keywords circadian rhythm sleep disorders, light therapy, melatonin, sleep, suprachiasmatic nucleus

Transcription

1 The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders Seithikurippu R Pandi-Perumal*, Ilya Trakht, D Warren Spence, Venkataramanujan Srinivasan, Yaron Dagan and Daniel P Cardinali SUMMARY Normal circadian rhythms are synchronized to a regular 24 h environmental light dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep wake disorder, jet lag and shiftwork sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep wake rhythms seen in CRSDs. keywords circadian rhythm sleep disorders, light therapy, melatonin, sleep, suprachiasmatic nucleus Review criteria PubMed was used to search for citations from MEDLINE and other life science journals for biomedical articles (published up to 1 October 2007) including electronic early-release publications. Search terms included circadian rhythm sleep disorders, CRSD, delayed sleep phase syndrome, DSPS, advanced sleep phase syndrome, ASPS, jet lag, shift-work sleep disorder, non-24 h sleep wake syndrome and melatonin. Full publications were obtained and references were checked for additional material when appropriate. SR Pandi-Perumal is the President and Chief Executive Officer of Somnogen Inc. and I Trakht is an Assistant Professor in the Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons at Columbia University, New York, NY, USA. DW Spence is a PhD student at the University of Toronto, Toronto, ON, Canada. V Srinivasan is an Associate Professor in the Department of Physiology, School of Medical Sciences at University Sains Malaysia, Kota Bharu, Kelantan, Malaysia. Y Dagan is a Senior Emergency Physician and Head of the Medical Education Department in the Faculty of Medicine at Tel Aviv University, Tel Aviv, Israel. DP Cardinali is Professor of Physiology and Director of the Neuroscience Laboratory in the Faculty of Medicine at University of Buenos Aires, Buenos Aires, Argentina. Correspondence *Somnogen Inc., th Street, New York, NY , USA sleepresearch@gmail.com Received 2 November 2007 Accepted 7 May 2008 Published online 15 July doi: /ncpneuro0847 INTRODUCTION Circadian rhythm sleep disorders (CSRDs) have become an important focus of attention in recent years. Many major industrial, air and train accidents have been attributed to fatigue caused by a malfunctioning circadian timekeeping system, 1 and there is evidence that on-the-job performance is negatively affected by night-shift work. 2 Poor-quality sleep, another condition that often afflicts nightshift workers, leads to further decrements in alertness and performance. Synchronization of sleep wake rhythm and rest activity cycles with the light dark (LD) cycle of the external environment is essential for maintaining normal performance and health. The hormone melatonin, which is produced mainly in the pineal gland, is thought to have a role in this physiological adaptation, 3 a supposition that is supported by the association of pathological conditions such as CRSDs with disturbances in the rhythm of melatonin secretion. 4,5 Remission of CRSD symptoms following normalization of the melatonin secretion cycle is further evidence of the central role of chronobiological factors in these disorders. 6 According to Arendt, 7 the melatonin secretion cycle represents a convenient means of observing the body s circadian timekeeping system. In this Review, we discuss the possible involvement of melatonin secretion in CRSDs such as non- 24 h sleep wake rhythm disorder, delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), shift-work sleep disorder and jet lag. We will also consider the increasing evidence that strategic application of exogenous melatonin, sometimes in combination with light therapy, can be beneficial in resynchronizing sleep patterns in patients with these disorders. 6,8,9 The reader is referred to two American Academy of Sleep Medicine reviews 10,11 and an American Academy of Sleep Medicine report 12 for a comprehensive discussion of CRSDs and their treatment. 436 nature clinical practice NEUROLOGY august 2008 vol 4 no 8

2 CIRCADIAN RHYTHMS Circadian rhythms are the most thoroughly investigated of all the biological rhythms. Although anchored genetically, circadian rhythms are synchronized (entrained) by, and maintain phase relationships with, exogenous factors such as environmental time cues. These rhythms are usually synchronized to a regular 24 h environmental LD cycle, although the phase varies between individuals (Box 1). The rhythms will persist, albeit with a period deviating from 24 h, when external time cues are suppressed or removed, such as when an individual is placed in complete social isolation or is subjected to constant light or darkness. 