Abstract
Delayed sleep–wake phase disorder (DSWPD) is a circadian rhythm sleep disorder characterised by a delay in the main sleep period, with patients experiencing difficulty getting to sleep and waking up at socially appropriate times. This often causes insomnia and compromised sleep, results in impairment to daytime function and is associated with a range of comorbidities. Besides interventions aimed at ameliorating symptoms, there is good evidence supporting successful phase advancement with bright light therapy or melatonin administration. However, no treatment to date addresses the tendency to phase delay, which is a common factor amongst the various contributing causes of DSWPD. Circadian phase markers such as core body temperature and circulating melatonin typically correlate well with sleep timing in healthy patients, but numerous variations exist in DSWPD patients that can make these unpredictable for use in diagnostics. There is also increasing evidence that, on top of problems with the circadian cycle, sleep homeostatic processes actually differ in DSWPD patients compared to controls. This naturally has ramifications for management but also for the current approach to the pathogenesis itself in which DSWPD is considered a purely circadian disorder. This review collates what is known on the causes and treatments of DSWPD, addresses the pitfalls in diagnosis and discusses the implications of current data on modified sleep homeostasis, making clinical recommendations and directing future research.
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Preamble
Delayed sleep–wake phase disorder (DSWPD) is a circadian rhythm sleep disorder characterised by a delay in the main sleep period with patients experiencing difficulty getting to sleep and waking up at socially appropriate times. This is associated with insomnia and/ or daytime sleepiness and results in impairment of daytime function. According to the International Classification of Sleep Disorders (ICSD-3) this delay is recurrent for at least 3 months and is not better explained by another sleep, mental or medical disorder. Furthermore, patients allowed to sleep ad libitum will maintain a delayed sleep phase but experience improved sleep quality and duration.
Besides significant impairment to daytime function [1] this often results in extreme sleep inertia, increased sleep onset latency and poor sleep quality [2]. Attempts to cope with symptoms (e.g. napping and recovery sleep, stimulant or hypnotic use) can in themselves further delay the sleep phase or disrupt sleep [1, 3]. Sleep deprivation causes significant cognitive and functional compromise and is in itself a significant health risk [4]. However, independent of sleep duration, DSWPD and circadian misalignment, in general, are associated with impaired cognitive function [2], adverse metabolic changes [5, 6], increased incidence of a range of psychiatric disturbances [7, 8] and generally compromised quality of life [1, 9].
As with most circadian disorders, understanding of DSWPD remains disparate, particularly with regard to aetiology. This review seeks to provide an up-to-date summary of present knowledge on the causes and treatment of DSWPD, as well as discuss the complexities of diagnosis. Furthermore, in evaluating current findings on sleep homeostasis in DSWPD patients, this review will call into question the purely circadian pathogenesis of DSWPD and emphasise the need to review assumptions on sleep homeostasis in clinical treatment.
Diagnosis
Assessment of the delayed phase may be made by recording sleep and activity itself, by self-assessment of diurnal preference or by measuring diurnal variations in physiological variables. The latter most often refers to either timing of minimum core body temperature (CTmin) or the evening melatonin surge also known as dim light melatonin onset (DLMO). Behavioural and activity indicators have to be used with care, however, because amongst the comorbidities of DSWPD are some that further confound symptoms. Examples of these are secondary insomnia [10, 11], substance misuse [12], depression [7, 9] and other psychiatric disorders [7, 13].
Self-assessment of evening preference, usually by the Horne and Östberg morningness-eveningness questionnaire [14], is associated with delayed sleep periods [15,16,17], delayed body temperature rhythms [18] and delayed melatonin rhythms [19]. However, this will have to be considered alongside more direct measures of phase delay, particularly to assess whether the evening preference is sufficient to constitute DSWPD [1].
In healthy individuals sleep diaries can predict DLMO within about an hour [20,21,22,23], but this is not the case in patients suffering from insomnia [24] or circadian disorders [25]. In DSWPD patients specifically there seems to be a tendency for a sleep period to be more delayed than a circadian period, compared to controls [9, 26], and in evening types in general there was a weaker association between sleep periods and circadian rhythm [27]. If there is a need to use sleep diaries to assess phase delay, then they should be from days of unrestricted sleep (e.g. weekends and holidays) [23] and can be supported with actigraphy measurements [28].
Delayed DLMO is highly sensitive and specific for DSWPD [29, 30] and is useful for distinguishing DSWPD from conditions that may present similarly but have either an extrinsic circadian or non-circadian cause (e.g. jet lag and primary insomnia, respectively) [29, 31]. However, there can be unpredictable variations in the temporal relationship between DLMO and sleep in circadian disorders [32]. Although the phase relationship between DLMO and sleep onset is similar in DSWPD patients and controls [30, 33, 34], Shibui et al. [30] reported delayed sleep offset relative to DLMO in DPSD patients. Furthermore, DLMO appears to have a different predictive value on sleep propensity in DSWPD patients compared to controls [35]. Despite its diagnostic value, it seems that the relationship of DLMO to sleep variables and certain assumptions regarding the significance of DLMO should be reconsidered in DPSD patients.
Similar constraints exist with CTmin as a metric. Numerous studies have reported differences in the interval between CTmin and both sleep onset and offset in DSWPD patients compared to controls (i.e., in which part of the sleep period CTmin occurs) [9, 11, 35,36,37,38]. More generally, CTmin is also easily confounded by factors such as posture, activity and arousal [39] and even in healthy individuals there appears to be interindividual variation in the relationship between CTmin and sleep period [31].
