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Sleep Medicine Reviews (2008)
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Clinical review
A practical approach to circadian rhythm
sleep disorders
Bjørn Bjorvatn a,b,c,*, Ståle Pallesen b,c,d
a
Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31,
N-5018 Bergen, Norway
b
Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Norway
c
Bergen Sleep Disorders Center, Bergen, Norway
d
Department of Psychosocial Science, University of Bergen, Norway
KEYWORDS
Circadian rhythm
disorders;
Bright light;
Melatonin;
Nadir;
Sleep regulation
Summary Circadian rhythm sleep disorders are common in clinical practice. The
disorders covered in this review are delayed sleep phase disorder, advanced sleep
phase disorder, free-running, irregular sleepewake rhythm, jet lag disorder and
shift work disorder. Bright light treatment and exogenous melatonin administration
are considered to be the treatments of choice for these circadian rhythm sleep
disorders. Circadian phase needs to be estimated in order to time the treatments
appropriately. Inappropriately timed bright light and melatonin will likely worsen
the condition. Measurements of core body temperature or endogenous melatonin
rhythms will objectively assess circadian phase; however, such measurements are
seldom or never used in a busy clinical practice. This review will focus on how to
estimate circadian phase based on a careful patient history. Based on such estimations of circadian phase, we will recommend appropriate timing of bright light and/
or melatonin in the different circadian rhythm sleep disorders. We hope this
practical approach and simple recommendations will stimulate clinicians to treat
patients with circadian rhythm sleep disorders.
ª 2008 Elsevier Ltd. All rights reserved.
Introduction
* Corresponding author. Department of Public Health and
Primary Health Care, University of Bergen, Kalfarveien 31, N-5018
Bergen, Norway. Tel.: þ47 55 58 61 00; fax: þ47 55 58 61 30.
E-mail address: [email protected] (B. Bjorvatn).
Circadian rhythm sleep disorders are caused by
a misalignment between the endogenous circadian
timing system and the external 24-h environment.
The disorders typically result in complaints of
insomnia and/or excessive sleepiness, in addition
to impairment in normal functioning and quality of
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doi:10.1016/j.smrv.2008.04.009
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2
life. Many clinicians face patients suffering from
such complaints, but there is lack of evidencebased guidelines on how to diagnose, examine and
treat these disorders.1,2 This review provides
a practical approach to handling the different
circadian rhythm sleep disorders, as they are
defined in the International Classification of Sleep
Disorders.3 Although the practical approach presented here is not based on firm evidence drawn
from controlled clinical trials, the approach is
based on well-researched basic principles of
circadian entrainment.
We would also like to emphasize that although
there is a definite need for more research on practical
issues concerning treatment, the clinical approach
which is presented here will likely help many of the
patients suffering from circadian rhythm sleep disorders. Based on our long-term clinical experience in
diagnosing and treating such disorders, we have found
that treating these patients is usually easier than
many clinicians believe.
To be able to treat patients with circadian
rhythm sleep disorders, it is important to understand how sleep is regulated. Thus, we will initially
focus on sleep regulation, and how to determine
circadian phase. Then we will cover each separate
circadian rhythm sleep disorder,3 and specify
a simple and clinical approach on how to treat
patients suffering from these disorders. The
advantage of a clinical approach is that the specific
interventions can be adjusted, if the treatment
does not help or if the condition actually worsens.
This is especially important in these disorders,
where the timing of the treatment is crucial. This
means that if treatment is instituted at the inappropriate circadian time, the patients are likely to
get worse.
The treatment options in ordinary clinical
practice for circadian rhythm sleep disorders
comprise bright light treatment and exogenous
melatonin administration. How to use these
treatment options will be covered under each
specific circadian rhythm sleep disorder. Chronotherapy has been used for the treatment of some
of the circadian rhythm sleep disorders, but we
will not discuss this any further in our review, due
to the difficulties of implementing such an
approach and lack of data documenting its efficacy. Furthermore, we will not cover use of
hypnotics or other medications, due to space
limitations.
We have epidemiological data for many of the
different circadian rhythm sleep disorders, but the
number of patients who actually seek treatment
for these disorders is much less. The reasons may
be many. One probable reason is lack of knowledge
B. Bjorvatn, S. Pallesen
about the disorders and their possible treatments,
both among health professionals and patients.
Sleep regulation
Sleep is regulated by an interplay of different
factors. The main focus has been on the interaction between the homeostatic and the endogenous
circadian processes.4 The homeostatic process
accumulates as a function of prior wakefulness,
i.e., there is more homeostatic factor the longer
you are awake.5 This factor is believed to be of
main importance for sleep quality; that is, the
longer you are awake, the deeper the following
sleep episode will be (increased slow wave
activity). The circadian factor on the other hand
plays an important role in sleep quantity; that is,
sleep duration is for the most part determined by
when you go to bed. In other words, sleep length is
not dependent on the sleep homeostatic factor,
but largely dependent on when you go to sleep
according to your own circadian rhythm.4 Night
workers have experienced this as their sleep
duration is usually shorter (often less than 6 h)
than normal when going to bed in the morning,
even though they often have been awake for more
hours before going to bed than daytime workers.6
From a practical point of view, this interaction
between the homeostatic and circadian processes
means that it is important to be awake for
a substantial amount of time to get sleep of high
quality, and to have regular bed and rise times in
order to have a stable sleep duration.
