the circadian rhythm in adult attention dei

The circadian rhythm in adultattention-deficit/hyperactivitydisorder: current state ofaffairsExpert Rev. Neurother. 13(10), 11071116 (2013)

JJ Sandra Kooij* andDenise BijlengaPsyQ Psycho-Medical Programs,

Expertise Center Adult ADHD,

Carel Reinierszkade 197, 2593 HR,

The Hague, The Netherlands

*Author for correspondence:

Tel.: +31 0 88 357 3020

Fax: +31 0 88 358 4205

[email protected]

Adults with ADHD often have sleep problems that are caused by a delay of their internalcircadian rhythm system. Such individuals are often typified as evening or night persons.This review focuses on the link between ADHD symptoms and the evening typology throughmultiple pathways. Etiology of the internal circadian rhythm system, the genetic basis forevening typology, overlap between ADHD symptoms and evening preference and risk factorsfor various chronic health conditions, including metabolic syndrome and cancer, arediscussed. The treatment perspectives to reset the delayed rhythm in adults with ADHDinvolve psychoeducation on sleep hygiene, melatonin in the afternoon or evening and brightlight therapy in the morning.

KEYWORDS: ADHD bright light therapy cancer risk chronotype circadian rhythm chronic conditions delayed sleep phase syndrome melatonin metabolic syndrome sleep hygiene sleep-onset insomnia

Circadian rhythmCircadian rhythms have evolved throughoutevolution under influence of the Earths rota-tion, which produces natural light and darkcycles. Circa diem means almost a day, thuscircadian rhythm refers to the fact that ourinternal biological clock has a rhythm of about24 h. Our biological clock is synchronizedevery day to the external dark and light cycleby external Zeitgebers: signals such as light,environmental temperature and availability offood [1]. Besides these natural Zeitgebers, themodern humans circadian timing system isalso influenced by other external Zeitgebers:social time, which is dictated by the mechani-cal clock that for example tells us when wehave to get up for work. The internal circadianpacemaker system is located in the suprachias-matic nucleus (SCN) of the brain, which con-trols many complex internal systems, and thatis influenced by the external Zeitgebers and byendogenous clock synchronizing signals suchas various hormonal statuses. The individualssleep/wake cycle is directed by the SCN.Information from external Zeitgebers, such as

diminishing light in the evening reaching theretina of the eye, is translated to informationabout the time of the day by the SCN. TheSCN then signals the pineal gland to producemelatonin (the sleep hormone). Both thesleep pressure, which has been built up duringthe day, and the circulatory melatonin resultin sleepiness and eventually sleep [1,2].

The SCNs output, which dictates an indi-viduals circadian rhythm and sleep-onsettimes, can differ highly between individuals.Classification of individuals within a popula-tion according to their circadian rhythm istermed chronotype classification. The MunichChronotype Questionnaire and the Horne andOstberg morningness/eveningness question-naire are developed to classify ones chrono-type [1,3]. Many people are known as typicalmorning or evening chronotypes, but mostpeople are in between [4]. A persons chrono-type is genetically regulated [5]. Chronotype isindependent of ethnicity or socioeconomic sta-tus, but can alter somewhat with age anddiffers between genders in adolescence [6,7]. Forinstance, a higher percentage of adolescentswill be classified as evening chronotype than

THEMED ARTICLE y ADHD Review

www.expert-reviews.com 10.1586/14737175.2013.836301 2013 Informa UK Ltd ISSN 1473-7175 1107

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adults [4] . In the general population, about 226% of adultsare classified as evening chronotypes [6,8]. The wide prevalencerange is due to the age of the adults examined and howevening chronotype has been classified. Individuals with an eve-ning chronotype more often work in night shifts than morningchronotypes, as the study by Paine et al. has shown [6]. Peoplethus tend to adjust their work schedule to their internal circa-dian rhythm, although causation cannot be inferred from thisobservational study. Studies have also shown that being an eve-ning chronotype is associated with higher unemploymentrates and poorer health state when compared with morningchronotypes [6,9].