Treatment
Exogenous melatonin administration shifts phase [40, 41] according to a phase response curve roughly inverse to that of light [23, 42] – taken in the early evening prior to DLMO it advances the circadian phase. This is seen as advances in the sleep period (including both onset and offset) [43] as well as in the endogenous melatonin rhythm [44], though not in body temperature rhythm [45]. Patients also show improved sleep and quality of life parameters including reduced sleep onset latency, subjective sleep improvement [46] and reduced daytime sleepiness [47].
Timing of administration affects the magnitude of phase shift [41] but dose variation does not [41, 48], although different doses may have different optimum timings for a maximum phase shift [49]. High and low doses also give very similar improvements in sleep parameters [50]. Mundey [41] recommends individual phase response curves should be measured prior to melatonin administration (see the section on variations), where DLMO is a particularly significant landmark around which administration should be planned [51]. Exogenous melatonin administration is the recommended treatment for DSWPD under the 2015 American Academy of Sleep Medicine guidelines [52] and various examples of treatment protocols have been described [42, 48, 53]. Patients are widely reported to relapse after treatment, however, [41, 43, 46], and the timing of relapse seems associated with the severity of phase delay prior to treatment [46].
Light alone is a sufficient zeitgeber for clock entrainment [54]. Morning exposure to bright light (i.e. shortly after CTmin) advances the circadian phase and sleep period according to a phase response curve [55,56,57,58,59]. These results have been replicated in patients with circadian rhythm disorders, including DSWPD. In DSWPD patients morning bright light therapy advanced the circadian phase as measured by DLMO [60] and CTmin [61], also consistently advancing the sleep period, however changes in sleep parameters have been very mixed [52, 62, 63]. Yamadera et al. [64] found it improved sleep quality and reduced daytime sleepiness and Cole et al. [65] also found it improved sleep quality but not morning sleepiness or total sleep time. Rosenthal et al. [61] and Faulkner et al. [63] both reported improved sleep onset latency, however, the latter found no significant improvement in sleep quality, daytime sleepiness or total sleep time and only a mild improvement in sleep efficiency.
Besides timing, intensity and duration of light treatment affect the magnitude of phase shift and change in sleep parameters [57, 61, 66], however, optimal dose and duration have yet to be determined [67]. It is generally recommended that individual phase response curves to light be assessed prior to treatment [55, 56, 59, 68] (see discussion on variations elsewhere in the text). Maximal effect is seen in the blue light spectrum (420–500 nm) [69,70,71,72], and using lower-intensity white light for longer periods may prove more effective [73]. If side effects such as headaches are encountered light intensity and duration can be decreased but the length of treatment increased instead [74, 75]. Compliance can be poor [41] and even where achieved symptom relapse is still deemed likely [1, 76] and ‘booster administrations’ may be needed [75]. Inpatient delivery has shown high response rates, suggesting the importance of compliance, but even in these cases the rate of symptom relapse following discharge has been high. [77, 78]
Bright light therapy and melatonin administration do not contraindicate each other, and it has been hypothesised that their effects may be synergistic [79]. Various studies have found combination therapy of light and melatonin to produce greater phase advance in healthy patients than either therapy alone, although results appear to be additive rather than synergistic [80,81,82]. A case series by Samaranayake et al. has confirmed this finding in DSWPD patients [83]. Surprisingly, though, a randomised clinical trial in a DSWPD population showed patients treated with both melatonin and bright light had no significant difference in phase shift or sleep parameters compared to patients receiving either or neither treatment [66, 84].
Hypnotic agents such as benzodiazepines, benzodiazepine receptor antagonists and some antihistamines, amongst others, may be used to promote and maintain sleep. However, this can be associated with reduced sleep quality, daytime sleepiness or cognitive impairment and other adverse effects [85]. More importantly, although hypnotics can advance sleep onset, studies are lacking on their effect on the circadian phase and sleep homeostasis. This is particularly the case in a DSWPD population in which there are likely to be pre-existing variations in both circadian rhythm and sleep homeostasis. There is little evidence supporting the treatment of DSWPD using hypnotics [13, 52].
Besides melatonin, melatonin receptor antagonists (MRAs) have also been developed and from preclinical studies these present potential for the treatment of sleep and circadian disorders. MRAs have also been clinically shown to decrease SOL [86,87,88,89] and shift the circadian phase [90,91,92]. However this is largely in healthy populations and therapeutic use in DSWPD has yet to be demonstrated save for two recent successful case reports using ramelteon [93, 94]. Of these, Shimura et al. in particular [94] suggest that ramelteon should be administered at very low doses for DSWPD. It also remains to be seen how MRAs will compare with melatonin in clinical use.
Suvorexant, an orexin receptor antagonist (ORA), has been shown to improve SOL and sleep maintenance while maintaining normal sleep architecture [95,96,97], and is approved for the treatment of insomnia in Japan and the United States of America. Treatment resulted in phase advance in two cases [98], and three patients who did not respond to ramelteon as monotherapy responded when suvorexant was added [99]. The mechanism of action of ORAs suggests that it could be useful in DSWPD, at least to advance sleep onset in phase-shifting protocols. Unfortunately, few studies have investigated this.
Another drug that may be promising is aripiprazole which, being a partial agonist of dopamine and serotonin, is believed to influence coordination of these neurotransmitters with melatonin, as well as increase wakefulness by increasing histamine secretion [100, 101]. This has proven effective for DSWPD in several cases [101,102,103], resulting in phase advance, decreased total sleep time and increased daytime wakefulness, however, there is currently still little evidence supporting aripiprazole therapy.