Also habits and behavioral factors have large
influences on sleep. We all go to bed at regular
hours, not necessarily because we are very sleepy/
tired, but because we know we need to do so, to
get enough sleep. Many people experience a high
level of sleepiness early in the evening/afternoon,
but avoid going to bed knowing that it is not time
for bed yet. Behavioral factors can override both
the homeostatic and circadian factors. For
instance, a night worker is able to stay awake even
though both the homeostatic and the circadian
factors favor sleep in the middle of the night. In
these instances behavioral factors, like talking to
someone, walking around, drinking coffee,
increasing illumination, etc., help the night
workers to stay awake. Similarly, many teachers
have experienced students falling asleep at 9 a.m.,
even though both the homeostatic and circadian
factors favor wakefulness. In this instance, lack of
stimulation may be a behavioral factor explaining
the increase in sleepiness and risk of falling asleep;
that is, a boring lecture, sitting in a dark room,
lack of sensory input, etc.
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Medicine Reviews (2008), doi:10.1016/j.smrv.2008.04.009
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Estimating circadian phase in every day clinical practice
Core body temperature and endogenous
melatonin rhythms
For the treatment of circadian rhythm sleep disorders,
an understanding of the circadian timing system is of
crucial importance. Of central importance is the
determination of the circadian phase, i.e., the nadir
of the core body temperature rhythm, or the endogenous melatonin rhythm. For simplicity, we will
primarily focus on the nadir of the core body
temperature rhythm, and the role of this nadir when
recommending correct timing of treatment of the
different circadian rhythm sleep disorders.
The core body temperature usually peaks in the
late afternoon or evening hours, and reaches its
lowest point, nadir, in the early morning (Fig. 1).
Sleep normally occurs on the downward slope of
the core body temperature rhythm and normally
ends about 2 h following nadir. A similar coupling
between the sleep/wake-rhythm and the rhythmicity of the melatonin secretion is also normally
present. Melatonin secretion usually increases
soon after the onset of darkness, peaks in the
middle of the night and gradually falls during the
second half of the night. Sleep usually takes place
when the melatonin level is high, and wakefulness
normally coexists with low plasma melatonin
levels. Based on the close correspondence
between sleep/wakefulness and body temperature/melatonin, the core body temperature and
melatonin (measured in saliva, urine or plasma)
constitute the two most common physiological
measures of circadian rhythm.1,7,8 Interestingly,
mammals continue to show periodic regularity in
sleep and wakefulness also in the absence of light
or other time signalling stimuli (zeitgebers). This
has also been demonstrated in studies with human
subjects, kept isolated in underground bunkers.
However, the period of the sleep/wake-rhythm
under such conditions was reported to be
37.4
Temperature in °C
37.2
37.0
36.8
36.6
36.4
36.2
36.0
19 21 23
1
3
5
7
9
11 13 15 17
Time of day
Figure 1
Core body temperature rhythm.
3
somewhat longer than 24 h, approximately 25 h.9
Several studies have now confirmed that humans
are in possession of an endogenous circadian
rhythm, with a period length under controlled
conditions of about 24.2 h.10 The main site of this
endogenous rhythm has been located in the
suprachiasmatic nuclei (SCN), situated bilaterally
above the optic chiasm in the anterior basal
hypothalamus.11 Ablation of the SCN in mammals
has been shown to eliminate circadian rhythms,
and transplantation restores the rhythm to the
period of the donor animal.12
There exist several major input fiber systems in
the SCN. The most important stems from photoreceptors in the retina, which convey signals to the
suprachiasmatic nucleus via a monosynaptic
pathway, the retinohypothalamic tract. Recently,
it was discovered that the retinal rod and cone
cells are not required for photoentraiment, but
that there exists a subset of retinal cells (2500 of
a total of 100 000 cells) containing a light-sensing
pigment, melanopsin, which is assumed to be
involved in circadian photoentrainment.13 There
exists an important connection between the SCN
and the pineal gland. Melatonin, which is the only
known hormonal output from the pineal gland,
affects the SCN by inhibiting firing.14 Hence, the
SCN and pineal gland seem to be able to influence
each other in a mutual way.
Estimation of circadian phase
To be able to measure the circadian phase of
a patient in an objective manner, either core body
temperature or melatonin (in saliva, urine or
blood) must be assessed. In laboratory based
studies core body temperature rhythm is normally
measured by the so-called constant routine
protocol. This protocol implies that the patient
takes on a semi-recumbent position in a laboratory
environment for several (often 26) consecutive
hours. The light intensity is required to be less
than 50 lux and the patient normally receives
a meal of 100 kcal every hour.15 The commonly
used circadian parameter obtained from this
protocol is the nadir (time of the lowest level
measured) of the core body temperature.
Measurement of the circadian rhythm based upon
melatonin comprises several samples (normally
with a 30 or 60 min interval) of either saliva, urine
or plasma. The level of illumination currently
recommended for sampling is 10 lux.16 The most
commonly used parameter from these measures is
the dim light melatonin onset (DLMO), normally
defined as the time when the melatonin level
reaches 2 pg/ml in plasma17 or when a level of
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4
4 pg/ml is reached in saliva.18 Alternatively, the
threshold for DLMO can be defined as the mean of
3 daytime samples plus two times the standard
deviation of these 3 daytime samples.19
Measurements as described above are cumbersome and expensive, and for these reasons seldom
or never performed in a busy clinical practice.
Thus, we will here emphasize how to estimate
circadian phase by taking a careful patient history.
As a rule of thumb, the nadir of the core body
temperature is located about 2 h before habitual
time of awakening. For patients with stable
circadian rhythms, that is, stable bed and rise
times, estimation of nadir is relatively easy. For
instance, if the patient usually wakes up at about 8
a.m. every day, the nadir of the core body
temperature rhythm is likely to be some time
around 6 a.m. Some patients may have stable bed
and rise times during the workweek, but during the
weekend, this rhythm is delayed by several hours.
