A practical approach to circadian rhythm sleep disorders

* CorrespondPrimaryHealthBergen, Norwa

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1087-0792/$ -doi:10.1016/j.

Sleep Medicine Reviews (2009) 13, 47e60

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CLINICAL REVIEW

A practical approach to circadian rhythmsleep disorders

Bjørn Bjorvatn a,b,c,*, Stale Pallesen b,c,d

a Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31,N-5018 Bergen, Norwayb Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Norwayc Bergen Sleep Disorders Center, Bergen, Norwayd Department of Psychosocial Science, University of Bergen, Norway

KEYWORDSCircadian rhythmdisorders;Bright light;Melatonin;Nadir;Sleep regulation

ing author. DepartmenCare,Universityof Bergy. Tel.: þ47 55 58 61 00ess: bjorn.bjorvatn@is

see front matter ª 200smrv.2008.04.009

Summary Circadian rhythm sleep disorders are common in clinical practice. Thedisorders covered in this review are delayed sleep phase disorder, advanced sleepphase disorder, free-running, irregular sleepewake rhythm, jet lag disorder andshift work disorder. Bright light treatment and exogenous melatonin administrationare considered to be the treatments of choice for these circadian rhythm sleepdisorders. Circadian phase needs to be estimated in order to time the treatmentsappropriately. Inappropriately timed bright light and melatonin will likely worsenthe condition. Measurements of core body temperature or endogenous melatoninrhythms will objectively assess circadian phase; however, such measurements areseldom or never used in a busy clinical practice. This review will focus on how toestimate circadian phase based on a careful patient history. Based on such estima-tions of circadian phase, we will recommend appropriate timing of bright light and/or melatonin in the different circadian rhythm sleep disorders. We hope thispractical approach and simple recommendations will stimulate clinicians to treatpatients with circadian rhythm sleep disorders.ª 2008 Elsevier Ltd. All rights reserved.

t of Public Health anden,Kalfarveien31,N-5018; fax: þ47 55 58 61 30.f.uib.no (B. Bjorvatn).

8 Elsevier Ltd. All rights reser

Introduction

Circadian rhythm sleep disorders are caused bya misalignment between the endogenous circadiantiming system and the external 24-h environment.The disorders typically result in complaints ofinsomnia and/or excessive sleepiness, in additionto impairment in normal functioning and quality of

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48 B. Bjorvatn, S. Pallesen

life. Many clinicians face patients suffering fromsuch complaints, but there is lack of evidence-based guidelines on how to diagnose, examine andtreat these disorders.1,2 This review providesa practical approach to handling the differentcircadian rhythm sleep disorders, as they aredefined in the International Classification of SleepDisorders.3 Although the practical approach pre-sented here is not based on firm evidence drawnfrom controlled clinical trials, the approach isbased on well-researched basic principles ofcircadian entrainment.

We would also like to emphasize that althoughthere is a definite need for more research on practicalissues concerning treatment, the clinical approachwhich is presented here will likely help many of thepatients suffering from circadian rhythm sleep disor-ders. Based on our long-term clinical experience indiagnosing and treating such disorders, we have foundthat treating these patients is usually easier thanmany clinicians believe.

To be able to treat patients with circadianrhythm sleep disorders, it is important to under-stand how sleep is regulated. Thus, we will initiallyfocus on sleep regulation, and how to determinecircadian phase. Then we will cover each separatecircadian rhythm sleep disorder,3 and specifya simple and clinical approach on how to treatpatients suffering from these disorders. Theadvantage of a clinical approach is that the specificinterventions can be adjusted, if the treatmentdoes not help or if the condition actually worsens.This is especially important in these disorders,where the timing of the treatment is crucial. Thismeans that if treatment is instituted at the inap-propriate circadian time, the patients are likely toget worse.

The treatment options in ordinary clinicalpractice for circadian rhythm sleep disorderscomprise bright light treatment and exogenousmelatonin administration. How to use thesetreatment options will be covered under eachspecific circadian rhythm sleep disorder. Chrono-therapy has been used for the treatment of someof the circadian rhythm sleep disorders, but wewill not discuss this any further in our review, dueto the difficulties of implementing such anapproach and lack of data documenting its effi-cacy. Furthermore, we will not cover use ofhypnotics or other medications, due to spacelimitations.

We have epidemiological data for many of thedifferent circadian rhythm sleep disorders, but thenumber of patients who actually seek treatmentfor these disorders is much less. The reasons maybe many. One probable reason is lack of knowledge

about the disorders and their possible treatments,both among health professionals and patients.

Sleep regulation

Sleep is regulated by an interplay of differentfactors. The main focus has been on the interac-tion between the homeostatic and the endogenouscircadian processes.4 The homeostatic processaccumulates as a function of prior wakefulness,i.e., there is more homeostatic factor the longeryou are awake.5 This factor is believed to be ofmain importance for sleep quality; that is, thelonger you are awake, the deeper the followingsleep episode will be (increased slow waveactivity). The circadian factor on the other handplays an important role in sleep quantity; that is,sleep duration is for the most part determined bywhen you go to bed. In other words, sleep length isnot dependent on the sleep homeostatic factor,but largely dependent on when you go to sleepaccording to your own circadian rhythm.4 Nightworkers have experienced this as their sleepduration 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 morehours before going to bed than daytime workers.6

From a practical point of view, this interactionbetween the homeostatic and circadian processesmeans that it is important to be awake fora substantial amount of time to get sleep of highquality, and to have regular bed and rise times inorder to have a stable sleep duration.