Improving sleep hygiene does not constitute therapy for DSWPD, much less monotherapy. Whilst aspects of this may improve sleep parameters in healthy patients, those with circadian disorders can have altered sleep homeostatic processes (see elsewhere in the text). For instance in DSWPD patients sleep pressure builds more slowly, and sleep deprivation tends not to advance the sleep phase. Variations in circadian processes, such as altered phase response curves, can also mean DSWPD patients do not respond to sleep hygiene measures as healthy patients do. The bidirectional relationship between sleep homeostasis and clock function (see elsewhere in the text) further undermines assumptions that the benefits of sleep hygiene will apply to DSWPD patients. Most importantly, even if sleep hygiene measures improve sleep in DSWPD patients there is no evidence they can shift the circadian phase, or ameliorate the physiological ill effects of circadian misalignment.
Cognitive behavioural therapy has been described as an adjunct to light therapy for DSWPD, to good effect [104, 105]. It may be useful to maintain desired effects of a successful phase shift, as well as to treat comorbidities of DSWPD that may exacerbate its sequelae, such as substance abuse, insomnia or impaired daytime function. [75, 104]. However, no evidence exists in support of it as sole therapy.
Czeisler et al. [106] described implementing progressive phase delays until the intrinsic rhythm adequately matched zeitgeber time. This was intended to take advantage of DSWPD patients’ long-running clocks and tendency to phase delay. Furthermore, patients with more extreme delays may need many hours’ advance to reach a desired bedtime such that delaying may be quicker [75]. Chronotherapy has also been shown to reduce period length [36], which in turn reduces the tendency to phase delay. However, progressive delays may end up risking light exposure at unfavourable times in the PRC [75], and relapse is likely [76, 107]. There have been no randomised clinical trials to date and case studies have given mixed results [13].
Causes
Genetic influence on circadian phenotype in humans has been demonstrated with twin studies [108] and pedigrees [109], and up to 50% of the variance in circadian phenotype has been shown to be heritable [110]. In particular, a 54-base pair long variable number tandem repeat polymorphism on the human period 3 gene (hPer3) has been associated with diurnal preference, where the shorter allele correlates strongly with eveningness and DSWPD [111, 112].
A single nucleotide polymorphism in the human clock gene (hClock) has also been demonstrated to correlate with diurnal preference, though not specifically with DSWPD [113]. Subsequent mutation screening of hClock in DSWPD and control subjects also suggests variations here are unlikely to be associated with DSWPD [114].
There is growing evidence that a long period (tau) is implicated in DSWPD. In other taxa, mutations altering circadian phenotypes generally do so by changing tau length [113]. In humans numerous clinical studies have associated long periods with a phase delay, both in body temperature [11, 36, 115] and melatonin [116] rhythms. A longer period means a constant tendency for phase delay relative to zeitgeber time, which was described early on by Czeisler et al. [106]. However, age-related changes in both melatonin and CT rhythms cannot be accounted for by changes in period length alone [117, 118] and it remains to be investigated whether longer periods can account for the delays observed in DSWPD.
Another suggestion from Czeisler et al. [106] is that DSWPD patients have an altered PRC to light, where the phase advance section is shorter than in controls, thus phase advance is less likely to happen. Evidence for this has generally been lacking [9] but this hypothesis, along with lengthened periods, formed the basis for chronotherapy as described by Czeisler et al. (see elsewhere in the text).
DSWPD patients are more sensitive to the melatonin-suppressing effects of light exposure in the pre-DLMO part of the curve [119, 120], rendering them more prone to phase delay with light exposure. Furthermore, Micic et al. [34] found that, besides being delayed, the melatonin output of DSWPD patients showed a smaller surge than those of controls. The mechanisms have yet to be elucidated.
Lifestyle changes are also purported to cause DSWPD [1], mainly the use of electronic devices with bright display screens. Exposure to light from common electronic devices at relevant portions of the PRC has been shown to cause suppressed melatonin secretion, phase delay, increased SOL and poorer quality sleep [121, 122], increasing the likelihood of a diagnosis of DSWPD. Besides electronic light, evening and morning types have been shown to have different patterns of total light exposure relative to both zeitgeber time and their respective circadian clocks, and the general pattern in evening types tends to lengthen the period [123, 124].
Another crucial lifestyle factor would be the use of stimulants and hypnotics which, on top of altering sleep homeostasis, can cause circadian changes [3, 125]. Individuals already experiencing circadian misalignment or sleep disturbances (e.g. jetlag, insomnia) are more likely to reach for these which may perpetuate existing symptoms [1, 75].
Lack et al. [75] also describe a more psychologically motivated vicious cycle in phase delays. No matter the initiating cause, an individual with a delayed clock will perform more of their daily activities in the evening, including those involving exposure to bright light. They may also wish to prolong this productive period by going to bed later, and when attempting to sleep at conventional times often find themselves unable which only increases anxiety and arousal. On the other hand, waking at conventional times, which may be on or around the time of CTmin, results in adverse sensations of grogginess and discomfort. Avoiding these sensations is a further incentive to sleep through these periods where possible, further contributing to phase delay [126], particularly if they sleep through the phase advance portion of the PRC to light [37].
DSWPD is also highly comorbid with a range of psychiatric disorders [7, 8]. For instance, in borderline personality disorder the prevalence of DSWPD is shown to be significantly higher than in the wider population [127,128,129]. However, the presence of circadian disorders has also been shown to predict earlier symptom relapse in bipolar disorder [130]. It remains difficult to distinguish which is the cause and which the effect and so psychiatric disorders should be considered a correlation which could be a potential cause.