13 A series of transcription translation feedback loops, comprising both positive and negative elements that are formed from proteins encoded by clock genes, lies at the core of the circadian clock. The circadian system provides output signals that are capable of regulating the expression of other, clock-controlled, genes. 13 Mutations of clock genes can affect virtually every parameter of the circadian rhythm, including its amplitude, period and phase, and in some extreme cases mutations can render the system completely arrhythmic. Such mutations can have profound effects on sleep and other forms of cyclical behavior. In mammals, cellular clocks are governed by a master timekeeping system located in the brain. In all animals, 14 including humans, 15 the biological clock or regulator of these rhythms resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. In the absence of temporal cues such as the LD cycle, circadian rhythms become freerunning, but they can be readjusted to 24 h by exposure to light input, which is conveyed to the SCN through the monosynaptic retinohypothalamic pathway. 14,15 In humans, the endogenous free-running period is slightly longer than 24 h. 16 Without constant adjustment of the circadian pacemaker, the body s endogenous rhythms can be phase delayed by up to an hour each day, which has a considerable impact on overall health and performance. 17 Abnormal phase positions, which are prominent features of CRSDs, can severely desynchronize the pattern of sleeping and waking, as well as other circadian rhythms Circadian and homeostatic regulation of sleep Sleep stages occur in cycles that repeat themselves approximately every min. These stages manifest as sleep onset (stage I), superficial sleep Box 1 Chronotyping. The study of human rhythms in behavioral and cognitive functions has revealed that temporal preferences vary markedly among individuals and populations. These preferences, which tend to correlate with individuals self-reports of their own alertness and performance efficiency, have been characterized in a descriptive system known as chronotypes. This typology classifies individuals along a continuum ranging from extreme morning types ( larks ) to extreme evening types ( owls ), with the majority of the population positioned between these two extremes. 162,163 It is interesting to note that chronotypes, which are usually assessed by means of specific questionnaires such as the Horne Ostberg Morningness Eveningness Questionnaire or the Munich Chronotype Questionnaire, 162,163 show a predictable change with developmental age, with evening types being particularly prevalent among adolescents, and morning types being more prevalent among older individuals. 164 Attempts to correlate chronotypes with circadian gene polymorphisms have produced contradictory results. 93,165,166 Conflicts between social and biological timing (collectively termed social jet lag ) usually result from changes in sleep habits between work or school days and free days, and these conflicts are often associated with considerable sleep debt and decrements in daytime alertness. 90 The morningness eveningness score is a notable predictor of the circadian phase of core body temperature rhythm. 162,163 A statistically significant association between morningness eveningness type and time of peak melatonin levels has also been found. 20 Evening-type individuals have been found to be well suited to night-shift work. 141 Genetic screening has shown that polymorphisms in human clock genes are correlated with alterations in sleep or diurnal preferences. 165,167,168 For example, in delayed sleep phase syndrome a correlation with certain polymorphisms in PER3 has been demonstrated, 93,166 whereas a mutation in PER2 is associated with familial advanced sleep phase syndrome. 121 In addition, certain types of depression, such as bipolar disorder, might also be related to alterations in clock genes or their regulators. 169 Patients with depression exhibit profound changes in their circadian rhythms, an alteration that might predict the onset of depressive symptoms in some cases. 170 (stage II), deep sleep (slow-wave sleep; stages III and IV) and rapid eye movement (REM) sleep (stage V). A normal sleep cycle begins with light non-rem sleep and goes through the four stages of non-rem sleep. The cycle then rapidly passes through the same stages in reverse order before reaching REM sleep, which occurs about 90 min after sleep onset. According to Borbely, 25 the daily sleep wake cycle is strongly influenced by two separate processes: an endogenous biological clock that drives the circadian rhythm of the sleep wake cycle, and a homeostatic component that influences sleep propensity. 26 Findings from a study in which these two interacting processes were analyzed by use of a forced desynchrony model indicated that the homeostatic component drives slow-wave sleep, whereas REM sleep seems to be driven by the circadian component. 27,28 The SCN is necessary for the circadian timing of both REM and non-rem sleep The exact mechanism underlying this timing system, and in particular how it regulates REM sleep, is not fully august 2008 vol 4 no 8 PANDI-PERUMAL ET AL. nature clinical practice NEUROLOGY 437