Also habits and behavioral factors have largeinfluences on sleep. We all go to bed at regularhours, not necessarily because we are very sleepy/tired, but because we know we need to do so, toget enough sleep. Many people experience a highlevel of sleepiness early in the evening/afternoon,but avoid going to bed knowing that it is not timefor bed yet. Behavioral factors can override boththe homeostatic and circadian factors. Forinstance, a night worker is able to stay awake eventhough both the homeostatic and the circadianfactors favor sleep in the middle of the night. Inthese instances behavioral factors, like talking tosomeone, walking around, drinking coffee,increasing illumination, etc., help the nightworkers to stay awake. Similarly, many teachershave experienced students falling asleep at 9 a.m.,even though both the homeostatic and circadianfactors favor wakefulness. In this instance, lack ofstimulation may be a behavioral factor explainingthe increase in sleepiness and risk of falling asleep;that is, a boring lecture, sitting in a dark room,lack of sensory input, etc.

Estimating circadian phase in every day clinical practice 49

Core body temperature and endogenousmelatonin rhythms

For thetreatmentofcircadianrhythmsleepdisorders,an understanding of the circadian timing system is ofcrucial importance. Of central importance is thedetermination of the circadian phase, i.e., the nadirof the core body temperature rhythm, or the endog-enous melatonin rhythm. For simplicity, we willprimarily focus on the nadir of the core bodytemperature rhythm, and the role of this nadir whenrecommending correct timing of treatment of thedifferent circadian rhythm sleep disorders.

The core body temperature usually peaks in thelate afternoon or evening hours, and reaches itslowest point, nadir, in the early morning (Fig. 1).Sleep normally occurs on the downward slope ofthe core body temperature rhythm and normallyends about 2 h following nadir. A similar couplingbetween the sleep/wake-rhythm and the rhyth-micity of the melatonin secretion is also normallypresent. Melatonin secretion usually increasessoon after the onset of darkness, peaks in themiddle of the night and gradually falls during thesecond half of the night. Sleep usually takes placewhen the melatonin level is high, and wakefulnessnormally coexists with low plasma melatoninlevels. Based on the close correspondencebetween sleep/wakefulness and body tempera-ture/melatonin, the core body temperature andmelatonin (measured in saliva, urine or plasma)constitute the two most common physiologicalmeasures of circadian rhythm.1,7,8 Interestingly,mammals continue to show periodic regularity insleep and wakefulness also in the absence of lightor other time signalling stimuli (zeitgebers). Thishas also been demonstrated in studies with humansubjects, kept isolated in underground bunkers.However, the period of the sleep/wake-rhythmunder such conditions was reported to be

Time of day

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Tem

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36.2

36.4

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Figure 1 Core body temperature rhythm.

somewhat longer than 24 h, approximately 25 h.9

Several studies have now confirmed that humansare in possession of an endogenous circadianrhythm, with a period length under controlledconditions of about 24.2 h.10 The main site of thisendogenous rhythm has been located in thesuprachiasmatic nuclei (SCN), situated bilaterallyabove the optic chiasm in the anterior basalhypothalamus.11 Ablation of the SCN in mammalshas been shown to eliminate circadian rhythms,and transplantation restores the rhythm to theperiod of the donor animal.12

There exist several major input fiber systems inthe SCN. The most important stems from photo-receptors in the retina, which convey signals to thesuprachiasmatic nucleus via a monosynapticpathway, the retinohypothalamic tract. Recently,it was discovered that the retinal rod and conecells are not required for photoentraiment, butthat there exists a subset of retinal cells (2500 ofa total of 100 000 cells) containing a light-sensingpigment, melanopsin, which is assumed to beinvolved in circadian photoentrainment.13 Thereexists an important connection between the SCNand the pineal gland. Melatonin, which is the onlyknown hormonal output from the pineal gland,affects the SCN by inhibiting firing.14 Hence, theSCN and pineal gland seem to be able to influenceeach other in a mutual way.

Estimation of circadian phase

To be able to measure the circadian phase ofa patient in an objective manner, either core bodytemperature or melatonin (in saliva, urine orblood) must be assessed. In laboratory basedstudies core body temperature rhythm is normallymeasured by the so-called constant routineprotocol. This protocol implies that the patienttakes on a semi-recumbent position in a laboratoryenvironment for several (often 26) consecutivehours. The light intensity is required to be lessthan 50 lux and the patient normally receivesa meal of 100 kcal every hour.15 The commonlyused circadian parameter obtained from thisprotocol is the nadir (time of the lowest levelmeasured) of the core body temperature.Measurement of the circadian rhythm based uponmelatonin comprises several samples (normallywith a 30 or 60 min interval) of either saliva, urineor plasma. The level of illumination currentlyrecommended for sampling is 10 lux.16 The mostcommonly used parameter from these measures isthe dim light melatonin onset (DLMO), normallydefined as the time when the melatonin levelreaches 2 pg/ml in plasma17 or when a level of

Figure 2 Phase-response curve for light (full line) andmelatonin (dotted line) based upon Khalsa et al.24 andLewy et al.8 A phase-response curve illustrates therelationship between the timing and the effect ofa treatment designed to affect circadian rhythms. Thedifferences in effect between light and melatonin arenot necessary as shown in this figure but will depend onthe doses of light and melatonin.