Sleep homeostasis
Based on Borbely’s [131] two-process model, sleep is regulated by the combined effects of a circadian process entrained to the time of day (process C) as well as a homeostatic process responding to sleep pressure (process S). DSWPD and other circadian disorders have been considered to be caused by and to modulate just process C but there is increasing evidence that this may not be the case. Firstly, not just circadian rhythms but also sleep homeostatic mechanisms have been shown to differ in patients with circadian disorders, suggesting that the causes and results of such disorders may not be purely circadian in origin. More interestingly, even in healthy human subjects and animal models the two processes have been shown to modulate not just each other’s output (i.e. sleep regulation) but also their mechanisms [132, 133]. The finer details of this bidirectional relationship and its role in DSWPD aetiology require far more research to evaluate, as does the question of whether the two-process model remains viable in DSWPD.
Circadian clock genes have a role in sleep homeostasis and affect how patients respond to sleep deprivation [132]. Sleep homeostasis in evening types has been shown to differ from that in controls. In evening types sleep pressure builds more slowly than in morning types, as measured by theta wave activity in waking EEGs [134], though eventually reaching similar maxima [135, 136]. Sleep pressure also dissipates more slowly in evening types, with morning types showing more slow wave activity during the initial NREM segment of a sleep period [137].
Data from DSWPD patients in particular show that some sleep variables are significantly different from those in controls. DSWPD patients have decreased total sleep time and sleep efficiency [38], as well as altered distribution of sleep wave patterns and longer SOL even at preferred bedtimes [11]. Sleep homeostatic responses also differ, with DSWPD patients less likely to either have daytime recovery sleep or to advance sleep period following sleep deprivation [138]. Such differences significantly undermine the basis of traditional sleep hygiene practices as therapy for DSWPD.
While evidence of varied sleep homeostasis may often be assumed to be sequelae of DSWPD it also raises the question of whether DSWPD symptoms are the product of, or at least perpetuated by, altered sleep homeostasis. Other authors [34, 138] have suggested that the aetiology of DSWPD may not purely be circadian in origin, and that other physiological processes may be involved in or may even cause the period or sleep delays. Another example of this may be the smaller melatonin peaks observed in DSWPD patients (see elsewhere in the text).
Conversely, circadian processes appear to vary with changes in sleep pressure as well. Many subjective and physiological factors such as cognitive function, mood and EEG activity patterns vary across the circadian day, but the amplitude of this variation has been shown to vary with sleep pressure [139, 140]. Numerous factors that vary with sleep history, such as temperature, cytokine levels and redox state, are likely to contribute to changes in the expression of clock genes [141]. There is also increasing evidence from human and nonhuman studies that variations in the sleep–wake cycle modify entrainment in the suprachiasmatic nucleus where the ‘central’ clock is [142, 143]. In a murine model, sleep deprivation alters clock gene mRNA levels [144] and also modifies the binding of clock transcription factors to regulatory sequences of target clock genes [145]. It is noteworthy that sleep history can modify circadian processes at the level of gene expression, although human studies are lacking and much more work is required to characterise these effects. This may go some way in explaining ‘extrinsic’ causes of circadian disorders (e.g. evening electronic device use, travel across time zones) but when considering the ‘intrinsic’ factors in DSWPD it raises the question of whether genetic expression or sleep disturbance came first.
Recommendations and directions
Treatments for DSWPD should be considered to fall into one of two mechanistic levels. The first seeks to modulate sleep–wake behaviour, typically with the use of stimulants and hypnotics or sleep hygiene strategies, and is something many patients are likely to have attempted in some manner. The other category of treatments aims to shift circadian phase itself so that desired patterns of sleep–wake behaviour and daytime function are a result of cohesive central control rather than simply downstream modification. Some interventions, such as prescribed bedtimes or melatonin administration, can fall into either or both of these categories depending on how they are used.
Whilst the latter category addresses aetiology at its essentially circadian level, relapses are common even where treatment has been successful (see elsewhere in the text). In this author’s opinion, there would ideally be a third and yet more fundamental level of intervention, that would correct or adequately circumvent the very tendency to phase delay in the first place. This is currently completely hypothetical and is likely to remain so until much more is known about the pathogenesis. The cause or causes themselves, if found, might not be easily corrected, particularly if genetic in nature. However it is well worth further research to characterise the physiological, neural and molecular mechanisms underlying the aetiology – these comprise a rational target for therapy but are also likely to lend significant insight into other circadian and sleep disorders.
It must be noted that the premise for this whole paper is that DSWPD requires treatment in order for the patient to benefit. Two recent case reports [146] showed improvements in sleep parameters in patients who stopped treatment but were able to change their sleep schedules to suit them due to restrictions during the coronavirus disease 2019 pandemic. This raises the possibility of eliminating circadian mismatch without any treatment at all – the ‘intervention’ in this case would be modification to social demands placed on patients, which are necessary for the manifestation of pathology. Much more research is needed to characterise this, but benign neglect is an option worth considering if patients can be granted appropriate social accommodations and support.
This paper’s discussion of diagnostics reveals numerous complexities in how phase markers and tools of phase assessment relate to sleep variables. In particular, it highlights the need to consider that these may be very different in a population with sleep disorders compared to controls. Despite the practical difficulties associated with DLMO it remains the best-supported diagnostic metric and also the most useful for informing therapy as current knowledge stands. It also allows for quantitative measurement of the magnitude of delay. Once again, a more thorough understanding of the underlying mechanisms would be instrumental. If the relationships between phase measurements and sleep variables can be better predicted then diagnostic processes can be refined accordingly.