Estimation of nadir is more complicated in such
cases. Furthermore, use of medications/drugs,
alcohol or irregular work schedules can make
estimation of nadir very difficult. Before instituting treatment, it may be helpful to instruct the
patient to sleep until she or he wakes up (without
an alarm clock). It is likely that nadir will be about
2 h before his/her awakening. Previous studies
have shown that subjective sleep data from uninterrupted sleep can be used as a reasonable good
estimate of circadian phase,20,21 and that sleep
offset correlates higher with different phase
markers than sleep onset.21,22
Nadir is, in addition to being the lowest point on
the core body temperature rhythm, the time
where it is most difficult to stay awake.23 Night
workers often experience an increase in sleepiness
during the night until about 4 or 5 in the morning,
and after that, they usually become less sleepy.
Since the time point when the patient is most
sleepy during the night corresponds to the nadir,
this may be used as an additional help for estimating the nadir, particularly in night work and jet
lag. For other circadian rhythm sleep disorders,
where the patients may not have been awake
during their regular sleep episode, this approach
for estimating the nadir may not be possible.
Bright light treatment
An important function of the SCN is to adjust the
output signals and the endogenous rhythm in
accordance with external time signalling stimuli
(zeitgebers). The afferent connections of the SCN
indicate that it is particularly sensitive to light,
and light is now considered the most important
B. Bjorvatn, S. Pallesen
zeitgeber. The process by which light synchronizes
the SCN to a 24-h day is called entrainment. A
human living in a natural habitat will adhere to
a 24-h day, primarily due to light exposure. But the
SCN is not equally sensitive to the effect of light at
all time points during the day, and the type of
effect light exposure has on the circadian rhythm
is also related to the duration of the light exposure. Studies, using a variety of experimental
designs, have now consistently shown that the
effect of light on circadian rhythms follows a socalled phase-response curve (PRC).24 According to
the PRC, light can have two opposite effects on the
circadian rhythm (Fig. 2). Light exposure before
the nadir of the core body temperature rhythm
causes a phase delay, whereas light administered
after nadir produces a phase advance. Thus, light
in the evening normally causes phase delay, and
light in the morning causes phase advance. Also,
light exposure close to the nadir produces the
greatest phase shifts. It follows that the further
away from nadir light exposure takes place, the
less effect it exerts.25 The magnitude of phase
shifts is also a function of the dose and duration of
the light exposure. In general, high intensity light
doses and long durations of light exposure cause
the greatest phase shifts.26 For long durations of
light that fall on both the phase advance and delay
portions of the PRC, the direction of the resulting
phase shift is influenced by where most of the light
falls.24,27,28 Hence, light can advance or delay the
circadian rhythm depending on time of light
exposure.
Today, bright light is typically administered by
portable units yielding about 10 000 lux, and
Figure 2 Phase-response curve for light (full line) and
melatonin (dotted line) based upon Khalsa et al.24 and
Lewy et al.8 A phase-response curve illustrates the
relationship between the timing and the effect of
a treatment designed to affect circadian rhythms. The
differences in effect between light and melatonin are
not necessary as shown in this figure but will depend on
the doses of light and melatonin.
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Estimating circadian phase in every day clinical practice
exposure time is about 30e45 min per day. Studies
have also investigated the effects of presenting
light of different wavelengths. Visible light with
short wavelengths (blue light) has a stronger
melatonin suppressing effect and a stronger phase
shifting effect on the human circadian rhythm
compared to light with longer wavelengths.1
During light exposure the patient is instructed to
keep his gaze directed at the light source, but not
to continuously stare into the light. A potential
problem with small apparatus is that even small
changes in head position sometimes can lead to
substantial reductions in the light intensity that
reaches the eyes, hence reducing the therapeutic
effect.29 Light treatment can be self-administered
at home, according to a therapeutic regime. To the
extent that the timing of light treatment is important in order to obtain a therapeutic effect,
compliance is sine qua non.29 Patients may read the
newspaper, watch television, or eat while being
exposed to bright light. Bright light of 10 000 lux for
at least 30 min is recommended, but light of less
intensity or shorter duration will be better than no
light at all. Furthermore, whenever outdoor light of
sufficient intensity is available, being outdoors is
preferable to sitting in front of a light box.
Side effects
The side effects of bright light therapy are usually
mild and of short-term duration. Side effects have
primarily been investigated in patients with
seasonal and nonseasonal mood disorders. Thus,
information is by and large lacking for sleep
disorders without mood disturbance.29 One of the
most potential damaging consequences of bright
light is permanent injuries of the eyes.30 However,
in a longitudinal study with thorough ophthalmologic examinations performed before and after
short-term treatment of 10 000 lux (2e8 weeks) of
50 patients, and before and after 3e6 years of
treatment with 10 000 lux of 17 patients, with
cumulative treatment durations of 60e1250 h, no
ocular abnormalities were detected.31 We have no
knowledge of any study that has documented eye
damage due to light therapy administered
according to the standard procedures. In the study
by Pallesen et al.,32 investigating the effects of
bright light treatment in older adults suffering
from early morning awakening, the most common
side effects were eyestrain (29%) and headache
(19%). Unexpectedly, the number of side effects
was greater in the placebo compared to the active
treatment condition. Most of the side effects were
transient.33 Some rare cases of mania as a side
effect of phototherapy have been reported, also in
5
patients who prior to light treatment only had
shown symptoms of unipolar depression.34,35
Melatonin treatment
Exogenously administered melatonin has phase
shifting properties, and the effect follows a phaseresponse curve (PRC) that is about 12 h out of
phase with the PRC of light.1,8,36 Melatonin
administered in the afternoon or early evening will
phase advance the circadian rhythm, whereas
melatonin administered in the morning will phase
delay the circadian rhythm (Fig. 2). The magnitude
of phase shifts is time-dependent, and the
maximal phase shifts result when melatonin is
scheduled around dusk or dawn.36 The effect of
exogenous melatonin is minimal when administered during the night, at least during the first-half
of the night.37 Furthermore, similar to the effects
of bright light, melatonin administered at an
inappropriate time can actually worsen the
patient’s condition.
