bright sunny day can accomplish the same benefit as special light fixtures (light boxes). Bright light therapy combined with the use of melatonin as a chronobiotic and avoidance of light before bedtime may be the most effective treatment. Melatonin administration shifts circadian rhythms according to a phase response curve (PRC) that is essentially the inverse of the light PRC. When taken in the late afternoon or evening, it resets the clock earlier; when taken in the morning, it shifts the clock later. Therefore, successful entrainment depends on the appropriate timing of melatonin administration. The accuracy needed for successfully timing the administration of melatonin requires a period of trial and error, as does the dosage. In addition to natural fluctuations within the circadian rhythm, seasonal changes including temperature, hours of daylight, light intensity and diet are likely to affect the efficacy of melatonin and light therapies since these exogenous zeitgebers would compete for hormonal homoeostasis. Further to this there are unforeseen disruptions to contend with even when a stabilised cycle is achieved; such as travel, exercise, stress, alcohol or even the use of light emitting technology close to a subjective evening/night.

Hypnotics and/or stimulants (to promote sleep and wakefulness, respectively) have sometimes been used. Typically a sleep diary is requested to aid in evaluation of treatment, though the emergence of modern actigraphy devices can also assist in the logging of sleep data. Additionally, graphs can now be generated using mobile phone applications, utilising internal accelerometers which are present in most smartphones in use today. The graphs and basic sleep diary records can be shared with a physician. However, due to the lack of clinical accuracy they should not be used for diagnosis, but instead to monitor the cycle and general progress of any medications in use.

Blind

In the 1980s and 1990s, several trials of melatonin administration to totally blind individuals without light perception produced improvement in sleep patterns, but it was unclear at that time if the benefits were due to entrainment from light cues.[39][40][41][42] Then, using endogenous melatonin as a marker for circadian rhythms, several research groups showed that appropriately timed melatonin administration could entrain free-running rhythms in the totally blind.[43][44] For example, Sack et al.[43] found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained. When the dose was gradually reduced to 0.5 mg in three of the subjects, entrainment persisted. Subsequently, it was shown that treatment initiated with the 0.5 mg dose produced entrainment.[45][46] One subject who failed to entrain at a higher dose was successfully entrained at a lower dose.[47] A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion.[6]

Products containing melatonin are available as dietary supplements in the United States[48] and Canada, available over the counter. These "supplements" do not require FDA approval. As prescription drugs may be prescribed off-label, treatment recommendations for non-24 in the blind may vary.

There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s.[49] In 2005 Ramelteon (Rozerem®) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia treatment in adults.[50] Melatonin in the form of prolonged release (trade name Circadin®) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years and older, for primary insomnia.[51] Tasimelteon (trade name Hetlioz®) received FDA-approval in January 2014 for persons diagnosed with non-24.[52] TIK-301 (Tikvah Therapeutics, Atlanta, USA) has been in phase II clinical trial in the United States since 2002 and the FDA granted it orphan drug designation in May 2004, for use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception as well as individuals with tardive dyskinesia.[53]

History

The ability of melatonin administration to entrain free-running rhythms was first demonstrated by Redman, et al. in 1983 in rats who were maintained in a time-free environment.[54]

Sighted

The first report and description of a case of non-24, a man living on 26-hour days, was "A man with too long a day" by Ann L. Eliott et al. in November 1970.[55] The related and more common delayed sleep phase disorder was not described until 1981.

Blind

In the first detailed study of non-24 in a blind subject, researchers reported on a 28-year-old male who had a 24.9-hour rhythm in sleep, plasma cortisol, and other parameters. Even while adhering to a typical 24-hour schedule for bedtime, rise time, work, and meals, the man’s body rhythms continued to shift.[56]

Research directions

Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing.[57] It has been suggested that there are non-photic time cues that are important for maintaining entrainment, but these cues await to be characterized.