4 pg/ml is reached in saliva.18 Alternatively, thethreshold for DLMO can be defined as the mean of3 daytime samples plus two times the standarddeviation of these 3 daytime samples.19

Measurements as described above are cumber-some and expensive, and for these reasons seldomor never performed in a busy clinical practice.Thus, we will here emphasize how to estimatecircadian phase by taking a careful patient history.

As a rule of thumb, the nadir of the core bodytemperature is located about 2 h before habitualtime of awakening. For patients with stablecircadian rhythms, that is, stable bed and risetimes, estimation of nadir is relatively easy. Forinstance, if the patient usually wakes up at about 8a.m. every day, the nadir of the core bodytemperature rhythm is likely to be some timearound 6 a.m. Some patients may have stable bedand rise times during the workweek, but during theweekend, this rhythm is delayed by several hours.Estimation of nadir is more complicated in suchcases. Furthermore, use of medications/drugs,alcohol or irregular work schedules can makeestimation of nadir very difficult. Before insti-tuting treatment, it may be helpful to instruct thepatient to sleep until she or he wakes up (withoutan alarm clock). It is likely that nadir will be about2 h before his/her awakening. Previous studieshave shown that subjective sleep data from unin-terrupted sleep can be used as a reasonable goodestimate of circadian phase,20,21 and that sleepoffset correlates higher with different phasemarkers than sleep onset.21,22

Nadir is, in addition to being the lowest point onthe core body temperature rhythm, the timewhere it is most difficult to stay awake.23 Nightworkers often experience an increase in sleepinessduring 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 mostsleepy during the night corresponds to the nadir,this may be used as an additional help for esti-mating the nadir, particularly in night work and jetlag. For other circadian rhythm sleep disorders,where the patients may not have been awakeduring their regular sleep episode, this approachfor estimating the nadir may not be possible.

Bright light treatment

An important function of the SCN is to adjust theoutput signals and the endogenous rhythm inaccordance with external time signalling stimuli(zeitgebers). The afferent connections of the SCNindicate that it is particularly sensitive to light,and light is now considered the most important

zeitgeber. The process by which light synchronizesthe SCN to a 24-h day is called entrainment. Ahuman living in a natural habitat will adhere toa 24-h day, primarily due to light exposure. But theSCN is not equally sensitive to the effect of light atall time points during the day, and the type ofeffect light exposure has on the circadian rhythmis also related to the duration of the light expo-sure. Studies, using a variety of experimentaldesigns, have now consistently shown that theeffect of light on circadian rhythms follows a so-called phase-response curve (PRC).24 According tothe PRC, light can have two opposite effects on thecircadian rhythm (Fig. 2). Light exposure beforethe nadir of the core body temperature rhythmcauses a phase delay, whereas light administeredafter nadir produces a phase advance. Thus, lightin the evening normally causes phase delay, andlight in the morning causes phase advance. Also,light exposure close to the nadir produces thegreatest phase shifts. It follows that the furtheraway from nadir light exposure takes place, theless effect it exerts.25 The magnitude of phaseshifts is also a function of the dose and duration ofthe light exposure. In general, high intensity lightdoses and long durations of light exposure causethe greatest phase shifts.26 For long durations oflight that fall on both the phase advance and delayportions of the PRC, the direction of the resultingphase shift is influenced by where most of the lightfalls.24,27,28 Hence, light can advance or delay thecircadian rhythm depending on time of lightexposure.

Today, bright light is typically administered byportable units yielding about 10 000 lux, and


exposure time is about 30e45 min per day. Studieshave also investigated the effects of presentinglight of different wavelengths. Visible light withshort wavelengths (blue light) has a strongermelatonin suppressing effect and a stronger phaseshifting effect on the human circadian rhythmcompared to light with longer wavelengths.1

During light exposure the patient is instructed tokeep his gaze directed at the light source, but notto continuously stare into the light. A potentialproblem with small apparatus is that even smallchanges in head position sometimes can lead tosubstantial reductions in the light intensity thatreaches the eyes, hence reducing the therapeuticeffect.29 Light treatment can be self-administeredat home, according to a therapeutic regime. To theextent that the timing of light treatment is impor-tant in order to obtain a therapeutic effect,compliance is sine qua non.29 Patients may read thenewspaper, watch television, or eat while beingexposed to bright light. Bright light of 10 000 lux forat least 30 min is recommended, but light of lessintensity or shorter duration will be better than nolight at all. Furthermore, whenever outdoor light ofsufficient intensity is available, being outdoors ispreferable to sitting in front of a light box.

Side effects

The side effects of bright light therapy are usuallymild and of short-term duration. Side effects haveprimarily been investigated in patients withseasonal and nonseasonal mood disorders. Thus,information is by and large lacking for sleepdisorders without mood disturbance.29 One of themost potential damaging consequences of brightlight is permanent injuries of the eyes.30 However,in a longitudinal study with thorough ophthalmo-logic examinations performed before and aftershort-term treatment of 10 000 lux (2e8 weeks) of50 patients, and before and after 3e6 years oftreatment with 10 000 lux of 17 patients, withcumulative treatment durations of 60e1250 h, noocular abnormalities were detected.31 We have noknowledge of any study that has documented eyedamage due to light therapy administeredaccording to the standard procedures. In the studyby Pallesen et al.,32 investigating the effects ofbright light treatment in older adults sufferingfrom early morning awakening, the most commonside effects were eyestrain (29%) and headache(19%). Unexpectedly, the number of side effectswas greater in the placebo compared to the activetreatment condition. Most of the side effects weretransient.33 Some rare cases of mania as a sideeffect of phototherapy have been reported, also in

patients who prior to light treatment only hadshown symptoms of unipolar depression.34,35

Melatonin treatment

Exogenously administered melatonin has phaseshifting properties, and the effect follows a phase-response curve (PRC) that is about 12 h out ofphase with the PRC of light.1,8,36 Melatoninadministered in the afternoon or early evening willphase advance the circadian rhythm, whereasmelatonin administered in the morning will phasedelay the circadian rhythm (Fig. 2). The magnitudeof phase shifts is time-dependent, and themaximal phase shifts result when melatonin isscheduled around dusk or dawn.36 The effect ofexogenous melatonin is minimal when adminis-tered during the night, at least during the first-halfof the night.37 Furthermore, similar to the effectsof bright light, melatonin administered at aninappropriate time can actually worsen thepatient’s condition.