Delayed sleep phase syndromeA minority of adults in the general population experience sleepdisorders which are caused by a misalignment of their circadianrhythm with social time, that is, they do not sleep and wake atsocially preferred times. The DSM-IV describes various circadianrhythm sleep disorders, of which the delayed sleep phase syn-drome (DSPS) is very common in various psychiatric popula-tions such as personality disorders, (seasonal) depression, anxiety,bipolar disorder, schizophrenia, autism and in ADHD [1014].The prevalence of DSPS in the adult general population is esti-mated at 0.133.1% [1518]. According to DSM-IV criteria,DSPS is characterized by a chronic pattern of late sleep and laterising, an inability to fall asleep and wake up at earlier preferredtimes, sleepiness during the day, insomnia at night and impairedfunctioning in social and occupational contexts [19]. Therefore, inorder to establish a diagnosis of DSPS, one has to get an impres-sion of the individuals natural sleep rhythm, which is therhythm without the compensation of medication, alcohol ordrugs, and without having any daytime obligations, like whenon a holiday. The depicted algorithm for DSPS in FIGURE 1 canbe used to clinically assess DSPS using DSM-IV criteria.

Besides asking questions about ones natural sleep rhythm, itis possible to objectify the individuals internal circadian rhythmby measuring ones salivary melatonin profile under dim lightconditions. In healthy individuals, melatonin levels are low dur-ing the day, increase in the evening, remain high throughout thenight and decrease close to the individuals wake-up time [20].The time in the evening when the salivary melatonin concentra-tion reaches a threshold is termed the dim-light melatonin onset(DLMO). The DLMO is a good indicator for ones circadianrhythm; the DLMO of a healthy adult sleeper occurs about14 h after lights on in the morning, which is about 9 PM, andsleepiness and sleep occurs about two hours after DLMO [21]. Inindividuals with DSPS, the DLMO occurs much later [22].

Delayed sleep in ADHDADHD is characterized by childhood onset, chronically highlevels of inattention, impulsivity and hyperactivity that usuallycontinue into adolescence and adulthood, and result inimpaired social, academic or occupational functioning [19]. Theprevalence rate of ADHD in children and adults is about35% [2325]. Many children with ADHD experience sleep

problems including difficulty falling asleep, interrupted sleep,restless sleep and decreased sleep efficiency, which are inde-pendent of stimulant medication use [2633]. This has beenshown in children using questionnaires as well as objectivemeasures such as the Multi Sleep Latency Test, actigraphy,polysomnography and by measuring the childs DLMO insaliva. van der Heijden et al. reported in their review that chil-dren with ADHD more often have disordered breathing duringsleep, increased nocturnal activity, insomnia and they may havea disturbed sleep architecture (e.g., reduced REM sleep period)but results from studies on sleep architecture are inconsis-tent [34]. These children can have difficulty getting up in themorning, more sleepiness during the day and bedtime resist-ance in the evening. In ADHD children between 6 and 12 yearsold, a prevalence of delayed sleep of 73% has been found [35].

In adults with ADHD not using stimulant medication, asmany as 80% are late chronotypes and have sleep-onset diffi-culties if they go to bed at an earlier bedtime [36]. More than60% of the adults with ADHD are sleepy during the day,which leads to an increase of their daytime attention prob-lems [37]. Adults with ADHD and a delayed sleep phase reportlower sleep quality, difficulty getting to sleep and difficulty get-ting up [38]. These complaints may lead to a chronic sleepdebt, for instance, when people have to get up early for school,family life or work [9,39]. Up to 80% of a consecutive sample ofadults with ADHD has been diagnosed with sleep-onset insom-nia (SOI), with delayed DLMO [34,36]. Most of the adults withADHD who have sleeping problems have had these since child-hood [37,40]. Moreover, the number of ADHD symptoms arepositively correlated with the severity of sleep problems, bothamong ADHD patients and in groups form the general popu-lation [9,41,42]. Based on clinical experience, many adults withADHD and DSPS have short sleep duration [9]. The interrelat-edness of comorbid disorders in adults with ADHD and theirimpact on a delayed sleep is yet unknown.

