Non-24-hour sleep–wake disorder (non-24, N24SWD,
[ or N24) is one of several chronic ]circadian rhythm sleep disorder
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep–wake disorders (CRSWD), are a family of sleep disorders that affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise eit ...
s (CRSDs). It is defined as a "chronic steady pattern comprising ..daily delays in sleep onset and wake times in an individual living in a society".[ Symptoms result when the non-entrained ( free-running) endogenous ]circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder
Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
, depression, and traumatic brain injury
A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...
. The American Academy of Sleep Medicine
The American Academy of Sleep Medicine (AASM) is a United States professional society for the medical subspecialty of sleep medicine which includes disorders of circadian rhythms. It was established in 1975.
The organization's functions includ ...
(AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.
People with non-24 experience daily shifts in the circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
such as peak time of alertness, body temperature minimum, metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
and hormone
A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
secretion. These shifts do not align with the natural light–dark cycle. 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. 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
Daylight saving time (DST), also referred to as daylight savings time, daylight time (Daylight saving time in the United States, United States and Daylight saving time in Canada, Canada), or summer time (British Summer Time, United Kingdom, ...
, travel to different time zones, illness, medications (especially stimulant
Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...
s or sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
s), changes in daylight hours in different seasons, and growth spurt
Human height or stature is the distance from the bottom of the feet to the top of the head in a human body, standing erect. It is measured using a stadiometer, in centimetres when using the metric system or SI system, or feet and inches when u ...
s, which are typically known to cause fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
. They also show lower sleep propensity after total sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either Chronic (medicine), chronic ...
than do normal sleepers.
Non-24 can begin at any age, not uncommonly in childhood. It is sometimes preceded by delayed sleep phase disorder.
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". Attempts to keep conventional hours by people with the disorder generally result in insomnia
Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
(which is not a normal feature of the disorder itself) and excessive sleepiness,[ to the point of falling into ]microsleep
A microsleep is a sudden temporary episode of sleep or drowsiness which may last for a few seconds where an individual fails to respond to some arbitrary sensory input and becomes unconscious.International Classification of Sleep Disorders, , pa ...
s, as well as myriad effects associated with acute and chronic sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either Chronic (medicine), chronic ...
. People with non-24 who force themselves to live to a normal workday "are not often successful and may develop physical and psychological complaints during waking hours, i.e. sleepiness, fatigue, headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
, decreased appetite
Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...
, or depressed mood. Patients often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."
In blind people
It has been estimated that non-24 occurs in more than half of all people who are totally blind. The disorder can occur at any age, from birth onwards. It generally follows shortly after loss or removal of a person's eyes, as the photosensitive ganglion cell
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence ...
s in the retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
are also removed.
Without light to the retina, the suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive r ...
(SCN), located in the hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, 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. 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.
Symptoms
People with this disorder might find it difficult to follow a regular clock scheme, as their biological clock can shift so much that they are sleepy during the day and experience insomnia during night. Another common diagnostic feature is the cyclical nature of non-24: people will experience certain periods, whether they be weeks or months, of sleeping during the day (symptomatic periods) that alternate with periods of sleeping during normal nighttime hours (asymptomatic periods).
Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either Chronic (medicine), chronic ...
and can include:
* Apraxia
Apraxia is a motor disorder caused by damage to the brain (specifically the posterior parietal cortex or corpus callosum), which causes difficulty with motor planning to perform tasks or movements. The nature of the damage determines the di ...
including ideational apraxia, ideomotor apraxia, kinetic apraxia, limb apraxia, verbal apraxia
* Cognitive dysfunction
* Difficulties concentrating
* Confusion
In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
* Depressed mood
* Diarrhea
* Extreme nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
* Extreme fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
* Hair loss
* Headaches
* Impaired balance
Balance may refer to:
Common meanings
* Balance (ability) in biomechanics
* Balance (accounting)
* Balance or weighing scale
* Balance, as in equality (mathematics) or equilibrium
Arts and entertainment Film
* Balance (1983 film), ''Balance'' ( ...
* Photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicit ...
* Joint pain
* Loss of muscle coordination (ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
)
* Menstrual irregularities
* Muscle pain
* Suicidal thoughts
* Weight gain
* Hallucinations
Causes
The possible causes of non-24-hour sleep-wake disorder are 2-fold: (1), extrinsic: isolation from daily light cycles (such as working in an environment completely devoid of natural lighting); and (2), intrinsic: where some condition, such as blindness or malfunctioning biochemical response to light in the subject, prevent normal levels of light-activated melatonin
Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...
release. Melatonin is responsible for sleep regulation, and its release is controlled by the amount of light entering the eyes.
