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1 Oxford Handbooks Online Circadian Rhythm Disorders I: Phase-Advanced & Phase-Delayed Syndromes Leon C. Lack and Helen R. Wright The Oxford Handbook of Sleep and Sleep Disorders Edited by Colin A. Espie and Charles M. Morin Print Publication Date: Mar 2012 Online Publication Date: Sep 2012 Subject: Psychology, Clinical Psychology, Cognitive Neuroscience DOI: /oxfordhb/ Abstract and Keywords The circadian rhythm sleep disorders of delayed sleep phase disorder (DSPD) and advanced sleep phase disorder (ASPD) are associated with circadian rhythms timed too late and too early, respectively. Because of the potent effect of the circadian rhythms on sleepiness/alertness, these timing abnormalities can then lead to sleep onset difficulties or early morning awakening insomnia, respectively. The timing differences may arise from circadian period lengths longer or shorter than 24 hours, differential responsiveness to the phase delaying or advancing effects of bright light, differences in accumulation rate of homeostatic sleep drive, or subjective sleepiness rhythm differences. In any case, chronobiologic interventions including bright light therapy and melatonin administration are indicated as treatment in addition to appropriate behavioral and cognitive therapies. Furthermore, the overlap between DSPD with sleep onset insomnia and ASPD with early morning insomnia suggests that chronobiologic interventions would be a useful adjunct to the present cognitive/behavioral treatment package for insomnia. Keywords: circadian phase delay, circadian phase advance, bright light therapy, melatonin, core body temperature, sleep onset insomnia, early morning awakening insomnia Introduction The International Classification of Sleep Disorders, 2nd Edition (ICSD-2; American Academy of Sleep Medicine, 2005) devotes a chapter to circadian rhythm sleep disorders. This recognizes the strong impact that our circadian rhythms (circa = about, dian = a day) have on our ability to sleep or be alert across the 24-hour period. This potency of the circadian rhythm influence will be elaborated upon later in this chapter. The ICSD-2 lists eight identified types of circadian rhythm sleep disorders: 1. delayed sleep phase disorder 2. advanced sleep phase disorder 3. irregular sleep wake rhythm 4. free-running type 5. jet lag disorder 6. shift work disorder 7. circadian rhythm disorder due to medical condition 8. circadian rhythm disorder due to drug or substance. Box 28.1 A Case of Delayed Sleep Phase Disorder Damien has a problem causing him distress and jeopardizing his university studies. He simply cannot fall Page 1 of 32

2 asleep until very late at night (2 a.m.). This would not be a problem if he were a night shift worker, but it results in too little sleep when, on three days/week, he must get to class by 9 a.m. He struggles to awake at 8 a.m. after only six hours of sleep and has frequently slept through his alarm and missed his early classes. When he manages to get to these classes, he finds it difficult to maintain attention and has occasionally drifted off to sleep. Very likely because of the physical and mental absences, his grades have been poor in these classes. He has found that going to bed earlier (11 p.m.) does not produce an earlier sleep time, only more time awake, tossing and turning, and feeling increasingly frustrated and anxious. Damien has always been an evening type of person who can work well and enjoys socializing late at night. He finds the mornings aversive, taking a long time to fully awake and feel normal. In high school it was often a time of conflict with parents trying to wake him in time to get to school. Breakfast was often skipped for lack of time and appetite. When the opportunity arises (e.g., weekends or vacations) to catch up on lost sleep, he has no difficulty sleeping soundly until late in the morning and on occasion has been known to sleep until the early afternoon. However, despite providing some relief from his almost chronic sleep debt, he finds it even more difficult getting to sleep when returning to a more conventional bedtime after his late sleep-ins. While the subsequent chapter in this text will deal with jet lag and shift work disorder and other chapters may touch on irregular and free-running types, the present chapter will focus on the first two and common circadian rhythm sleep disorders, delayed sleep phase disorder (DSPD) and advanced sleep phase disorder (ASPD). We will describe the clinical features of these disorders, their prevalence, their etiology (both chronobiological and psychological), and their treatments. Chronobiologic treatments include both bright light therapy and melatonin administration. Psychological therapies include proven behavioral treatments as well as (p. 598) newer cognitive therapies. To introduce these two circadian rhythm disorders, a couple of fictitious but relatively typical cases are briefly described. The case of Damien elaborates a typical case of DSPD. It illustrates a sleep/wake difficulty arising mainly from a circadian rhythm disorder (DSPD), in which the underlying circadian rhythms are timed later than normal. The case of Laura elaborates a typical ASPD case. Laura s sleeping/waking difficulty can be described as advanced sleep phase disorder (ASPD) associated with circadian rhythms timed too early. Box 28.2 A Case of Advanced Sleep Phase Disorder Laura has a sleep problem almost opposite to Damien s. She has always been a morning type of person and preferred doing things in the morning, when she feels more alert and energetic, than in the evening. When younger she could sleep well between 10 p.m. and 6 a.m. Now, at the age of 62, she realizes that her sleep has been getting increasingly fragmented, particularly in the morning. In the evening she often struggles to stay awake until her normal bedtime at 9 p.m., especially when watching TV or reading, and has been known to inadvertently fall asleep briefly. She has no difficulty getting to sleep at bedtime, but she sleeps solidly for only three to four hours. After that she experiences increasingly long wakeful periods in between short intervals of light sleep. This is often accompanied by frustration and worry about detrimental health consequences. By 4 a.m. she cannot sleep any longer, so she usually gets out of bed, particularly in the summer when it is warmer and lighter outside. She has tried going to bed later in the hope of being able to sleep later in the morning, but this only results in even less sleep. If Laura goes to bed earlier (e.g., 7 8 p.m.), she can get more total sleep, at least for a few nights, until she finds she is waking even earlier than before. If she keeps shifting her bedtime earlier, it will encroach on her social/domestic/work life. She feels a constant conflict between the 24-hour world and a body clock that tends to keep getting earlier. These two cases also may be diagnosed respectively as sleep onset insomnia (SOI) and early morning awakening (EMA) insomnia. Indeed, we will see later that there is considerable overlap and shared etiology between these circadian rhythm disorders and these two types of insomnia. The implications of finding circadian rhythm timing abnormalities associated with these sleep/wake disorders is that (p. 599) effective treatments should include the manipulation of circadian rhythms. Page 2 of 32

3 Descriptions of disorders Delayed sleep phase disorder (DSPD) Weitzman and colleagues defined delayed sleep phase syndrome (DSPS) as a delay of the usual sleep period by as much as 2 6 hours later than normal (Weitzman, Czeisler, Coleman, Spielman, Zimmerman, & Dement, 1981). According to the most recent International Classification of Sleep Disorders (ICSD-2)(American Academy of Sleep Medicine, 2005), the terminology has been altered slightly to delayed sleep phase disorder (DSPD). The major sleep period of individuals with DSPD may be as late as 5 a.m. to 2 p.m. but more typically from 2 a.m. to 10 a.m. When sleeping at those delayed times, sleep is reported to be relatively normal. However, when confronted with the need to awaken at an earlier time to meet societal or family obligations, they have great difficulty obtaining adequate sleep at these more normal bedtimes (e.g., 12 midnight to 7 a.m.). With a midnight bedtime they will experience sleep onset insomnia and not be able to initiate sleep until perhaps 2 a.m. 3 a.m. If they are able to arise at 7 a.m. (probably with the help of alarm clocks and other family members), total sleep time will be reduced. Repeated nights of this imposed regime will see little improvement in total sleep and will result in an accumulated sleep debt and impaired daytime functioning and well-being, including daytime sleepiness, fatigue, irritability, and diminished ability to concentrate (especially in the mornings). The increased homeostatic sleep drive (see Chapter 2) from this accumulated sleep debt should facilitate an earlier sleep onset, but it appears to be not enough to provide adequate sleep length. Given an opportunity to sleep later and longer, such as on weekends or holidays, the individual with DSPD will do so, readily sleeping until perhaps mid-afternoon. Advanced sleep phase disorder (ASPD) ASPD is a consistent early-timed sleep period in which the typical sleep onset time and wake-up time are earlier than normal by at least a few hours (AASM, 2005). The pattern is exemplified by the case of Laura, for whom the typical sleep onset and wake times were 9 p.m. and 4 a.m., respectively, but most preferred sleep times for a better sleep would probably be even earlier from 8 p.m. to 3 a.m. At the typical sleep period (often a compromise between the preferred based on circadian rhythm timing and what is more socially acceptable), there is early morning awakening insomnia, inadequate total sleep time, and resulting daytime tiredness and distress. Clinical features DSPD Although the difficulty initiating sleep at a more normal time defines this disorder, it initiates a cascade of other problems that complicates the treatment of DSPD. The resulting daytime impairment (especially in the mornings) from inadequate sleep jeopardizes performance in the workplace, school, or with other social obligations and can result in job loss, school failure, and other social disruptions (Gionnatti, 2002; Carskadon et al., 1998; Lack, 1986; Valdez et al., 1996; Thorpy, Korman, Spielman, & Glovinsky, 1988). Once unemployed or out of school, the DSPD late sleep pattern can become well ensconced and a significant impediment to getting re-employed or returning to effective study. These difficulties can, in turn, have psychological and social costs, making it more difficult to muster the motivational resources to adhere to the relatively strict and multifactorial treatment regime required in these cases. Furthermore, there is considerable evidence that those with DSPD have a greater risk of psychological/psychiatric difficulties such as depression, hypochondriasis, conversion hysteria, and social withdrawal (Kamei et al., 1998; Regestein & Monk, 1995; Dagan et al., 1998; Shirayama et al., 2003; Takahashi et al., 2000). This group would be more psychologically vulnerable and, therefore, particularly challenging to treat successfully (Regestein & Monk, 1995). In addition, although DSPD sufferers usually claim a desire to normalize their sleep timing, there may be secondary gain or reward in being able to avoid environments or responsibilities about which they are unconfident or simply to avoid the mornings that have become aversive to them (Alvarez, Dahlitz, Vignau, & Parkes, 1992; Ferber, 1983; Crowley, Acebo, & Carskadon, 2007; Ferber, 1995). It is therefore apparent that there are multifactorial contributors to DSPD that complicate a differential diagnosis, make it difficult to determine a prevalence estimate, and usually Page 3 of 32