Sleep problems are present in medication-nave adults withADHD. However, the stimulant ADHD medications mayimpact sleep, but the effects on sleep are not clear. In mice,stimulant medication has shown to alter the functioning of theSCN which resulted in a delayed circadian rhythm and shortersleep at the expense of the non-REM sleep [43]. However, inthis study the methylphenidate solution in water was freelyavailable and the mice drank the water at various times duringtheir waking period. In children with ADHD, stimulant medi-cations have negatively impacted sleep onset and sleep durationin some studies [44,45], but another study only found negativeeffects in the younger age group of children 68 years old, andnot in the groups of children 912 years old [46], and still otherstudies did not show an impact of stimulant ADHD medica-tions on important sleep parameters in general [47,48]. In thestudy by Boonstra et al., among adults with ADHD, the sleepwas later and the duration was shorter, but objective sleepquality was better after methylphenidate as compared with pla-cebo [49]. In adults with ADHD, we have indications from clin-ical experience that a low-dose stimulant before bedtime may

Review Kooij & Bijlenga

1108 Expert Rev. Neurother. 13(10), (2013)

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be beneficial because it reduces rebound symptoms and restless-ness, thereby enabling falling asleep. This has been confirmedin the study among adults by Sobanski et al. [50].

Risk of chronic conditionsThe timing system of the SCN not only dictates the onset andoffset of the melatonin production; it orchestrates all other

physiological rhythms, synchronizing them all with each otherand with the time of the day [51]. Therefore, in adult patientswith ADHD with a delayed sleep not only the melatonin pro-duction and the sleep/wake rhythm is delayed, but so is theirentire internal circadian rhythm [36,52,53]. From clinical experi-ence we know that they tend to compensate for being tired bygetting to sleep at an earlier bedtime on one day, and being

Complaintsabout sleeping

on time?

No DSPSNo

No

Yes

Yes

Unable to fallasleep on a

preferred time?

Preferred timeafter

11:30pm?

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>6 months?

Yes

Distress/impairment insocial, occupational,

or other areas offunctioning?

Not due to other sleep,substance abuse, ormental disorder, or amedical condition?

Yes

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Yes

No

Sleep onsetlatency

>30 minutes?

Yes

No

No

No

Yes

Figure 1. Algorithm for delayed sleep phase syndrome (based on DSM-IV criteria).DSPS: Delayed sleep phase syndrome.

The circadian rhythm in adult attention-deficit/hyperactivity disorder Review

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very late the next evening; there often seems to be no habitualsleep time. This may lead to further disturbance of physiologi-cal rhythms. Their appetite hormones status may also be outof phase, which results in many ADHD patients to skip theirbreakfast because of lack of appetite in the morning whileshowing higher rates of binge eating later during the day [54].Our theory thus concludes that this unhealthy lifestyle may bea result of their delayed internal circadian rhythm. In studiesamong healthy adults it has been shown that after one night ofshort sleep, individuals made poorer food choices (i.e., morecarbohydrate intake), had increased appetite and had, amongother blood values, unfavorable plasma glucose, insulin, leptin(an anorexigenic hormone) and cortisol levels [5557].

A delayed sleep phase and its concurrent chronic sleep debthas been acknowledged as a risk for various serious health con-ditions such as obesity, diabetes, hypertension, cardiovasculardiseases, immune suppression and even cancer [22,5767]. Patientswith ADHD and a delayed sleep phase may be at increasedrisk of such conditions; association studies between ADHDsymptoms, short sleep, overweight, obesity and increased riskof some serious chronic conditions have already shownthis (FIGURE 2) [9,68]. Of course, the unhealthy lifestyle that isoften seen in ADHD (i.e., smoking, alcohol and drug abuse)also contributes to negative health outcomes. But after control-ling for these lifestyle factors in an observational study, theassociation between short sleep and the risk of chronic diseasesremained significant [9]. Vice versa, an increased ADHD preva-lence (27%) has been found in patients with severe obesity(BMI 35), and this is even stronger increased in morbid obe-sity (BMI 40), where an ADHD prevalence of 43% has beenfound [54,69,70]. The strong relationship between ADHD andBMI is possibly explained by deficits in the dopamine systemin the brain which affects insulin receptor activity [71]. InADHD, a (relative) dopamine deficiency is presumed, disrupt-ing the dopamine reward system. This same mechanism couldalso be underlying compulsive or addiction-related behaviors

such as binge eating, which lead to overweight and obe-sity [72,73]. The physical health may be at risk in patients withADHD and a delayed sleep phase. A delayed circadian rhythmmay increase the risk of developing psychiatric conditionssuch as seasonal affective disorder (i.e., winter depression;FIGURE 2) [11,39]. Patients with ADHD and a delayed sleep arethus at increased risk of major physical and mental healthconditions through multiple pathways.