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. At least one case of a sighted person developing non-24 was preceded by head injury; another patient diagnosed with the disorder was later found to have a "large pituitary adenoma
An adenoma is a benign tumor of epithelium, epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organ (anatomy), organs, including the adrenal glands, pituitary gland, thyroid, prosta ...
that involved the optic chiasma
In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, ...
". Thus the problem appears to be neurological. Specifically, it is thought to involve abnormal functioning of the suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive r ...
(SCN) in the hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
.
See also subsequent:
Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder. "Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy". According to the American Academy of Sleep Medicine (AASM), "patients with free-running (FRD) rhythms are thought to reflect a failure of entrainment".
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". 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). In 2002 Uchiyama et al. examined five sighted non-24 patients who showed, during the study, a sleep–wake cycle averaging 25.12 hours. 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. The literature usually refers to a "one- to two-hour" delay per 24-hour day (i.e. a 25- to 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, 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.
Blind
As stated above, the majority of patients with non-24 are totally blind. The failure of entrainment is explained by the loss of photic input to the circadian
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., endogenous) and responds to the environment (is entrai ...
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. 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
Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...
secretion, indicating preserved neural pathways between the retina and hypothalamus.
Circadian rhythm
All living animals have an internal clock, the circadian rhythm, which is close to 24 hours' duration. For humans, the average duration is 24 hours and 20 minutes, and individually some people have more or less than 24 hours. Everyday exposure to the morning light resets the circadian rhythm to 24 hours, so that there is no drifting.
However, people with non-24 have a circadian rhythm significantly longer (or, rarely, shorter) than 24 hours. This makes it difficult to reset to 24 hours daily, just like it is difficult for people with a rhythm close to 24 hours to try to reset to 25 hours daily. The majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of light (photic) input to reset the circadian clock. Their brains may have normal circadian clocks that do not receive input from the eyes about environmental light levels, as the clocks require a functioning retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
, optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
, and visual processing center. This makes the sleep pattern variable from one day to the next, with different wake-up time and bedtime every day.
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
A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exact ...
: by daily shifts in their sleep times, which often results in satisfactory sleep but with negative social and occupational consequences.
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, the disorder is also known as: non-24-hour sleep–wake syndrome or disorder,[ free-running disorder (FRD), hypernychthemeral syndrome,] hypernychthemeral sleep-wake cycle disturbance, circadian rhythm sleep disorder— free-running type or nonentrained type, non-24-hour circadian rhythm disorder. or just N24 for short in everyday speech.
The disorder is an invisible disability
Invisible disabilities, also known as hidden disabilities or non-visible disabilities (NVDs), are disabilities that are not immediately apparent. They are typically chronic illnesses and conditions that significantly impair normal activities of ...
that can be "extremely debilitating in that it is incompatible with most social and professional obligations".
Mechanisms
The internal circadian clock
A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exact ...
, located in the hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
of the brain, generates a signal that normally is slightly longer (occasionally shorter) than 24 hours, on average 24 hours and 11 minutes. 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 people who do not have non-24-hour sleep-wake disorder 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. 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
Jet lag is a temporary physiological condition that occurs when a person's circadian rhythm is out of sync with the time zone they are in, and is a typical result from travelling rapidly across multiple time zones (east–west or west–east). ...
") when their endogenous circadian rhythms drift out of synchrony with the social/solar 24-hour day, but they conform to a conventional schedule. Eventually, their circadian rhythms will drift back into normal alignment, when symptoms temporarily resolve. Thus the overall pattern involves periodic 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.
The AASM AASM may refer to:
* American Academy of Sleep Medicine
* Anglo-American School of Moscow
* Armement Air-Sol Modulaire, a French munition
* Australian Active Service Medal
{{disambig ...
suggests that non-24 might be different disorders in sighted and blind people, with different internal and external contributing factors—as these can affect treatment response, different treatments could be needed.[This assumes that multiple treatments exist.] Future studies should therefore try to identify and assess these factors.
Diagnosis
This disorder can have symptomatic periods, where "the time of high sleep propensity gradually shifts, such that patients experience daytime hypersomnolence and nighttime insomnia".
In sighted people, the diagnosis is typically made based on a history of persistently delayed sleep onset that follows a non-24-hour pattern. Hayakawa et al. (2005) reported on the basis of 57 cases of sighted patients that the average day length was 24.9 ± 0.4 hours (with the range of 24.4–26.5).