4 require a multi-component therapy. Hopefully, this will lead to a more realistic understanding of these complex disorders of interacting physiological, psychological, and social factors with the aim of applying more appropriate and effective therapies. (p. 600) ASPD The example of Laura above includes many of the clinical features of advanced sleep phase disorder. Despite Laura s struggle to stay awake until a more socially acceptable bedtime, she still has an early timed sleep period. The classification of this as a disorder arises from the difficulty with unwanted early awakening resulting in inadequate sleep and associated daytime sleepiness, fatigue, and other impairments. Sleepiness is particularly strong in the early evening and can result in unintentional naps while reading or watching TV. If the nap is long enough (>30 minutes), it is likely to include deeper sleep and further shorten the nocturnal bedroom sleep. The ASPD sufferer may consume an evening caffeine drink in order to maintain alertness until bedtime. However, with a half-life of 5 8 hours, the caffeine can still contribute to sleep disruption later in the sleep period (Caldwell & Caldwell, 2005; Landolt et al., 1995). The frustration and anxiety arising during these early awakenings, particularly about the subsequent daytime impairment, can lead to the development of psychophysiological or conditioned insomnia (AASM, 2005) of the early morning awakening type. If these negative experiences are frequently associated with the bed, bedroom environment, time of night, and desire to return to sleep, the subsequent conditioning/learning can lead to an automatically evoked alerting response upon awakening in the same context on future occasions and perpetuate the insomnia. Prevalence of DSPD and ASPD Estimated prevalence rates for DSPD have ranged from 0.13% to 10% of the population (Weitzman et al., 1981; Lack, 1986; Pelayo, Thorpy, & Glovinsky, 1988; Schrader, Bovim, & Sand, 1993; Yazaki, Shirakawa, Okawa, & Takahashi, 1999). It appears to be more common in adolescents and young adults (7% 17%) and may be the most frequent cause of childhood onset insomnia (Schrader, 1990). Maturational changes at pubescence in circadian period length or phase with no diminution of sleep need may predispose adolescents to DSPD (Carskadon et al., 1998; Crowley et al., 2007). In addition, the changed social milieu of adolescence demanding greater social engagement and exacerbated by technological changes such as cell phones and online computer access, increased academic workload, and enhanced entertainment distractions will tend to delay bedtimes, diminish sleep length, and delay weekend sleep periods. The large range of prevalence estimates may be due to criterion differences between studies in the amount of delay required of the sleep period to qualify for the diagnosis. Less severe cases of DSPD (e.g., 1:00 a.m. to 9:00 a.m. sleep period) are likely to be more prevalent than the more extreme delayed cases (e.g., 4:00 a.m. to 1:00 p.m.). A recent study found the habitual sleep onset times of patients diagnosed with DSPD varied between about 11:30 p.m. and 5:15 a.m., with a majority before 2:00 a.m. (Mundey, Benloucif, Harsanyi, Dubocovich, & Zee, 2005). The population distribution of typical sleep onset times may be normal such that the amount of delay of sleep onset required to qualify for a diagnosis of DSPD is somewhat arbitrary along a putatively single mode normal distribution. A more severe criterion (e.g., sleep onset after 3 a.m.) may yield quite a small prevalence in the general population (Schrader, Bovim, Sand, 1993) while a less demanding criterion (e.g., sleep onset later than 1 a.m.) may result in a much higher prevalence. This begs the question as to what should be considered as the most clinically relevant criteria. A phase delay of preferred sleep period (e.g., 2 a.m. 10 a.m.) may suit the occasional night shift worker or university student with no morning classes and may not be considered a disorder. The critical difficulty would seem to be, when trying to conform to a more conventional wake-up time, having difficulty initiating sleep early enough to obtain adequate total sleep. In this sense, DSPD would be considered to overlap with sleep onset insomnia (SOI), estimated to have a substantial 8% population prevalence (Kim, Uchiyama, Okawa, Liu, & Ogihara, 2000). It is estimated that DSPD accounts for about 10% of patients with all types of chronic insomnia seen in sleep clinics (AASM, 2005). If this population of sleep clinic insomnia is representative of the general population of chronic insomnia, then, given an estimate of chronic insomnia prevalence of about 10% of the population (Ohayon, 2002), one could derive a population estimate of about 1% for the prevalence of DSPD. Page 4 of 32

5 However, there is some evidence that chronic sleep onset insomnia may share common etiology with DSPD, and for clinical purposes, share common treatments. Morris, Lack, and Dawson (1990) showed that a group of sleep onset insomniacs with mean sleep onset time of 12:45 a.m. also had circadian temperature rhythms delayed four hours later than the good sleep control group. Lack, Wright, and Paynter (2007) found a group (N = 16) of chronic sleep onset insomniacs with mean sleep (p. 601) onset latency of 59 minutes to have a mean dim-light melatonin onset at 12:20 a.m. that is over three hours delayed from normal. Therefore, the overlap between chronic sleep onset insomnia and DSPD may be considerable, with many or most sufferers of chronic sleep onset insomnia having a circadian delay that would qualify for DSPD. Since the estimated prevalence of chronic sleep onset insomnia ranges from 5.1% to 8.3% (Ohayon, 2005; Kim et al., 2000), the prevalence of DSPD, at least in more mild forms, may be substantial (3% 4% of the population). In the end, the attempt to establish a strict definition, differential diagnosis, and a precise prevalence rate implies a distinct pathology that may be unrealistic for conditions that are usually multifactorial. What is more important is to identify the contributing causes to a disorder in order to apply appropriate treatments. In this case, treatment for sleep onset insomnia, as well as DSPD, should then include circadian rhythm retiming. Since its initial description, the prevalence of ASPD has been suggested to be low. This may, in part, be due simply to the ease with which an early sleep pattern (e.g., 8 p.m. 4 a.m.), although socially awkward at times, can be accommodated by the normal working environment (Campbell, 1999) and therefore not be presented for treatment. It is suggested to be more common in middle-age and older adults with a prevalence of about 1% (AASM, 2005). However, just as DSPD most certainly overlaps with sleep onset insomnia, ASPD overlaps with early morning awakening insomnia. Participants selected on the basis of chronic early morning awakening insomnia have been shown to have circadian temperature and melatonin rhythms timed 2 4 hours earlier than normal controls or normative data (Lack & Wright, 1993; Lack, Mercer, & Wright, 1996; Lack, Wright, Gibbon, & Kemp, 2005). Since early morning awakening insomnia is moderately common at 4.8% 8.0% (Kim et al., 2000; Ohayon, 2005), particularly in the older population (6.8% and 13.3%), then a fair estimate of ASPD prevalence would be 2% 3% of the population. Many readers will be aware that sleep disturbance, especially early morning awakening insomnia, is highly prevalent in cases of major depression and is a clinical symptom of depression (AASM, 2005). Chapter 23, Sleep and Psychiatric Disorders, elaborates these relationships. However, even though depressed people are likely to have insomnia, having insomnia does not necessarily imply depression. For example, in the three previously cited separate studies of participants selected for early morning awakening insomnia (Lack & Wright, 1993; Lack, Mercer, & Wright, 1996; Lack, Wright, et al., 2005; total N = 49), only one (2%) scored in the depressed range (Carney et al., 2009). This leads us to the question of the etiology of both sleep onset and early awakening insomnia as well as DSPD and ASPD. Etiology of DSPD and ASPD From the first descriptions of DSPD it has been assumed that its etiology is based on a delay of circadian rhythms (Weitzman et al., 1981), while ASPD has been suggested to result from an advance (earlier timing) of circadian rhythms (Strogatz, Kronauer, & Czeisler, 1987). To understand the role of circadian rhythms in this disorder and facilitate a more informed treatment, it is necessary to discuss the relationship between circadian rhythms and sleep. Although this issue was introduced in Chapter 2, it would be useful to elaborate on the aspects of circadian rhythms that are of particular importance to circadian rhythm sleep disorders. Normal biological determiners of sleep The two major biological determiners of sleep have been named Process S for sleep homeostasis and Process C for circadian determination of sleepiness (see Chapter 2 for more detail). Process S simply refers to the increase of sleep drive or pressure during continued wakefulness, much as going without food increases hunger and foodseeking drive. Similarly, the process of sleeping reduces sleep drive as eating reduces hunger drive. On average, sleep needs to occupy about a third of our time (8 out of 24 hours) to maintain a normal balance between sleep and wakefulness. Less sleep than this ratio will usually result in symptoms of generally insufficient sleep time (e.g., sleepiness, irritability, lapses of attention). These effects (particularly the increased pressure to fall asleep) are utilized temporarily in some effective treatments for insomnia (e.g., stimulus control, bedtime restriction therapy; Page 5 of 32

6 see Chapter 22). A more extreme degree of sleep deprivation and its consequently heightened sleep pressure has been recently used effectively to retrain sleep initiation in those with sleep onset insomnia (Harris, Lack, Wright, Gradisar & Brooks, 2007). Sleep homeostasis may play an indirect role in the development of DSPD and ASPD. For example, DSPD emerges in adolescence as a prominent sleep disorder (Carskadon, 1990). During adolescence, perhaps because of various social and lifestyle (p. 602) changes, there is a decreased amount of time in bed that is not matched by a comparable decrease of sleep need (Carskadon et al., 1980). This will result in sleep loss and then recovery sleep when the opportunity for longer sleep arises. However, the recovery sleep often involves sleeping in later, such as on weekends, and leads to circadian phase delays (Burgess et al., 2006; Yang et al., 2001; Taylor et al., 2008). Furthermore, evening chronotype individuals, who are prime candidates for the development of DSPD, appear to accumulate Process S more slowly during wakefulness and dissipate it more slowly during sleep than do morning types (Taillard, Philip, Coste, Sagaspe, & Bioulac, 2003; Mongrain, Carrier, & Dumont, 2006; Schmidt et al., 2009). This characteristic may also be present in DSPD individuals, leading them to postpone bedtime and wake-up time and resulting in phase delays of their circadian system. Possibly contributing to ASPD, more common in the older population (Dijk & Duffy, 1999), is the decrease of sleep homeostatic drive in healthy older adults (Klerman & Dijk, 2008). In this case the decreased sleep need with age is manifested more in earlier awakenings rather than later bedtimes. With earlier awakenings, morning light exposure then can cause an advance in circadian rhythms. Thus Process S may indirectly contribute to these circadian rhythm disorders. Independent of the Process S determiner of sleep is the circadian rhythm system. Of the two biological processes S and C, the circadian effect, C, is presumed to be the most immediate contributor to DSPD and ASPD. Therefore, the circadian process will be discussed in more detail. Effects of circadian rhythms on sleep Click to view larger Fig Examples of three circadian rhythms of Core Body Temperature, Melatonin, and Sleep Propensity for an individual normally sleeping from 11 p.m. to 7 a.m. Note the two periods of low sleep propensity, the Wake maintenance Zone from about 6 p.m. to 10 p.m. during which it would be difficult to fall asleep, and the Wake Up Zone during which ongoing sleep will tend to be disrupted. Circadian rhythms refer to the 24-hour oscillations in virtually every biochemical, hormonal, and physiological variable measured across a 24-hour period. For example, Figure 28.1 illustrates the normal relationship between the sleep period and two examples of the circadian rhythms: core body temperature and melatonin hormone levels. Although our own behavior and environmental stimulation can acutely influence the values of these measures, in a constant controlled bed rest dimly lit environment they continue to oscillate unabated, showing a strong endogenous origin of the rhythms (Czeisler et al., 1985; Monk et al., 1992). (p. 603) This endogenous component exerts a very strong effect on our subjective and objective sleepiness, that is, how sleepy we feel and how quickly we will fall asleep. Figure 28.1 indicates the lowest sleep propensity occurring at about the time of the maximum in the core temperature rhythm (6 9 p.m.) and maximum circadian sleep propensity soon after the maximum melatonin level and at about the same time as the minimum core temperature (Tmin). Temperature and melatonin themselves are not the determiners of sleepiness, but all three of these rhythms (sleepiness, temperature, and melatonin) as well as almost every other biological and behavioral Page 6 of 32