What may, in fact, be quite useful in the assessment and management of DSWPD is a way to quantify the severity of the disease, which is currently lacking. The duration of phase delay can easily be measured, but from a clinical perspective it would also be crucial to assess and subsequently track the level of physiological compromise and psychological distress caused to the patient. This could take the form of an index combining a range of sleep variables, particularly considering that these are still difficult to predict in a DSWPD population and considering the sleep homeostatic differences in these patients. Another possibility is a patient questionnaire, which would better capture the qualitative impact of the disorder. This can easily be combined with more objective sleep metrics. The variables to be included and their relative weighting remain to be determined, in both the index and the questionnaire, and the development and validation of these tools lie without the scope of this review.
Numerous genetic and non-genetic factors have been associated with DSWPD, although causation has been established for a few of these. It’s unclear which of these factors, if any, are necessary or sufficient conditions for the disorder. There seem to be many possible ways to arrive at the same symptomatology.
This is a disorder that is generally thought of as circadian in both cause and effect, however, it looks as though there are significant differences in sleep homeostasis as well. This is a vital point to consider and certainly a concept warranting much more attention, not least for the chicken-and-egg questions raised but crucially also because the variations in sleep homeostatic processes would likely affect how the disorder can be diagnosed and treated. It is important to question the assumptions that DSWPD patients’ sleep homeostatic processes are as expected in healthy patients.
References
Magee M, et al. Diagnosis, cause, and treatment approaches for delayed sleep-wake phase disorder. Sleep Med Clin. 2016;11(3):389–401.
Wright KP Jr, et al. Sleep and wakefulness out of phase with internal biological time impairs learning in humans. J Cogn Neurosci. 2006;18(4):508–21.
Wittmann M, et al. Social jetlag: misalignment of biological and social time. Chronobiol Int. 2006;23(1–2):497–509.
Luyster FS, et al. Sleep: A Health Imperative. Sleep. 2012;35(6):727–34.
Scheer FAJL, et al. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci. 2009;106(11):4453–8.
Buxton OM, et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci translat med. 2012;4(129):43–129.
Reid KJ, et al. Systematic evaluation of Axis-I DSM diagnoses in delayed sleep phase disorder and evening-type circadian preference. Sleep Med. 2012;13(9):1171–7.
Kripke DF, et al. Delayed sleep phase cases and controls. J Circadian Rhythms. 2008;6:6.
Okawa M, Uchiyama M. Circadian rhythm sleep disorders: Characteristics and entrainment pathology in delayed sleep phase and non-24 sleep–wake syndrome. Sleep Med Rev. 2007;11(6):485–96.
Cvengros JA, Wyatt JK. Circadian rhythm disorders. Sleep Med Clin. 2009;4(4):495–505.
Campbell SS, Murphy PJ. Delayed sleep phase disorder in temporal isolation. Sleep. 2007;30(9):1225–8.
Hasler BP, et al. Circadian rhythms, sleep, and substance abuse. Sleep Med Rev. 2012;16(1):67–81.
Culnan E, McCullough LM, Wyatt JK. Circadian rhythm sleep-wake phase disorders. Neurol Clin. 2019;37(3):527–43.
Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976;4(2):97–110.
Lack L, Bailey M. Endogenous circadian rhythms of evening and morning types. Sleep Research. 1994;23:501.
Mongrain V, et al. Phase relationships between sleep-wake cycle and underlying circadian rhythms in Morningness-Eveningness. J Biol Rhythms. 2004;19(3):248–57.
Taillard J, et al. Validation of horne and ostberg morningness-eveningness questionnaire in a middle-aged population of french workers. J Biol Rhythms. 2004;19(1):76–86.
Kerkhof GA, Van Dongen HP. Morning-type and evening-type individuals differ in the phase position of their endogenous circadian oscillator. Neurosci Lett. 1996;218(3):153–6.
Gibertini M, Graham C, Cook MR. Self-report of circadian type reflects the phase of the melatonin rhythm. Biol Psychol. 1999;50(1):19–33.
Martin SK, Eastman CI. Sleep logs of young adults with self-selected sleep times predict the dim light melatonin onset. Chronobiol Int. 2002;19(4):695–707.
Crowley SJ, et al. Estimating dim light melatonin onset (DLMO) phase in adolescents using summer or school-year sleep/wake schedules. Sleep. 2006;29(12):1632–41.
Burgess HJ, et al. The relationship between the dim light melatonin onset and sleep on a regular schedule in young healthy adults. Behav Sleep Med. 2003;1(2):102–14.
Burgess HJ, Eastman CI. The dim light melatonin onset following fixed and free sleep schedules. J Sleep Res. 2005;14(3):229–37.
Wright H, Lack L, Bootzin R. Relationship between dim light melatonin onset and the timing of sleep in sleep onset insomniacs. Sleep Biol Rhythms. 2006;4(1):78–80.
Keijzer H, et al. Evaluation of salivary melatonin measurements for Dim Light Melatonin Onset calculations in patients with possible sleep–wake rhythm disorders. Clin Chim Acta. 2011;412(17–18):1616–20.
Wyatt JK, Stepanski EJ, Kirkby J. Circadian Phase in Delayed Sleep Phase Syndrome: Predictors and Temporal Stability Across Multiple Assessments. Sleep. 2006;29(8):1075–80.
Archer SN, et al. Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes. Sleep. 2008;31(5):608–17.
Sadeh A. The role and validity of actigraphy in sleep medicine: An update. Sleep Med Rev. 2011;15(4):259–67.
