173

Review Article
Diagnosis of circadian rhythm sleep disorders*
Diagnóstico dos transtornos do sono relacionados ao ritmo circadiano

Denis Martinez1, Maria do Carmo Sfreddo Lenz2, Luiz Menna-Barreto3

Abstract
Insomnia and excessive sleepiness are common in the investigation of sleep-disordered breathing. Circadian rhythm sleep disorders are
perhaps the most often overlooked conditions in the differential diagnosis of these symptoms. Circadian rhythm sleep disorders manifest as
misalignment between the sleep period and the physical/social 24-h environmental cycle. The two most prevalent circadian rhythm sleep
disorders are delayed sleep phase (common in adolescents) and advanced sleep phase (common in the elderly), situations in which the sleep
period is displaced to a later or earlier time, respectively. It is important to keep these two disorders in mind, since they can be confused with
insomnia and excessive sleepiness. However, there are nine possible diagnoses, and all nine are of clinical interest. Since light is the principal
cue used in synchronizing the biological clock, blind individuals and night-shift/swing-shift workers are more prone to develop circadian
rhythm sleep disorders. In this article, the new international classification of circadian rhythm sleep disorders is reviewed.
Keywords: Circadian rhythm; Sleep disorders; Sleep initiation and maintenance disorders; Sleep stages; Sleep apnea syndromes.

Resumo
Queixas de insônia e sonolência excessiva são comuns na investigação dos distúrbios respiratórios do sono; os transtornos do sono rela-
cionados ao ritmo circadiano talvez sejam as causas mais freqüentemente esquecidas no diagnóstico diferencial destes sintomas. Estes
transtornos se manifestam por desalinhamento entre o período do sono e o ambiente físico e social de 24 h. Os dois transtornos do sono
relacionados ao ritmo circadiano mais prevalentes são o de fase atrasada (comum em adolescentes) e avançada do sono (comum em idosos),
situações nas quais o período de sono se desloca para mais tarde e mais cedo, respectivamente. As possíveis confusões com insônia e
sonolência excessiva tornam importante ter sempre em mente estes transtornos. Entretanto, há nove possíveis diagnósticos, e todos são de
interesse clínico. Como a luz é o principal sinal para sincronizar os relógios biológicos, pessoas cegas e trabalhadores em turnos e noturno
são os mais propensos a desenvolver transtornos do sono relacionados ao ritmo circadiano. Neste artigo, revisa-se a nova classificação inter-
nacional dos transtornos do sono relacionados ao ritmo circadiano.
Descritores: Ritmo circadiano; Transtornos do sono; Distúrbios do início e da manutenção do sono; Fases do sono; Síndromes da apnéia
do sono.

Introduction
Insomnia and drowsiness are complex symptoms that The most common cause of drowsiness among indi-
are difficult to quantify due to the various dimensions that viduals who seek medical assistance due to sleep disorders
each symptom presents. Insomnia, for example, can cause is obstructive sleep apnea-hypopnea syndrome (OSAHS).
significant suffering and functional damage. However, if Apnea and hypopnea are episodes of sleep-disordered
quantified in terms of number of sleep hours lost, it can be breathing of more than 10 s in duration that cause hypox-
trivial. Likewise, drowsiness can go unnoticed or be denied emia during sleep and do not appear during waking. The
by the patient, while it causes great concern to family diagnosis of OSAHS is made based on the occurrence of
members who observe naps in inappropriate situations, sleep-disordered symptoms such as drowsiness or insomnia,
even behind the wheel of a motor vehicle. accompanied by five or more episodes of apnea or hypopnea

* Study carried out in the Department of Internal Medicine at the Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul –
and Department of Cardiology in the Porto Alegre Hospital de Clínicas, Porto Alegre, Brazil.
1. Associate Professor in the Department of Internal Medicine. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto
Alegre, Brazil.
2. Technician. Sleep Disorder Clinic, Porto Alegre, Brazil.
3. Coordinator of the Multidisciplinary Group of Development and Biological Rhythms. Institute of Biomedical Sciences of the Universidade de São Paulo – USP,
University of São Paulo – São Paulo, Brazil.
Correspondence to: Denis Martinez. Rua Ramiro Barcelos, 2350, Bairro Rio Branco, CEP 90035-9030, Porto Alegre, RS, Brasil.
Tel 55 51 2101-8344. E-mail: [email protected]
Submitted: 10 June 2007. Accepted, after review: 10 September 2007.