7 measure (the circadian system) are being driven in synchrony by the central body clock, a small nucleus located in the hypothalamus of the brain called the suprachiasmatic nucleus (SCN) (Winfree, 1982). Positioned just above the optic chiasm, the SCN receives collateral input from the optic nerves and thus can be stimulated by the effects of retinal light reception. It has long been established that light stimulation can re-time the body clock or circadian system through this retinohypothalamic connection (Czeisler et al., 1989). We will discuss later exactly how this ocular light stimulation can delay or advance circadian phase or timing. Free-Running Studies The evidence for the strong effect of the circadian system on sleepiness/alertness has come from research in two types of studies. Mid-20th century studies in caves or bunkers underground presented individuals with totally time-free environments in which they could exercise, eat, and sleep when they felt like it, presumably following their endogenously determined circadian rhythms since they had no clues or concerns about real clock time. Two important findings came from these studies. The most consistent was that these young adults in isolation tended to delay bedtimes and wake times each day by about an hour (Aschoff, 1965; Webb, 1974; Wever, 1984). This suggested that the endogenous period length (the time taken for one complete cycle) of most young adults is somewhat longer than 24 hours. More recent laboratory-based studies suggest the average for both young and older adults is about 24.2 (S.D. = 0.13) hours (Duffy, Rimmer, & Czeisler, 2001; Dijk, Duffy, Riel, Shanahan, & Czeisler, 1999). The clinical implication is that, in the absence of time cues or other entraining stimuli, most people will have a tendency for their circadian rhythms to drift later or phase delay, possibly resulting in sleeping difficulty at one s usual bedtime. The second important finding arose after many days in this free-running condition when some participants showed a spontaneous uncoupling or desynchronizing between their core body temperature rhythm and sleep wake cycle (Aschoff & Wever, 1981). When researchers investigated the relationship between the two rhythms, they found that certain circadian phases were avoided as bedtimes and thus were termed wake-maintenance zones, about 6 9 hours before the core temperature minimum (Tmin) and 4 7 hours after Tmin (Strogatz, 1986; Strogatz, Kronauer, & Czeisler, 1987). The most popular choice of bedtime was around the Tmin, and a second popular time about 10 hours later. In terms of clock times for normally entrained individuals with Tmin at about 4 a.m., the wake-maintenance zones would reside about 6 10 p.m. and 8 11 a.m. The circadian sleepy zones would be about 2 7 a.m. for the major zone and 1 3 p.m. for the afternoon minor sleepy zone. These zones are evident in Figure 28.1 and highlight that two alert zones bracket the major sleep period. It is these two alert zones that are thought to be the main cause of the problem for DSPD and ASPD. Forced Desynchrony Studies It must be remembered, however, that this model was suggested by the times avoided or selected as bedtimes or typically awoke from sleep in the free-running studies. The question remained as to whether these zones actually determined the ability to fall asleep if sleep was attempted at those times. The second type of study, forced desynchrony, addressed that question. These studies, in a controlled laboratory environment, experimentally imposed sleep wake cycles or days of different lengths that were beyond the ability of the circadian rhythms to track with the same period length. For example, the 28-hour day enforced an 18.7-hour period of wakefulness followed by a 9.3-hour opportunity for sleep repeated dozens of times over a span of weeks. Since the endogenous circadian rhythms could not stray more than about half an hour from 24 hours, they could not follow the enforced 28-hour cycle length and thus remained close to a 24-hour period length. This procedure ensured that there would be imposed bedtimes and sleep periods at all circadian phases eventually over the weeks of the experiment. Other forced desynchrony studies have used other sleep wake cycle lengths of 3 hours (Weitzman et al., 1974), 1.5 hours (Carskadon & Dement, 1975), 30 minutes (Lack & Lushington, 1996), and 20 minutes (p. 604) (Lavie, 1986) and could be carried out over only a day or two. In each case the allotted period for sleep was always one third of the total cycle length in order to keep Process S within its normal homeostatic range. On the whole, the results of all these studies were consistent with the free-running studies. They showed reduced ability (longer) to fall asleep in the two wake-maintenance zones and faster sleep onsets in the sleepy zones while keeping the amount of prior time awake the same at all sleep onsets. They also found more awakenings and awake time in bed when it coincided with the second wake-maintenance zone, thus sometimes referred to as a wake-up zone, as indicated in Figure Page 7 of 32

8 DSPD and ASPD a result of circadian timing abnormality? DSPD Associated With Circadian Phase Delays Click to view larger Fig The timing of typical sleep for delayed sleep phase disorder in this example between about 2 a.m. and a necessary awakening at 8 a.m. or later awakening given an opportunity to sleep in. Now, with an appreciation of the strong effect of the circadian system on sleep propensity, it is apparent how disturbances of the timing of the circadian system can lead to DSPD and ASPD. The circadian rhythm can become delayed for a number of exogenous factors such as flying eastward across several time zones, a period of night shift work, or even the shift onto daylight saving time in the spring (Kantermann, Juda, Merrow, & Roenneberg, 2007). There are also a number of endogenous factors such as intrinsic period length and differential response to entraining cues that will be discussed later. If, for any reason, the circadian system becomes delayed by a few hours, the wake-maintenance zone would extend across the time of normal bedtime and inhibit sleep onset until passage of this zone (Strogatz, Kronauer, & Czeisler, 1987). The circadian rhythm phase changes suggested as etiologic for DSPD are illustrated in Figure In this case the whole circadian system, including the indicative core temperature, melatonin, and sleep propensity rhythms, is delayed from the normal timing (as shown in Figure 28.1) by about 4 hours. The wake-maintenance zone, normally timed about 6 10 p.m., would also be delayed by the same amount. This would force a delay of sleep onset in this case to 2 a.m. This model, illustrated in Figure 28.2, provides the circadian etiology of DSPD for which the initial case of Damien was an exemplar. Given the circadian phase delay, attempts to sleep at normal bedtimes will result in sleep onset insomnia, insufficient sleep, morning lethargy, and daytime symptoms of sleep loss. Later bed periods (e.g., 3 a.m. 11 a.m.) will result in relatively normal sleep or a recovery sleep (e.g., on weekends or holidays) from previous sleep loss. The ability to sleep (p. 605) late is also allowed by the delayed wake-up zone and is illustrated in Figure 28.2 as Extended sleep with opportunity. There is considerable evidence showing significantly delayed circadian rhythms of core body temperature and melatonin in cases of DSPD. The delays from normal in different studies have ranged from 2.3 to 6 hours (Oren, Turner, & Wehr, 1995; Ozaki, Uchiyama, Shirakawa, & Okawa, 1996; Uchiyama, Okawa, Shibui, Liu, et al., 2000; Watanabe et al., 2003; Wyatt, Stepanski, & Kirkby, 2006). ASPD Associated With Circadian Phase Advances Opposite to DSPD, if the circadian system becomes advanced (timed earlier) by a few hours, advanced sleep phase disorder (ASPD) can result. In this case, the wake-up zone would begin perhaps as early as 3 4 a.m. and terminate sleep before an adequate amount of sleep has been obtained. This is illustrated in Figure 28.3 in which the core body temperature, melatonin, and sleep propensity rhythms (including the wake-maintenance and wakeup zones) have become phase advanced from normal by about 3 hours. This provides the etiologic model for ASPD of which our earlier case of Laura was an exemplar. Perhaps because ASPD is less common and presents less frequently for treatment, there are fewer studies of its chronobiology. Nevertheless, if one includes cases of early morning awakening insomnia (a clinical symptom of ASPD) along with more classically defined ASPD, studies have confirmed circadian rhythm advances of 2 4 hours compared with normal controls (Campbell, Dawson, & Anderson, 1993; Jones et al., 1999; Reid et al., 2001; Lack & Wright, 1993; Lack, Mercer, & Wright, 1996; Lack, Wright, Gibbon, & Kemp, 2005). Page 8 of 32

9 Click to view larger Fig The timing of typical sleep for advanced sleep phase disorder in this example between about 10 p.m. and awakening stimulated by the start of a phase advanced wake up zone at about 4 a.m. In summary, delayed sleep phase disorder, as well as sleep onset insomnia, are associated with phase delay of the circadian system, while advanced sleep phase disorder, as well as early morning awakening insomnia, are associated with phase advance of the circadian system. In a sense this difference of underlying circadian abnormal timing is implicit in the description or diagnosis of the disorders. Eventually, with less invasive and less expensive circadian rhythm assessment, these circadian rhythm criteria may become a standard part of the practical diagnosis. In any case, if these timing differences were causal in the disorders, manipulation of circadian rhythm timing would be suggested as treatment. Indeed, as we will see, circadian timing treatments (p. 606) such as bright light therapy and melatonin administration are based on this assumption. Retiming circadian rhythms This would be an opportune time to review the methods that can be used to retime the circadian system. The environmental stimuli that can change the timing of the rhythms are called entraining stimuli or zeitgebers (time givers). Light is considered the most effective tool for retiming circadian rhythms. Melatonin administration has also been shown to be effective, and other zeitgebers may emerge with further research. Light A pulse (30 minutes 6 hours) of light stimulation to the eyes can change the timing (phase) of the circadian system. However, exactly when that pulse occurs is critical to whether the circadian phase is delayed or advanced and by how much. Several studies have determined the phase response curve (PRC) that is, the resultant direction and magnitude of the phase change generated by the timing of light stimulation relative to the initial timing of the circadian rhythm (Lewy et al., 1983; Czeisler et al., 1989; Minors, Waterhouse, & Wirz-Justice, 1991; Dawson, Lack, & Morris, 1993). For example, these studies show that the closer the light stimulus occurs to the core body temperature minimum (Tmin), the greater will be the phase change. However, the critical point is that bright light before the temperature minimum will produce a phase delay, and bright light after Tmin will produce a phase advance to an earlier time. The phase response curve to bright light is shown in Figure 28.4 as the solid curve. Because morning bright light (if it occurs after the Tmin) will phase-advance the circadian rhythm, it should therefore be an effective therapeutic intervention for a phase-delayed rhythm. Conversely, evening bright light (before Tmin) can phase-delay the rhythm and should be effective for delaying the circadian rhythm of those with an abnormally advanced or early timed sleep phase. Page 9 of 32

10 Click to view larger Fig The phase response curves for bright light administration (solid curve) and exogenous melatonin administration (dashed curve) in this example for a normally entrained individual with typical sleep period from 11 p.m. to 7 a.m. and endogenous core temperature minimum (Tmin) at about 4 a.m. Points above the no change horizontal axis represent changes to an earlier time for the rhythm (phase advances) and points below the axis as phase delays following bright light or melatonin administration. Light intensity and duration also affect the magnitude of phase change, with higher intensity and longer duration on any one treatment session producing greater phase change. More recently it has been demonstrated that shorter wavelength light, that is, light in the blue-green end of the visible spectrum ( nm), is more effective than longer wavelength light in suppressing melatonin secretion (Brainard et al., 2001; Thapan, (p. 607) Arendt, & Skene, 2001; Wright & Lack, 2001) as well as phase delaying (Wright & Lack, 2001) and phase advancing (Warman, Dijk, Warman, Arendt, & Skene, 2003; Wright & Lack, 2004) the melatonin rhythm in good sleepers. Melatonin Administered melatonin has also been shown to be effective in shifting the circadian rhythm to a more desired time (Lewy & Sack, 1997). Melatonin administered in the evening about 4 to 8 hours prior to the onset of endogenous melatonin will phase-advance the rhythm, and melatonin administered close to the melatonin offset at about midmorning will produce a phase delay, with optimal phase changes occurring when exogenous melatonin overlaps the endogenous onset or offset (Lewy & Sack, 1997). A phase response curve (PRC) for melatonin administration has been demonstrated to be about 12 hours out of phase with the PRC for light at least with regards to the phaseadvance effects (Lewy et al., 1998). Achieving a maximal phase advance would involve melatonin administration to a normally entrained individual in the early evening (5 7 p.m.) and bright light in the morning (5 7 a.m.). Would the combination of both zeitgebers prove more effective than either alone? It appears that their effects are additive, as the combination of late afternoon melatonin administration with morning bright light was significantly more effective in phase-advancing the melatonin circadian rhythm than morning bright light alone (Revell et al., 2006). Figure 28.4 also shows what is known of the phase response curve (PRC) for the administration of exogenous melatonin (Lewy & Sack, 1997) similar to that drawn by Burgess, Sharkey, and Eastman (2002) but amended somewhat to consider more recent data (Burgess, Revell, & Eastman, 2008). For the light PRC of Figure 28.4, it is assumed that a relatively bright (e.g., 2,000 lux) single two-hour pulse of white light with the timing of the pulse taken as the midpoint of the pulse entered at the appropriate time as indicated by the horizontal axis. For melatonin, the time of administration would be the time of ingestion, and the dose of 1 mg would be in the low to moderate pharmacologic range. The subject is assumed to be the normally entrained example in Figure 28.1 with the timing of sleep period from 11 p.m. to 7 a.m., Tmin at about 4 a.m., and dim light melatonin onset (DLMO) at about 9 p.m. Points on the Figure 28.4 curves above the horizontal axis indicate a resulting phase advance from a pulse of light or melatonin administration at the indicated time. Points below the axis indicate resultant phase delays. Although the phase advance peaks are about 12 hours different for the two PRCs, the phase delay maximums appear relatively close in time. This is partly understood by the fact that the time of administration precedes maximum blood plasma levels that are reached perhaps an hour later. Then melatonin is metabolized relatively quickly but, starting at a supraphysiologic level, it may take 2 4 hours to drop to below effective levels. The fact that a maximum phase delay in the light administration PRC appears about 0.4 hours more than the maximum phase advance assumes an equal delay and advance effect but takes into account the 0.2-hour Page 10 of 32