3 understood. Studies in rats have shown that REM sleep tendency is promoted by the SCN during the resting phase, but the amount of REM sleep, once initiated, is determined primarily by the homeostatic mechanism. 32 It has also been hypothesized that circadian modulation of REM sleep propensity can occur through indirect projections from the SCN to the mesopontine tegmental nuclei, which are involved in REM sleep generation. 33 The firing rate of neurons in the SCN correlates with sleep state, and SCN neurons fire more rapidly during REM sleep than during non-rem sleep. 33 Collectively, these findings support a role for the circadian component of the sleep wake cycle in the regulation of REM sleep. Melatonin and the sleep wake rhythm Endogenous melatonin In all animals, melatonin is synthesized primarily in the pineal gland. 34 In humans, synthesis of melatonin also occurs in other tissues, including the retina, gut and bone marrow; however, circulating melatonin derives exclusively from the pineal gland. The biosynthesis of melatonin occurs predominantly at night. The circadian rhythm of melatonin production is regulated by the SCN, 35 but the duration, phase and amplitude of the hormone s production are influenced by changes in LD cycles. The retinohypothalamic pathway conveys information about the LD cycle to the SCN. Ganglionic photoreceptor cells in the retina are involved in the perception of light, which regulates melatonin synthesis. 36 The regulatory effect of light is variable and dependent on wavelength, with blue light in the range nm having the most pronounced suppressant effect on melatonin production. 37 Once synthesized, melatonin is immediately secreted into the bloodstream, binding mostly to albumin in the plasma. 38 The hormone then passes through the choroid plexus to the cerebrospinal fluid. 39 Endogenous melatonin, which can be measured in saliva or urine, is often referred to as a hormonal fingerprint, having a profile that is unique yet consistently predictable (on a daily and weekly basis) within the individual. 40 Circulating melatonin levels show high interindividual variability and are presumed to be genetically determined. 41 In most people, the plasma melatonin level begins to increase steadily between 1900 h and 2300 h and reaches its peak value between 0200 h and 0400 h. 6 The levels then decline, reaching their lowest values during daytime hours. The rhythm is well preserved from childhood to adulthood, but after the age of approximately 55 years the amount of melatonin produced begins to decline. 42 The extent to which the age-related decline in melatonin production contributes to insomnia in older individuals remains to be established. It has been shown, however, that with aging, the timing of the melatonin peak is delayed into the morning hours, 43,44 which might explain why elderly individuals have reduced levels of melatonin in the blood during the night compared with younger individuals. 45 In a study of 517 individuals aged 55 years and over, a marked decline in the secretion of 6-sulfatoxymelatonin, the principal urinary melatonin metabolite, was noted in those who experienced insomnia (mean 9.0 µg/night, compared with 18.0 µg/night in unaffected age-matched individuals). 46 Melatonin exerts its physiological actions through specific cell membrane receptors. The MT 1 and MT 2 melatonin receptor subtypes, which belong to the G-protein-coupled receptor family, have been identified in the plasma membranes of both neural and peripheral tissues. 47,48 The MT 1 receptor decreases neuronal firing rates, whereas the MT 2 receptor regulates phase shifts. 49 Another putative melatonin receptor, initially described as the MT 3 receptor, was found to be homologous to quinone reductase 2, 50 and nuclear receptors for melatonin have also been described. 51 In addition, melatonin exerts direct nonreceptor-mediated effects on intracellular proteins such as calmodulin 52 or tubulin 53 and has strong free-radical scavenging properties. 54 Through its actions on MT 1 and MT 2 receptors, melatonin plays a substantial part in both sleep induction and the regulation of the circadian component of the sleep wake cycle. The temporal pattern of melatonin production by the pineal gland correlates closely with the timing of sleep in humans, and melatonin secretion correlates with the onset of evening sleepiness. 55 Melatonin is also a major regulator of the circadian rhythm of core body temperature (cbt) in humans, 56 and, in normal adults, the deepest level of sleep occurs when the cbt has reached its lowest level. Melatonin secretion peaks at the time of maximum sleepiness and reaches its nadir at the peak of cbt, alertness and performance. 57 Administration of exogenous melatonin Exogenous melatonin is believed to affect sleep regulation largely through a phase-resetting mechanism, and the hormone s capability to 438 nature clinical practice NEUROLOGY PANDI-PERUMAL ET AL. august 2008 vol 4 no 8