Melatonin has, in addition to phase shiftingproperties, soporific effects. This is seen espe-cially when taking melatonin medication duringthe daytime, when endogenous melatonin is low.36

This effect may account for some of its benefit inthe treatment of jet lag and shift work disorder.

There is no consensus regarding the appropriatedose or formulation of melatonin. Most studies usefast-release melatonin, but sustained-releasepreparations are commercially available. Thedoses used in most studies range from 0.5 to 5 mg.Several studies show that the effects of melatoninare not clearly dose-related,1 and the phaseshifting effect is considered less than those asso-ciated with light exposure.

Side effects

In general, melatonin seems to be well-tolerated,and few serious side effects have been reported todate. However, there is a lack of long-termstudies, and little is known about the possible druginteractions.36 Side effects may include elevationof blood pressure, headache, dizziness, nauseaand drowsiness.38

Delayed sleep phase disorder

Case history

John, a 17-year-old high school student, seekshelp because of problems of falling asleep at


night. He rarely gets any sleep until 3 a.m. in themorning, and he has major problems waking up inthe morning in time for school. He has missedschool many days because of this problem, and hewill not pass the exams, if this continues. Whenallowed, he can easily sleep until noon or 1 p.m.Thus, he is able to sleep for more than 7 h in freeperiods/weekends, and he does not feel especiallytired or sleepy when he gets up around noon.However, when he is forced up (usually by hisparents) early in the morning, he often fallsasleep during his classes.

Delayed sleep phase disorder (DSPD) is assumedto be a frequent circadian rhythm sleep disorder,39

and is defined in ICSD-23 as ‘‘a delay in the phaseof the major sleep period in relation to the desiredsleep time and wake-up time, as evidenced bya chronic or recurrent complaint of inability to fallasleep at a desired conventional clock timetogether with the inability to awaken at a desiredand socially acceptable time’’. When allowed tochoose their preferred schedule, patients areassumed to exhibit normal sleep quality andduration for age and maintain a delayed, butstable, phase of entrainment to the 24-h sleepewake pattern.3 However, some studies suggestthat sleep quality may be poorer even when bedand wake times are self-selected.40 More studiesare needed to explore these issues. The disorder isbelieved to be particularly common in youngpeople, but more epidemiological studies arewarranted to gain more knowledge about itsprevalence.41 Studies have found a prevalenceranging from 0.13 to 0.17% in adult populations42,43

and 7.3% in adolescents.44,45 The peak of onset ofDSPD seems to be in childhood or earlyadolescence.41

In terms of biology, DSPD is believed to becaused by anomalies of the mechanisms regulatingthe circadian rhythms (see review by Crowleyet al.46). The subjects may have long endogenouscircadian rhythms making it difficult to adjust toa 24-h sleepewake period, in particular when thelight exposure is not optimal.47 The time fromnadir to spontaneous awakening has been shown tobe altered in patients suffering from DSPD,40,48

causing a tendency to be asleep at times when thecircadian system is particularly sensitive for thephase advancing effects of light. It has been sug-gested that the circadian dysregulation may belinked to genetic factors, and genetic markersrelated to DSPD have been found.49

In addition to biological vulnerability, socialfactors and habits are believed to play an impor-tant role in the development of DSPD. Habits suchas staying up late and ‘‘sleeping in’’ will phase

delay the circadian rhythm. Television, computers,Internet and cellular phones have made greaterenticements for being awake at night,50 poten-tially causing a delay of sleep onset. As caffeineand nicotine have stimulating effects on thecentral nervous system, use of these drugs in theevening can lead to difficulties in initiating sleep.During puberty, a biological based delay of thecircadian rhythm of about 2 h seems to occur,51

while the need for sleep at the same time seems toincrease.52 Studies, however, indicate thatadolescents do not take this into consideration andgo to bed later than recommended and sleep induring weekends and holidays.46

Treatment with bright light

Timed bright light has been shown to effectivelyphase advance the rhythm,53 but no standardizedguidelines regarding the duration, intensity ortiming of light exposure have been established.This is despite the fact that light has for long beenknown to be the most important modulator of ourcircadian rhythms.27

As light exposure prior to nadir causes a phasedelay, subjects suffering from DSPD should avoidlight during this phase, for example by wearingdark goggles in the evening. Moreover, it is veryimportant not to wake the patient up too early inthe morning, and start bright light treatment.Patients suffering from DSPD are likely to havenadir late in the morning, i.e., after 9 a.m., andbright light introduced in the early morning willphase delay the rhythm. Surprisingly, in somescientific studies bright light seems to be admin-istered at inappropriate times, that is, before thenadir,53,54 and also recent reviews still advice earlymorning bright light in the treatment of delayedsleep phase disorder.45