J Bras Pneumol. 2008;34(3):173-180

174 Martinez D, Lenz MCS, Menna-Barreto L

per hour of sleep.(1,2) Typically, OSAHS causes drow-

siness, increasing the risk of accidents, especially a

traffic accidents. When OSAHS involves professional

drivers, the risk increases,(3) leading to the death of
passengers and bystanders.(4) The clinical impor-
tance of OSAHS has increased so greatly that the b
study of sleep-disordered breathing has become
mandatory for a residency in pulmonary disease.
Due to the epidemiological relevance of OSAHS,
there are currently more pulmonologists than
neurologists or psychiatrists who specialize in sleep c
disorders. The treatment of OSAHS results in better
quality of life and reduced mortality rates. In order
to institute treatment, a hypothetical diagnosis
should be followed by investigation and differential 181920212223241 2 3 4 5 6 7 8 9
diagnosis. Time
Among the causes of insomnia and drowsiness Figure 1 - Diagrams representing melatonin secretion
that are unrelated to respiratory diseases, the most (dashed line) and the sleep period (solid line) in normal
neglected causes might be those related to circa- individuals (a), individuals with advanced sleep phase (b)
dian rhythm sleep disorders (CRSDs). These disorders and individuals with delayed sleep phase (c). In normal
individuals, melatonin secretion begins early in the
manifest as misalignment between the sleep period
evening and peaks around midnight, when the person lies
and the physical/social 24-h environmental cycle, down and falls asleep without difficulty; in the morning,
related to alterations in internal timing mechanisms. the effect of melatonin has worn off, and the person arises
These disorders present two typical patterns, which without any drowsiness. In the advanced phase, melatonin
are principally seen in the adolescent and in the peaks at 10 pm, causing irresistible drowsiness, and its
elderly. The complaint that adolescents report can effect wears off by 4 am, resulting in early awakening. In
mimic insomnia when they lie down at regular times the delayed phase, if the individual tries to go to bed at
and it takes them hours to fall asleep. However, it 11 pm, initiating sleep will be difficult, since melatonin
levels have not yet begun to increase; when getting up in
can also mimic drowsiness when they cannot get
the morning, melatonin will be near peak and drowsiness
up in the morning. The elderly can appear to have will be maximal, causing symptoms that can be confused
drowsiness when they fall asleep at 8 pm, while with sleep-disordered breathing.
watching television, but they can also seem to have
insomnia when they wake up in the middle of the
night and cannot go back to sleep (Figure 1). These
cases of pseudo-insomnia or drowsiness are actu-
ally the most common models of CRSD, with serious greater chance of obtaining food. These temporal
consequences to the quality of life of the individual. niches distinguish, for example, diurnal species from
Therefore, they should always be considered in the nocturnal species, as in the case of the thrush and
differential diagnosis of OSAHS. the owl, respectively. In addition to diurnal cycles,
there is the adaptation to seasons, which is essential
Sleep and timing mechanisms to survival. Seasonal behavior is also controlled by
internal calendars.(5)
Practically all living forms have timing mecha- Homo sapiens are diurnal, adapted to perform
nisms, or oscillators, which improve their chances of their activities during the light phase of the light/
survival on a planet marked by light/dark cycles and dark cycle and rest during the dark phase. The
seasons. For plants, the presence or absence of sun development of our visual system and our depend-
represents the furnishing of energy or the need to ence on luminous information characterize us as a
save energy. For animals, in addition to their ‘spatial diurnal species.(6) The principal sleep period in our
niche’, a ‘temporal niche’ is necessary, a time when species is therefore during the dark phase. However,
they are less exposed to predators and stand a there can be other moments of rest over the course