4 readjust disturbed circadian rhythms to their correct phase position has led to its increasing clinical use as a chronobiotic agent Administration of exogenous melatonin, even at very low doses, can induce sleepiness at night. 61 Unlike some other hypnotic drugs, melatonin does not cause hangover effects the next morning. 45,61 A meta-analysis of 17 studies involving 284 individuals concluded that melatonin is effective at reducing sleep-onset latency and increasing sleep efficiency. 62 Another survey, however, which included a wider range of age-groups, failed to confirm a clinically meaningful effect of exogenously administered melatonin on sleep. 63 It is important to stress that this report showed that melatonin produced a statistically significant increase in sleep efficiency (an increase of about 10 min in the amount of time spent asleep per 8 h spent in bed) in people with secondary sleep disorders, but the authors considered this effect to be clinically unimportant. The authors conclusions might, however, merit reconsideration, as the noted effect was of comparable magnitude to that observed with some marketed hypnotics. A potential confounding factor is that low levels of endogenous melatonin secretion might be a prerequisite for exogenous melatonin to be effective. 46 The appropriate dose and formulation of melatonin for the adjustment of circadian rhythms has yet to be established. It has been argued that to induce sleep effectively, melatonin should be administered during the day at a dose that reproduces physiological levels that occur at night. 61 However, daytime injection of melatonin to attain normal nocturnal levels in the blood and saliva of young adults was shown to produce marked thermoregulatory changes without subjective effects on sleep. 64,65 The conditions during which melatonin is administered seem to be crucial for defining the effectiveness of a given dose, particularly with respect to acute changes in sleepiness and cbt. On daily administration of 2 mg melatonin at 1700 h without controlling for light or posture, a phase advance of sleepiness or sleep was evident only after 3 4 days of treatment. 66 By contrast, under controlled conditions (dim light, recumbence following melatonin administration), administration of a single dose of melatonin (ranging from 0.05 to 5 mg ) at 1700 h produced acute dose-dependent phase advances with respect to sleepiness, endogenous melatonin and cbt. 67 Similarly, acute induction of sleepiness and lowering of cbt by use of 5 mg melatonin administered at 1700 h occurred only if the individual was recumbent. 68 The daily administration of 1.5 mg melatonin (surge-sustained release, with peak values comparable to 0.5 mg fast release) at 1600 h, followed by 16 h of dim light and recumbence, for 8 days led to 3 4-hour phase advances of endogenous melatonin and cortisol rhythms, together with an earlier timing and redistribution of sleep. 69 Notably, the amount of total sleep time was unchanged, thereby emphasizing the importance of melatonin s ability to regulate sleep timing, as opposed to its hypnotic effect. Indeed, the combination of artificial advancement of the evening rise in melatonin over several days with recumbence and very dim light seems to be a highly effective method of advancing circadian rhythms. It should be noted that melatonin secretion might be impaired by several widely prescribed medications such as β-adrenergic blockers 70 or NSAIDs. 71 In some cases of severe sleep disruption following use of β-adrenergic blockers, a regimen of melatonin replacement therapy has been found to be effective at restoring normal sleep patterns CIRCADIAN RHYTHM SLEEP DISORDERS Delayed sleep phase syndrome Characteristics DSPS is the most frequently occurring CRSD. 23,75 Dagan and Eisenstein 76 found that 83.5% of 322 cases of CRSD were of the DSPS type; among individuals with DSPS, 64.3% reported an onset of symptoms in early childhood, 25.3% at the beginning of puberty and 10.4% during adulthood. A minor brain injury or a head trauma can trigger the development of DSPS, 77,78 and the syndrome can also occur following whiplash injury. 79 Other risk factors for DSPS include frequent episodes of jet lag or night-shift work, viral infections and fluvoxamine use Regestein and Monk 81 reported that 75% of their patients with DSPS had a prior history of depression. DSPS persisted in these individuals even after remission of the depression, indicating that DSPS might be a cause rather than a consequence of depression. DSPS is caused by altered physiological timing in the biological clock, 86 such that sleep onset and wake time are delayed. 80 The time of sleep onset is delayed in some cases to h. Neither sleep architecture nor the maintenance of sleep are affected in DSPS, 80,81 but individuals with this disorder experience chronic sleep-onset insomnia, which, combined with forced early august 2008 vol 4 no 8 PANDI-PERUMAL ET AL. nature clinical practice NEUROLOGY 439