Our clinical approach to these patients is to askthe patient to sleep without an alarm clock untilshe/he wakes up. This may be late morning, orfor some patients in the afternoon. This proce-dure will make sure that the treatment is givenafter the nadir of the core body temperaturerhythm. It is highly unlikely that any patient willwake up before his/her nadir. In our 17-year-oldcase history, John slept until 1 p.m., and wasadvised to obtain 30 min of bright light treatment(10 000 lux) immediately following rise time. Thenext day John was instructed to get up 1 h earlier(with help of alarm clock or parents), and startbright light treatment. The third day, bright lighttreatment was started at 11 a.m., the fourth dayat 10 a.m., and so on. Such a procedure will‘‘push’’ the circadian rhythm in the right


direction, and light exposure will be administeredat about the same time point in the PRC from dayto day. Some patients may find it very difficult toget up 1 h earlier from day to day, and thetreatment can be adjusted, i.e., advancing brightlight 30 min earlier from day to day. When thepatient has reached the desired sleepewakerhythm, usually after less than 1 week of treat-ment, bright light therapy may be terminated.For most patients, however, treatment in someform should probably be continued in order toprevent relapse. Whether bright light treatmentneeds to be given every day, or more intermit-tently, for instance maintenance treatment 2e4days per week, is unclear and likely to differ frompatient to patient. In John’s case, he used brightlight every day for 3 weeks, and then continuedwith bright light at a more intermittent mannerand successfully completed his studies. Delayedsleep phase disorder and its treatment ofteninvolve family or other close relationships. Lackof school achievements may upset the parents.Adolescents who sleep until noon can cause greatdistress for the rest of the family. Often parentsand siblings exert great effort to wake up thepatient at an appropriate time in the morning.Also, during treatment the patient may need helpin waking up in time for light exposure. Whentreatment is successful, tensions and conflictscentred around bedtime and wake-up timeusually lessen.

Compliance with bright light treatment is oftenpoor, because it involves structuring the dailyschedule, which may be difficult for the relevantage group. Our clinical experience is that severalpatients improve initially with this kind of treat-ment, but the compliance gradually deteriorates.Many young subjects are particularly unwilling tofollow strict bed and rise time schedules duringweekends. For some patients compliance may beimproved by using a light visor instead ofa stationary lamp, as the former allows for move-ment and execution of simple tasks during lightexposure. The use of outdoor light if available,instead of sitting in front of a light box, may alsobe used to improve compliance.

Treatment with melatonin

Administration of melatonin in the evening hasbeen shown to phase advance the rhythm,8,55 butsimilar to bright light, a standardized approach fordose, duration and timing is lacking. In clinicalpractice it is often recommended to administermelatonin 5e7 h before the regular time for sleeponset, in order to obtain maximal phase

advance.55 In a well-controlled double-blindtreatment study with subjects suffering from DSPDit was found that administration of melatonin inthe evening decreased sleep onset latency.56 Onsome subjective measures of fatigue and alertnessthe subjects in the melatonin group improvedrelative to the subjects in the placebo-group.Biological markers of circadian rhythms showedthat the subjects in the melatonin-group phaseadvanced.56 In another study employing a similardesign, therapeutic effects of melatonin onseveral sleep and circadian parameters, and onalertness in the morning, were found.18

In our clinical practice, we usually first recom-mend bright light treatment. For those patientswhere bright light does not work, or the effect isnot satisfactory, exogenous melatonin is recom-mended, either alone or in combination withbright light. When melatonin and bright lighttreatment are employed together, melatonin iscommonly administered about 12 h before thebright light exposure.57

One clinically effective method is to timemelatonin similar to the way bright light is timed.To use John’s case as an illustration, melatonin willbe administered 12 h before bright light treatmenton day 1, i.e., at 1 a.m. On day 2, melatonin istaken at midnight, day 3 at 11 p.m., and so on.Using this method, the patient ends up withexogenous melatonin at about 8 p.m. and brightlight at about 8 a.m. In clinical practice, thecombined treatment seems to facilitate circadianadaptation more than each treatment alone.However, to our knowledge only one scientificpaper has addressed this.58

Advanced sleep phase disorder

Advanced sleep phase disorder (ASPD) is charac-terized by a habitual sleep period that is of normalquality and duration, but with a sleep onset andwake-up time that are several hours earlier thandesired.3 ASPD is assumed to be a rare disorder andusing strict criteria in a random sample ofapproximately 7700 adults, representative of theNorwegian population, no case of ASPD wasdetected.43 The prevalence in middle-aged andolder adults is estimated to be 1%.3 The etiology ofadvanced sleep phase disorder is not well known,but studies have shown that there exists evidencein some cases suggesting that such a sleep distur-bance runs in families,59 and it has been hypoth-esized to represent an autosomal dominantcircadian rhythm variant.60 As sleep disturbancesrelated to sleep phase advance increase withage,61 it has been suggested that this is


a consequence of a phase advance of the endog-enous circadian pacemaker.62

Treatment

Few studies have investigated the effects of brightlight treatment for advanced sleep phasedisorder. In one study, 16 subjects suffering fromadvanced sleep phase disorder were randomizedto 10 days of evening bright light treatment(4000 lux for 2 h) or to a red dim light placebocondition. On completion of the treatment, therewas no difference in the nocturnal awakeningsbetween the two groups for the first two-thirds ofthe night, but for the last third of the night thereduction in nocturnal awakenings was signifi-cantly greater in the treatment compared to theplacebo-group.63 However, negative studies arealso published.32,64,65

To treat patients with ASPD, bright light should begiven as close to bedtime as possible. This will likelydelay the circadian rhythm, and thus delay wake-uptime. One reason why the effects of bright light maynot be as clear as in DSP, is that light is given manyhours before the nadir. As discussed earlier, thecloser to nadir the treatment is given, the largerthe phase shifts.24 But to wake up the patients in themiddle of the night (just before nadir) is normallynot an acceptable treatment option.