Melatonin has, in addition to phase shifting
properties, soporific effects. This is seen especially when taking melatonin medication during
the daytime, when endogenous melatonin is low.36
This effect may account for some of its benefit in
the treatment of jet lag and shift work disorder.
There is no consensus regarding the appropriate
dose or formulation of melatonin. Most studies use
fast-release melatonin, but sustained-release
preparations are commercially available. The
doses used in most studies range from 0.5 to 5 mg.
Several studies show that the effects of melatonin
are not clearly dose-related,1 and the phase
shifting effect is considered less than those associated with light exposure.
Side effects
In general, melatonin seems to be well-tolerated,
and few serious side effects have been reported to
date. However, there is a lack of long-term
studies, and little is known about the possible drug
interactions.36 Side effects may include elevation
of blood pressure, headache, dizziness, nausea
and drowsiness.38
Delayed sleep phase disorder
Case history
John, a 17-year-old high school student, seeks
help because of problems of falling asleep at
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6
night. He rarely gets any sleep until 3 a.m. in the
morning, and he has major problems waking up in
the morning in time for school. He has missed
school many days because of this problem, and he
will not pass the exams, if this continues. When
allowed, he can easily sleep until noon or 1 p.m.
Thus, he is able to sleep for more than 7 h in free
periods/weekends, and he does not feel especially
tired or sleepy when he gets up around noon.
However, when he is forced up (usually by his
parents) early in the morning, he often falls
asleep during his classes.
Delayed sleep phase disorder (DSPD) is assumed
to be a frequent circadian rhythm sleep disorder,39
and is defined in ICSD-23 as ‘‘a delay in the phase
of the major sleep period in relation to the desired
sleep time and wake-up time, as evidenced by
a chronic or recurrent complaint of inability to fall
asleep at a desired conventional clock time
together with the inability to awaken at a desired
and socially acceptable time’’. When allowed to
choose their preferred schedule, patients are
assumed to exhibit normal sleep quality and
duration for age and maintain a delayed, but
stable, phase of entrainment to the 24-h sleepe
wake pattern.3 However, some studies suggest
that sleep quality may be poorer even when bed
and wake times are self-selected.40 More studies
are needed to explore these issues. The disorder is
believed to be particularly common in young
people, but more epidemiological studies are
warranted to gain more knowledge about its
prevalence.41 Studies have found a prevalence
ranging from 0.13 to 0.17% in adult populations42,43
and 7.3% in adolescents.44,45 The peak of onset of
DSPD seems to be in childhood or early
adolescence.41
In terms of biology, DSPD is believed to be
caused by anomalies of the mechanisms regulating
the circadian rhythms (see review by Crowley
et al.46). The subjects may have long endogenous
circadian rhythms making it difficult to adjust to
a 24-h sleepewake period, in particular when the
light exposure is not optimal.47 The time from
nadir to spontaneous awakening has been shown to
be altered in patients suffering from DSPD,40,48
causing a tendency to be asleep at times when the
circadian system is particularly sensitive for the
phase advancing effects of light. It has been suggested that the circadian dysregulation may be
linked to genetic factors, and genetic markers
related to DSPD have been found.49
In addition to biological vulnerability, social
factors and habits are believed to play an important role in the development of DSPD. Habits such
as staying up late and ‘‘sleeping in’’ will phase
B. Bjorvatn, S. Pallesen
delay the circadian rhythm. Television, computers,
Internet and cellular phones have made greater
enticements for being awake at night,50 potentially causing a delay of sleep onset. As caffeine
and nicotine have stimulating effects on the
central nervous system, use of these drugs in the
evening can lead to difficulties in initiating sleep.
During puberty, a biological based delay of the
circadian rhythm of about 2 h seems to occur,51
while the need for sleep at the same time seems to
increase.52 Studies, however, indicate that
adolescents do not take this into consideration and
go to bed later than recommended and sleep in
during weekends and holidays.46
Treatment with bright light
Timed bright light has been shown to effectively
phase advance the rhythm,53 but no standardized
guidelines regarding the duration, intensity or
timing of light exposure have been established.
This is despite the fact that light has for long been
known to be the most important modulator of our
circadian rhythms.27
As light exposure prior to nadir causes a phase
delay, subjects suffering from DSPD should avoid
light during this phase, for example by wearing
dark goggles in the evening. Moreover, it is very
important not to wake the patient up too early in
the morning, and start bright light treatment.