11 average phase delay occurring from the average 24.2 hour period length (Khalsa, Jewett, Cajochen, & Czeisler, 2003). The indication in the melatonin PRC in Figure 28.4 of an equal amount of phase delay and advance is derived from data that melatonin administration has a somewhat stronger phase advance effect than phase delay. Circadian characteristics other than phase differences If the cause of DSPD and ASPD were simply circadian phase delay and advance, the indicated treatment would clearly be to change phase using effective zeitgebers such as bright light and melatonin. Yet there are niggling questions that suggest the solution is not as simple as this. Why does it seem so difficult to effectively and permanently alleviate DSPD and ASPD with the required amount of circadian timing manipulation in the order of only a few hours (3 5 hours)? Normal good sleepers usually experience jet lag after flying across several time zones (5 10 hour time zones). However, this jet lag, assumed to be a result of the time required to shift circadian timing from home to the destination clock time, usually lasts for about the number of days of time zones changed. After that adjustment the traveler s circadian system usually stays appropriately synchronized with that destination environment with no continuing difficulty sleeping during the destination nighttime. However, the timing abnormalities in DSPD and ASPD of only a few hours seem curiously resistant to correction or overcoming this social jet lag (Wittmann, Dinich, Merrow, & Roenneberg, 2006). Are there other attributes of the circadian system that might contribute to this resistance to correction? (p. 608) Intrinsic Period Length Differences The period length of a rhythm is the time taken to complete one cycle. By definition, circadian rhythms take about 24 hours to complete one cycle. However, not everyone, in fact almost no one, has a period length of exactly 24 hours. There are individual differences in the period length of the circadian system that are stable over time and age (Czeisler et al., 1999). This is not surprising given that there are individual differences in virtually all biological and behavioral characteristics. These stable period length differences are most likely genetically determined (Xu et al., 2007; Brown et al., 2008), the mechanisms of which are being actively investigated (Archer, Viola, Kyriakopoulou, von Schantz, & Dijk, 2008). The putative role of period length is that those with inherently longer circadian period lengths will have a tendency to phase-delay and thus develop DSPD, and those with shorter period lengths (less than 24 hours) will have a tendency to advance and develop ASPD. With a longer period length (say 24.5 hours), there would be a tendency for one s whole circadian system, including feelings of sleepiness at night and alertness in the morning, to delay by half an hour per day. Most individuals with circadian period lengths only slightly longer than 24 hours (mean of 24.2 hours, SD of 0.13 hour) stay synchronized and in phase with the 24-hour world with little trouble. Presumably this is because they get sufficient exposure to entraining effects such as morning light that would put the brakes on the tendency to phase-delay. Conversely, those with a period length shorter than 24 hours would have a tendency to phase-advance their circadian rhythms as well as sleep onset and wake-up times. The fact that the mean period length for the population appears longer than 24 hours may account for the apparently greater prevalence of DSPD than ASPD. It may also account for the observation that overcoming jet lag is more rapid after westward time zone transitions requiring phase delays than eastward time zone transitions requiring phase advances (Haimov & Arendt, 1999). Since 1981 it has been predicted that those with DSPD would have exceptionally longer period lengths (e.g., 25 hours) (Czeisler et al., 1981). It is suggested that their stronger-than-normal tendency to phase-delay is eventually kept in check by the need to arise by certain times in the late morning in order to meet social/work obligations and exposure to entraining stimuli (e.g., light) at that time. However, there is a limited range of entrainment possible by even the most potent entraining stimuli (perhaps 1 2 hours in either direction for a single exposure to entraining stimuli). To remain at a stable, albeit delayed, sleep phase (e.g., 3 a.m. 11 a.m.), the DSPD sufferer with an endogenous period length of 25 hours would effectively have to phase-advance his or her rhythm by 1 hour every day. This amount of advance may be close to the maximum possible range of entrainment. Thus, phase advancing back to a more socially desirable sleep time would require more than a one-hour phase advance per day and may be almost beyond the possible range of entrainment. There is some experimental evidence suggestive of the role of period length differences in DSPD and ASPD. Horne and Ostberg (1976) developed a morningness-eveningness questionnaire to identify diurnal preferences. Evening Page 11 of 32

12 types tend to sleep later and prefer to do things later in the day than morning types. There is considerable evidence that evening types, as do those with DSPD, also have later timed circadian rhythms of cortisol (Bailey & Heitkemper, 1991), core temperature rhythm (Baehr, Revelle, & Eastman, 2000; Lack, Bailey, Lovato, & Wright, 2009), and melatonin rhythm (Lack & Bailey, 1994; Griefahn, 2002; Mongrain, Lavoie, Selmaoui, Paquet, & Dumont, 2004). It has always been assumed that there is a strong relationship between extreme eveningness or morningness (chronotype) and DSPD or ASPD such that DSPD and ASPD patients will be evening and morning types, respectively. However, evening and morning types will not necessarily develop DSPD and ASPD. So, extreme chronotype is probably necessary but not sufficient to result in one of these circadian rhythm disorders. In any case, an examination of any research regarding period lengths in evening and morning chronotypes should be relevant also to individuals with DSPD and ASPD. Only two studies have evaluated the period lengths in relation to different chronotypes. Duffy, Rimmer, and Czeisler (2001) evaluated temperature circadian period length from an extended 30-day forced desynchrony routine in a group of 17 participants who varied in chronotype but were not specifically selected as extreme evening or morning types. They found a significant correlation (r = 0.60, p < 0.01) between eveningnessmorningness score and assessed period length, with greater eveningness related to longer period lengths as predicted. However, the group included no extreme chronotypes and none had a period length greater than 24.4 hours. More recently, Brown et al. (2008) compared groups of more extreme evening and morning chronotypes. They measured (p. 609) the period lengths of isolated dermal cells as a surrogate for the intact circadian system. The mean period lengths of dermal cells from the evening types (24.7 hours) was significantly longer than that from the morning types (24.3 hours). In summary, there is some evidence that eveningness-morningness is related to circadian period length. Whether this implies that period length difference is at the basis of DSPD and ASPD is only now being explored. Campbell and Murphy (2007) were the first to investigate the free-running period length of a DSPD extreme evening chronotype individual. In a time isolation laboratory experiment over a 17-day period the circadian temperature rhythm and sleep wake cycle stayed synchronized and had a joint period length of 25.4 hours. This compared with the average spontaneous free-running period length from three normal controls of 24.4 hours. The longer period lengths generally found moreso in the spontaneous free-running experiments than in forced desynchrony studies has been attributed to possible delaying effects of light during the wakeful periods in the free-running studies. Most normal participants, including those in this study, chose bedtimes very close to their core temperature minimum times that would have exposed them to some light (albeit low light intensity) just before their temperature minimum (Tmin) and none for several hours after the Tmin. This differential light exposure, as we can see in reference to Figure 28.4, is likely to enhance phase delays and possibly exaggerate the estimated period length. On the other hand, their one DSPD participant chose bedtimes almost 4 hours before his Tmin and thus should not have differential light exposure tending to delay his rhythms. Therefore, any confounding effect of ambient light on circadian period length estimates in these data would tend to diminish the difference in period length estimates, thus strengthening the conclusion that DSPD is associated with a longer-than-normal period length. However, it is clear that additional research is required to confirm longer period lengths in DSPD patients and shorter in ASPD patients. The disincentive of long and expensive time isolation studies or forced desynchrony studies make recent suggestions of shorter (3 5 day) protocols an attractive alternative for this research endeavor (Burgess & Eastman, 2008). Abnormal Phase Angle Between The Circadian And Sleep Phases Another possible circadian contributor to DSPD has been suggested to be the different phase relationship between circadian rhythm timing and the typical sleep period. In normally entrained good sleepers, the timing of Tmin is usually late in the sleep period, within 2 3 hours of normal wake-up time that would present morning light at a relative effective phase advance time. However, it appears that DSPD individuals, in their normal environment, sleep relatively late in circadian phase such that the interval from Tmin to wake-up time is usually greater than four hours (Okawa & Uchiyama, 2007). It may simply be the case that this phase relationship results in an absence of light exposure at the most opportune time for phase-advancing rhythms (immediately after Tmin). Thus, with the failure to activate this more potent phase advance portion of the phase response curve, the longer period length and greater tendency to phase-delay in DSPD patients is not effectively opposed with a normally lighted environment. Page 12 of 32

13 There does not appear to be comparable studies on clinically diagnosed ASPD patients. However, there are three studies (totaling 43 patients) of those with early morning awakening insomnia that had advanced circadian rhythms (Lack, Mercer, & Wright, 1996; Lack & Wright, 1993; Lack, Wright, Gibbon, & Kemp, 2005). Their average Tmin was about three hours earlier than normal at 1:30 a.m. However, they, like the DSPD patients, also slept at a relatively late circadian phase from about 11 p.m. to about 5 a.m., with their Tmin closer to sleep onset than their typical wake-up time. These patients struggled to stay awake to a normal bedtime and then had no difficulty falling asleep. Their sleep was then probably truncated by the beginning of the wake-up zone as illustrated in Figure If they had chosen earlier but less socially acceptable bedtimes, at say 9 p.m., they would have a normal phase relationship between their sleep and circadian rhythms and would have been clearly diagnosed with ASPD. Their choice of staying up later has contributed to them being diagnosed as early morning insomnia rather than ASPD. Underlying both cases is a phase-advanced circadian system. It is unknown whether cases of ASPD obtaining adequate sleep at early times would have a relatively early timed sleep phase, thus exposing more of the phaseadvance portion of their PRC to early light upon awakening. Distorted Phase Response Curve Another possible contributor to both DSPD and ASPD is an asymmetrical phase response curve. We have already seen the average PRC with an approximately 0.4-hour greater magnitude in the (p. 610) delay than advance portion, which could be a result of an average period length 0.2 hours longer than 24 hours. That assumes equal delay and advance effects from the same light stimulus but with an endogenous bias to delay. However, the delay and advance effects may not be equal in different individuals. The DSPD person may obtain a smaller phaseadvance effect than delay effect from equal light pulses optimally placed for advance or delay (Weitzman et al., 1981). There is some evidence to support this possibility. Aoki, Ozeki, and Yamada (2001) found that DSPD patients showed greater melatonin suppression than normal controls to a 2-hour 1,000-lux light pulse just before their respective Tmin. Since the amount of melatonin suppression in the early morning before Tmin is significantly correlated with the magnitude of subsequent circadian phase delay (Kubota et al., 2002), we may conclude that DSPD sufferers get larger phase-delay effects than normal from light stimulation. Conversely, the ASPD sufferer may have a less effective delay than advance portion of their PRC, although there appears to be no evidence relevant to that possibility. Psychological/behavioral contributions to DSPD and ASPD Although it has been suggested that a DSPD client has normal sleep when allowed to sleep at his or her most preferred time, there is some evidence to the contrary. Wagner, Moline, Pollack, and Czeisler (1986) found the mean sleep latency to be 32 minutes of a group of six DSPD patients attempting sleep at their preferred delayed time compared to 11 minutes sleep latency for a group of eight normal controls. Campbell and Murphy (2007) recently found that a DSPD patient in a two-week time isolation experiment, when allowed to self-select bedtimes, still had an average sleep latency of 38 minutes compared with 17 minutes for the controls. It seems likely that psychophysiological or conditioned insomnia contributes to the sleep onset difficulties of DSPD patients. The bedroom and attempts to sleep will be associated with the frustration and/or anxiety elicited by the difficulty initiating sleep at early bedtimes on those occasions when early awakenings are necessary. Repeated experiences of this associative process could lead to the development of chronic sleep onset insomnia (Bootzin & Nicassio, 1978) even when attempting sleep at a later optimal circadian phase. Alternatively, what may have originated as psychophysiological insomnia, with resulting delayed sleep onset, would predictably lead to a delayed endogenous circadian rhythm. This sleep onset insomnia, combined with the attempt to maintain a regular wake-up time for social/work/study commitments, will lead to sleep loss during the normal workweek and the attempt to catch up on sleep given the opportunity (e.g., weekend). This would usually be in the form of sleeping-in and delayed exposure to morning light. This effectively releases the brakes on the tendency to phase-delay and causes a net phase delay by the beginning of the following workweek and renewed sleep onset difficulties (Burgess & Eastman, 2006; Taylor et al., 2008; Yang et al., 2001). Furthermore, recent research suggests common cognitive elements and a degree of overlap between DSPS and psychophysiological insomnia (Marchetti, Biello, Broomfield, MacMahan, & Espie, 2006). Therefore, DSPD sufferers are likely to have some persistent conditioned sleep onset insomnia that will not resolve immediately when they Page 13 of 32