Short sleep & cancerIn a group of shift workers, short sleep has been related tobreast cancer [74]. The International Agency for Research onCancer concluded in 2007 that shift-work that involves circa-dian disruption is probably carcinogenic to humans [75]. Espe-cially after working many years in nightshifts, the risk forbreast cancer in women, but also the risk for prostate cancer inmen, is substantially increased [7678]. In a systematic review, aconvincing number of 15 out of 16 epidemiological studieswere suggestive of a positive association, with 10 of these pro-viding statistically significant results, for the association betweencircadian disruption (e.g., shift work), sleep loss and prostatecancer risk [79]. Melatonin has been described as a protectiveagent against cancer development by anti-oxidative propertiesthat is involved in DNA repair after cell damage [8082].A possible explanation for the associations between short sleepand increased cancer risk is that short sleep and overall lowerlevels of circulatory melatonin are interrelated, resulting inhigher risk of damaged cells and the survival of cancer cells.Also, the use of bright light in the evening and night, such asworking on the computer where light is emitted close to theeyes, induces suppression of melatonin production by thepineal gland. This leads to both lower circulatory melatoninlevels and to later, and shorter, sleep. This has been confirmedby a study of Flynn-Evans et al., who found that women withtotal visual blindness had a lower risk of breast cancer thanblind women with light perception [83]. In research with rats

and mice it has been shown thatchanges in the duration of the naturallight and dark periods increased the riskof metabolic syndrome and cancergrowth, and shortened the lifespan ofthe animals. Melatonin in drinkingwater alleviated these effects [84]. Also inhuman research, melatonin is increas-ingly studied as a potential aid forprevention of, and decrease of cancergrowth [85].

Patients with ADHD and their sup-posedly genetically driven delayed sleeppattern often sleep too short on achronic basis. Many of these patientswork in night shifts and/or are activelate at night using bright light, that is,behind the computer. Thus hypotheti-cally, the risk of developing cancer is

Patient A is a man with ADHD, 35 years of age, married with two children. He loves his job as a school teacher. His problem is that he has a pattern of getting to bed too late, and difficulty getting up in the morning. He always skips breakfast. He is rarely on time at work, which is worse in wintertime as compared to summertime. It has led to several dismissals from jobs, which makes him feel ashamed. Whatever he tried, he couldn't get himself to feel awake at an earlier time in the morning. During the winter he tends to feel physically very tired, gloomy, and he gains weight because he eats too many sweets and carbohydrate-rich foods. Besides ADHD, the diagnoses Delayed Sleep Phase Syndrome (DSPS) and seasonal affective disorder have been established. The treatment consisted of the following steps. First the patient gained education about an optimal sleep hygiene. Then, the patient was treated for his difficulty to get up in the morning and for the seasonal affective disorder by the use of bright white light (10.000 lux) at a distance close to the eyes, for 30 minutes just before his required wake-up time. The lamp is set by a timer. In order to phase advance his sleep onset, he is prescribed 3 mg of melatonin at 1 hour before his preferred bedtime. This combined approach of early morning bright light and evening melatonin intake works very quickly; his total sleep time almost immediately increases from 5 to 8 hours per night. He is now able to get to work on time and feels more alert and active at work. His mood improves after two weeks of bright light treatment. After a month of this treatment regime, he even starts to lose weight because he has breakfast every morning, less carbohydrate craving, and less food binges in the afternoon. He now feels ready for the treatment of his ADHD with stimulant medication.

Figure 2. Clinical case vignette.



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increased within this population; a disturbing association thatdeserves further study.