5 awakening, frequently results in marked daytime sleepiness. It has been shown that the peak of melatonin secretion occurs between 0800 h and 1500 h in some patients with DSPS, which demonstrates the abnormal phase position of melatonin in this disorder. 80 DSPS is characterized by a chronic inability to fall asleep at the desired clock time, although affected individuals usually show a normal sleep pattern with normal length of sleep duration and are able to awaken spontaneously refreshed. 81 The minimum criterion for the diagnosis of DSPS is delayed sleep onset for at least a month, or excessive daytime sleepiness with sleep-log evidence of delayed sleep. 87 A week of 24 h actigraphy and temperature monitoring should provide results that are consistent with this history, and the patient should have no other insomnia disorder. The usual criterion of a year-long history of being unable to fall asleep before 0200 h and difficulty in waking up before 1000 h should be present. 23 A heightened sensitivity to light, which has been reported in 47% of patients with DSPS, can be involved in the pathophysiology of this disorder. 80,88 Patients with DSPS also have disturbances in several circadian rhythms, such as cbt and the secretion of growth hormone, melatonin or cortisol, 89 as well as hunger. Under certain conditions, the length of the endogenous circadian period can be increased, and this in turn can produce the symptoms of DSPS. Longer endogenous circadian periods might underlie the preference of young individuals for late bedtimes, 86 and DSPS might be exacerbated by behavioral factors, such as staying up late watching television. 90 Insufficient exposure to outdoor sunlight can also favor the occurrence of DSPS. 91 A delayed melatonin secretory pattern, with peak melatonin secretion sometimes delayed until daytime, could also underlie DSPS. 5,92 Archer et al. 93 investigated the link between DSPS and a length polymorphism in the PER3 clock gene, and they found that the length of the PER3 repeat region is a potential genetic marker for DSPS. This finding has been supported by a number of other studies Treatment DSPS can be treated with a procedure known as chronotherapy, which involves systematic delay of bedtimes and wake times over a period of several days until the desired bedtime is achieved. Once achieved, strict adherence to the new sleep wake cycle is crucial for maintaining a positive response. 28,97 Although effective, chronotherapy is demanding and compliance is low. Bright light therapy (>2,500 lx) has been attempted for the treatment of DSPS. 6,98 Owing to an interdependence with other cyclical processes, the timing of light therapy administration is critical. Phase advances are typically induced only when light exposure is scheduled after the minimum cbt is reached, whereas phase delays can be achieved only if light exposure is scheduled before the minimum cbt is reached. Accurate assessment of the minimum cbt can be difficult, and, in view of the fact that the peak of 24 h melatonin secretion occurs when the lowest cbt level is reached, salivary melatonin measurement is usually used for scheduling exposure to bright light. 99 Indeed, since its initial validation, 100 salivary melatonin has repeatedly been used as a circadian phase marker for the study of patients with CRSDs. 101 The duration of exposure to bright light in the treatment of DSPS differs from that used to treat other chronobiological disorders. Rosenthal and co-workers 102 used bright light of 2,500 lx to treat DSPS. Patients were exposed to bright light daily for 2 h within the period from 0600 h to 0900 h and were then asked to wear goggles to shield their eyes from any further influence of light. After 1 week of this treatment regimen, marked advances in the individuals time of sleep onset, as well as improved daytime alertness, were evident. Various pharmacological treatment methods for DSPS have been reported. 23,88,103 In view of the fact that melatonin has been shown to be an effective chronobiotic with few adverse effects, it has become the drug of choice for the treatment of DSPS. 104 In some case reports, vitamin B 12 has also been shown to be beneficial in treating this disorder, 105,106 although a double-blind placebo-controlled study failed to support this finding. 107 Dahlitz and co-workers 104,108 were the first group to provide evidence from a placebocontrolled study to demonstrate the efficacy of melatonin in the treatment of patients with DSPS. A 5 mg daily dose of melatonin was administered orally at 2200 h for a period of 4 weeks to patients with DSPS. The melatonin treatment advanced the sleep-onset time by an average of 82 min (range min), and the mean waking time advanced by 117 min on average. 104,108 The total duration of sleep remained unaltered (mean about 8 h), but there was a marked improvement in sleep quality. 440 nature clinical practice NEUROLOGY PANDI-PERUMAL ET AL. august 2008 vol 4 no 8