Patients suffering from DSPD are likely to have
nadir late in the morning, i.e., after 9 a.m., and
bright light introduced in the early morning will
phase delay the rhythm. Surprisingly, in some
scientific studies bright light seems to be administered at inappropriate times, that is, before the
nadir,53,54 and also recent reviews still advice early
morning bright light in the treatment of delayed
sleep phase disorder.45
Our clinical approach to these patients is to ask
the patient to sleep without an alarm clock until
she/he wakes up. This may be late morning, or
for some patients in the afternoon. This procedure will make sure that the treatment is given
after the nadir of the core body temperature
rhythm. It is highly unlikely that any patient will
wake up before his/her nadir. In our 17-year-old
case history, John slept until 1 p.m., and was
advised to obtain 30 min of bright light treatment
(10 000 lux) immediately following rise time. The
next day John was instructed to get up 1 h earlier
(with help of alarm clock or parents), and start
bright light treatment. The third day, bright light
treatment was started at 11 a.m., the fourth day
at 10 a.m., and so on. Such a procedure will
‘‘push’’ the circadian rhythm in the right
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Estimating circadian phase in every day clinical practice
direction, and light exposure will be administered
at about the same time point in the PRC from day
to day. Some patients may find it very difficult to
get up 1 h earlier from day to day, and the
treatment can be adjusted, i.e., advancing bright
light 30 min earlier from day to day. When the
patient has reached the desired sleepewake
rhythm, usually after less than 1 week of treatment, bright light therapy may be terminated.
For most patients, however, treatment in some
form should probably be continued in order to
prevent relapse. Whether bright light treatment
needs to be given every day, or more intermittently, for instance maintenance treatment 2e4
days per week, is unclear and likely to differ from
patient to patient. In John’s case, he used bright
light every day for 3 weeks, and then continued
with bright light at a more intermittent manner
and successfully completed his studies. Delayed
sleep phase disorder and its treatment often
involve family or other close relationships. Lack
of school achievements may upset the parents.
Adolescents who sleep until noon can cause great
distress for the rest of the family. Often parents
and siblings exert great effort to wake up the
patient at an appropriate time in the morning.
Also, during treatment the patient may need help
in waking up in time for light exposure. When
treatment is successful, tensions and conflicts
centred around bedtime and wake-up time
usually lessen.
Compliance with bright light treatment is often
poor, because it involves structuring the daily
schedule, which may be difficult for the relevant
age group. Our clinical experience is that several
patients improve initially with this kind of treatment, but the compliance gradually deteriorates.
Many young subjects are particularly unwilling to
follow strict bed and rise time schedules during
weekends. For some patients compliance may be
improved by using a light visor instead of
a stationary lamp, as the former allows for movement and execution of simple tasks during light
exposure. The use of outdoor light if available,
instead of sitting in front of a light box, may also
be used to improve compliance.
Treatment with melatonin
Administration of melatonin in the evening has
been shown to phase advance the rhythm,8,55 but
similar to bright light, a standardized approach for
dose, duration and timing is lacking. In clinical
practice it is often recommended to administer
melatonin 5e7 h before the regular time for sleep
onset, in order to obtain maximal phase
7
advance.55 In a well-controlled double-blind
treatment study with subjects suffering from DSPD
it was found that administration of melatonin in
the evening decreased sleep onset latency.56 On
some subjective measures of fatigue and alertness
the subjects in the melatonin group improved
relative to the subjects in the placebo-group.
Biological markers of circadian rhythms showed
that the subjects in the melatonin-group phase
advanced.56 In another study employing a similar
design, therapeutic effects of melatonin on
several sleep and circadian parameters, and on
alertness in the morning, were found.18
In our clinical practice, we usually first recommend bright light treatment. For those patients
where bright light does not work, or the effect is
not satisfactory, exogenous melatonin is recommended, either alone or in combination with
bright light. When melatonin and bright light
treatment are employed together, melatonin is
commonly administered about 12 h before the
bright light exposure.57
One clinically effective method is to time
melatonin similar to the way bright light is timed.
To use John’s case as an illustration, melatonin will
be administered 12 h before bright light treatment
on day 1, i.e., at 1 a.m. On day 2, melatonin is
taken at midnight, day 3 at 11 p.m., and so on.
Using this method, the patient ends up with
exogenous melatonin at about 8 p.m. and bright
light at about 8 a.m. In clinical practice, the
combined treatment seems to facilitate circadian
adaptation more than each treatment alone.
However, to our knowledge only one scientific
paper has addressed this.58
Advanced sleep phase disorder
Advanced sleep phase disorder (ASPD) is characterized by a habitual sleep period that is of normal
quality and duration, but with a sleep onset and
wake-up time that are several hours earlier than
desired.3 ASPD is assumed to be a rare disorder and
using strict criteria in a random sample of
approximately 7700 adults, representative of the
Norwegian population, no case of ASPD was
detected.43 The prevalence in middle-aged and
older adults is estimated to be 1%.3 The etiology of
advanced sleep phase disorder is not well known,
but studies have shown that there exists evidence
in some cases suggesting that such a sleep disturbance runs in families,59 and it has been hypothesized to represent an autosomal dominant
circadian rhythm variant.60 As sleep disturbances
related to sleep phase advance increase with
age,61 it has been suggested that this is
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a consequence of a phase advance of the endogenous circadian pacemaker.62
Treatment
Few studies have investigated the effects of bright
light treatment for advanced sleep phase
disorder. In one study, 16 subjects suffering from
advanced sleep phase disorder were randomized
to 10 days of evening bright light treatment
(4000 lux for 2 h) or to a red dim light placebo
condition. On completion of the treatment, there
was no difference in the nocturnal awakenings
between the two groups for the first two-thirds of
the night, but for the last third of the night the
reduction in nocturnal awakenings was significantly greater in the treatment compared to the
placebo-group.63 However, negative studies are
also published.32,64,65
To treat patients with ASPD, bright light should be
given as close to bedtime as possible. This will likely
delay the circadian rhythm, and thus delay wake-up
time. One reason why the effects of bright light may
not be as clear as in DSP, is that light is given many
hours before the nadir. As discussed earlier, the
closer to nadir the treatment is given, the larger
the phase shifts.24 But to wake up the patients in the
middle of the night (just before nadir) is normally
not an acceptable treatment option.