Classifications

Since 1979, the disorder has been recognized by the American Academy of Sleep Medicine:

Since 2005, the disorder has been recognized by name in the U.S. National Center for Health Statistics and the U.S. Centers for Medicare and Medicaid Services in their adaptation and extension of the WHO's International Statistical Classification of Diseases and Related Health Problems (ICD):

Since 2013, the disorder has been recognized by the American Psychiatric Association:

See also

References

Notes

  1. 1 2 3 4 5 6 7 8 9 American Academy of Sleep Medicine (2001). The International Classification of Sleep Disorders, Revised (ICSD-R) (PDF). ISBN 0-9657220-1-5. Retrieved 30 April 2016.
  2. ↑ "Peripheral and Central Nervous System Drugs Advisory Committee Meeting. Tasimelteon." (PDF). FDA. November 14, 2013. Retrieved May 7, 2014.
  3. 1 2 3 Oren, Dan A.; Thomas A. Wehr (December 10, 1992). "Hypernyctohemeral Syndrome after Chronotherapy for Delayed Sleep Phase Syndrome". New England Journal of Medicine (Letter to the Editor) (Massachusetts Medical Society) 327 (24): 1762. doi:10.1056/NEJM199212103272417. PMID 1435929.
  4. 1 2 "Human Biological Clock Set Back an Hour". Harvard University Gazette. July 15, 1999. Retrieved December 9, 2007.
  5. 1 2 Fadden, James S.P.; Sharkey, Katherine. "Non-24-Hour Sleep-Wake Disorder". National Organization for Rare Disorders. Retrieved 6 May 2016.
  6. 1 2 3 4 5 6 7 8 9 Okawa M, Uchiyama M (December 2007). "Circadian rhythm sleep disorders: characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep–wake syndrome". Sleep Med Rev 11 (6): 485–96. doi:10.1016/j.smrv.2007.08.001. PMID 17964201. as PDF
  7. 1 2 "Circadian Rhythm Sleep Disorder" (PDF). American Academy of Sleep Medicine. 2008. Retrieved August 8, 2009.
  8. 1 2 3 Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H (July 1992). "Circadian rhythm abnormalities in totally blind people: incidence and clinical significance". J. Clin. Endocrinol. Metab. 75 (1): 127–34. doi:10.1210/jc.75.1.127. PMID 1619000.
  9. ↑ Uchimaya, Makoto; Lockley, Steven W. (2009). "Non-24-Hour Sleep–wake Syndrome in Sighted and Blind Patients". Sleep Med Clin 4 (2): 195–211. doi:10.1016/j.jsmc.2009.02.002.
  10. 1 2 Zeitzer JM, Dijk DJ, Kronauer R, Brown E, Czeisler C (August 2000). "Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression". J. Physiol. (Lond.) 526 (Pt 3): 695–702. doi:10.1111/j.1469-7793.2000.00695.x. PMC 2270041. PMID 10922269.
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  17. ↑ "Blindness Statistics". National Federation of the Blind. Retrieved October 27, 2011.
  18. 1 2 Czeisler CA, Shanahan TL, Klerman EB, et al. (January 1995). "Suppression of melatonin secretion in some blind patients by exposure to bright light". N. Engl. J. Med. 332 (1): 6–11. doi:10.1056/NEJM199501053320102. PMID 7990870.
  19. 1 2 El-Ad, Baruch (April 9, 2009). "Circadian rhythm sleep disorder: free-running type" (Clinical Summary). MedLink Neurology. Retrieved August 8, 2009. (search, upper left, for "non-24")
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    See also subsequent:
    Stores G (2007). "Clinical diagnosis and misdiagnosis of sleep disorders". J. Neurol. Neurosurg. Psychiatr. 78 (12): 1293–7. doi:10.1136/jnnp.2006.111179. PMC 2095611. PMID 18024690.
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  23. 1 2 3 McArthur AJ, Lewy AJ, Sack RL (1996). "Non-24-hour sleep–wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment". Sleep 19 (7): 544–53. PMID 8899933.