Medical classification
International Classification of Sleep Disorders (ICSD)
Since 2005, the disorder has been recognized by name in the U.S. National Center for Health Statistics
The National Center for Health Statistics (NCHS) is a U.S. government agency that provides statistical information to guide actions and policies to improve the public health of the American people. It is a unit of the Centers for Disease Control ...
and the U.S. Centers for Medicare and Medicaid Services
The Centers for Medicare & Medicaid Services (CMS) is a federal agency within the United States Department of Health and Human Services (HHS) that administers the Medicare program and works in partnership with state governments to administer ...
in their adaptation and extension of the WHO
The World Health Organization (WHO) is a specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Geneva, Switzerland, and has 6 regional offices and 15 ...
's '''' (ICD):
* ICD-9-CM: Circadian rhythm sleep disorder, free-running type; code 327.34 became effective in October 2005. Prior to the introduction of this code, the nonspecific code 307.45, Circadian rhythm sleep disorder of non-organic origin, was available, and as of 2014 remains the code recommended by the DSM-5.
* ICD-10-CM
The ICD-10 Clinical Modification (ICD-10-CM) is a set of diagnosis codes used in the United States of America. It was developed by a component of the U.S. Department of Health and Human services, as an adaption of the ICD-10 with authorizatio ...
: Circadian rhythm sleep disorder, free running type; code G47.24 was due to take effect October 1, 2014.
Since 2013, the disorder has been recognized by the American Psychiatric Association
The American Psychiatric Association (APA) is the main professional organization of psychiatrists and trainee psychiatrists in the United States, and the largest psychiatric organization in the world. It has more than 39,200 members who are in ...
:
* DSM-5
The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiat ...
, 2013: Circadian rhythm sleep–wake disorders, Non-24-hour sleep–wake type; ICD-9-CM code 307.45 is recommended (no acknowledgement of 327.34 is made), and ICD-10-CM code G47.24 is recommended when it goes into effect.
Treatment
Tasimelteon
The Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved in January 2014 the melatonin agonist tasimelteon for the treatment of non-24 for blind people. This is the first FDA-approved drug for any circadian rhythm sleep disorder
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep–wake disorders (CRSWD), are a family of sleep disorders that affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise eit ...
, since melatonin is unregulated. In the largest treatment study with non-24 patients, it was demonstrated that tasimelteon safely and effectively treated totally blind patients: entrainment occurred in 20% (8 of 40) of patients receiving the drug compared with 3% (1 of 38) receiving placebo
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
. In a separate meta-analysis, melatonin supplementation achieved a 67% (12 of 18) entrainment rate. Studies directly comparing tasimelteon and melatonin have yet to be performed. Study authors noted that the lower rates of entrainment with tasimelteon may have been due to short duration of treatment.
Melatonin, light therapy and dark therapy
Melatonin
Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...
administration 1 hour before bedtime is considered another treatment for non-24. However, it is important to note that melatonin may only treat the inability to sleep and may not help to improve the daytime sleepiness.
Light therapy, which involves a bright light exposure of thousands of lux of white light or about 400 lux of blue light on awakening to counteract the tendency for circadian rhythms to delay (similar to treatment for delayed sleep phase disorder and seasonal affective disorder), is not currently recommended until more studies appear, although it has been found to be effective in some cases. This can be combined with dark therapy (or scototherapy), which involves filtering blue light (using software, screen filters or (amber-color) glasses) and preferring red-colored lights with a low amount of lux in the few hours before bedtime to avoid melatonin suppression.
Both melatonin administration and light therapy work by shifting circadian rhythms according to a phase response curve (PRC), with the melatonin PRC being essentially the inverse of the light PRC. Furthermore, light can suppress melatonin secretion. Both have a duration of approximately 12 hours, in opposite phase: light PRC spikes at the beginning of the day and lowers throughout the day with a depression after 8 hours for the last 4 hours, whereas natural melatonin spikes at the start of the biological night and drops around the time of waking up or light perception. The first 8 hours are called the "advance zone" whereas the last few hours the "delay zone". The change from advancement to delay zones is progressive, passing through a long area of no effect (a "dead zone"), but the change from delay to advancement is abrupt, occurring a few hours before wake-up time or bedtime for light or melatonin respectively. When melatonin supplementation is taken in the melatonin PRC advance zone (i.e., the last few hours before bedtime), it resets the clock earlier; when taken in the melatonin PRC delay zone (i.e., few hours before and after wake-up time), it shifts the clock later. In other words, melatonin has most effect when it is taken at times when natural melatonin is not normally present, thus during the day: when taken in the morning, melatonin causes phase delays (shifts to a later time), and when taken in the afternoon/evening it causes phase advances (shifts to an earlier time). However, for a sleep phase delayed person, the time of biological morning and biological afternoon/evening might differ depending on the circadian clock shift in the affected person. This means that if melatonin is taken during the usual bedtime and wake-up time (i.e., usual nighttime), it may have no effect. Therefore, successful entrainment depends on both the melatonin dosage and the appropriate timing of melatonin administration. The accuracy needed for successfully timing the administration of melatonin might require a period of trial and error, as does the dosage. However, entrainment was also observed when giving a dose of melatonin as low as 0.05 mg and without any timing, by just continuing melatonin administration at the same time every day until their circadian rhythm shifted enough to coincide with melatonin administration (which took from 1 to 2 months).