For these patients, exogenous melatonin
administration is not a good alternative. Based on
circadian principles, melatonin should be given in
the morning (after nadir). However, due to the
potential sedating effect of melatonin, this is
seldom recommended in clinical practice.45
To conclude, evening bright light may be beneficial
in advanced sleep phase disorder, but more studies
are warranted in order to draw firm conclusions.
Free-running
The non-24-h sleepewake syndrome consists of
a chronic pattern comprising 1e2 h daily delays in
sleep onset and wake time. The sleepewake
pattern resembles that found in normal individuals
living in isolation from environmental time cues,
hence the sleepewake rhythm is said to be freerunning. If patients suffering from non-24-h sleepe
wake syndrome arise continually at conventional
social times progressively less sleep is achieved,
accompanied by daytime sleepiness. The prevalence of this syndrome is low and the majority of
patients described in the literature have been
blind.2 The failure to entrain circadian rhythms is
related to the lack of photic input to the circadian
pacemaker.
B. Bjorvatn, S. Pallesen
Treatment
Scientific studies are sparse, and mostly based on
single case reports.2 In one study, a 40-year-old
sighted woman with a free-running sleepewake
rhythm was treated with bright light of 2500 lux for
2 h each day upon awakening. Clock time of light
exposure was held constant for 6 days and then
advanced 30 min until she was arising at 10 a.m.
The subject continued the light treatment at
home, and managed to live on a 24-h day for a 30day follow-up study.66
In blind people without photic input through the
eyes (e.g., severe cataract), several studies show
that exogenous melatonin is effective in entraining
the circadian rhythm.67,68
To conclude, in sighted patients with a freerunning rhythm, bright light may be tried. One
approach is to use a similar method as for delayed
sleep phase disorder. That is, start bright light
treatment after awakening, and then gradually
advance the timing of the bright light from day to
day, until entrainment. Then, continue with bright
light, either intermittently, or if necessary, every
day. A different approach is to start bright light
treatment when the patient’s rhythm is in phase
with the environment. In blind people (with no
photic input) and in sighted people with unsatisfactory effect of bright light, try melatonin. Intake
of melatonin (5e7 h before bedtime) may be
started when the rhythm is phase aligned. A
different approach is to start melatonin administration 12 h after the last awakening, and then
advance the timing of intake from day to day until
entrainment. However, more clinical studies are
clearly warranted for this disorder.
Irregular sleepewake rhythm
Irregular sleepewake rhythm is characterized by
lack of a clearly defined circadian rhythm of sleep
and wake.3 Sleep and wake periods are variable in
length throughout the 24-h day. Prevalence of this
disorder is unknown.
An irregular sleepewake rhythm is commonly
associated with neurological impairment, i.e.,
dementia, and much of the research has focused on
this patient population.2,45 It has also been found to be
related to psychomotor retardation in children.2,69
Estimation of nadir in this disorder is difficult as
no main sleep episode seems to be present.
Instead a polycyclic sleepewake pattern occurs
during the day. Irregular sleepewake rhythm is
assumed partially to be caused by lack of stimuli,
such as light, social activity and work, which normally entrain the circadian rhythm.2,45
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Estimating circadian phase in every day clinical practice
The aim of the treatment is to increase the
amplitude of the circadian rhythm. Specifically,
this has been done by introducing scheduled social
and physical activities. In addition, exposure to
morning bright light and administration of evening
melatonin may also be effective in alleviating the
symptoms.2,45 However, if the patient suffers from
early morning awakening, bright light in the
evening is more appropriate, and morning light
should be avoided.
The diagnosis of irregular sleepewake rhythm
is problematic, since the diagnostic criteria of
ICSD-2 specify that the disorder should not be
better explained by a medical, neurological or
mental disorder.3 Hence, in demented patients
and in mentally retarded children making the
diagnosis of a circadian rhythm sleep disorder is
questionable.
Jet lag disorder
Case history
Ann, a Norwegian 38-year-old scientist, is going to
Baltimore, USA for a conference. She will be away
for 10 days, and she usually adjusts her circadian
rhythm without major problems on westbound
travels. However, she usually experiences severe
problems adjusting back to Norwegian time zone,
when returning from such events. Often she
complains of insomnia at night and sleepiness
during the early day for up to 1 week or more
following 6 h time zone changes. She wonders if
there is anything to do with this jet lag.
Jet lag disorder typically consists of insomnia
and excessive daytime sleepiness associated with
transmeridian jet travel. There is associated
impairment of daytime function, general malaise
and gastrointestinal disturbance.3 The symptoms
occur because the endogenous circadian rhythm
becomes misaligned to the external clock time.
Following rapid travel, the endogenous circadian
system remains aligned to the environmental time
cues of the home time zone. Because the adjustment process of the circadian system is slow,
averaging 60 min of phase adjustment per day
after a phase advance shift (eastbound flight), and
90 min per day after a phase delay shift (westbound flight), symptoms can last for several days
after the flight.70 However, the adjustment
process can be modified. Eastbound flights are
considered more problematic than westbound
flights. One important reason is that for most
people the endogenous period of the sleep/wakerhythm is slightly longer than 24 h,10 thus facilitating adaptation on westbound travels.