6 To maximize the effectiveness of melatonin treatment, the timing of administration is crucial. 98 Lewy et al. 109 found that the maximum advance in circadian time was achieved when melatonin was administered 5 h before the onset of endogenous melatonin secretion. On this basis, Nagtegaal et al. 110 administered melatonin 5 h before the onset of the evening rise in endogenous melatonin secretion (the dim-light melatonin onset, or DLMO) for a period of 4 weeks to individuals with DSPS, and they found evidence of phase advancement in the sleep wake rhythm. The onset of the nocturnal melatonin profile was found to be phase advanced by 1.5 h. Following this report, Kayumov et al. 5 administered melatonin to a group of 22 patients with DSPS who had their sleep time restricted to the 8 h period between 2400 h and 0800 h. Melatonin at a dose of 5 mg/day was administered 3 4 h before sleep onset for a period of 4 weeks. This regimen produced statistically significant phase advances in the sleep period and decreases in sleep-onset latency compared with placebo. 5 In another study of patients with DSPS, it was found that the largest phase advance in the timing of circadian rhythms occurred when melatonin (0.3 3 mg) was given 6 7 h before bedtime. 111 No adverse effects of melatonin were noted in any of these studies. Melatonin has been shown in placebo-controlled studies to be effective at treating children with idiopathic chronic sleeponset insomnia, 112,113 although the risks of using melatonin in children (e.g. hormonal effects) have not yet been adequately evaluated. Advanced sleep phase syndrome Characteristics The characteristic pattern of ASPS includes complaints of persistent early evening sleep onset and early morning awakenings. 87,114 In patients with this condition, sleep onset typically occurs at around 2000 h and wakefulness occurs at around 0300 h. 115 The quality of sleep is progressively impaired by increased night-time awakenings. 116 ASPS has been attributed to agerelated attenuation of the rhythm of melatonin secretion, which, in turn, can disrupt the phase relationships of the sleep wake cycle, as well as other circadian rhythms. 46,117 Consistent with this idea, some studies have revealed that ASPS is associated with an advancement in the rhythm of melatonin secretion. 114,118 In cases of familial ASPS, for example, the melatonin rhythm was shown to be phase advanced by 3.5 h compared with unaffected family members. 114 The idea that decrements in sleep quality are attributable to a decline in the production of melatonin with advancing age was also supported by a study in which 372 elderly individuals with insomnia were given melatonin therapy at a dose of 2 mg/day in the form of controlled-release melatonin tablets. 46 This treatment was found to markedly improve sleep quality, and the individuals also showed improvements in measures of alertness and behavioral integrity. A severe disturbance of melatonin secretion has also been reported in patients with senile dementia of the Alzheimer s type, some of whom show the characteristics of ASPS. 119,120 Genetic testing has indicated that ASPS can be an inherited sleep wake rhythm disorder with an autosomal dominant mode of inheritance. 96,114, In one large family, for example, ASPS was associated with a Ser662Gly substitution in exon 17 of the circadian clock gene PER2. 96,121 Treatment In both elderly individuals and patients with dementia, the administration of exogenous melatonin has been found not only to enhance sleep quality, but also to improve the sleep wake rhythm Asayama and co-workers 130 found melatonin to be effective at both prolonging sleep time and reducing activity at night in patients with dementia of the Alzheimer s type. Jet lag Characteristics Rapid transmeridian flight across several time zones results in a temporary mismatch between the endogenous circadian rhythms and the new environmental LD cycle. 131 As a result, endogenous rhythms shift in the direction of the flight: an eastbound flight will result in a phase advance of rhythms, whereas a westbound flight will produce a phase delay. 8 This shift leads to a transient desynchronization of circadian rhythms, giving rise to a cluster of symptoms collectively referred to as jet lag. These symptoms typically include transient alterations in sleep patterns (e.g. disturbed night-time sleep, impaired daytime alertness and performance), mood and cognitive performance (e.g. irritability, distress) and appetite (e.g. anorexia), along with other physical symptoms such as disorientation, fatigue, gastrointestinal disturbances and light-headedness. 131,132 august 2008 vol 4 no 8 PANDI-PERUMAL ET AL. nature clinical practice NEUROLOGY 441

