Circadian Rhythm Sleep-Wake Disorders
11.2 Delayed Sleep-Wake Phase Disorder .1 Description
Delayed sleep-wake phase disorder (DSWPD) is a CRSWD in which there is a habitual delay in the phase of the sleep-wake cycle, such that the major bout of sleep occurs at a later-than-desired clock time. Thus, DSWPD is characterized by recur- rent late sleep and correspondingly late rising and an inability to fall asleep and wake up at scheduled times during work or school days (Weitzman et al. 1981).
More specifically, when allowed to follow preferred sleep schedules, as on week- ends or nonwork days, DSWPD patients demonstrate a significant delay in the major sleep episode, typically falling asleep between 1 and 4 am and awakening in the late morning or afternoon (International Classification of Sleep Disorders 2014).
Due to a delayed sleep onset, their sleep is curtailed in the morning (if trying to get up at a socially desirable time) when their circadian sleep propensity and melatonin levels are still elevated. There is sleep inertia (problems of arising at an “appropriate time”) and excessive daytime sleepiness.
11.2.2 Risk Factors
As the most common CRSWD, DSWPD represents 5–10% of individuals diag- nosed with chronic insomnia disorder in sleep clinics and has an estimated preva- lence of 0.13–0.17% in the general population (Schrader et al. 1993; Yazaki et al.
1999). It is more common amongst adolescents and young adults, with studies reporting a prevalence of about 4–16% in these populations (Thorpy et al. 1988;
Sivertsen et al. 2013; Saxvig et al. 2012). The shift in diurnal preference, from
“morningness” in younger children to “eveningness” in adolescents, appears to be associated with various biological and environmental changes during pubertal development (Crowley et al. 2007).
There are several reports of genetic predispositions to extreme diurnal preference and DSWPD, including polymorphisms and haplotypes in the circadian clock gene PER3 (Archer et al. 2003; Pereira et al. 2005; Jones et al. 2007; Lazar et al. 2012;
Archer et al. 2010; Ebisawa et al. 2001). Moreover, studies have found other genetic variants that appear to be associated with DSWPD, including arylalkylamine N-acetyltransferase which is an important part of the melatonin synthesis pathway (Hohjoh et al. 2003); casein kinase I epsilon, which is a key post-translational mod- ulator of the molecular clock (Takano et al. 2004); and an increased frequency of human leukocyte antigen (HLA-DR1) (Hohjoh et al. 1999).
There is substantial evidence that evening-type individuals are more likely to have affective disorders, including major depression (Drennan et al. 1991;
Merikanto et al. 2013), seasonal affective disorder (SAD) (Natale et al. 2005) and bipolar disorder (Wood et al. 2009). Furthermore, “eveningness” may even predict earlier onset and increased severity of these states (Gaspar-Barba et al. 2009;
Mansour et al. 2005). A recent report looking at a large cohort of outpatients with a
history of mood disorders found that depression severity was significantly associ- ated with delayed sleep-wake and activity rhythms in adolescents and young adults (Robillard et al. 2014). It is therefore not surprising that rates of co-morbidity are high between DSWPD and depression (Thorpy et al. 1988; Takahashi et al. 2000;
Regestein and Pavlova 1995), seasonal affective disorder (SAD) (Lee et al. 2011) and bipolar disorder (Dagan et al. 1998). Studies suggest that 40–75% of DSWPD patients are co-diagnosed with depression; however, this can vary based on the sam- ple population (Thorpy et al. 1988; Takahashi et al. 2000; Regestein and Pavlova 1995). Interestingly, individuals with bipolar disorder may display a more pro- nounced phase delay in the gold standard test of melatonin secretion (dim light melatonin onset, DLMO) and sleep onset than individuals with unipolar depression (Robillard et al. 2013a; Robillard et al. 2013b) (Fig. 11.1). We have recently shown that sleep disturbances (and particularly DSPWD) occur in an adolescent inpatient psychiatric facility in inpatients with a more complex psychopathology. This sug- gests that DSWPD may be linked with severity of psychopathology (Shahid et al.