14 can sleep at their self-selected bedtime or if they are treated only for their delayed circadian rhythms. The treatment of this psychophysiological insomnia is detailed in Chapter 22 and would consist mainly of the behavioral therapy, stimulus control therapy (Bootzin, 1972). In addition, there are likely to be attitudinal or behavioral bias factors present with DSPD clients. The circadian phase-delayed individual is likely to feel alert and energetic in the evenings, as indicated by their evening preference in the Morning/Evening Questionnaire (Horne & Östberg, 1976). It is plausible that clients would be reluctant to cut short this generally positive experience. The choice of delaying bedtime will, however, again lead to later awakenings and the further delay of the circadian system as explained above. Therefore, the tendency to prolong their positive evening periods needs to be addressed in any comprehensive treatment of DSPD. In addition to the possible conditioned sleep onset insomnia at the beginning of the attempted sleep period, there is likely to be an active or conditioned avoidance of the aversive morning hours at the end of the sleep period. This would most simply be accomplished with a prolongation of sleep. If this apparently rewarding resumption or maintenance of sleep becomes a frequent habit, it could become especially difficult to resist and may account for the notorious difficulty treating DSPD (Ferber, 1995; Regestein & Monk, 1995). Therefore, this possible tendency of conditioned avoidance and dislike of the morning times also needs to be addressed in therapy. (p. 611) Similarly, with the ASPD sufferer, there are likely to be contributing conditioned and attitudinal factors. The attempt to delay bedtime to a later, more socially acceptable time (e.g., 10 p.m.) is likely to produce an aversive experience of extreme tiredness with a rewarding effect from going to bed and rapid sleep onset. Then, spontaneous early awakening (e.g., 4 a.m.) is likely to bring the frustration and anxiety of unsuccessfully trying to resume sleep and, if experienced frequently, lead to conditioned early morning awakening insomnia. Once awake, the ASPD client may arise and get early morning light exposure, leading to further phase advance. One further study, to the extent that evening and morning types represent DSPD and ASPD tendencies, attempted to determine which factors were more causal in the perpetuation of DSPD and ASPD (Lack, Bailey, Lovato, & Wright, 2009). Morning and evening types had endogenous circadian rhythms of core temperature, melatonin, objective sleepiness (measured as sleep latency), and subjective sleepiness evaluated in an ultradian (45-minute wake/15-minute sleep opportunity) routine over 27 hours in a bed rest, dimly lit, constant laboratory environment. The mean phases differed between groups for the temperature and melatonin rhythms by about two hours, the same difference that was evident in their typical sleep period timing and their sleep propensity curves in the laboratory. However, the subjective sleepiness rhythms differed by 6 9 hours. If it were the circadian phase differences that were driving the difference in sleep period timing, one would predict the circadian phase differences to be larger than the typical sleep period differences. This prediction assumes that these large circadian differences are often resisted to some extent by choosing more normal and more similar sleep periods. Therefore, it seems possible from this study that the circadian phase differences were not driving the sleep period difference. Instead, it is possible that the different timing of feelings of sleepiness drive the sleep period differences as well as the circadian rhythm differences. Of course, this same methodology needs to be used now with clinically determined DSPD and ASPD patients. The large differences between chronotypes in the timing of subjective sleepiness rhythms begs the question of their origin. The answer may lie in the other main determiner of biological sleepiness, Process S. Recent studies have found evidence suggesting that evening types appear to accumulate homeostatic sleep drive (Process S) more slowly during wakefulness than do morning types and dissipate it more slowly during sleep (Taillard, Philip, Coste, Sagaspe, & Bioulac, 2003; Mongrain, Carrier, & Dumont, 2006; Schmidt et al., 2009). This process may contribute to the extreme evening types and DSPD sufferers delaying bedtime past the time of being able to fall asleep simply because of not subjectively feeling sleepy. Uchiyama et al. (2000) have found that DSPD patients sleep at relatively late circadian phase, and non-24-hour free-running patients, who are unable to stabilize their sleep period to the 24-hour world, have an even later choice of sleep period relative to circadian phase. This suggests that the subjective choice to delay bedtime may be driving the delay of circadian phase rather than vice versa. The conclusion from these studies suggests the need to consider differences of timing in sleep inclination or subjective sleepiness as well as circadian rhythm phase differences. In summary, the clinician should consider all the possible etiologies of DSPD and ASPD and, therefore, the Page 14 of 32

15 appropriate therapies additional to those that address circadian factors (Campbell, 1999). These suggested circadian and behavioral etiologies are summarized in Table Evidence for a circadian rhythm treatment for DSPS/SOI and ASPS/EMA Since there is fairly strong evidence of abnormal circadian phase in DSPD and ASPD, it makes sense to consider manipulating circadian phase for their treatment. The practice parameters for the treatment of circadian rhythm sleep disorders (Morgenthaler et al., 2007) indicate that morning bright light exposure may be efficacious for the treatment of DSPD and evening light may be appropriate for ASPD. Over the past decade, different light intensities of various lengths have been administered at different times, with most demonstrating effectiveness in changing circadian phase or improving sleep parameters. However, optimal duration and dosage of light exposure are yet to be determined. Morning bright light for DSPD and sleep onset insomnia The effectiveness of morning bright light therapy has been investigated in individuals with psychophysiologic insomnia, including those experiencing sleep onset difficulties. In an early study (Guilleminault et al., 1995), patients with psychophysiologic (p. 612) Table 28.1 Summary of suggested circadian and behavioural etiologies for Delayed and Advanced sleep Phase Disorder Suggested etiologies DSPD ASPD Circadian Phase Timing Delayed Advanced Circadian Period Length Long (>25 hours?) Short (<24 hours) Non-symmetrical PRC Stronger Delay Portion Stronger Advance Portion Abnormal sleep/tmin phase relationship Delayed wake-up time masks early light?, No evidence to support sleep period at a relative early circadian phase Chronotype preferences effects on light exposure Prefer staying up later and morning avoidance Prefer getting up early and evening avoidance Conditioned Insomnia effects on light exposure Conditioned sleep onset insomnia and delay of wake-up to catch-up sleep Conditioned early morning insomnia and compensatory advance of bedtime insomnia were exposed to 45 minutes of bright light (3,000 lux) five minutes after awakening. The patients also followed stimulus control instructions (Bootzin, 1972; Bootzin & Nicassio, 1978). Following four weeks of therapy, compared to a control group and an exercise group, the bright light group showed statistically significant improvement in sleep variables. In a follow-up study, Kirisoglu and Guilleminault (2004) then compared the effectiveness of 20 minutes as opposed to 45 minutes of morning bright light exposure in older individuals with psychophysiologic insomnia. Bright light (10,000 lux) was administered over a 60-day period, with subjects instructed to sit in front of the light box beginning five minutes after awakening. At the 3-month and 6-month followup, the group exposed daily to 45 minutes of light had greater decreases of subjective (sleep diary) and objective (actigraphy) sleep onset latencies and longer total sleep times and lower fatigue scores than the 20-minute exposure group. It appeared from these studies that the longer duration of light exposure is more effective than 20 minutes in those with sleep onset difficulties. However, since no circadian rhythm parameters were assessed, the improvements in sleep could not be attributed to a phase advance from morning bright light. Individuals selected for sleep onset insomnia were also shown to have a delayed sleep phase indicated by a late melatonin onset (12:28 a.m.) (Lack, Wright, & Paynter, 2007). Over a one-week period, they were either exposed Page 15 of 32