Genetic overlap between ADHD & DSPSThere are various indications that the overlap between ADHDand delayed sleep has an epigenetic basis. This means thatsome genes that are involved in the expression of ones circa-dian preference are also involved in the expression of onesbehavior which we typify as ADHD symptoms. Various genes,for example, PER1, PER2, PER3, CRY1, CRY2, CLOCK,BMAL1 and CK1e, have been linked to the control of theinternal circadian rhythm [5,8688]. Some polymorphisms in theCLOCK gene and in the PER3 gene have been linked to aphase delay and shorter sleep duration in humans [89,90], andthe PER3 gene also plays a role in sleep homeostasis [91]. How-ever, other studies did not confirm these findings [92,93]. TheCLOCK gene has also already been linked to ADHD, and tobipolar, and depressive disorder [94,95]. The BMAL1 andPER2 genes are also involved in both delayed sleep and inADHD: both genes showed decreased circadian rhythmicity inADHD subjects as compared with healthy adults [52]. More-over, Chen et al. showed that deregulations in the PER1,PER2 and PER3 gene are all correlated to the risk of breastcancer [86]. The investigators suggest that disturbances in thesegene expressions cause disruption of the circadian clock and thederegulation of cell cycle, favoring the proliferation of breastcancer cells. The transcriptional deregulation of PERs may berooted in a disrupted melatonin secretion, as we have describedin the previous paragraph. This leads to the suggestion thatapart from the epigenetic view that a delayed sleep leads tounhealthy life-style and thus to a higher risk of chronic dis-eases, there may be even a more direct link between geneexpressions that are involved in ADHD symptomatology,delayed sleep and also in a higher risk of cancer. However, thisspeculative view needs further study to fully understand thegenetic link between the conditions.

Treatment perspectivesSleep hygiene first

Before considering any medical treatment, adult ADHDpatients with sleep problems are informed about the advantagesof a good sleep hygiene, although sleep hygiene alone will notbe sufficient for most patients. Sleep hygiene is a list of simplelifestyle measures that have proven to be involved in a betternights rest for people who have problems getting to sleep, tomaintain sleep or to increase sleep quality [96]. Cannabis andsleep medication are often used to facilitate falling asleep, butshould be stopped in order to be able to evaluate the sleephygiene measures properly in the light of treatment. Sleephygiene involves the following measures.

Alcohol and caffeinated drinks should be limited, and after8pm it is better to drink less in general in order to avoid anight time trip to the toilet and an interrupted sleep. Patientsare advised not to use the computer, iPad or TV late in theevening as the bright light that falls into the eyes from the

screen will suppress melatonin production [9]. An alternativemay be to wear orange colored goggles in the evening whileusing light emitting devices; orange goggles have been shownto be more protective against the downregulation of melatoninthan regular sunglasses [97]. A comfortable bed and pillow,blackout curtains and good ventilation in the bedroom are gen-eral measures that contribute to more comfort in bed. Wearingbed socks in case of cold extremities is another practical advice,that is based on studies showing that people with cold extrem-ities have more sleep-onset difficulties because body tempera-ture and melatonin levels are closely related [98]. Sportingactivities during daytime are beneficial for melatonin levels andsleep [99]. However, sporting within 3 h before bedtime are notadvisable because the adrenaline levels may be still too high tobe able to fall asleep. Compensation for short nights by nap-ping more than 30 min during the day may diminish sleeppressure and further delay the sleep phase, and should thereforebe avoided. Also, frequent use of sunglasses during the day isdiscouraged as these prevent light getting into the eyes. It isadvisable to maintain fixed bedtimes during the week, and notto sleep in more than an hour during weekends. Treatmentwith melatonin and/or bright light may help to achieve andmaintain a stable rhythm.