2012). Evidently, there is a strong association between mood disorders and DSWPD;
however, there is currently limited knowledge on the causative mechanisms or reci- procity of these relationships.
Studies have shown that about 30% of children and over 80% of adults with attention-deficit/hyperactivity disorder (ADHD) report difficulties falling asleep at a reasonable time (Van Veen et al. 2010; Corkum et al. 1999). Moreover, both chil- dren and adults with ADHD and sleep onset insomnia also demonstrate a delayed wake time and melatonin secretion, while sleep maintenance is similar to age- matched ADHD controls without sleep difficulties, demonstrating that this charac- teristic is due to DSWPD (Van Veen et al. 2010; Van der Heijden et al. 2005).
Moreover, ADHD individuals of all ages are more often evening chronotypes and frequently score as extreme evening chronotypes, as compared to controls (Bijlenga et al. 2013; Baird et al. 2012). Therefore, individuals with ADHD are a particularly high-risk group for DSWPD.
11.2.3 History
A detailed history of an individual’s sleep and activity pattern should be noted.
Typically, sleep onset difficulty starts in the teenage years as the sleep propensity shifts later. Individuals with CRSWD describe that their peak of alertness and cognitive performance is in the evening and at night. If allowed to choose an ideal sleep period (e.g., on the weekends or in the summer break), those with CRSWD go to bed very late. In these situations, they do not have sleep onset insomnia and their sleep quality is good. With respect to differential diagnosis, delayed bedtime because of safety concerns in post-traumatic stress disorder, prolonged evening routines in obsessive compulsive disorder, diurnal improvement of mood in depression or social activities (communication with friends) at night should be considered.
75
Normal
Time
Time Phase Delayed
melatonin pg/mLmelatonin pg/mL
50
25
19:00 20:00 21:00 22:00 23:00 0:00 1:00 2:00
20:00 21:00 22:00 23:00 24:00 1:00 2:00 3:00 0
75
50
25
0
Fig. 11.1 Dim light melatonin onset (DLMO) test. The DLMO test involves sitting in a dark room (<30 lux, in order to avoid melatonin suppression by light) from approximately 7 pm to 3 am. Hourly samples (blood or, preferably from the patients’ perspective, saliva) are collected. Additional samples may be needed for cases in which there may be extreme advanced or delayed melatonin rhythm.
Samples are processed to determine melatonin levels, and an individual’s melatonin profile is graphed. There are several methods to define DLMO, including when levels reach a fixed threshold of 3 or 4 pg/mL or when levels rise more than two standard deviations above at least three baseline values (or combinations of both). The graph below shows a normal pattern (DLMO at around 9 pm) and a delayed pattern of melatonin secretion in a DSWPD patient (DLMO at around 12 am)
11.2.4 Investigations
In addition to a detailed patient sleep history, current diagnostic tools assess both behavioural sleep-wake patterns and the endogenous timing of the circadian system.
Sleep logs and actigraphy are recommended for at least 7 and preferably 14 days to discern patients’ rest-activity schedules and patterns. Several questionnaires, includ- ing the Morningness-Eveningness Questionnaire (MEQ) (Appendix B) and the Munich Chronotype Questionnaire (MCQ), can also help determine an individual’s preferred timing of various activities across a 24-h day (Zavada et al. 2005; Horne and Ostberg 1976). Similar questionnaires can be found for paediatric and adoles- cent populations (Werner et al. 2009). It is common for DSWPD patients to show extreme evening preference on questionnaires.
Most authorities state that overnight polysomnography (PSG) is typically not required. However, it may useful in assessing co-morbidity of other sleep disor- ders, such as sleep apnoea and periodic limb movement disorder (International Classification of Sleep Disorders 2014). If PSG is performed under a preferred or ad libitum schedule, sleep quantity and quality is generally normal for age; how- ever, there may be a slight delay in sleep onset (Lack and Wright 2007; Saxvig et al. 2013).