Rahman SA, et al. Clinical efficacy of dim light melatonin onset testing in diagnosing delayed sleep phase syndrome. Sleep Med. 2009;10(5):549–55.
Shibui K, Uchiyama M, Okawa M. Melatonin rhythms in delayed sleep phase syndrome. J Biol Rhythms. 1999;14(1):72–6.
Keijzer H, et al. Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders. Sleep Med Rev. 2014;18(4):333–9.
Rodenbeck A, et al. Altered circadian melatonin secretion patterns in relation to sleep in patients with chronic sleep-wake rhythm disorders. J Pineal Res. 1998;25(4):201–10.
Chang A-M, et al. Sleep timing and circadian phase in delayed sleep phase syndrome. J Biol Rhythms. 2009;24(4):313–21.
Micic G, et al. Nocturnal melatonin profiles in patients with delayed sleep-wake phase disorder and control sleepers. J Biol Rhythms. 2015;30(5):437–48.
Uchiyama M, et al. Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep–wake syndrome in humans. Neurosci Lett. 2000;294(2):101–4.
Ozaki N, et al. Body temperature monitoring in subjects with delayed sleep phase syndrome. Neuropsychobiology. 1988;20(4):174–7.
Ozaki S, et al. Prolonged interval from body temperature nadir to sleep offset in patients with delayed sleep phase syndrome. Sleep. 1996;19(1):36–40.
Watanabe T, et al. Sleep and circadian rhythm disturbances in patients with delayed sleep phase syndrome. Sleep. 2003;26(6):657–61.
Brown EN, Czeisler CA. The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data. J Biol Rhythms. 1992;7(3):177–202.
Arendt J, et al. Some effects of melatonin and the control of its secretion in humans. Ciba Found Symp. 1985;55:177.
Mundey K, et al. Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep. 2005;28(10):1271–8.
Lewy AJ, et al. The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int. 1998;15(1):71–83.
Dahlitz M, et al. Delayed sleep phase syndrome response to melatonin. Lancet. 1991;337(8750):1121–4.
van Geijlswijk IM, Korzilius HPLM, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010;33(12):1605–14.
Nagtegaal JE, et al. Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset. J Sleep Res. 1998;7(2):135–43.
Dagan Y, et al. Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int. 1998;15(2):181–90.
Kayumov L, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63(1):40–8.
Revell VL, et al. Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light. J Clin Endocrinol Metab. 2006;91(1):54–9.
Burgess HJ, et al. Human phase response curves to three days of daily melatonin: 05 mg versus 30 mg. J Clin Endocrinol Metabol. 2010;95(7):3325–31.
Suhner A, et al. Comparative Study to Determine the Optimal Melatonin Dosage form for the Alleviation of Jet Lag. Chronobiol Int. 1998;15(6):655–66.
Lewy A. Clinical implications of the melatonin phase response curve. Oxf Univer J Clinical Endocrinol. 2010;95:3158–60.
Auger, R.R., et al., 2015 Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 11(10): 1199–236.
Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol. 2008;586(2):639–47.
Czeisler CA, et al. Bright Light Induction of Strong (Type 0) Resetting of the Human Circadian Pacemaker. Science. 1989;244(4910):1328–33.
Minors DS, Waterhouse JM, Wirz-Justice A. A human phase-response curve to light. Neurosci Lett. 1991;133(1):36–40.
Khalsa SB, et al. A phase response curve to single bright light pulses in human subjects. J Physiol. 2003;549(Pt 3):945–52.
Lack L, Wright H, Paynter D. The treatment of sleep onset insomnia with bright morning light. Sleep Biol Rhythms. 2007;5(3):173–9.
Honma K. A human phase response curve for bright light pulses. Jpn J Psychiat Neurol. 1988;42:167–8.
Khalsa SBS, et al. A phase response curve to single bright light pulses in human subjects. J Physiol. 2003;549(3):945–52.
Lack L, et al. Morning blue light can advance the melatonin rhythm in mild delayed sleep phase syndrome. Sleep Biol Rhythms. 2007;5(1):78–80.
Rosenthal NE, et al. Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome. Sleep. 1990;13(4):354–61.
van Maanen A, et al. The effects of light therapy on sleep problems: A systematic review and meta-analysis. Sleep Med Rev. 2016;29:52–62.
Faulkner SM, et al. Light therapies to improve sleep in intrinsic circadian rhythm sleep disorders and neuro-psychiatric illness: A systematic review and meta-analysis. Sleep Med Rev. 2019;46:108–23.
Yamadera H, Takahashi K, Okawa M. A multicenter study of sleep-wake rhythm disorders: therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics. Psychiatry Clin Neurosci. 1996;50(4):203–9.
Cole RJ, et al. Bright-light mask treatment of delayed sleep phase syndrome. J Biol Rhythms. 2002;17(1):89–101.
Wilhelmsen-Langeland A, et al. A Randomized controlled trial with bright light and melatonin for the treatment of delayed sleep phase disorder: effects on subjective and objective sleepiness and cognitive function. J Biol Rhythms. 2013;28(5):306–21.
Morgenthaler TI, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. Sleep. 2007;30(11):1445–59.
St Hilaire MA, et al. Human phase response curve to a 1 h pulse of bright white light. J Physiol. 2012;590(13):3035–45.
Brainard GC, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci. 2001;21(16):6405–12.
Wright HR, Lack LC. Effect of light wavelength on suppression and phase delay of the melatonin rhythm. Chronobiol Int. 2001;18(5):801–8.
Wright HR, Lack LC, Kennaway DJ. Differential effects of light wavelength in phase advancing the melatonin rhythm. J Pineal Res. 2004;36(2):140–4.