Treatment with exogenous melatonin

Many chronic sleep problems are treated with benzodiazepines,which often result in habituation and addiction to these medi-cations. Delayed sleep can be alternatively treated using exoge-nous melatonin. van der Heijden et al. showed in children withADHD that 3 mg melatonin before bedtime has favorableeffects on sleep-onset latency, and that the time of DLMOadvances during this treatment regime [100]. Studies in blindadults who lack synchronization with light have shown thatlower doses of melatonin at the end of the afternoon are just aseffective to advance the circadian rhythm [101] and are preferredover the higher doses. Similar research needs to be carried outwith children and adults with ADHD and delayed sleep. Thereis increasing evidence for the efficacy of melatonin in patientswith DSPS [2]. A meta-analysis of 9 studies including 91 adultsand 226 children with DSPS showed that melatonin treatmentadvanced mean endogenous melatonin onset by more than anhour, and time of sleep onset by 40 min. Melatonin decreasedsleep-onset latency by 23 min. The wake-up time and totalsleep time did not change significantly [102]. There are indica-tions from clinical practice and a laboratory study [Lewy AJ, 2012,Pers. Comm.] that melatonin in tablets is sensitive to light, that is,its effect may be lost in an open or transparent container. Mel-atonin tablets should be packaged in opaque capsules or con-tainers, and tablets that have been exposed to light should notbe used to avoid suboptimal treatment effects.

Melatonin has few side effects as far as known. Drowsinessduring the day may occur after long-term usage of highdoses (such as 35 mg). When melatonin is used at the wrongtime (before 4pm or after 12am), the circadian phase may shiftin the wrong direction. The timing of the melatonin



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administration by using an alarm clock is therefore crucial toits effect. So far, researchers do not report any serious sideeffects or other harmful effects in the more than 25 years ofmelatonin prescription experience [Lewy AJ, 2008, Pers. Comm.], butlong-term health outcomes are yet unknown. Some concernshave been raised about possible harmful effects on the retinaafter long-term use of melatonin and about a reduction ofsperm mobility and lower sex drive when using high doses inmen by the Society for Light Treatment and BiologicalRhythms [201]. Synthetic melatonin instead of melatoninderived from animals should be used in order to avoid the pos-sible transfer of viruses. While there are indications of favorableeffects of melatonin on the immune system, the use by patientswith auto-immune rheumatoid arthritis should be avoidedbecause this disease can be exacerbated by melatonin [105]. Preg-nant and breastfeeding women should also not take melatoninbecause of uncertain effects on the (unborn) child.

Melatonin as a sleep-inducing drug

Adult patients are prescribed a relatively high dose of melatoninof 35 mg an hour before their preferred bedtime in order tobe able to get to sleep quickly. This will have an immediateeffect if the patient is exhausted by a lack of sleep. The dura-tion of the treatment is unknown with this dose of melatonin.If the patient experiences drowsiness during the day, the doseshould be reduced or replaced by a low dose (0.10.5 mg) atthe end of the afternoon (see section Using melatonin to shiftthe circadian rhythm).

Using melatonin to shift the circadian rhythm

To phase advance the sleep phase, 0.10.5 mg daily dose ofmelatonin is prescribed for adults. The best dose varies betweenindividuals. A low dose of exogenous melatonin at the end ofthe afternoon signals the brain to start producing endogenousmelatonin at an earlier time in the evening, thus phase advanc-ing the patients entire circadian rhythm. This low dose doesnot induce immediate drowsiness. The optimal time to takethe melatonin is individually variable. In practice, the DLMOis not an easy-to-use indicator as specialized laboratories maybe scarce and the analyses of salivary melatonin samples maybe too costly for daily clinical practice. As the time betweenDLMO and the time of falling asleep is more or less 2 h, theDLMO can be estimated upon the patients reported time ofusually being able to fall asleep minus 2 h. The low-dose mela-tonin is ultimately taken about 6 h before DLMO. In the firstweek, the time of melatonin intake is 1.5 h before initialDLMO and is then further advanced every week in stages(every week 1.5 h earlier) up to 6 h before original DLMO (or8 h before the initial sleep time), but never before 4pm [104].At earlier times it may induce an opposite effect; the same istrue after 12am. There is an optimal window for phase advancetreatment, which is between 4 and 7pm [107]. If the patient canfall asleep on a preferred time, this low-dose melatonin is con-tinued as a maintenance dose to keep the sleep rhythmin phase.