We have shown that in a proportion of “phase delay” individuals, as described by self-report and sleep diaries or actigraphy, there may be a relatively easy sleep onset at what is viewed as a regular time if the person is put to sleep in a laboratory. If they are put to bed after a DLMO study (in our laboratory, shortly after 3 am), there may be a long sleep onset. Both of these patterns are somewhat paradoxical, suggesting that behavioural rather than biological factors are responsible for the late bedtime.
Thus, these observations are clinically relevant and useful. We therefore feel that overnight sleep studies are beneficial in helping to clarify the diagnosis. Key body rhythm markers, including core body temperature and the nightly secretion of mela- tonin by the pineal gland, are important in revealing circadian timing abnormalities relative to the sleep-wake cycle. In normally entrained individuals, the rise in mela- tonin secretion during the biological night from nearly absent daytime levels occurs typically about 2–3 h before sleep onset, while the nadir of the core body tempera- ture is about 2 h before sleep offset (Benloucif et al. 2005).
Determining the onset of melatonin secretion appears to be a more stable phase marker than core body temperature (Benloucif et al. 2005; Klerman et al. 2002) and is a more reliable, practical and more socially acceptable clinical measure to con- firm the presence of a CRSWD (Sack et al. 2007). Melatonin can be measured in plasma and saliva or as its primary metabolite 6-sulfatoxymelatonin in urine.
One needs to recognize that, particularly amongst adolescents, some “choose” to go to bed late and others are “compelled” to go to bed late by virtue of their biology.
It is nothing short of cruel to attempt to adjust the delayed phase in a teenager with a shifted biological clock by behavioural means as this invariably fails. Conversely, being persuaded by a change in sleep pattern that it must be a biological problem is naïve. This is the reason that DLMO testing needs to be more widely applied. There is no other hormonal disorder that would be treated without the relevant test.
Moreover, many treatments for CRSWD are phase dependent (as discussed later on); thus proper phase assessment not only helps with diagnostic specificity but also guides treatment.
11.2.5 Treatment
In order to properly realign the endogenous circadian system with environmental time, the management of DSWPD requires a comprehensive treatment approach involving environmental, behavioural and/or pharmacological factors. This may include chronotherapy, bright light therapy, exogenous melatonin administration and techniques to improve sleep hygiene.
Chronotherapy involves implementing a transient phase delaying regimen where sleep-wake times are progressively delayed by about 3 h every 2 days until sleep onset finally reaches the desired bedtime (Czeisler et al. 1981). Once an appropriate earlier bedtime is established, it is important for individuals to enforce a regular sleep-wake schedule and avoid delaying their circadian rhythms by stay- ing up late on weekends or by being exposed to light late in the evening. Although a potentially successful treatment method, compliance is often difficult to main- tain because of the daily restrictions placed on an individual’s personal and soci- etal lifestyle. Moreover, the long-term effectiveness of chronotherapy is variable, including common accounts of relapse (Ito et al. 1993). In reality, for most, this is only a textbook solution.
Bright light therapy is a common treatment method for CRSWD patients and involves appropriately timed bright light and darkness to adjust an individual’s circadian phase and thus their sleep-wake cycle. As explained by the human PRC to light, exposure to light in the late subjective night or early morning phase advances circadian rhythms (resets pacemaker to an earlier time), whereas expo- sure to light in the early subjective night or late evening generates phase delays (resets pacemaker to a later time) (Czeisler et al. 1986; Khalsa et al. 2003). In DSWPD patients, a 2–3-h exposure to bright light at ~2500 lux given on awaken- ing with limited light exposure in the evenings has been shown to phase advance body temperature, melatonin rhythms and sleep onset and to increase objective measures of daytime alertness (Rosenthal et al. 1990; Cole et al. 2002). Considering that the timing of light is crucial, caution should be taken to administer the morn- ing light exposure after the core body temperature nadir (during the appropriate advance portion of the PRC), so as to avoid administering the bright light stimulus before the core body temperature nadir and inadvertently furthering the delayed circadian phase. Moreover, it is important to monitor and maintain treatment in order to keep the phase advancement of the sleep-wake schedule and prevent drift- ing back to a delayed pattern (Rosenthal et al. 1990; Wilhelmsen-Langeland et al.