J Bras Pneumol. 2008;34(3):173-180

Diagnosis of circadian rhythm sleep disorders 175

of the day. The system that controls sleep-related alterations of this cycle that go beyond the limits
behaviors is complex(7) and comprises various of normality. Such alterations primarily occur under
elements,(8) comparable to an orchestra.(9) The center chronic conditions such as those seen in night-shift/
that conducts the concert of the chronobiology swing-shift workers. These alterations are identified
of the mammals is the suprachiasmatic nucleus as secondary CRSDs and merit specific treatment
(SCN) of the hypothalamus.(10) Located next to the following correct diagnosis.
optic nerve, this area of the hypothalamus receives The diagnosis of sleep disorders is approached in
connections from the retina that inform the system several classifications. However, the most consistent
of the existence of light. Melatonin(11) is secreted by international effort is that of medical societies
the pineal gland, according to the stimulus of the dedicated to sleep disorders. The second version of
SCN in the absence of light, translating the photic the International Classification of Sleep Disorders
information into chemical stimulus to all cells. (ICSD)(23) includes two new CRSDs that are of clin-
Exposure to light interacts with the SCN and can ical interest, bringing the total number of possible
alter biological clock cycles. Intense light late in the diagnoses to nine (Table 1).
afternoon turns the biological clock back. Intense A diagnosis of CRSD can be made under certain
light early in the morning moves the biological conditions. First, the disorder must be accompa-
clock forward.(12) Regular repetition of nocturnal nied by insomnia, excessive sleepiness or both, with
sleep episodes characterizes the so-called sleep- social/occupational impairment or jeopardizing
wake cycle. In addition to sleep, all functions of other areas. Second, the pattern of the disorder
the nervous system present oscillations. The various should be persistent or recurrent. Finally, the
components of human performance are erroneously cause should be either an alteration in the timing
considered stable phenomena. Evidence derived mechanism or the lack of synchronization between
from laboratory studies, under controlled conditions the endogenous circadian rhythm and exogenous
and through manipulations of the sleep-wake cycle, factors that affect the hour or the duration of sleep.
demonstrates that performance is strongly affected These considerations are important since the sleep-
by cyclic phenomena.(13) Living organisms are not wake cycle usually presents some variability, which
machines that, once switched on, function uninter- also makes it possible to adapt to changes of habit
ruptedly and with minimal oscillations.(14) Physical on weekends.
and mental oscillations in human beings are of Having met these general criteria, we should
relevant magnitude and high risk.(15) Fatal accidents look for specific diagnoses such as those reviewed
represent the gloomiest side of drop in performance below.
associated with circadian rhythms. The cycles that
involve sleep and the processes that control it suffer
disturbances of clinical interest,(16,17) which will be
reviewed in this article. Chart 1 - Classification of circadian rhythm sleep
As any biological system, oscillators responsible disorders.
for the regularity of the sleep-wake cycle are subject Primary disorders
to mutations,(18) as in the case of familial syndrome 1) Delayed sleep phase
of advanced sleep phase, a dominant autosomal 2) Advanced sleep phase
condition characterized by early sleep times and 3) Sleep-wake cycle irregular pattern
awakenings in the middle of the night. In addition 4) Non-24-h sleep-wake cycle
to genetic aspects, there are chronobiological disor- Secondary disorders
ders secondary to various factors, such as: aging(19); 5) Jet lag
stress(20); chronotype (morning or evening)(21); and 6) CRSD secondary to work at irregular hours
organic diseases.(22) 7) CRSD secondary to diseases
Despite the relative flexibility of sleeping and 8) CRSD secondary to the use of drugs or
waking up time, human beings tend to maintain medications
24-h sleep-wake cycles. Deviations from this regu- Other
larity typically occur on weekends, on vacations 9) Other CRSDs
and during time zone changes. However, there are CRSD: circadian rhythm sleep disorder.