16 to bright light (2,500 lux) or dim red light (<100 lux). Light was administered for one hour starting hours before their baseline weekday waking time. The control group showed no change in circadian phase or in sleep variables. Those exposed to bright light had a significant advance of their melatonin onset by 1 hour 21 minutes, a significant decrease in actigraphy sleep latency of 34 minutes, an advance of sleep onset time, and an increase of total sleep time. A number of studies have evaluated the effectiveness of morning bright light in individuals with a delayed sleep phase but with no complaints of insomnia. In a brief report, Watanabe and colleagues (Watanabe et al., 1999) exposed participants with DSPD to three hours of bright light administered 1.5 hours after their Tmin for five consecutive mornings. Their Tmin, sleep onset, and wake-up times significantly advanced. In a study comparing different light intensities (Rosenthal et al., 1990), patients with DSPD were exposed to two hours of bright light (2,500 lux) or dim light (300 lux) for a two-week period with exposure between 6 a.m. to 9 a.m. The bright light group also wore dark goggles after 4 p.m. to avoid light exposure that could potentially cause a phase delay. Again, sleep onset time and Tmin were significantly earlier following bright light. Using a bright light mask, volunteers with DSPD were exposed to either bright white light (2,700 lux) or dim red light (0.1 lux) in the mornings for 26 days (Cole et al., 2002). The bright light mask was statistically and clinically beneficial for those with a later melatonin rhythm. In a pilot study (Lack, Bramwell, Wright, & Kemp, 2007), short-wavelength blue light was used in an attempt to phase advance the circadian and sleep/wake rhythm of individuals with DSPD. Light was administered via (portable) light glasses comprising blue light-emitting diodes. Over a one-week period, participants were initially exposed (p. 613) to two hours of light commencing immediately after waking and then advanced each day by 30 minutes until wake-up time occurred at 6 a.m. A control group followed the same procedure but without blue light exposure. Participants in the control group had no change in timing of melatonin onset, while those in the blue light group showed a significant phase advance of 2.5 hours. As predicted by the phase response curve, participants with later circadian phases had the greater phase advances. However, in this DSPD group, there were no significant changes in sleep parameters during the post-treatment week, although the blue light group did wake 50 minutes earlier following treatment compared to the control group, who woke only 15 minutes earlier. During the post-treatment week participants were not given any instructions regarding maintenance of their early wake-up time and quickly reverted to later bed and wake times. Further studies need to evaluate a longer post-treatment maintenance regime. Evening bright light for ASPD and early morning awakening insomnia Since, as discussed earlier, ASPD overlaps with early morning awakening insomnia, it is relevant to discuss circadian rhythm treatments of early morning awakening insomnia. Evening bright light has been used to treat early morning awakening insomnia and sleep maintenance insomnia with varying results. In an early study, Lack and Wright (1993) used two late evenings of bright (2,500 lux) light exposure to treat individuals with EMA insomnia. This produced significant (2 4 hour) delays of core temperature and melatonin circadian rhythms, a delayed wakeup time, and over an hour increase of total sleep. A further study (Lack, Wright, Kemp, & Gibbon, 2005) again exposed volunteers to two evenings of a 4-hour bright (2,500 lux) light stimulation ending at midnight on the first night and 1 a.m. on the second night. Compared to a dim red light control group, the bright light group had a significant delay in Tmin, a greater increase in total sleep time, and a greater reduction in negative daytime symptoms. In both studies, the early morning awakening insomniacs pre-treatment had an advanced temperature minima between 2 2:30 a.m. and wake-up times between 5 5:30 a.m. Therefore, these early morning awakening insomniacs had at least mild clinical symptoms of advanced sleep phase disorder. However, Pallesen and colleagues (2005) were unable to produce any therapeutic effects after exposing individuals with mild early morning awakening insomnia to evening light. Volunteers, aged over 55 years, had an average bedtime about 11:15 p.m. and final wake-up time about 6:00 a.m. They were exposed to either 30 minutes of bright light (10,000 lux) or 200 lux dim light starting 1 hour before their bedtime over 21 evenings. Both groups experienced improved subjective sleep measures; however, the only significant measure attributable to the bright light stimulus was time spent in bed after the final wake-up time. The authors acknowledge the limitations of the study, including lack of circadian measures to confirm an initially advanced circadian rhythm or circadian delay from the light therapy and possible lack of compliance. Furthermore, the timing of the light stimulus may not have Page 16 of 32

17 been late enough, that is, not as near to the temperature minimum as would be recommended for a phase delay (e.g., in Figure 28.4, within 5 hours of Tmin). Evening bright light has also been administered to older volunteers with sleep maintenance insomnia. In two studies (Campbell, Dawson, & Anderson, 1993; Suhner, Murphy, & Campbell, 2002), volunteers with an advanced temperature rhythm but not an earlier timed sleep pattern were exposed to light (4,000 lux) for 2 hours in the evening. In the earlier study, Tmin was delayed by over 3 hours and sleep efficiency was significantly increased after 12 evenings of light therapy. However, in the later study, the delay in Tmin was only 94 minutes with no significant improvements in sleep variables. Although the timing of the light pulse was similar in the two studies (between 8:00 11:00 p.m.), the authors note that compliance was probably greater in the first study due to daily contact with participants. More improved sleep was associated with a greater phase delay, possibly indicating variation between clients of therapy compliance, with the more compliant gaining greater benefit. In a further study (Palmer et al., 2003), older adults with self-reported ASPD were exposed to evening light of either 265 lux or 2 lux over a one-month period. The average times of light exposure were between 7:17 and 9:49 p.m. with participants finishing light stimulation within one hour of bedtime. The enhanced evening light exposure was no more effective than dim light in delaying the timing of the sleep pattern or urinary melatonin rhythm. However, despite being self-reported morning types, the baseline objective and subjective sleep data and melatonin rhythms appeared to be rather normal for a group of healthy 70-year-olds. (p. 614) Therefore, the early timing of relatively low-intensity, long-wavelength light would predictably have little capacity to effect a circadian or sleep delay. It can be seen from these studies that morning and evening bright light can be effective in phase changing the circadian rhythm and sleep wake pattern of those with delayed or advanced sleep phase disorder; however, the timing and brightness of the light pulse is a crucial factor. The light stimulus needs to be as close to the estimated Tmin as possible. Exogenous melatonin administration treatment of DSPD Other zeitgebers that have been shown to phase-change circadian rhythms and sleep wake schedules are exogenous melatonin and, more recently, melatonin agonists. As shown in Figure 28.4, the timing of melatonin ingestion is important. There is a phase-delay portion of the melatonin PRC for melatonin administered during the latter part of the typical sleep period that would lend it to the possibility of treating ASPD or early morning awakening insomnia. However, to our knowledge, melatonin has not been used to treat the disorders associated with phase advances. Numerous studies have utilized the phase-advance portion of the melatonin PRC by administering exogenous melatonin to individuals with DSPD. However, the dose and time of administration has varied considerably between studies. In an early clinical trial, oral melatonin (5 mg) was administered to patients with DSPD who attended a sleep disorders center (Oldani et al., 1994). Administration time was approximately 9.5 hours before sleep onset time estimated from individual ambulatory sleep monitoring. After 4 weeks of treatment, sleep onset and wake-up time advanced by an average of 2 hours. In a larger DSPD clinical study, Dagan and colleagues (1998) administered 5 mg melatonin at 10:00 p.m. over a 6- week period. Before treatment, participants mean sleep onset time was 3:09 a.m. and wake-up time 11:31 a.m. as indicated on actigraphy measured over a 4- to 7-day period. A survey questionnaire completed 12 to 18 months following treatment showed that most respondents reported an improvement in their condition during administration, but most of those then experienced a relapse. Further analyses indicated that those with the more severe DSPD tended to experience an immediate relapse. However, no circadian measures were taken or posttreatment sleep variables measured. Placebo-controlled studies have been carried out to determine the effectiveness of melatonin on the sleep and functioning of patients with DSPD. In an early study, Dahlitz and colleagues (1991) administered 5 mg to participants over a 4-week period, timed 5 hours before individual baseline sleep onset times (10 p.m.). Compared to placebo, participants experienced a phase advance of their sleep onset and offset of 1.4 and 2 hours, respectively. However, no circadian measures were taken posttreatment. In a similar study, Kayumov et al. (2001) also administered 5 mg melatonin over a 4-week period between 7:00 p.m. and 9:00 p.m., approximately 6 to 8 Page 17 of 32

18 hours before their delayed habitual bedtime. During an imposed sleep time (12:00 a.m. to 8:00 a.m.), sleep onset latencies were significantly less with melatonin than in the placebo condition. However, it is unclear whether their unconstrained sleep pattern or melatonin profile advanced significantly following the treatment period. Nagtegaal and colleagues (1998) administered 5 mg melatonin to DSPD patients 5 hours before their individually determined DLMOs over at least a 2-week period. Melatonin onset advanced by approximately 1.5 hours, and sleep onset advanced by 38 minutes. PSG showed a decrease of sleep latency of 9 minutes, and sleep logs indicated that individuals felt more refreshed while taking melatonin. Furthermore, a follow-up study of DSPD patients treated with melatonin showed that they experienced an improvement in physical and social functioning and mental health (Nagtegaal et al., 2000; Kayumov et al., 2001). In one study involving adolescents with DSPD, melatonin (3 to 5 mg) was administered over a 6-month period, taken approximately 2 hours before their bedtime (Szeinberg, Borodkin, & Dagan, 2006). During the treatment period, the adolescents were going to bed earlier, had shorter sleep latencies, and were sleeping longer and experiencing less daytime sleepiness. To determine the most effective dose of melatonin and time of administration to effect phase change in individuals with DSPD, Mundey et al. (2005) administered 0.3 mg, 3.0 mg, or placebo over a 2-week period. The timing of melatonin administration varied from 1.5 to 6.5 hours before DLMO, corresponding to clock times of 3:00 9:30 p.m. There was no difference in the average magnitude of phase shift between the two doses of melatonin; however, the time of administration was important. They found that the earlier the time of administration, the greater the eventual phase advance of DLMO. In fact, when melatonin was taken up to 7 hours before DLMO, the advance (p. 615) was more than 2.5 hours compared to an advance of 1 hour when administration was only 2 hours prior to DLMO. When the nightly doses were administered only 2 hours prior to the initial DLMO, the initial phase advances should have been significant (20 30 minutes). However, once that advance had occurred, the melatonin administration would be closer to the DLMO and in a less effective phase-advance portion of the PRC for advances (see Figure 28.4). With earlier administrations there would be greater scope for continuing some further phase advance. Although results indicated an average advance of Tmin of 1.63 hours, there was only a trend for an advance of the sleep cycle, with participants falling asleep 27 minutes earlier and waking 47 minutes earlier, just before 9:00 a.m. This is another instance in which retiming the circadian system seems to have a less permanent effect on changing the timing of the sleep period. Melatonin agonists More recently, melatonin receptor agonists also have been shown to produce phase advances in DLMO (Kräuchi et al., 1997) as well as Tmin (Leproult et al., 2005) in healthy adults. Other studies have also demonstrated the effectiveness of various melatonin agonists in decreasing the sleep onset latency of individuals with primary insomnia (Erman et al., 2006; Roth et al., 2006; Zammit et al., 2007; Zemlan et al., 2005). However, their efficacy in treating primary insomnia associated with circadian rhythm disorders is yet to be evaluated. Summary Bright light therapy and melatonin administration have the capacity to re-time circadian rhythms and, individually, have been efficacious in the treatment of the circadian rhythm disorders DSPD and ASPD as well as sleep onset insomnia and early morning awakening insomnia associated with abnormally timed rhythms. Since Revell et al. (2006) have shown that the phase-changing effects of melatonin and bright light therapy are additive, their combined use would be recommended for the treatment of DSPD and ASPD. In fact, a recent short report of combined morning bright light and evening melatonin administration suggested it was a promising treatment for DSPD (Samaranayake, Fernand & Warman, 2010). The parameter of critical importance is the timing of these two therapies with respect to the pre-treatment circadian rhythm phase. Determining pretreatment circadian phase in DSPD/SOI and ASPD/EMA In order to optimize the timing of bright light or melatonin therapy for DSPD, a reliable estimate of the timing of the endogenous temperature minimum or melatonin phase in any particular client is necessary. In the case of bright Page 18 of 32