2013). The theory behind this is good, but in clinical practice, it is often very dif- ficult to do. Patients, particularly those with DSWPD who are liable to lie in in the morning, rarely have the time to sit in front of a light before rushing off to work or school. One of us (CS) has gone as far as admitting a patient to an inpatient ward
(approximately 20 years ago) to try to ensure this was correctly done. However, on discharge the patient rapidly reverted to a delayed pattern. Exogenous melatonin can also phase shift the circadian pacemaker when given during the biological day, that is, when endogenous levels are nearly absent. As demonstrated by the human melatonin PRC, exogenous melatonin induces phase shifts opposite to light expo- sure; melatonin administration in the afternoon/evening generates phase advances, and melatonin administration in the morning generates phase delays (Lewy et al.
1998). In DSWPD patients, previous studies have shown that melatonin given dur- ing the afternoon or early evening can shift circadian rhythms (core body tempera- ture and/or melatonin rhythms), as well as sleep-wake times to an earlier phase (Dahlitz et al. 1991; Nagtegaal et al. 1998; Kayumov et al. 2001; Mundey et al.
2005). These studies vary in terms of dosage and scheduling of melatonin admin- istration. In one double-blind placebo-controlled crossover study, we showed that DSWPD subjects treated with 5 mg melatonin at 7 pm for 4 weeks led to a reduced PSG-determined sleep onset latency and normalization of urinary 6-sulfatoxymel- atonin, as compared to placebo (Kayumov et al. 2001). A separate double-blind placebo-controlled study tested two different doses (0.3 mg vs. 3 mg) administered between 1.5 and 6.5 h prior to DLMO for 4 weeks (Mundey et al. 2005).
Interestingly, both doses demonstrated comparable maximal phase advances, with a greater magnitude observed with earlier times of melatonin administration rela- tive to DLMO. Similarly, in normally entrained individuals, the melatonin PRC to two different doses (0.5 mg vs. 3 mg) demonstrated comparable maximal magni- tudes of phase delays and advances, with peak phase advancements occurring 3–5 h prior to DLMO (Lewy et al. 1998; Burgess et al. 2010). In our clinic, our standard procedure after obtaining the results of the DLMO showing a delayed rise is to give each patient two packets of pills marked “A” and “B” with the instruction to take one pill from “A” for a month and one pill from “B” for a month, both at 7 pm every night. This is a single-blind exercise using placebo and melatonin. The patient returns in 2 months, and 95% will have clearly identified the active treat- ment and wish to remain on the melatonin. Evidently, exogenous melatonin is an effective and recommended treatment of DSWPD; however, in order to establish more specific dose and scheduling guidelines, additional large-scale controlled tri- als are warranted (Morgenthaler et al. 2007).
Recent studies have also suggested that a combination of exogenous melatonin and bright light therapy has an additive effect on phase resetting (Wirz-Justice et al.
2004; Burke et al. 2013). When early evening melatonin is combined with morning bright light, a greater phase advance is observed than with either treatment alone, suggesting that this may be an efficient and effective treatment for DSWPD (Burke et al. 2013). Moreover, proper sleep hygiene is important for DSWPD patients in order to promote appropriate scheduling of social activities and regular sleep-wake schedules. Photic and non-photic treatments for DSWPD have been shown to improve symptoms of co-morbid psychiatric conditions, including depression (Rahman et al. 2010) and ADHD (Rybak et al. 2006). Nevertheless, DSWPD patients may require conventional treatments for these co-morbid conditions as well (see Clinical Vignette B).
11.3 Advanced Sleep-Wake Phase Disorder