Warman VL, et al. Phase advancing human circadian rhythms with short wavelength light. Neurosci Lett. 2003;342(1–2):37–40.
Dewan K, et al. Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity. Sleep. 2011;34(5):593–9.
Chesson AL, et al. Practice parameters for the use of light therapy in the treatment of sleep disorders standards of practice committee. Amer Acad Sleep Med. 1999;22(5):641–60.
Lack LC, Wright HR, Bootzin RR. Delayed sleep-phase disorder. Sleep Med Clin. 2009;4(2):229–39.
Wyatt JK. Circadian rhythm sleep disorders. Pediatr Clin North Am. 2011;58(3):621–35.
Takeshima M, et al. Inpatient phase-advance therapy for delayed sleep-wake phase disorder: a retrospective study. Nat Sci Sleep. 2018;10:327–33.
Iwamitsu Y, et al. Psychological characteristics and the efficacy of hospitalization treatment on delayed sleep phase syndrome patients with school refusal. Sleep Biol Rhythms. 2007;5(1):15–22.
Sack RL, Lewy AJ, Hughes RJ. Use of melatonin for sleep and circadian rhythm disorders. Ann Med. 1998;30(1):115–21.
Wirz-Justice A, et al. Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset. J Pineal Res. 2004;36(3):192–4.
Paul MA, et al. Phase advance with separate and combined melatonin and light treatment. Psychopharmacology. 2011;214(2):515–23.
Burke TM, et al. Combination of light and melatonin time cues for phase advancing the human circadian clock. Sleep. 2013;36(11):1617–24.
Samaranayake CB, Fernando A, Warman G. Outcome of combined melatonin and bright light treatments for delayed sleep phase disorder. Aust N Z J Psychiatry. 2010;44(7):676–676.
Saxvig IW, et al. A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: Effects on subjective and objective sleep. Chronobiol Int. 2014;31(1):72–86.
Pagel JF, Parnes BL. Medications for the treatment of sleep disorders: an overview. Prim Care Companion J Clin Psychiatry. 2001;3(3):118–25.
Mini L, Wang-Weigand S, Zhang J. Ramelteon 8 mg/d versus placebo in patients with chronic insomnia: post hoc analysis of a 5-week trial using 50% or greater reduction in latency to persistent sleep as a measure of treatment effect. Clin Ther. 2008;30(7):1316–23.
Simpson D, Curran MP. Ramelteon: a review of its use in insomnia. Drugs. 2008;68(13):1901–19.
Zammit G, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007;3(5):495–504.
Zemlan FP, et al. The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial. J Clin Psychiatry. 2005;66(3):384–90.
Dodson ER, Zee PC. Therapeutics for circadian rhythm sleep disorders. Sleep Med Clin. 2010;5(4):701–15.
Richardson GS, et al. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med. 2008;4(5):456–61.
Zee PC, et al. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med. 2010;11(6):525–33.
Takeshima M, et al. Ramelteon for delayed sleep-wake phase disorder: a case report. Clin Psychopharmacol Neurosci. 2020;18(1):167–9.
Shimura A, Kanno T, Inoue T. Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. J Clin Sleep Med. 2022;18:2861–5.
Coleman PJ, et al. The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol. 2017;57:509–33.
Sutton EL. Profile of suvorexant in the management of insomnia. Drug Des Devel Ther. 2015;9:6035–42.
Keks NA, Hope J, Keogh S. Suvorexant: scientifically interesting, utility uncertain. Australas Psychiatry. 2017;25(6):622–4.
Oka Y, et al. Dual orexin receptor antagonist for the treatment of circadian rhythm sleep-wake disorders. J Neurol Sci. 2017;381:297.
Izuhara M, et al. Prompt improvement of difficulty with sleep initiation and waking up in the morning and daytime somnolence by combination therapy of suvorexant and ramelteon in delayed sleep-wake phase disorder: a case series of three patients. Sleep Med. 2021;80:100–4.
Matsui K, et al. Effect of aripiprazole on non-24-hour sleep-wake rhythm disorder comorbid with major depressive disorder: a case report, in Neuropsychiatr Dis Treat. New Zealand. 2017;13:1367–71.
Suzuki H, et al. Effect of aripiprazole monotherapy in a patient presenting with delayed sleep phase syndrome associated with depressive symptoms. Psychiatry Clin Neurosci. 2018;72(5):375–6.
Takaki M, Ujike H. Aripiprazole is effective for treatment of delayed sleep phase syndrome. Clin Neuropharmacol. 2014;37(4):124.
Omori Y, et al. Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation. Neuropsychiatr Dis Treat. 2018;14:1281–6.
Danielsson K, et al. Cognitive behavioral therapy as an adjunct treatment to light therapy for delayed sleep phase disorder in young adults: a randomized controlled feasibility study. Behav Sleep Med. 2016;14(2):212–32.
Gradisar M, et al. A randomized controlled trial of cognitive-behavior therapy plus bright light therapy for adolescent delayed sleep phase disorder. Sleep. 2011;34(12):1671–80.
Czeisler CA, et al. Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep. 1981;4(1):1–21.
Ito A, et al. Long-term course of adult patients with delayed sleep phase syndrome. Psychiatry Clin Neurosci. 1993;47(3):563–7.
Hur Y-M, Lykken DT. Genetic and environmental influence on morningness–eveningness. Personality Individ Differ. 1998;25(5):917–25.
Ancoli-Israel S, et al. A pedigree of one family with delayed sleep phase syndrome. Chronobiol Int. 2001;18(5):831–40.