Treatment with bright white light in the morning

Recent study has shown that there is a geographic variationacross the US states in prevalence of ADHD in children, whichcorresponds narrowly to the solar intensity of that state [108].Exposure to sufficient bright light during the day helps to con-solidate the daynight rhythm. Walks in the early morning andat lunch time, when the amount of light is at its maximum,are to be recommended. In winter, when it is still dark in themorning, a lamp with bright white light that is connected to atimer can help to wake up earlier and more easily [108]. Thecommercially available light devices for this purpose seem notto provide enough light (i.e., 75 W) to wake-up sleep phasedelayed adult ADHD patients who are still in their mid-sleep. We currently experiment using bright white lights(10,000 lux), also used for the treatment of seasonal affectivedisorder, at 20 cm from and directed to the eyes, or construc-tion lights (500 W), that are cheaper and oriented at the ceil-ing and not directly onto the eyes. The duration of lighttreatment needed to reset the rhythm properly and the dura-tion of the effect of the treatment have not been studied as yet.In clinical practice, usually 3 weeks are advised to advance therhythm in adults, and this may be repeated when the original,genetically driven, delayed rhythm returns. A laboratory studyamong 11 adults comparing the effects of 3 mg sustained-release melatonin versus placebo, with or without green lighttreatment, concluded that there is an additive effect of brightlight to the treatment with melatonin alone [109].

Expert commentaryNow that the etiology, associations with chronic conditionsand genetic risk factors of DSPS and ADHD have been dis-cussed, some treatment perspectives will follow. Effective treat-ment options for DSPS in adult patients with ADHD consistof psychoeducation about an optimal sleep hygiene, medicaltreatment with the use of different dosages and intake schedulesof exogenous melatonin and bright light therapy [109]. The aimof the treatment is to phase advance the circadian rhythm sothat the patient can sleep and get up without problems at pre-ferred times. The aim is to overcome excessive daytime sleepi-ness, and possibly to prevent the development of chronicphysical and mental health conditions, although this is subjectto further study.

Five-year viewChronic short sleep in adults with ADHD is highly prevalent,and the possible long-term serious implications for health ingeneral have to be studied in depth in the coming years.A start would be to take sleep debts more seriously in psychiat-ric patients, and especially in those with ADHD. The possiblepreventive effect of improving sleep duration on chronic dis-eases needs to be studied. Treatment with melatonin and lightmust be further studied regarding dosage, timing, long-termeffects as well as the duration of treatment needed for sustainedeffect on the sleep/wake rhythm. To study the potential preven-tive effects of the treatment of short sleep with melatonin



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and/or bright light on serious chronic diseases like obesity, car-diac disease and cancer is very important. The optimal studywould probably involve comparison of the health conditions oftreated versus untreated adult patients with ADHD anddelayed sleep onset in a longitudinal study design. However,such a study would take at least 1020 years in order tobe able to evaluate the emergence of chronic diseases. Yet, theimportance of prevention cannot be overestimated. Thereforeon the short term, we will focus on the impact of the treatmentof late sleep on several biological markers that may be indicatorsof negative metabolic development. Meanwhile, there should bemore attention for late, and thus short sleep in the general

population due to the widespread use of light at night, in orderto develop prevention of adverse metabolic, cardiovascular andcarcinogenic diseases at the population level.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial con-

flict with the subject matter or materials discussed in the manuscript.

This includes employment, consultancies, honoraria, stock ownership or

options, expert testimony, grants or patents received or pending or

royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

The majority of adult attention-deficit/hyperactivity disorder (ADHD) patients have sleep difficulties during their lifetime, many of which

are related to a delayed sleep onset and offset, or delayed sleep phase syndrome.

This genetically driven sleep pattern or evening chronotype leads to a chronic short sleep duration that has been associated with

several physical conditions like obesity, diabetes, high blood pressure, cardiovascular disease and cancer.

The importance of sufficient hours of sleep in adults with ADHD thus not only pertains to their daily functioning without sleepiness, but

also to several serious health risks in the long term.

Treatment of late sleep with higher or low doses of melatonin at different times, and light therapy in the morning may reset

the rhythm.

Whether this indeed increases sleep duration and prevents the development of chronic diseases is subject to further study. Not only the

adult ADHD populations health, but the health condition of the Western population in general may benefit, because sleep short and

the daily use of light late at night are widespread nowadays.

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