J Bras Pneumol. 2008;34(3):173-180

176 Martinez D, Lenz MCS, Menna-Barreto L

Circadian rhythm sleep disorders Chart 2 - Sleep hygiene measures for patients with
circadian rhythm sleep disorders.
Respect the biological clock
Delayed sleep phase syndrome
Maintain regular hours for sleeping and getting
Delayed sleep phase syndrome is characterized up, using an alarm clock
by late sleeping and waking, on most nights, usually Avoid variations of over 2 h in getting up time on
weekends
with a delay of more than 2 h in relation to conven-
Avoid staying in bed for over 7.5 h, including naps
tional or socially acceptable times. The patient has
Exercise at least 6 h before sleeping
difficulty in initiating sleep and prefers to wake
Avoid exciting or emotionally disturbing activities
up later. When allowed to follow their preferred
near bed time
schedule, their circadian rhythm is chronically and
Avoid activities that demand a high level of
persistently delayed, damaging their social life. concentration immediately before going to bed
Except for the delayed sleep schedule, their sleep is Avoid mental activities such as thinking, planning,
normal. or recollecting in bed
Family history can be present in up to 40% of Precautions regarding drugs, habits and environment
the individuals with delayed phase. The prevalence Prior to sleeping, avoid products that contain
in the general population is 7 to 16%. It is more alcohol, tobacco, caffeine or any substance which
common among adolescents and young adults, the acts on the central nervous system
prevalence being highest in individuals of approxi- Ensure that the bed is comfortable, that the
mately 20 years of age.(24,25) It is estimated that mattress and sheets are of good quality, and that
10% of all patients with chronic insomnia who the covers are appropriate for the temperature
seek help in sleep clinics suffer from delayed phase Ensure that the bedroom is dark and quiet, with
syndrome. an average temperature of 24°C (ranging from
17 to 27 °C)
The exact mechanism of the development of
delayed phase syndrome is unknown. Genetic
factors, such as polymorphism in the timing mecha-
nism, principally of the hPer3 gene, are associated
with this syndrome. Environmental factors, including hours compromise treatment efficiency. Intense
decreased morning light exposure, excessive light light applied at the desired waking up time for 1 or
exposure late in the afternoon and late hours for 2 h readjusts the biological clock in a few days but
television and video-games can exacerbate phase also has practical limitations. Melatonin at a dose
delay. Changes in work shifts and trips involving of 0.3 to 3 mg late in the afternoon contributes to
time zone changes can precipitate this disorder. advancing the sleep phase.

Treatment Advanced sleep phase syndrome

In all CRSDs, it is fundamental to supervise the Advanced sleep phase syndrome is character-
adequate use of sleep hygiene measures (Table 2). ized by early sleeping and waking, on most nights,
Although these measures seem obvious, many usually several hours before conventional or socially
patients totally ignore them, thereby making treat- acceptable times.
ment impracticable, due to ingrained behaviors, Patients report drowsiness (sleep attacks) late
such as ingesting high doses of caffeine at night. in the afternoon or early in the evening, as well
A simple way of treating delayed sleep phase is to as early spontaneous awakening in the morning.
further delay sleep initiation, at a rate of 2 to 3 h When patients are allowed to maintain their own
every 2 days, until the desired time of sleep period schedule, sleep is normal for the age, except for the
is achieved, ideally from 11:30 pm to 7 am. This advanced phase.
method can be well accepted because it is easier The exact mechanism of the development of the
to prolong wakefulness than to anticipate sleep. advanced phase is unknown, although genetic and
However, in practice, the need for rigorous compli- environmental factors are known to be involved.
ance with the regimen and inconvenient intermediate Various members of the same family can be affected

J Bras Pneumol. 2008;34(3):173-180

Diagnosis of circadian rhythm sleep disorders 177

by phase advance. Mutation of the hPer2 gene has As would be expected, polysomnography, sleep
been found in individuals of the same family who diaries and actigraphy register the lack of a regular
are affected by this syndrome. sleep-wake cycle pattern. Monitoring other circa-
The prevalence in the general population is dian rhythms, such as body temperature, also
unknown, although it increases with age. It is esti- demonstrates the lack of rhythmicity. Sleep diaries
mated that it affects 1% of middle-aged adults and or actigraphy should be employed for at least seven
the elderly. The incidence is similar in both genders. days in order to demonstrate an irregular sleep-
One of the complications reported is the use of wake cycle pattern.
alcohol, sedatives, hypnotic agents or stimulants The sum of the total sleep time in 24 h is essen-
to treat insomnia and drowsiness symptoms, which tially normal for the age. To confirm the diagnosis,
can lead to abuse of these substances. the differential diagnosis of this disorder should
include other sleep disorders, clinical/neurological
Treatment problems and the use/abuse of medications/illicit
drugs.
The simplest treatment is to delay sleep time,
at a rate of 1 to 3 h every 2 days, until the desired Treatment
sleep period is achieved. This method is better
accepted in the advanced phase than in the delayed Strict compliance with desired time of the
phase, because intermediate hours do not surpass sleep period, together with filling waking hours
the desired waking period. The problem with the with physical and social activities, can correct the
elderly is the lack of physical, mental or social activ- disorder. Intense light, applied for 1 or 2 h at the
ities that can keep them awake until the desired desired waking time, can synchronize biological
sleeping time. Phototherapy (exposure to intense clocks. Melatonin at a dose of 3 mg late in the
light), applied late in the afternoon for 1 or 2 h, afternoon has proven useful in children with severe
can readjust the biological clock within a few days. psychomotor deficit but not in elderly patients with
Seasonal variations of light/dark cycle duration, in Alzheimer’s disease.
locations far from the equator, can require exposure
to artificial light in winter months. Non-24-h sleep-wake cycle