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 homeostasis. Further to this, there are unforeseen disruptions to contend with even when a stabilized cycle is achieved, such as travel, exercise
Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...
, stress, alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
, or even the use of light-emitting technology close to a subjective evening/night.
Prevalence
There are an estimated 140,000 people with non-24—both sighted and blind—in the European Union
The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...
, a total prevalence of approximately 3 per 10,000, or 0.03%. 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. The US National Organization for Rare Disorders (NORD) lists non-24 as a rare disease by its definition.
Blind
While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect up to 70% of totally blind individuals. It is estimated by researchers that of the 1.3 million blind people in the U.S., 10% have no light perception at all. Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, have non-24.
History
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. 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. 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: they found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained, and when the dose was gradually reduced to 0.5 mg in three of the subjects, entrainment persisted. Subsequently, it was observed that treatment initiated with the 0.5 mg dose could produce entrainment on some patients. Interestingly, one subject who failed to entrain at a higher dose was successfully entrained at a lower dose. A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion.
There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s. In 2005, ramelteon (trade name Rozerem) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia
Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
treatment in adults. 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. Tasimelteon (trade name Hetlioz) received FDA approval in January 2014 for blind persons diagnosed with non-24. 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
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep–wake disorders (CRSWD), are a family of sleep disorders that affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise eit ...
in blind individuals without light perception as well as individuals with tardive dyskinesia
Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
.
The first report and description of a case of non-24, a man living on 26-hour days, who happened to be sighted, was "A man with too long a day" by Ann L. Eliott et al. in November 1970. The related and more common delayed sleep phase disorder was not described until 1981.
The first detailed study of non-24 in a blind subject was by Miles Le and his colleagues in 1977. The 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.
Research
Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing. It has been suggested that there are non-photic time cues that are important for maintaining entrainment, but these cues are yet to be characterized.
Very preliminary research on light sensitivity suggest that not only insensitivity but also circadian hypersensitivity to light might be at play for patients with a delayed sleep phase disorder.
Society
NASA
The National Aeronautics and Space Administration (NASA ) is an independent agencies of the United States government, independent agency of the federal government of the United States, US federal government responsible for the United States ...
explored the potential impact on circadian rhythm and possible development of a sleep–wake disorder by human astronaut
An astronaut (from the Ancient Greek (), meaning 'star', and (), meaning 'sailor') is a person trained, equipped, and deployed by a List of human spaceflight programs, human spaceflight program to serve as a commander or crew member of a spa ...
s who would go on a mission to Mars
Mars is the fourth planet from the Sun. It is also known as the "Red Planet", because of its orange-red appearance. Mars is a desert-like rocky planet with a tenuous carbon dioxide () atmosphere. At the average surface level the atmosph ...
, by assessing mission personnel who worked remotely on the Phoenix Mars Lander project and were asked to follow a Mars day of 24.65 hours for 78 days.
See also
* Circadian rhythm sleep disorder
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep–wake disorders (CRSWD), are a family of sleep disorders that affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise eit ...
, the parent spectrum of sleep disorders including non-24-hour sleep-wake disorder.
* Delayed sleep phase disorder
* Advanced sleep phase disorder
* Irregular sleep–wake rhythm
* Seasonal affective disorder (SAD)
Notes
References
External links
This Night Owl Gene Mutation Turns People Into Sleep Martians
How Much Sleep Should Kids Get
{{DEFAULTSORT:Non-24-hour sleep-wake disorder
Circadian rhythm
Rare diseases
Sleep disorders
Syndromes
Circadian rhythm sleep–wake disorders