19 light therapy for DSPD, morning light exposure too early (i.e., before the Tmin instead of just after) will produce a counterproductive phase delay instead of the desired phase advance. The most accurate and gold standard procedure for determining temperature profiles is the laboratory-based 26-hour constant routine (Czeisler et al., 1985; Duffy & Dijk, 2002). Unfortunately, this procedure is costly in time and expense. Rahman and colleagues (2008) found that DLMO was an accurate tool for confirming a delayed circadian phase in individuals with DSPD. However, melatonin rhythm phase markers obtained from saliva or plasma samples over at least a 6-hour period can also be costly. Least costly and already a part of the diagnostic requirements for DSPD is the collection of sleep diary or wrist activity monitor data over at least a 7-day period to evaluate the client s typical sleep period timing. If there is a satisfactorily reliable relationship of sleep timing to the endogenous circadian system timing, then an effective light therapy schedule can be devised based on an estimate of endogenous core temperature minimum (Tmin) derived from this sleep period information. As previously discussed, in good sleepers with a normally timed circadian rhythm, Tmin occurs approximately 5 to 6 hours after sleep onset (Campbell, 1999) or 2 hours before spontaneous wake-up time (Baehr, Revelle, & Eastman, 2000). Similarly, DLMO occurs approximately 2 hours before typical sleep onset. More recent studies have suggested stronger correlation between DLMO and sleep midpoint and wake-up time than with bedtime (Burgess et al., 2003; Martin & Eastman, 2002). However, these relationships appear not to be as reliable in individuals with a delayed or advanced circadian rhythm. Three recent studies have measured melatonin rhythm markers in relation to the typical sleep periods of DSPD clients. Rodenbeck et al. (1998) found that typical wake-up time of DSPD was relatively later in comparison with the timing of the melatonin rhythm than in controls and that the sleep/circadian timing relationship was more variable in clients. Uchiyama, Okawa, Shibui, Kim, et al. (2000) also found the sleep phase of DSPD clients to be timed at a later circadian temperature phase (p. 616) than in good sleepers. On the other hand, Wyatt et al. (2006) found the average sleep period timing with respect to melatonin timing essentially the same in DSPD and controls. However, for the purpose of predicting an individual s circadian phase from sleep period timing, we need to know the correlation between these measures. Wright, Lack, and Bootzin (2006) found that the correlation between DLMO and sleep onset, midpoint of sleep, and wake-up time was not as strong in individuals with sleep onset insomnia as compared to those relationships found by Burgess et al. (2003) and Martin and Eastman (2002) in good sleepers. Therefore, caution needs to be exercised in predicting circadian phase from sleep times in sleep onset insomniacs and most probably those with DSPD. Unfortunately, to our knowledge, no study has assessed the timing of the endogenous temperature rhythms of DSPD clients in a constant routine procedure. Nevertheless, a synthesis of the evidence available would suggest that the endogenous Tmin would be timed on average about 2 4 hours before the end of the client s typical sleep period and rarely after the typical wake-up time. One small but important caveat to this rule of thumb hinges on the term typical. Many of the studies are not precise about their use of this term. Since DSPD clients are in conflict between the time of their optimal sleep according to their delayed circadian system and the time they would like to be able to sleep to meet normal societal demands, their typical sleep time may be anywhere between these two extremes and most likely variable as societal demands change across the normal week. Circumstances will be different for different individuals: Some may be unemployed and able to sleep closer to the circadian optimal trough phase while others are attempting to maintain a regular day job, losing sleep on workdays and attempting to catch up on weekends. Students, such as our example of Damien, who needs to wake early on three mornings a week, may be intermediate to these two extremes. Since we are attempting to estimate the endogenous Tmin from the client s sleep period, it is the sleep periods most likely to be at the circadian optimal time, the time at which there is minimal difficulty getting to sleep and sleep length seems to satisfy sleep need, from which best estimates will be derived. For the unemployed, this might account for most nights sleep. For the regularly employed, this might be on days off work (e.g., the weekend) or free days without social obligations, whenever that might be (Roenneberg, Wirz- Justice, & Merrow, 2003). Because these free days often follow a period during which sleep debt has accumulated, sleep length is probably extended by the need to repay this sleep debt (Roenneberg et al., 2003). Therefore, if two or more free days occur sequentially, it would be best to ignore the first and estimate the timing of Tmin as 2 4 hours before awakening on the second of the free days. Relevant to estimating Tmin in those with ASPD or EMA insomnia, studies using a constant routine procedure have Page 19 of 32

20 found that individuals with an early timed circadian rhythm (Tmin between 12:20 a.m. and 2:31 a.m.) who experienced early morning awakening insomnia had Tmins close to their midpoint of sleep rather than near the end of the sleep period (Lack & Wright, 1993; Lack, Mercer, & Wright, 1996; Lack, Wright, Kemp, & Gibbon, 2005). In the case of phase-advanced types who are more likely to be sleeping close to their circadian optimal time on workdays and later than optimal on free days, when social obligations are likely to delay their bedtime (Roenneberg et al., 2003), the workweek sleep times can be used to estimate Tmin. Thus, for ASPD/EMA insomnia, the midpoints of the workweek sleep period appear a good estimate of Tmin timing. Clinical management Circadian phase change therapies Since there is clear and strong evidential support for circadian phase abnormalities as etiologies in DSPD and ASPD and since circadian phase can be changed both with bright light exposure and melatonin administration, these therapies have been used successfully and should form the basis of clinical management. If abnormal period lengths or asymmetrical PRCs are also implicated, it would suggest that a one-off treatment to correct a circadian phase is unlikely to be a permanent solution and that continuous or periodic treatment will be necessary. For example, a DSPD client with a circadian delay of four hours and an intrinsic (possibly genetically determined and invariant) period length of 25 hours, even when successfully phase-advanced by four hours, will have a continuing strong tendency to phase-delay and will do so if not vigilant about maintaining a consistent wake-up time and early bright light exposure. Similarly, a DSPD client with a weaker phase-advance portion of their PRC to light will have a stronger tendency to delay than advance for equal light intensities before bed and after awakening. The clinical experience of treatment difficulty of circadian sleep disorders (p. 617) and the high relapse rate would suggest that these period length abnormalities and possibly asymmetrical PRCs are present. Pragmatically, treatments should probably assume as much. Behavioral and psychological therapies The evidence of comorbidity between circadian phase disorders and psychological/behavioral factors suggests that psychological/behavioral therapies should be included in the treatment of the circadian phase disorders. In the case of DSPD, psychophysiological or learned sleep onset insomnia would be apparent if the patient still has sleep onset difficulties (i.e., sleep latency > 30 minutes) even when sleeping at optimal self-selected times. In this case, stimulus control therapy (as detailed in Chapter 22) should be instituted parallel with circadian therapies. In particular, the instructions to go to bed only when feeling sleepy and avoid daytime naps are most important. In addition, discussions and strategies to counter the attitudinal bias to remain active in the evening and extend sleep in the morning need to be implemented. In cases of ASPD in which there is likely to be a learned insomnia upon awakening during the night, the behavioral therapy of bedtime or sleep restriction therapy is recommended and is detailed in Chapter 22 (Spielman, Saskin, & Thorpy, 1987). This can be incorporated into evening bright light therapy in which the period of light exposure extends past the normal bedtime. Cognitive therapies to counter the attitudinal preferences for being up and active in the morning period can also be helpful. Relaxation or meditative therapies (see Chapter 22) may also be useful, if well practiced, for facilitating sleep (Morin et al., 2006). These can be used at the beginning of the bed period in the case of sleep onset difficulties associated with DSPD and during or toward the end of the sleep period in the case of sleep maintenance and early awakening difficulties associated with phase advance disorders. Treatment of DSPD Determine Pretreatment Circadian Timing We presented Damien as an exemplar of a typical DSPD patient at the beginning of this chapter. Accordingly, we will use him as a treatment case study. He struggles to get to sleep by 2 a.m. and more so to arise at 8 a.m. He could more comfortably get to sleep by 3 a.m. and sleep until 11 a.m., as he usually does on weekends. Therefore, Page 20 of 32

21 we would estimate the time of his Tmin to be approximately 8 a.m. that would be about 3 4 hours delayed from normal. This circadian timing would account for his extreme difficulty arising at 8 a.m., made doubly difficult in that he would be attempting to arise after insufficient sleep (only 5 hours) and at his circadian maximum sleepiness time (see Figure 28.2). Establish Treatment Goals Simply wanting to be more normal is usually not enough motivation to maintain compliance to a difficult treatment regime. In Damien s case, the prospect of improved alertness and academic success, particularly in his morning classes, and the increased chances of attaining his long-term goals can be utilized for motivation. The first step toward these goals is to effect a phase advance of at least 3 hours. This should enable him to accomplish sleep onsets before midnight and successfully awake no later than 8 a.m. Bright Light Administration A bright light source first needs to be secured. In the case of phase-advancing a DSPD client such as Damien, a very effective and free light source usually available in the mornings is that of sunlight, preferably outdoors or at least next to a south- or east-facing window in the Northern Hemisphere (north-facing in the Southern Hemisphere). To maximize light intensity, avoid sunglasses, but most certainly do not look directly at the sun. In very overcast climates or very northern latitudes during the winter, enough sunlight may not be available, in which case a commercially available light source may be necessary in order to achieve a light intensity substantially above (>500 lux) normal ambient intensity (about 100 lux). It is also important to understand that the light needs to enter the pupil and should, therefore, be noticeably within the visual field, preferably no more than 45 degrees from the average direction of gaze. In Damien s case, he could set up a light source directed at his eyes next to his computer screen as he works at his computer in the mornings or as he is eating breakfast before leaving home. The timing of periods of light stimulation is critical. The maximum phase advance would be obtained for a light pulse starting soon after the time of the estimated Tmin. However, if our estimate is incorrect and the light pulse inadvertently occurs before Tmin, Damien will experience a counterproductive large phase delay. Therefore, it is usually wise to be somewhat conservative and start the light pulse at about the time of spontaneous (p. 618) awakening. In Damien s case this would be light stimulation from 11 a.m. to about 1 p.m. on the first morning. The longer the pulse, the greater the effect. However, as can be seen in Figure 28.4, the effect of additional time diminishes the more distant in time from Tmin. While morning bright light is the main treatment tool in this case, it is important to appreciate the potential counterproductive effect of bright light in the evening before bedtime. Even moderate ambient light before bedtime can have a small delaying effect as seen in Figure Therefore, Damien should try to ensure dim light conditions in the few hours before bedtime. If for some reason (e.g., summer daylight saving time) he is not able to avoid evening bright light, it would be helpful to wear some dark glasses, especially those that may have some selective filtering of the blue end of the visible spectrum (e.g., blue-blocking glasses), that would still allow adequate vision without the phase-delaying capacity of the blue light (Wright & Lack, 2001). The effect of this first morning of light therapy in conjunction with the administration of evening melatonin should secure a phase advance of at least 30 minutes. Therefore, the next morning the light pulse may start at 10:30 a.m. Each subsequent morning the light pulse should be advanced by 30 minutes until the target wake-up time which for Damien, at 8 a.m., would require seven days of treatment. However, it would be recommended to continue light therapy for a further week at the 8 a.m. start time in order to secure the circadian phase advance and, importantly, the advance of sleep onset time, which often lags behind. The second week the circadian advance can be maintained with shorter duration (30 60 minutes) light pulses. Thereafter, to prevent relapse, Damien needs to maintain a consistent wake-up time and provide periodic (2 3 times per week) bright light exposure for at least 30 minutes at the consistent wake-up time. We feel it is imperative for DSPD clients to avoid sleeping later. One morning sleeping later by a couple of hours could result in a phase delay of up to 1.5 hours and require a reinstitution of the bright light therapy over 3 4 days to re-establish the circadian timing target. Melatonin Administration For DSPD The maximum phase advance from a single melatonin administration should be obtained when the administration is timed about four hours before expected dim light melatonin onset or about 11 hours before estimated Tmin. In Damien s case, since estimated Tmin was at 8 a.m., melatonin administration on the first night before the first Page 21 of 32