For these patients, exogenous melatoninadministration is not a good alternative. Based oncircadian principles, melatonin should be given inthe morning (after nadir). However, due to thepotential sedating effect of melatonin, this isseldom recommended in clinical practice.45

To conclude, evening bright light may be beneficialin advanced sleep phase disorder, but more studiesare warranted in order to draw firm conclusions.

Free-running

The non-24-h sleepewake syndrome consists ofa chronic pattern comprising 1e2 h daily delays insleep onset and wake time. The sleepewakepattern resembles that found in normal individualsliving in isolation from environmental time cues,hence the sleepewake rhythm is said to be free-running. If patients suffering from non-24-h sleepewake syndrome arise continually at conventionalsocial times progressively less sleep is achieved,accompanied by daytime sleepiness. The preva-lence of this syndrome is low and the majority ofpatients described in the literature have beenblind.2 The failure to entrain circadian rhythms isrelated to the lack of photic input to the circadianpacemaker.

Treatment

Scientific studies are sparse, and mostly based onsingle case reports.2 In one study, a 40-year-oldsighted woman with a free-running sleepewakerhythm was treated with bright light of 2500 lux for2 h each day upon awakening. Clock time of lightexposure was held constant for 6 days and thenadvanced 30 min until she was arising at 10 a.m.The subject continued the light treatment athome, and managed to live on a 24-h day for a 30-day follow-up study.66

In blind people without photic input through theeyes (e.g., severe cataract), several studies showthat exogenous melatonin is effective in entrainingthe circadian rhythm.67,68

To conclude, in sighted patients with a free-running rhythm, bright light may be tried. Oneapproach is to use a similar method as for delayedsleep phase disorder. That is, start bright lighttreatment after awakening, and then graduallyadvance the timing of the bright light from day today, until entrainment. Then, continue with brightlight, either intermittently, or if necessary, everyday. A different approach is to start bright lighttreatment when the patient’s rhythm is in phasewith the environment. In blind people (with nophotic input) and in sighted people with unsatis-factory effect of bright light, try melatonin. Intakeof melatonin (5e7 h before bedtime) may bestarted when the rhythm is phase aligned. Adifferent approach is to start melatonin adminis-tration 12 h after the last awakening, and thenadvance the timing of intake from day to day untilentrainment. However, more clinical studies areclearly warranted for this disorder.

Irregular sleepewake rhythm

Irregular sleepewake rhythm is characterized bylack of a clearly defined circadian rhythm of sleepand wake.3 Sleep and wake periods are variable inlength throughout the 24-h day. Prevalence of thisdisorder is unknown.

An irregular sleepewake rhythm is commonlyassociated with neurological impairment, i.e.,dementia, and much of the research has focused onthispatientpopulation.2,45 Ithasalsobeenfoundtoberelated to psychomotor retardation in children.2,69

Estimation of nadir in this disorder is difficult asno main sleep episode seems to be present.Instead a polycyclic sleepewake pattern occursduring the day. Irregular sleepewake rhythm isassumed partially to be caused by lack of stimuli,such as light, social activity and work, which nor-mally entrain the circadian rhythm.2,45


The aim of the treatment is to increase theamplitude of the circadian rhythm. Specifically,this has been done by introducing scheduled socialand physical activities. In addition, exposure tomorning bright light and administration of eveningmelatonin may also be effective in alleviating thesymptoms.2,45 However, if the patient suffers fromearly morning awakening, bright light in theevening is more appropriate, and morning lightshould be avoided.

The diagnosis of irregular sleepewake rhythmis problematic, since the diagnostic criteria ofICSD-2 specify that the disorder should not bebetter explained by a medical, neurological ormental disorder.3 Hence, in demented patientsand in mentally retarded children making thediagnosis of a circadian rhythm sleep disorder isquestionable.

Jet lag disorder

Case history

Ann, a Norwegian 38-year-old scientist, is going toBaltimore, USA for a conference. She will be awayfor 10 days, and she usually adjusts her circadianrhythm without major problems on westboundtravels. However, she usually experiences severeproblems adjusting back to Norwegian time zone,when returning from such events. Often shecomplains of insomnia at night and sleepinessduring the early day for up to 1 week or morefollowing 6 h time zone changes. She wonders ifthere is anything to do with this jet lag.

Jet lag disorder typically consists of insomniaand excessive daytime sleepiness associated withtransmeridian jet travel. There is associatedimpairment of daytime function, general malaiseand gastrointestinal disturbance.3 The symptomsoccur because the endogenous circadian rhythmbecomes misaligned to the external clock time.Following rapid travel, the endogenous circadiansystem remains aligned to the environmental timecues of the home time zone. Because the adjust-ment process of the circadian system is slow,averaging 60 min of phase adjustment per dayafter a phase advance shift (eastbound flight), and90 min per day after a phase delay shift (west-bound flight), symptoms can last for several daysafter the flight.70 However, the adjustmentprocess can be modified. Eastbound flights areconsidered more problematic than westboundflights. One important reason is that for mostpeople the endogenous period of the sleep/wake-rhythm is slightly longer than 24 h,10 thus facili-tating adaptation on westbound travels.