Irregular pattern The non-24-h sleep-wake cycle disorder is

also known as non-24-h sleep-wake syndrome or
Individuals affected by the irregular pattern type hypernyctohemeral syndrome. It is characterized
of sleep disorder present an undefined pattern of by sleep symptoms that occur as a result of the
sleep-wake cycle circadian rhythm. Depending on longer (approximately 25-h) duration of the circa-
the time of day, the patient can present chronic dian timing mechanism cycle. Both insomnia and
insomnia or excessive sleepiness. Naps are common excessive sleepiness related to abnormal synchroni-
at any time of day or night in this syndrome. zation between the 24-h light/dark cycle and the
Included among the predisposing factors are endogenous sleep-wake circadian rhythm are likely
inadequate sleep hygiene and lack of exposure to to occur.
synchronizing external agents, such as sunlight, Blind individuals are more predisposed to this
physical activities and social activities, particularly disorder.
in the institutionalized elderly, and this can predis- Approximately 70% of individuals with total
pose to an irregular sleep-wake cycle pattern. sight loss report sleep disorder, and 40% of those
The physiopathology involves anatomical or are diagnosed with cyclic, chronic sleep disorder.
functional abnormalities of the circadian timing Rare cases have been described in individuals with
mechanism, which can result in an anarchic pattern normal vision, and the disorder can be induced by
of waking and sleeping. This pattern can also be certain environmental conditions, such as isola-
observed in association with neurological diseases, tion. Onset can occur at any age, and the disorder is
such as dementia, and in children with intellectual congenital in blind children. If left untreated, it can
disabilities. become chronic.

J Bras Pneumol. 2008;34(3):173-180

178 Martinez D, Lenz MCS, Menna-Barreto L

The attempt to regulate the sleep-wake cycle Treatment

can lead to abuse of alcohol, hypnotic agents,
sedatives and stimulants, which can exacerbate the Individuals taking flights to the East should
disorder. Depressive symptoms and mood disorders wake up early and avoid bright light in the morning
are typical comorbidities. but should try to get maximum exposure to light
The lack of luminous input for the circadian late in the afternoon. Individuals taking flights to
pacemaker is clearly the cause of the non-24-h the West should force themselves to remain awake
circadian rhythm. Sleep diaries or actigraphy for at during the day and should take pains to avoid falling
least seven days demonstrate a sleep-wake pattern asleep before dark. There is evidence that melatonin
that typically delays every day, since it has a duration at a dose of 2-5 mg, prior to sleeping on the first
of approximately 25 h. The differential diagnosis nights after arrival, is efficacious in preventing or
should include other sleep disorders and clinical/ reducing jet lag and should be recommended for
neurological problems, as well as the use/abuse of those who cross more than four time zones.(27)
medications/illicit drugs. Nonpharmacologic measures, such as avoiding the
ingestion of alcoholic beverages, maintaining proper
Treatment hydration and taking regularly scheduled naps, have
been suggested.(28)
Melatonin administered at appropriate times, at
a dose of 0.5 mg, late in the afternoon, regulates Secondary to working irregular hours
the sleep phase.(26)
Sleep disorder secondary to working irregular
Secondary to a rapid change of time zone hours is characterized by complaints of insomnia or
excessive sleepiness, since the working hours coin-
Sleep disorder secondary to a rapid change of cide with the habitual sleep phase, causing shortened
time zone is a temporary disorder, also known as total sleep time and unsatisfactory quality of sleep.
jet lag syndrome, caused by the desynchronization In this context, insomnia or excessive sleepiness are
between the sleep-wake cycle and the cycle gener- temporally associated with the work schedule that
ated by the circadian timing mechanism, usually recurrently overlaps habitual sleeping time and typi-
after a trip during which at least two time zones cally manifest at least once a month. Shift work can
are crossed. The syndrome is a temporary and self- be based on fixed hours or can be in swing-shifts.
limiting condition. Symptoms appear one to two Sleep disorder is more frequent among individuals
days after the trip and disappear within one week. working night shifts or early morning shifts. The
The most common complaints are sleep disorder, decreased alertness related to this disorder not only
decreased alertness, altered cognitive function, impairs work performance but can also increase the
malaise and gastrointestinal symptoms. The severity risk of accidents. Typically, the disorder will persist
of the symptoms depends on the number of time for as long as working hours remain irregular.
zones crossed and the direction of the trip. Trips to However, in some individuals, the disorder remains
the East, which require circadian rhythm advances, even after working hours have returned to normal.
are usually harder to adapt to. Exposure to light at Since there is no definitively efficacious treat-
inappropriate hours can prolong the time to adjust- ment for this disorder, patients are forced to live
ment of the circadian rhythm. with the symptoms or forego the extra income from
The disorder affects all age brackets. shift work. The efficacy of the use of stimulants to
However, older people can present more minimize the drowsiness of shift workers has been
pronounced symptoms. The cause is the desynchro- recently confirmed.(29)
nization between environmental and endogenous The prevalence of this disorder related to irreg-
day-night cycles, and the disorder is aggravated ular working hours depends on the prevalence of
by the loss of sleep. Further investigation is not irregular working hours in the population. In indus-
indicated, nor is polysomnography. We should trialized countries, it is estimated that 20% of the
recommend that, during the days following the work force consists of individuals who work irreg-
trip, travelers avoid risk situations that require quick ular hours, and that 2-5% of these workers suffer
reflexes. from some sort of sleep disorder. Although little is

