be needed. 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) name code source year citation non-24-hour sleep–wake rhythm disorder icsd-3 2014 non-24-hour sleep–wake syndrome (alternatively, non-24-hour sleep–wake disorder) 780.55-2 icsd-2 2005 non-24-hour sleep–wake syndrome (or non-24-hour sleep–wake disorder) 780.55-2 icsd revised 1997 non-24-hour sleep–wake syndrome (or non-24-hour sleep–wake disorder) 780.55-2 icsd 1990 non-24-hour sleep–wake syndrome c.2.d dcsad 1979 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): 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: 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: dsm-5, 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 (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, 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. 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 further information: phase response curve phase response curves for light and for melatonin administration melatonin 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, stress, alcohol, 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, 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 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 in blind individuals without light perception as well as individuals with tardive dyskinesia. 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 explored the potential impact on circadian rhythm and possible development of a sleep–wake disorder by human astronauts who would go on a mission to mars, 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.