Adaptation to the new time zone can be acceleratedby bright light treatment, applied according to thephase-responsecurve.71 Avoidanceof light isalsoveryimportant, as light exposure at the ‘‘wrong’’ circa-dian 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 bemore problematic than westbound travels; light isoften encountered at a ‘‘wrong’’ circadian time. Forexample, in our case history, Ann is travelling east-wards from Baltimore to Norway, a 6 h time zonechange. If the nadir of her core body temperaturerhythm in Baltimore is about 5 a.m., this will corre-spond to 11 a.m. Norwegian time. When she arrives atNorway in the morning, she may get exposed to brightlight before her nadir, causing phase delays, thushindering adaptation of the circadian rhythm.According to the phase-response curve, she shouldavoid light exposure (e.g., use dark sunglasses) priorto 11 a.m., and get bright light exposure after 11 a.m.Light after 11 a.m. will phase advance the rhythm.Thetimingofbright light is changedfromdaytoday,72

similar to the method for delayed sleep phasedisorder. In clinical practice, we often advance (ordelay) the timing of light with up to 2 h per day. InAnn’s case, she was advised to avoid light before 9a.m., and get exposed bright light after 9. a.m. thesecond day. The third day, Ann was advised to avoidlight before 7 a.m. and get bright light exposure after7 a.m. She will thus adjust her circadian rhythmwithin 2e3 days following a 6 h eastbound flight.Treatment with bright light can also be institutedprior to departure, if feasible and desirable.

For eastbound travels, the treatment regimeusually aims at adaptation of the circadian rhythmby phase advance. However, for eastbound travelsover 10 h or more time zones, it may be easier tophase delay the circadian rhythm. This is partlydue to the fact that for most people our internalclock is longer than 24 h. However, for morninglarks this may not apply.

For westbound travels over 6e9 time zones,natural light exposure on the ‘‘wrong’’ circadianphase is usually not a problem as it is for eastboundtravels. Thus, when travelling west, subjects areadvised to get as much outdoor light as possibleduring the daytime. This will facilitate adaptationof the rhythm. During night-time at the destina-tion, bright light should be avoided.


Several studies have shown that melatonin maysuccessfully be applied to reduce jet lag.73,74 In


clinical practice, best and fastest adaptation mayoccur by timing the treatment according to theindividual PRC. In our case history, Ann wasadvised to take melatonin 12 h after bright lightexposure, that is, at 11 p.m. on day 1. On day 2,melatonin was taken at 9 p.m., and at about 7e8p.m. on day 3. A simpler recommendation is toadminister melatonin every day between 10 and 12p.m. at the new destination. This normally corre-sponds well to the ideal timing of melatoninaccording to the PRC.73

Combined melatonin and bright light treatmentmay facilitate adaptation of the circadian rhythmeven faster than either treatment alone. However,scientific evidence is lacking. From a clinicalstandpoint, we advise such combination in peoplesuffering from severe jet lag. Treatment for jet lagusually lasts only 3e4 days, at the most.

Shift work disorder

Case history

Thomas (48 years) works 14 consecutive nights (7p.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 workingperiod, he struggles with re-adaptation back to hisnormal day-oriented rhythm. He wonders ifsomething can help him adapt more easily.

Shift work, and night work in particular, isassociated with negative effects, such as short-ened and disturbed sleep, fatigue, decreasedalertness, cognitive decrements, increasedinjuries and accidents, reproductive problems andrisks to cardiovascular and gastrointestinalhealth.75,76 These symptoms are experiencedbecause shift workers rarely shift their endogenouscircadian rhythms to align with the sleepewakeschedule demanded by their occupations. Nightworkers are therefore often in a constant state ofcircadian misalignment, and both work and sleepat the ‘‘wrong’’ circadian phase. The symptomsdue to circadian misalignment can be reducedeven if the optimal phase relationship is notcompletely established. The magnitude of phaseshift is positively related to the extent of improvedperformance and alertness during the night, andbetter daytime sleep at home.77


Several studies have shown that timed bright lightand darkness can promote adaptation to nightwork.76e80 In our case history, bright light timed

before nadir of the core body temperature rhythmwill facilitate adaptation to night work. Nadir isestimated based on a clinical interview withThomas. Thomas usually gets up at 7 a.m., andbased on prior night work experience, he is espe-cially sleepy at around 5 a.m. Hence, nadir of thecore body temperature rhythm is likely to be atabout 5 a.m. Thus, bright light is advised before hisnadir (30 min, 10 000 lux). In addition, he is advisedto avoid bright light after 5 a.m. on night 1. Night 2he is advised to get bright light at 6 a.m., and avoidlight after 7 a.m. Thomas will likely feel less sleepyduring the night and sleep better during the day themoment nadir is ‘‘pushed’’ to after the work period.Usually 2e4 days of treatment may be sufficient fora night worker. Following the 14-night workingperiod, Thomas will again be advised to get brightlight exposure. Timing of treatment is morecomplicated following the work period, becausenadir is difficult to estimate. In clinical practice, weadvise that a thorough interview may give an indi-cation of the nadir. Thomas experienced sleepinguntil about 5 p.m. towards the end of the 14-nightworking period. We may assume that nadir may be atabout 3 p.m. Thus, in order to phase delay thecircadian rhythm, bright light exposure was advisedbefore 3 p.m. Usually, we ask the subjects to receiveas much light as possible (natural or artificial light)before 3 p.m. Importantly, Thomas is advised toavoid bright light after 3 p.m., that is, use darksunglasses or stay inside. The next day, he is advisedto get exposed to bright light before 5 p.m., andavoid light after 5 p.m. Day 3: bright light exposurebefore 7 p.m., avoid after 7 p.m., and so on. In thiscase history, a phase delay was advised, also for there-adaptation following the night work period. Inother cases, a phase advance may be more appro-priate, i.e., when the nadir of the core bodytemperature rhythm is earlier in the day. Individualtreatment is advised, not only based on nadir esti-mations, but also on the worker’s circadian type(morning lark or evening owl). Evening owls adapteasier by phase delays, than by phase advances, dueto their endogenous circadian rhythm.