J Bras Pneumol. 2008;34(3):173-180

Diagnosis of circadian rhythm sleep disorders 179

known regarding the consequences of this disorder, use of illicit drugs or medications that alter sleep or
it is believed to be involved in the development the circadian rhythm.
of several diseases, such as hypertension,(30) breast
cancer and uterine cervical cancer.(31) Secondary to the use of drugs or
Monitoring through the use of actigraphy or medications
sleep diaries for a minimum of seven days, including
episodes of night shift work, can contribute to Cases of sleep disorders secondary to the use
confirming a temporal association. Polysomnography of drugs or medications meet the general criterion
can be useful when the disorder is severe or when for CRSDs and are caused by either illicit drugs or
the etiology of the sleep disorder is in question. medications.

Treatment Other types

Intense light during working hours and the use The ‘Other types’ category of sleep disorders
of dark glasses in the morning at the time workers was created to accommodate the cases that meet
leave work can impede the secretion of melatonin at the general criteria for CRSDs but do not meet the
night and facilitate it during the day, synchronizing criteria for the other specific classifications.
the sleep period with that of melatonin secretion.
The use of hypnotic agents or melatonin prior to
Final considerations
sleeping, for a limited time, can help fight insomnia. In this article, we reviewed all diagnostic catego-
Drowsiness can be prevented with naps before the ries listed in the most recent edition of the ICSD,
shift or during the shift break, as well as with the emphasizing the diagnostic aspects. With advances
use of caffeine. in the understanding of the causes of these disor-
ders and the development of new tests,(33) diagnosis
Secondary to diseases
will evolve, allowing greater accuracy.
A CRSD secondary to a disease primarily It is important that the diagnosis be correct,
occurs as the result of a morbid clinical or trau- so that individuals with CRSD are not exposed to
matic process,(32) and its characteristics depend on risks of accidents or unnecessary treatments (in
the associated disease. The patient can present some cases, for their entire lifetime)(34) such as the
innumerable symptoms, including insomnia and use of hypnotic agents without precise indication.
excessive sleepiness, as well as altered sleep-wake Adequate sleep hygiene and phototherapy (expo-
cycle patterns such as the delayed phase, advanced sure to intense light at scheduled times, according
phase or irregular pattern. to the sleep disorder),(35) as well as the use of
Insomnia or excessive sleepiness related to alter- melatonin(36,37) or melatonin receptor agonists,(38) all
ations of the circadian timing mechanism or to the constitute valid therapeutic options.
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