9
Treatment with bright light
Adaptation to the new time zone can be accelerated
by bright light treatment, applied according to the
phase-response curve.71 Avoidance of light is also very
important, as light exposure at the ‘‘wrong’’ circadian time can delay adaptation of the internal clock,
or even facilitate adaptation in the wrong direction.
This is also a reason why eastbound travels may be
more problematic than westbound travels; light is
often encountered at a ‘‘wrong’’ circadian time. For
example, in our case history, Ann is travelling eastwards from Baltimore to Norway, a 6 h time zone
change. If the nadir of her core body temperature
rhythm in Baltimore is about 5 a.m., this will correspond to 11 a.m. Norwegian time. When she arrives at
Norway in the morning, she may get exposed to bright
light before her nadir, causing phase delays, thus
hindering adaptation of the circadian rhythm.
According to the phase-response curve, she should
avoid light exposure (e.g., use dark sunglasses) prior
to 11 a.m., and get bright light exposure after 11 a.m.
Light after 11 a.m. will phase advance the rhythm.
The timing of bright light is changed from day to day,72
similar to the method for delayed sleep phase
disorder. In clinical practice, we often advance (or
delay) the timing of light with up to 2 h per day. In
Ann’s case, she was advised to avoid light before 9
a.m., and get exposed bright light after 9. a.m. the
second day. The third day, Ann was advised to avoid
light before 7 a.m. and get bright light exposure after
7 a.m. She will thus adjust her circadian rhythm
within 2e3 days following a 6 h eastbound flight.
Treatment with bright light can also be instituted
prior to departure, if feasible and desirable.
For eastbound travels, the treatment regime
usually aims at adaptation of the circadian rhythm
by phase advance. However, for eastbound travels
over 10 h or more time zones, it may be easier to
phase delay the circadian rhythm. This is partly
due to the fact that for most people our internal
clock is longer than 24 h. However, for morning
larks this may not apply.
For westbound travels over 6e9 time zones,
natural light exposure on the ‘‘wrong’’ circadian
phase is usually not a problem as it is for eastbound
travels. Thus, when travelling west, subjects are
advised to get as much outdoor light as possible
during the daytime. This will facilitate adaptation
of the rhythm. During night-time at the destination, bright light should be avoided.
Treatment with melatonin
Several studies have shown that melatonin may
successfully be applied to reduce jet lag.73,74 In
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clinical practice, best and fastest adaptation may
occur by timing the treatment according to the
individual PRC. In our case history, Ann was
advised to take melatonin 12 h after bright light
exposure, that is, at 11 p.m. on day 1. On day 2,
melatonin was taken at 9 p.m., and at about 7e8
p.m. on day 3. A simpler recommendation is to
administer melatonin every day between 10 and 12
p.m. at the new destination. This normally corresponds well to the ideal timing of melatonin
according to the PRC.73
Combined melatonin and bright light treatment
may facilitate adaptation of the circadian rhythm
even faster than either treatment alone. However,
scientific evidence is lacking. From a clinical
standpoint, we advise such combination in people
suffering from severe jet lag. Treatment for jet lag
usually lasts only 3e4 days, at the most.
Shift work disorder
Case history
Thomas (48 years) works 14 consecutive nights (7
p.m. to 7 a.m.) at an oil platform in the North Sea.
He suffers from severe sleepiness the first nights,
until his rhythm gradually adjusts. Similarly,
following return home after this 14-night working
period, he struggles with re-adaptation back to his
normal day-oriented rhythm. He wonders if
something can help him adapt more easily.
Shift work, and night work in particular, is
associated with negative effects, such as shortened and disturbed sleep, fatigue, decreased
alertness, cognitive decrements, increased
injuries and accidents, reproductive problems and
risks to cardiovascular and gastrointestinal
health.75,76 These symptoms are experienced
because shift workers rarely shift their endogenous
circadian rhythms to align with the sleepewake
schedule demanded by their occupations. Night
workers are therefore often in a constant state of
circadian misalignment, and both work and sleep
at the ‘‘wrong’’ circadian phase. The symptoms
due to circadian misalignment can be reduced
even if the optimal phase relationship is not
completely established. The magnitude of phase
shift is positively related to the extent of improved
performance and alertness during the night, and
better daytime sleep at home.77
Treatment with bright light
Several studies have shown that timed bright light
and darkness can promote adaptation to night
work.76e80 In our case history, bright light timed
B. Bjorvatn, S. Pallesen
before nadir of the core body temperature rhythm
will facilitate adaptation to night work. Nadir is
estimated based on a clinical interview with
Thomas. Thomas usually gets up at 7 a.m., and
based on prior night work experience, he is especially sleepy at around 5 a.m. Hence, nadir of the
core body temperature rhythm is likely to be at
about 5 a.m. Thus, bright light is advised before his
nadir (30 min, 10 000 lux). In addition, he is advised
to avoid bright light after 5 a.m. on night 1. Night 2
he is advised to get bright light at 6 a.m., and avoid
light after 7 a.m. Thomas will likely feel less sleepy
during the night and sleep better during the day the
moment nadir is ‘‘pushed’’ to after the work period.