Melatonin has also been shown to be efficient inalleviating the complaints associated with nightwork.77,80e82 However, most studies were doneunder simulated night work conditions. Similar tothe other circadian rhythm sleep disorders, thetiming of melatonin is important for the effect.And similarly, the timing of melatonin may bechanged from day to day, in order to maximize theeffect on the circadian rhythm.

Practice points

1. Circadian phase can in many instances beestimated by careful patient history.

2. Nadir of the core body temperaturerhythm is normally located at about 2 hbefore the habitual wake-up time, andcorresponds to the time point where it ismost difficult to stay awake.

3. The phase-response curve to melatonin isabout 12 h out of phase with the phase-response curve to light.

4. Bright light exposure before the nadirinduces phase delays, whereas bright lightafter the nadir induces phase advances.

5. Exogenous melatonin administration in thelate afternoon or evening induces phaseadvances, whereas melatonin adminis-tered in the morning induces phase delays.

6. Circadian rhythm sleep disorders caneffectively be treated by appropriatelytimed bright light and/or melatonin.

7. Do not start bright light treatment fordelayed sleep phase disorder in the earlymorning, but wait until the patient wakesup in a natural way (without an alarmclock). Bright light is subsequently admin-istered 1 h earlier per day untilentrainment.

8. Appropriate timing of melatonin adminis-tration is about 12 h after bright lighttreatment.

Research agenda

1. Scientific studies comparing the circadianphase measured objectively (by melatoninassays or core body temperature) and thecircadian phase estimated by carefulpatient history should be carried out.


Although both bright light and melatonin may beeffective in alleviating the complaints during nightwork, it is questionable whether night workers onrapid rotating schedules (e.g., 2e3 consecutivenights) should aim at adapting their circadianrhythms. If adaptation is successful, re-adaptationback to day-oriented life is likely impeded.Treatment based on circadian principles is bestapplied to shift schedules lasting 1 week or longer.

We have here focused on the treatment for re-aligning the circadian rhythm, but strategies toimprove sleep (hypnotics) and alertness (caffeine,modafinil, scheduled naps) can also be used.45

Such treatment options are not discussed in thispaper.

Summary

Bright light and melatonin can be used successfullyin the treatment of circadian rhythm sleep disor-ders. However, appropriate timing of the treat-ments is crucial for the effect. An estimation ofthe patient’s circadian phase is therefore impor-tant before the treatment is started. In clinicalpractice, a careful patient history may give suffi-cient information in order to estimate the circa-dian phase. The nadir of the core bodytemperature rhythm is about 2 h before thehabitual wake-up time.

Bright light administered before the nadir of thecore body temperature rhythm will phase delay,whereas bright light administered after the nadirwill phase advance the rhythm. Similarly, theeffect of melatonin is dependent on the timing oftreatment. Melatonin in the late afternoon orevening will phase advance, whereas melatonin inthe morning will phase delay the circadian rhythm.

Inclinical practice,bright light of about10 000 luxis usually administered daily for 30e45 min. Thedose of melatonin does not seem to be of greatimportance, and for most disorders we use 3 mgtablets.

In order to maximize the effects of treatment,the timing of both bright light and melatonin isoften changed from day to day. With such anapproach, the treatments are administered atabout the same time point in the phase-responsecurve from day to day.

Importantly, if the treatment effects are notsatisfactory, or if the patient’s condition actuallyworsens, you may have incorrectly estimated thecircadian phase! Try to estimate once more, andadjust the timing of bright light/melatoninaccordingly. This is the advantage in clinicalpractice (compared to a scientific protocol); it isalways possible to adjust treatment.

In all patients, a differential diagnosis mustalways be considered. In order to diagnose a circa-dian rhythm sleep disorder, the criteria state thatthe sleep disturbance should not be betterexplained by another current sleep disorder,medical or neurological disorder, mental disorder,medication use, or substance use disorder.

2. Studies examining the clinical effective-ness of bright light, melatonin andcombined bright light/melatonin in circa-dian rhythm sleep disorders are needed.

3. Comparisons between the effects of brightlight and melatonin in circadian rhythmsleep disorders. What treatment worksbest, and for whom?

4. Studies investigating long-term effective-ness of bright light and/or melatonin incircadian rhythm sleep disorders should beconducted.

5. Studies on how to implement treatmentfor circadian rhythm sleep disorders ingeneral clinical practice are necessary.

6. Studies investigating different light inten-sities and different doses of melatonin inthe treatment of circadian rhythm sleepdisorders are warranted.

7. Studies investigating safety issues associ-ated with long-term use of light and/ormelatonin are needed.


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A practical approach to circadian rhythm sleep disorders