22 morning of bright light therapy would be at 9 p.m. On subsequent nights the time of melatonin administration should be advanced by 30 minutes (i.e., 8:30 p.m., 8:00 p.m., etc.) along with the advances of morning bright light. Although most melatonin PRC studies have used moderate to high doses (>3 mg) on multiple nights at the same clock time, it should be at least equally effective to use smaller doses ( mg) at the optimal timing that should be advancing with the advancing circadian rhythm. In Damien s case, when the target sleep period is reached, the melatonin administration will be at 6 p.m. Behavioral Treatments And Psychological Considerations Since Damien is likely to have some degree of conditioned sleep onset insomnia, aspects of stimulus control therapy should be instituted with the circadian treatments (Bootzin, 1972; Bootzin & Nicassio, 1978). This was described earlier and detailed in Chapter 22. The bedroom should be reserved for sleeping only and not a place for work, television, talk on the phone, eating, worry, or other sleep-inhibiting activities. However, one instruction from stimulus control therapy that may not be helpful is Do not go to bed until you feel sleepy. Recent evidence suggests that extreme evening types, as in DSPD, fail to feel sleepy until well after they are able to fall asleep (Lack, Bailey, Lovato, & Wright, 2009). He should not expect his sleep onset time to advance in step with the advance of the scheduled wake times. As a result, he will lose some sleep during the treatment period until the lagging sleep onset time finally catches up with the target. Damien should be encouraged to view this partial sleep loss as tolerable and helpful in facilitating earlier sleep onsets. Being an evening preference/morning avoidance type of person, probably all his life, it would be helpful for Damien to recognize this long-term bias and to consider changes in his life to facilitate a change of this bias. Essentially, the treatment aims to shift Damien from an evening type to a more normal, middle-of-the-distribution type. This can be accomplished with his underlying circadian physiology and sleep wake cycle, at least in the short-term treatment period. However, maintenance of this change will be facilitated by a change of psychological bias. In practice, this could involve changing behaviors such as shifting the interesting (p. 619) and challenging tasks in his life from the evening to the morning and substituting relaxing, mundane activities for the two hours before bedtime. This will be helped by what is referred to as good sleep hygiene, such as avoiding caffeine in the latter half of the day, reducing overall daily consumption of caffeine, avoiding excessive alcohol, and avoiding late evening meals. An early evening meal will make breakfast more attractive. Encouraging Damien to attempt directly changing his attitudes about his evening preferences may also be helpful. He needs to appreciate that if these cognitive factors are not also addressed, it could lead to relapse. Although research is not available to provide specific practical instructions for this cognitive therapy, a first step, at least, would be for Damien to recognize the role of these factors so that he can consider ways to facilitate his own personal change of psychological bias. Treatment of ASPD Pre- And Posttreatment Circadian Timing Laura was our exemplar of a moderate case of advanced sleep phase disorder/early morning awakening insomnia and, therefore, would make a convenient treatment case. All the steps that were involved in Damien s case (e.g., estimating circadian timing, establishing treatment aims, bright light therapy regime, etc.) are also appropriate for Laura s case. Although she regularly attempts sleep from 10 p.m. to about 5 a.m., she usually gets only about 6 hours of total sleep. Her optimal sleep appears to be from about 8 p.m. to 3 a.m. Therefore, her estimated Tmin would be about midnight. Her goal is to be able to sleep from 10:30 p.m. to about 6 a.m. without struggling to stay awake until 10:30 p.m. and without difficulty maintaining sleep until 6 a.m., thereby obtaining an adequate amount of sleep. This would require a circadian delay of about four hours to a Tmin at 4 a.m. Evening Bright Light And Behavioral Therapy Combined Evening bright light should have the effect of phase-delaying her circadian system. However, as would be consistent with the PRC for light as illustrated in Figure 28.4, studies that have terminated light stimulation before typical bedtimes have had less success than studies in which bright light extended beyond typical bedtimes. Although it could be argued that this delay of typical bedtime would be difficult with low compliance, it could be effectively combined with bedtime restriction therapy that starts with a reduction of time in bed, usually with a delay of bedtime and advance of wake-up time (Spielman et al., 1987). Since it is very likely that Laura has some degree Page 22 of 32

23 of persistent psychophysiological or learned early morning awakening insomnia, this behavioral therapy would be indicated. Bedtime restriction therapy would suggest an initial bed period of about 6 hours. If three hours of bright light were used from 8 p.m. to 11 p.m., her initial restricted bed period would be from 11 p.m. to 5 a.m. This should produce a strong phase-delaying effect over only a few nights of therapy. At the same time, the bed restriction will help consolidate her sleep period and minimize periods of wakefulness in bed, starting the process of reversing the conditioned insomnia to the bed with the bed becoming eventually a cue for sleep. As bed period wakefulness diminishes and daytime sleepiness increases, the bed period can be extended gradually by first delaying the wake-up time to 5:30 a.m., then the bedtime to 10:30 p.m., then finally the wake-up time to 6 a.m. Melatonin Administration For ASPD Although melatonin administration has not yet been used in clinical trials for the treatment of ASPD, it may have a role in facilitating phase delay and minimizing periods of wakefulness. According to Figure 28.4, a phase-delay effect would be produced with melatonin administered 2 3 hours after estimated Tmin. In Laura s case the initial administration would be from 2:00 3:00 a.m., perhaps taken at any spontaneous awakening during this period. The optimal administration time would then need to be delayed (e.g., 30 minutes) on a daily basis as her circadian rhythms delay from both bright light and melatonin administration. This need be only a limited number of days (4 5) since the four-hour phase delay should be obtained within that period. One important caveat about the use of melatonin in this way is to beware of the mild sedating capacity of exogenously administered melatonin when it is still present in the bloodstream after endogenous melatonin has returned to the low daytime levels (e.g., from 8 a.m. onward, as in Figure 28.1). Driving safety during this period may be impaired despite evidence suggesting it is subjective sleepiness rather than psychomotor performance that is affected (Paul, Gray, Kenny, & Pigeau, 2003). Furthermore, potentially unwanted sedating effects can be minimized with the use of a low dose of melatonin (e.g., 0.1 mg) since the phase-delaying effect should not be diminished; however, with a (p. 620) short half-life (about 40 minutes), such a low dose will not persist in the body for long. Other Behavioral And Psychological Factors To help prevent relapse, it would be helpful to encourage Laura to substitute more interesting and stimulating activities in the evening for her typical sedentary activities. Although caffeine drinks with the evening meal may have been taken to help maintain alertness without apparent effect on sleep onset, with a long half-life (5 8 hours), especially in older individuals in which ASPD is more common, it can contribute to later wakefulness and should be avoided. Typically with ASPD individuals the evening meal tends to be early (5:00 6:00 p.m.). Along with the delay of bedtime, the evening meal can be delayed somewhat (6:30 p.m.) to help maintain nutritional levels without impairing sleep four hours later. Bright light exposure should be avoided for the first three hours after awakening to avoid its counterproductive phase-advancing effect. If outdoor activity in the morning is unavoidable, blue light blocking dark glasses would be helpful. Chronotherapy Another approach, termed chronotherapy, has been suggested for the treatment of the more extreme, but less common, cases of DSPD and ASPD. They involve the counterintuitive procedure of shifting the sleep period in the same direction as the circadian tendency. For DSPD it would involve systematic phase delays until the target sleep period is reached (Czeisler et al., 1981). For ASPD it would involve systematic advances of the sleep period. For example, a DSPD client whose self-selected sleep period is as late as 6 a.m. to 3 p.m. but who needs to sleep at the target period of 11 p.m. to 7 a.m. would require either a seven-hour phase advance or 17-hour phase delay. Although the 17-hour delay sounds like a longer trip, it goes in the same direction as the strong delay tendency of the DSPD client and may actually be accomplished in less time. This therapy also shifts the client s light dark cycle as well as the sleep period, therefore exposing the client to light before his or her scheduled bedtime in the phasedelay portion of the PRC and consequently facilitating the delay of the circadian rhythm (Hughes & Lewy, 1998). In addition, the DSPD client will have many bedtimes close to Tmin and after more than the usual number of hours awake. This will facilitate rapid sleep onsets during the therapy and would help ameliorate any conditioned insomnia. Page 23 of 32

24 Using chronotherapy, Czeisler and colleagues (1981) delayed the bedtime of volunteers with DSPD by 3 hours per bed rest period. Their pre-treatment average sleep period was from 4:50 a.m. to 1:00 p.m. Over a 5- to 6-day treatment period they managed to reach a new sleep period of 12:20 a.m. to 7:55 a.m. If, as the Campbell and Murphy (2007) data suggest, the endogenous period length of DSPD patients is as long as 25.5 hours with an unrestrained tendency to phase-delay spontaneously by 1.5 hours/day, the 3-hour daily delay in chronotherapy should be quite feasible. If, however, this is an overestimate of period length in the order of an hour, as data from evening types would suggest (Duffy, Rimmer, & Czeisler, 2001), then the spontaneous circadian delay of DSPD patients might be only 0.5 hours per day. In this case there is the potential for inadvertent bright light exposure during the course of treatment to occur following the Tmin that will inhibit the delay. Even assuming an extra 0.5- hour delay induced by light before Tmin in the first few days of treatment, after three days bedtime will have delayed from 5 a.m. to 2 p.m., but Tmin would have delayed only three hours from 10 a.m. to 1 p.m. There is the potential for bright light to occur after Tmin and stop further delays, with Tmin not progressing beyond 1 p.m. To ensure that the planned sleep onset time and light exposure occurs before the Tmin throughout the chronotherapy, more conservative 2-hour delays of sleep period could be recommended. Following this phase-delay therapy, it is important that, once the target bedtime is reached, individuals adhere to their new sleep schedule and consistent use of morning light exposure, and avoid sleeping in. Conversely, phase advance chronotherapy has been used in a single case study of an ASPD client (Moldofsky, Musisi, & Phillipson, 1986). An older volunteer, who during the baseline week slept between 6:30 p.m. and 2:30 a.m., was treated by successively phase advancing his bedtime by 3 hours every alternate day until his bedtime was 11:00 p.m. and wake time 7:00 a.m. This sleep time was maintained at follow-up 5 months later. Since chronotherapy for either DSPD or ASPD can take up to 10 days, during which some sleep periods will be in the day, careful planning to avoid the intrusion of other daytime commitments is necessary. In both of these disorders a decision needs to be made as to the direction of phase shift that would be more efficacious, practical, and preferable for the client. How extreme does the circadian phase (p. 621) abnormality have to be to recommend chronotherapy? We have found that generally for DSPD clients the crossover for the decision to advance or delay with chronotherapy occurs when the estimated Tmin from the ad lib sleep is about 10:00 a.m., that is, about five hours later than the normal Tmin, and when ad lib wake-up times are after noon. Phase advance with morning bright light and evening melatonin would generally be recommended as the more efficient direction of phase change for estimated Tmin earlier than 10 a.m., and chronotherapy for Tmin later than 10 a.m. However, some clients with estimated Tmin earlier than 10 a.m. may still prefer to undertake chronotherapy, as they find morning bright light aversive. Therefore, the decision to treat with advance or delay those DSPS clients with a delay from normal in the region of five hours (four to six hours) may rest more on convenience and palatability of the therapy rather than the precise amount of estimated delay. With extreme cases of ASPD (e.g., ad lib sleep period from 6 p.m. to 2 a.m. or earlier and estimated Tmin before midnight), advance chronotherapy may be recommended over the usual evening bright light/morning melatonin regime. Conclusions Delayed sleep phase disorder is associated with delayed circadian rhythms and sleep onset difficulties and most likely has a multifactorial etiology including abnormally long circadian periods, insufficient exposure to morning light, conditioned sleep onset insomnia, and an unhelpful preference for evening activity. Advanced sleep phase disorder is associated with advanced circadian rhythms, early morning awakening insomnia, and an unhelpful preference for morning activities. Treatments include manipulations of circadian phase or timing (morning bright light and evening melatonin administration to phase-advance DSPD patients and evening bright light and morning melatonin to phase-delay ASPD patients). Since the timing of these interventions is critical for the appropriate therapeutic effect, the pretreatment circadian timing must be determined or estimated as 2 4 hours before awakening from free or ad lib sleep. To address the non-circadian factors, stimulus control therapy for DSPD clients and bedtime restriction therapy for the ASPD clients can be useful adjuncts as well as elements of cognitive therapy for psychological bias factors. For more extreme cases, chronotherapy can be used to systematically shift the sleep period in the same direction as the circadian tendency until the target sleep period is attained. As the basic biology and psychology of these disorders becomes better understood, treatments can be refined to provide greater therapeutic effect. Page 24 of 32

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