7 Treatment Several reports have provided evidence, from both placebo-controlled field studies and laboratory studies, to support the efficacy of exogenous melatonin in alleviating the symptoms of jet lag, especially the sleep disturbances. 67,133,134 Melatonin has been shown to act as both a hypnotic and a chronobiotic. 133 Recommended melatonin ingestion times have been proposed for both eastward and westward flights. Melatonin capsules taken during the evening hours of the new time zone have been shown to be beneficial for both eastbound and westbound travelers, irrespective of the time of flight departure. 135,136 In the case of flights covering more than eight time zones, the combination of melatonin with adequate exposure to sunlight and physical exercise has been found to reduce the severity of the expected jet-lag symptoms. 60,135 A positive correlation between the preflight melatonin production rate and both sleep quality and morning alertness after the flight has also been noted. 135 Collectively, these studies demonstrate the practical value of melatonin treatment for reducing the adverse effects of jet-lag symptoms among transmeridian travelers. The scheduling of sunlight exposure at the correct time, and, more importantly, avoiding it at the wrong time, are very important for alleviating jet lag. 137 Preflight regimens of controlled light exposure have been advocated for reducing jet-lag symptoms in frequent travelers. 138 When carefully applied either on or after arrival, this technique has been found to be effective at promoting phase shifts in the appropriate direction. 139,140 People traveling east should phase advance their rhythms and, hence, should be exposed to afternoon light (after reaching their minimum cbt) and should avoid exposure to morning light (before reaching their minimum cbt) at their destination. Westbound travelers should phase delay their circadian clock, and they must, therefore, be exposed to light in the evening (before reaching their minimum cbt) and should avoid exposure to light in the early morning (after reaching their minimum cbt) at their destination. 138 Shift-work sleep disorder Characteristics In our modern industrialized society, it has been estimated that at least one-fifth of the total work force is engaged in rotating shift work. 141,142 These individuals are forced to forego their nocturnal sleep while they are on a night shift, and so they must sleep during the day. This inversion of the sleep wake rhythm with work at night at the low phase of the circadian temperature rhythm and sleep at the time of peak cbt can give rise to insomnia-like sleep disturbances. Sleep loss impairs the individual s alertness and performance, which can not only affect work productivity but also, in some cases, cause sleep-related accidents. 143 Sleep deprivation and the associated desynchronization of circadian rhythms are common in shift-work sleep disorder. 141 Treatment Many treatment procedures have been advocated for shift-work sleep disorder. Czeisler and coworkers 144 administered bright light in an attempt to improve the physiological adaptation of the circadian rhythms of night-shift workers to their inverted sleep wake schedules. In this study, bright light was found to be effective at resynchronizing alertness, cognition, performance and cbt to the new work schedules. Following the successful application of bright light, melatonin has been used in shift workers to accelerate the adaptation of their circadian rhythms and sleep wake rhythms to the new work schedules. 6,145 A phase delay in plasma melatonin was noted in shift workers when melatonin was administered at the morning bedtime following the night shift. 146 Such shifts in melatonin secretion have been associated with improved work performance. 147 Correctly timed administration of melatonin is advocated for hastening the adaptation of circadian rhythms in shiftworkers. Melatonin (1.5 mg at 1600 h daily) was found to advance the timing of both endogenous melatonin and cortisol rhythms without any deleterious effects on endocrine function or daytime mood and sleepiness. 69 Non-24 h sleep wake disorder Characteristics Non-24 h sleep wake disorder is seen mostly in blind individuals whose sleep wake cycle is not synchronized to the 24 h LD cycle. 148 These individuals experience recurrent insomnia and daytime sleepiness. Totally blind individuals exhibit free-running rhythms, and a high prevalence of sleep disturbances was found in a study conducted on 388 blind individuals with no light perception. 149 Both non-24 h sleep wake disorder and abnormal bedtime and wake times 442 nature clinical practice NEUROLOGY PANDI-PERUMAL ET AL. august 2008 vol 4 no 8