  24. ↑ Uchiyama M, Shibui K, Hayakawa T, Kamei Y, Ebisawa T, Tagaya H, Okawa M, Takahashi K (2002). "Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep–wake syndrome". Sleep 25 (1): 83–88. PMID 11833864.
  25. ↑ Uchiyama, Makoto; Okawa, Masako; Shibui, Kayo; Kim, Keiko; Tagaya, Hirokuni; Kudo, Yoshihisa; Kamei, Yuichi; Hayakawa, Tatsuro; Urata, Jujiro; Takahashi, Kiyohisa (2000). "Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase disorder and non-24-hour sleep–wake syndrome in humans". Neuroscience Letters 294 (2): 101–104. doi:10.1016/S0304-3940(00)01551-2. PMID 11058797.
  26. ↑ Klerman EB, Shanahan TL, Brotman DJ, Rimmer DW, Emens JS, Rizzo JF, 3rd; et al. (2002). "Photic resetting of the human circadian pacemaker in the absence of conscious vision". J Biol Rhythms 7 (6): 548–555. doi:10.1177/0748730402238237.
  27. ↑ Akaboshi S, Inoue Y, Kubota N, Takeshita K (2000). "Case of a mentally retarded child with non-24 hour sleep–wake syndrome caused by deficiency of melatonin secretion". Psychiatry & Clinical Neurosciences 54 (3): 379–380. doi:10.1046/j.1440-1819.2000.00723.x.
  28. ↑ Kokkoris CP, Weitzman ED, Pollak CP, Spielman AJ, Czeisler CA, Bradlow H (1978). "Long-term ambulatory temperature monitoring in a subject with a hypernychthemeral sleep–wake cycle disturbance". Sleep 1 (2): 177–190. PMID 756061.
  29. ↑ Shibui K, Okawa M, Uchiyama M, Ozaki S, Kamei Y, Hayakawa T, et al. (1998). "Continuous measurement of temperature in non-24 hour sleep–wake syndrome". Psychiatry and clinical neurosciences 52 (2): 236–7. doi:10.1111/j.1440-1819.1998.tb01050.x. PMID 9628171.
  30. ↑ Klein T, Martens H, Dijk DJ, Kronauer RE, Seely EW, Czeisler CA (1993). "Circadian sleep regulation in the absence of light perception: chronic non-24-hour circadian rhythm sleep disorder in a blind man with a regular 24-hour sleep–wake schedule". Sleep 16 (4): 333–43. PMID 8341894.
  31. ↑ Lewy AJ, Newsome DA (1983). "Different types of melatonin circadian secretory rhythms in some blind subjects". J Clin Endocrinol Metab 56 (6): 1103–1107. doi:10.1210/jcem-56-6-1103. PMID 6841552.
  32. ↑ Emens J, Lewy AJ, Laurie AL, Songer JB (2010). "Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods". Journal of Biological Rhythms 25 (5): 381–384. doi:10.1177/0748730410379080. PMID 20876818.
  33. ↑ Watanabe T, Kajimura N, Kato M, Sekimoto M, Hori T, Takahashi K (2000). "Case of a non-24 h sleep–wake syndrome patient improved by phototherapy". Psychiatry & Clinical Neurosciences 54 (3): 369–370. doi:10.1046/j.1440-1819.2000.00719.x.
  34. ↑ Shibui K, Uchiyama M, Iwama H, Ozaki S, Takahashi K, Okawa M (1998). "Periodic fatigue symptoms due to desynchronization in a patient with non-24-h sleep–wake syndrome". Psychiatry & Clinical Neurosciences 52 (5): 477–81. doi:10.1046/j.1440-1819.1998.00424.x. PMID 10215008.
  35. ↑ Hoban TM, Sack RL, Lewy AJ, Miller LS, Singer CM (1989). "Entrainment of a free-running human with bright light?". Chronobiol Int. 6 (4): 347–353. doi:10.3109/07420528909056941.
  36. ↑ Dagan Y, Ayalon L (2005). "Case study: psychiatric misdiagnosis of non-24-hours sleep–wake schedule disorder resolved by melatonin". J Am Acad Child Adolesc Psychiatry 44 (12): 1271–1275. doi:10.1097/01.chi.0000181040.83465.48. PMID 16292119.