Archer SN, Dijk D-J. Clock polymorphisms associated with human diurnal preference. In: Tafti M, Thorpy MJ, Shaw P, editors. The genetic basis of sleep and sleep disorders. Cambridge: Cambridge University Press; 2013. p. 197–207.
Ebisawa T, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001;2(4):342–6.
Archer SN, et al. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep. 2003;26(4):413–5.
Katzenberg D, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep. 1998;21(6):569–76.
Iwase T, et al. Mutation screening of the human clock gene in circadian rhythm sleep disorders. Psychiatry Res. 2002;109(2):121–8.
Micic G, et al. The endogenous circadian temperature period length (tau) in delayed sleep phase disorder compared to good sleepers. J Sleep Res. 2013;22(6):617–24.
Lazar AS, et al. Circadian period and the timing of melatonin onset in men and women: predictors of sleep during the weekend and in the laboratory. J Sleep Res. 2013;22(2):155–9.
Kendall AR, Lewy AJ, Sack RL. Effects of aging on the intrinsic circadian period of totally blind humans. J Biol Rhythms. 2001;16(1):87–95.
Czeisler CA, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284(5423):2177–81.
Aoki H, Ozeki Y, Yamada N. Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome. Chronobiol Int. 2001;18(2):263–71.
Watson LA, et al. Increased sensitivity of the circadian system to light in delayed sleep-wake phase disorder. J Physiol. 2018;596(24):6249–61.
Chang A-M, et al. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci. 2015;112(4):1232–7.
Suganuma N, et al. Using electronic media before sleep can curtail sleep time and result in self-perceived insufficient sleep. Sleep Biol Rhythms. 2007;5(3):204–14.
Goulet G, et al. Daily light exposure in morning-type and evening-type individuals. J Biol Rhythms. 2007;22(2):151–8.
Roenneberg T, Daan S, Merrow M. The art of entrainment. J Biol Rhythms. 2003;18(3):183–94.
Burke TM, et al. Effects of caffeine on the human circadian clock in vivo and in vitro. Sci trans med. 2015;7(305):146–305.
Taylor A, Wright HR, Lack LC. Sleeping-in on the weekend delays circadian phase and increases sleepiness the following week. Sleep Biol Rhythms. 2008;6(3):172–9.
Steinan MK, et al. Delayed sleep phase: An important circadian subtype of sleep disturbance in bipolar disorders. J Affect Disord. 2016;191:156–63.
Talih F, et al. Delayed sleep phase syndrome and bipolar disorder: pathogenesis and available common biomarkers. Sleep Med Rev. 2018;41:133–40.
Schrader H, Bovim G, Sand T. The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res. 1993;2(1):51–5.
Takaesu Y, et al. Circadian rhythm sleep-wake disorders predict shorter time to relapse of mood episodes in euthymic patients with bipolar disorder: a prospective 48-week study. J Clin Psychiatry. 2018;79(1):17115.
Borbély AA. A two process model of sleep regulation. Hum neurobiol. 1982;1(3):195–204.
Franken P, Dijk DJ. Circadian clock genes and sleep homeostasis. Eur J Neurosci. 2009;29(9):1820–9.
Dijk D-J, Lockley SW. Invited review: Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol. 2002;92(2):852–62.
Taillard J, et al. The circadian and homeostatic modulation of sleep pressure during wakefulness differs between morning and evening chronotypes. J Sleep Res. 2003;12(4):275–82.
Mongrain V, Dumont M. Increased homeostatic response to behavioral sleep fragmentation in morning types compared to evening types. Sleep. 2007;30(6):773–80.
Mongrain V, Carrier J, Dumont M. Chronotype and Sex Effects on Sleep Architecture and Quantitative Sleep EEG in Healthy Young Adults. Sleep. 2005;28(7):819–27.
Kerkhof GA, Lancel M. EEG slow wave activity, REM sleep, and rectal temperature during night and day sleep in morning-type and evening-type subjects. Psychophysiology. 1991;28(6):678–88.
Uchiyama M, et al. Poor compensatory function for sleep loss as a pathogenic factor in patients with delayed sleep phase syndrome. Sleep. 2000;23(4):553–8.
Dijk D-J, Franken P. Interaction of sleep homeostasis and circadian rhythmicity: Dependent or independent systems? Elsevier; 2005.
Van Dongen HPA, Dinges DF. Investigating the interaction between the homeostatic and circadian processes of sleep–wake regulation for the prediction of waking neurobehavioural performance. J Sleep Res. 2003;12(3):181–7.
Franken P. A role for clock genes in sleep homeostasis. Curr Opin Neurobiol. 2013;23(5):864–72.
Klerman EB, et al. Nonphotic entrainment of the human circadian pacemaker. Amer J Physiol-Regulatory. 1998;274(4):R991–6.
Antle M, Mistlberger R. Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster. J Neurosci. 2000;20(24):9326–32.
Franken P, et al. A non-circadian role for clock-genes in sleep homeostasis: a strain comparison. BMC Neurosci. 2007;8(1):1–11.
Mongrain V, et al. Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex. PLoS ONE. 2011;6(10):e26622.
Epstein LJ, et al. Resolving delayed sleep-wake phase disorder with a pandemic: two case reports. J Clin Sleep Med. 2022;18(1):315–8.
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Wu, A. Updates and confounding factors in delayed sleep–wake phase disorder. Sleep Biol. Rhythms 21, 279–287 (2023). https://doi.org/10.1007/s41105-023-00454-4
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DOI: https://doi.org/10.1007/s41105-023-00454-4