8 similar to those seen in ASPS or DSPS have been found in blind individuals, as have abnormal melatonin secretion patterns. 150 Non-24 h sleep wake rhythm disorder is believed to be rare among sighted individuals, although the exact prevalence is unknown. Fewer than 50 cases have been reported in the literature, and, of these, the vast majority have been in Japanese publications. 106,151,152 Only nine cases have been documented outside Japan; these were predominantly male and associated with avoidant or schizoid personalities The rarity of non-24 h sleep wake disorder among sighted individuals in Western populations might be attributable to underdiagnosis. The diagnosis of this condition is complicated by the fact that it can resemble either ASPS or DSPS. In a recent study, for example, patients with DSPS displayed almost identical polysomnographic features to patients with non-24 h sleep wake rhythm disorder. 5 Treatment The capability of melatonin to entrain the sleep wake cycle in blind individuals might depend on various factors, including melatonin dosage, formulation, timing and length of treatment, and the characteristics of the blind person and the person s environment. It is likely that a 0.5 mg fast-release formulation is sufficient for entrainment in most individuals; data on slow-release formulations are currently lacking. Initially, it was reported that entrainment is most likely to occur when treatment is started during the phase advance region of the phase response curve, 158 but subsequent studies 159,160 have shown that entrainment can also occur with treatment initiated during phase delay. Despite concerns that a melatonin dose of higher than 0.5 mg might compromise entrainment in some individuals, 160 entrainment has been achieved with doses of up to 10 mg in some cases. 161 Two studies have shown that melatonin can synchronize the sleep wake cycle of blind individuals to a 24 h cycle. 158,161 Lockley et al. 158 used 5 mg of melatonin to phase advance and normalize the rhythms of three totally blind people. Sack and his co-workers 161 administered 10 mg of melatonin for 3 9 weeks to 7 totally blind individuals, and they found that melatonin induced an average phase advance in sleep wake rhythms of up to 0.6 h. When complete entrainment was reached, the dose was gradually reduced and synchronization of sleep wake rhythms to the normal 24 h schedule was maintained with a low dose of 0.5 mg that resulted in plasma melatonin concentrations close to the physiological range. 161 In this study, the authors showed that the beneficial effects of melatonin could be attributed not only to its entrainment properties, but also to its direct soporific effects. CONCLUSIONS Normal circadian rhythms are synchronized to a regular 24 h environmental LD cycle. Both the SCN and melatonin seem to have important roles in this adaptation. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, results in severe sleep disturbances. Changes in the phase position of plasma melatonin levels have been documented in a number of CRSDs, including DSPS, ASPS, non-24 h sleep wake rhythm disorder, jet lag and shiftwork sleep disorder. Melatonin has been found to be useful in treating the disturbed sleep wake rhythms in these CRSDs, although further research with large numbers of patients will be needed to clarify whether disruption of melatonin secretion patterns is a cause or a consequence of these disorders. KEY POINTS Circadian rhythm desynchronization is common among patients who present with sleep disorders Circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep wake rhythm disorder, shift-work sleep disorder and jet lag The hormone melatonin is thought to have an important role in the synchronization of sleep wake rhythm and rest activity cycles with the light dark cycle Exogenous melatonin, sometimes in combination with light therapy, can be beneficial in resynchronizing sleep patterns in patients with CRSDs Well-conducted, large clinical trials are warranted to further assess the efficacy and safety of chronotherapy as a treatment for CRSDs References 1 Arendt J et al. (1995) Melatonin and adjustment to phase shift. J Sleep Res 4: Atkinson G et al. (2003) The relevance of melatonin to sports medicine and science. Sports Med 33: Srinivasan V et al. (2006) Melatonin in mood disorders. World J Biol Psychiatry 7: august 2008 vol 4 no 8 PANDI-PERUMAL ET AL. nature clinical practice NEUROLOGY 443

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