  37. ↑ Mukai M, Uchimura N, Takeuchi N, Waseda Y, Takaishi J, Sakamoto T, et al. (2000). "Therapeutic progress of two sibling cases exhibiting sleep–wake rhythm disorder". Psychiatry & Clinical Neurosciences 54 (3): 354–355. doi:10.1046/j.1440-1819.2000.00712.x.
  38. ↑ Siebler M, Steinmetz H, Freund HJ (1998). "Therapeutic entrainment of circadian rhythm disorder by melatonin in a non-blind patient". Journal of neurology 245 (6–7): 327–8. doi:10.1007/s004150050228. PMID 9669484.
  39. ↑ Arendt J, Aldhous M, Wright J (1988). "Synchronisation of a disturbed sleep–wake cycle in a blind man by melatonin treatment". Lancet 331 (8588): 772–773. doi:10.1016/S0140-6736(88)91586-3.
  40. ↑ Folkard S, Arendt J, Aldhous M, Kennett H (1990). "Melatonin stabilises sleep onset time in a blind man without entrainment of cortisol or temperature rhythms". Neuroscience Letters 113 (2): 193–8. doi:10.1016/0304-3940(90)90302-P. PMID 2377316.
  41. ↑ Lapierre O, Dumont M (1995). "Melatonin treatment of a non-24-hour sleep–wake cycle in a blind retarded child". Biological Psychiatry 38 (2): 119–22. doi:10.1016/0006-3223(95)00072-O. PMID 7578644.
  42. ↑ Tzischinsky O, Pal I, Epstein R, Dagan Y, Lavie P (1992). "The importance of timing in melatonin administration in a blind man". Journal of Pineal Research 12 (3): 105–8. doi:10.1111/j.1600-079X.1992.tb00035.x. PMID 1507054.
  43. 1 2 Sack RL, Brandes RW, Kendall AR, Lewy AJ (2000). "Entrainment of free-running circadian rhythms by melatonin in blind people". New England Journal of Medicine 343 (15): 1070–1077. doi:10.1056/NEJM200010123431503. PMID 11027741.
  44. ↑ Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. (2000). "Melatonin administration can entrain the free-running circadian system of blind subjects". Journal of Endocrinology 164 (1): R1–6. doi:10.1677/joe.0.164R001. PMID 10607943.
  45. ↑ Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL (2001). "Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin". Brain Research 918 (1–2): 96–100. doi:10.1016/S0006-8993(01)02964-X. PMID 11684046.
  46. ↑ Hack LM, Lockley SW, Arendt J, Skene DJ (2003). "The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects". Journal of Biological Rhythms 18 (5): 420–9. doi:10.1177/0748730403256796. PMID 14582858.
  47. ↑ Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA (2002). "Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period". Chronobiology International 19 (3): 649–658. doi:10.1081/CBI-120004546. PMID 12069043.
  48. ↑ "Experts compared, sleep tips, jet lag, seasonal affective disorder". Melatonin.com. Retrieved February 10, 2012.
  49. ↑ Rajaratnam, S. M. W., Cohen, D. A., Rogers, N. L. (2009). "Melatonin and Melatonin Analogues". Sleep Medicine Clinics 4 (2): 179–193. doi:10.1016/j.jsmc.2009.02.007.
  50. ↑ "Takeda Pharmaceuticals North America, Inc". Tpna.com. Retrieved February 10, 2012.
  51. ↑ http://www.ema.europa.eu
  52. ↑ Food and Drug Administration (January 31, 2014). "FDA NEWS RELEASE: FDA approves Hetlioz: first treatment for non-24 hour sleep–wake disorder in blind individuals". FDA.
  53. ↑ Rivara, S., Mor, M., Bedini, A., Spadoni, G., Tarzia, G. (2008). "Melatonin Receptor Agonists: SAR and Application to the Treatment of Sleep–Wake Disorders". Current Topics in Medicinal Chemistry 8 (11): 954–968. doi:10.2174/156802608784936719. PMID 18673165.
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  58. ↑ DSM-5 (2013), p. 390: "For ICD-9-CM, code 307.45 for all subtypes. For ICD-10-CM, code is based on subtype."

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