Usually 2e4 days of treatment may be sufficient for
a night worker. Following the 14-night working
period, Thomas will again be advised to get bright
light exposure. Timing of treatment is more
complicated following the work period, because
nadir is difficult to estimate. In clinical practice, we
advise that a thorough interview may give an indication of the nadir. Thomas experienced sleeping
until about 5 p.m. towards the end of the 14-night
working period. We may assume that nadir may be at
about 3 p.m. Thus, in order to phase delay the
circadian rhythm, bright light exposure was advised
before 3 p.m. Usually, we ask the subjects to receive
as much light as possible (natural or artificial light)
before 3 p.m. Importantly, Thomas is advised to
avoid bright light after 3 p.m., that is, use dark
sunglasses or stay inside. The next day, he is advised
to get exposed to bright light before 5 p.m., and
avoid light after 5 p.m. Day 3: bright light exposure
before 7 p.m., avoid after 7 p.m., and so on. In this
case history, a phase delay was advised, also for the
re-adaptation following the night work period. In
other cases, a phase advance may be more appropriate, i.e., when the nadir of the core body
temperature rhythm is earlier in the day. Individual
treatment is advised, not only based on nadir estimations, but also on the worker’s circadian type
(morning lark or evening owl). Evening owls adapt
easier by phase delays, than by phase advances, due
to their endogenous circadian rhythm.
Treatment with melatonin
Melatonin has also been shown to be efficient in
alleviating the complaints associated with night
work.77,80e82 However, most studies were done
under simulated night work conditions. Similar to
the other circadian rhythm sleep disorders, the
timing of melatonin is important for the effect.
And similarly, the timing of melatonin may be
changed from day to day, in order to maximize the
effect on the circadian rhythm.
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Estimating circadian phase in every day clinical practice
Although both bright light and melatonin may be
effective in alleviating the complaints during night
work, it is questionable whether night workers on
rapid rotating schedules (e.g., 2e3 consecutive
nights) should aim at adapting their circadian
rhythms. If adaptation is successful, re-adaptation
back to day-oriented life is likely impeded.
Treatment based on circadian principles is best
applied to shift schedules lasting 1 week or longer.
We have here focused on the treatment for realigning the circadian rhythm, but strategies to
improve sleep (hypnotics) and alertness (caffeine,
modafinil, scheduled naps) can also be used.45
Such treatment options are not discussed in this
paper.
Summary
Bright light and melatonin can be used successfully
in the treatment of circadian rhythm sleep disorders. However, appropriate timing of the treatments is crucial for the effect. An estimation of
the patient’s circadian phase is therefore important before the treatment is started. In clinical
practice, a careful patient history may give sufficient information in order to estimate the circadian phase. The nadir of the core body
temperature rhythm is about 2 h before the
habitual wake-up time.
Bright light administered before the nadir of the
core body temperature rhythm will phase delay,
whereas bright light administered after the nadir
will phase advance the rhythm. Similarly, the
effect of melatonin is dependent on the timing of
treatment. Melatonin in the late afternoon or
evening will phase advance, whereas melatonin in
the morning will phase delay the circadian rhythm.
In clinical practice, bright light of about 10 000 lux
is usually administered daily for 30e45 min. The
dose of melatonin does not seem to be of great
importance, and for most disorders we use 3 mg
tablets.
In order to maximize the effects of treatment,
the timing of both bright light and melatonin is
often changed from day to day. With such an
approach, the treatments are administered at
about the same time point in the phase-response
curve from day to day.
Importantly, if the treatment effects are not
satisfactory, or if the patient’s condition actually
worsens, you may have incorrectly estimated the
circadian phase! Try to estimate once more, and
adjust the timing of bright light/melatonin
accordingly. This is the advantage in clinical
practice (compared to a scientific protocol); it is
always possible to adjust treatment.
11
In all patients, a differential diagnosis must
always be considered. In order to diagnose a circadian rhythm sleep disorder, the criteria state that
the sleep disturbance should not be better
explained by another current sleep disorder,
medical or neurological disorder, mental disorder,
medication use, or substance use disorder.
Practice points
1. Circadian phase can in many instances be
estimated by careful patient history.
2. Nadir of the core body temperature
rhythm is normally located at about 2 h
before the habitual wake-up time, and
corresponds to the time point where it is
most difficult to stay awake.
3. The phase-response curve to melatonin is
about 12 h out of phase with the phaseresponse curve to light.
4. Bright light exposure before the nadir
induces phase delays, whereas bright light
after the nadir induces phase advances.
5. Exogenous melatonin administration in the
late afternoon or evening induces phase
advances, whereas melatonin administered in the morning induces phase delays.
6. Circadian rhythm sleep disorders can
effectively be treated by appropriately
timed bright light and/or melatonin.
7. Do not start bright light treatment for
delayed sleep phase disorder in the early
morning, but wait until the patient wakes
up in a natural way (without an alarm
clock). Bright light is subsequently administered 1 h earlier per day until
entrainment.
8. Appropriate timing of melatonin administration is about 12 h after bright light
treatment.
Research agenda
1. Scientific studies comparing the circadian
phase measured objectively (by melatonin
assays or core body temperature) and the
circadian phase estimated by careful
patient history should be carried out.
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12
B. Bjorvatn, S. Pallesen
2. Studies examining the clinical effectiveness of bright light, melatonin and
combined bright light/melatonin in circadian rhythm sleep disorders are needed.
3. Comparisons between the effects of bright
light and melatonin in circadian rhythm
sleep disorders. What treatment works
best, and for whom?
4. Studies investigating long-term effectiveness of bright light and/or melatonin in
circadian rhythm sleep disorders should be
conducted.
5. Studies on how to implement treatment
for circadian rhythm sleep disorders in
general clinical practice are necessary.
6. Studies investigating different light intensities and different doses of melatonin in
the treatment of circadian rhythm sleep
disorders are warranted.
7. Studies investigating safety issues associated with long-term use of light and/or
melatonin are needed.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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