A practical approach to circadian rhythm sleep disorders

Circadian rhythm sleep disorders are common in clinical practice. The disorders covered in this review are delayed sleep phase disorder, advanced sleep phase disorder, free-running, irregular sleep-wake rhythm, jet lag disorder and shift work disorder. Bright light treatment and exogenous melatonin administration are considered to be the treatments of choice for these circadian rhythm sleep disorders. Circadian phase needs to be estimated in order to time the treatments appropriately. Inappropriately timed bright light and melatonin will likely worsen the condition. Measurements of core body temperature or endogenous melatonin rhythms will objectively assess circadian phase; however, such measurements are seldom or never used in a busy clinical practice. This review will focus on how to estimate circadian phase based on a careful patient history. Based on such estimations of circadian phase, we will recommend appropriate timing of bright light and/or melatonin in the different circadian rhythm sleep disorders. We hope this practical approach and simple recommendations will stimulate clinicians to treat patients with circadian rhythm sleep disorders.     

Correlation between the circadian sleep propensity rhythm and hormonal rhythms under ultra-short sleep–wake cycle

The aim of this study was to clarify effects of hormonal and temperature rhythms on circadian fluctuations of sleep propensity. Ten healthy females underwent 24-h sleep deprivation and entered the circadian sleep propensity assessment setting under the ultra-short sleep-wake schedule. During the experiment, sleep propensity rhythm, rectal temperature, and 24-h serum hormone profiles (melatonin, cortisol and thyroid-stimulating hormone) were investigated. The circadian sleep propensity rhythms had two apparent peaks (afternoon and nocturnal peaks) and a trough (nocturnal sleep gate). The timings of the nocturnal sleep gate and the nocturnal peak were correlated exclusively with temperature and melatonin rhythms (P < 0.05), while that of the afternoon peak was significantly correlated with habitual wake time and melatonin rhythm. These results indicate that the circadian sleep propensity rhythm is influenced not only by the circadian pacemaker, but also by sleep habit.     

Circadian rhythm sleep disorders in the blind and their treatment with melatonin

People who are blind, in addition to having to cope with partial or no sight, have an added handicap; the transmission of ocular light from the retina to their circadian clock is impaired. At its worse, for example in people with both eyes enucleated, this lesion results in desynchronisation of the biological clock (located in the hypothalamic suprachiasmatic nuclei) from the 24h day/night environment. While in a desynchronised state, symptoms akin to jet lag are experienced (e.g., daytime sleepiness, poor night sleep, reduced alertness and performance during waking). This is a lifelong condition. Daily administration of exogenous melatonin is the current treatment of choice for this so-called "non-24h sleep/wake disorder". Melatonin has been shown to correct the underlying circadian rhythm abnormality as well as improve sleep and reduce daytime napping. The effectiveness of melatonin therapy depends upon its time of administration relative to the timing of the person's circadian clock. If practicable, assessment of an individual's circadian phase (by measurement of the endogenous melatonin rhythm in plasma, saliva or urine) is recommended prior to commencing treatment to optimise melatonin's effectiveness.     

The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders

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 shift-work 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.     

Circadian rhythm sleep disorders: lessons from the blind

As totally blind people cannot perceive the light-dark cycle (the major synchroniser of the circadian pacemaker) their circadian rhythms often "free run" on a cycle slightly longer than 24 h. When the free-running sleep propensity rhythm passes out of phase with the desired time for sleep, night-time insomnia and daytime sleepiness result. It has recently been shown that daily melatonin administration can entrain the circadian pacemaker, thereby correcting this burdensome circadian sleep disorder. The primary purpose of this review is to elevate awareness of circadian sleep disorders in totally blind people (especially free-running rhythms) and to provide some guidance for clinical management. An additional goal is to show how research on sleep and circadian rhythms in the totally blind can contribute insights into the scientific understanding of the human circadian system. 2001 Harcourt Publishers Ltd     

Chronobiotic protocol and circadian sleep propensity index: new tools for clinical routine and research on melatonin and sleep

Twenty years ago, chronobiology was a major topic in medical research, especially in psychiatry. Over time, however, clinicians lost interest in the subject because studies had failed to lead to any practical benefits for patient diagnosis or therapy. Today, the field of chronobiology appears to be on the verge of a renaissance. Over the past decade, our understanding of the basic mechanisms of the circadian timing system (CTS) has increased so rapidly that experts in the field sometimes speak of a "clockwork explosion." It has become apparent that, in order to treat circadian rhythm disturbances, new diagnostic tools are needed so that researchers and physicians can make reliable measurements of CTS functionality (e.g., phase position and circadian rhythm amplitude). Although clinicians do have a phase marker for the CTS at their disposal, there are still no reliable markers for CTS output strength as measured by rhythm amplitude. The amplitude is considered to be the most important factor in CTS output because it determines the degree of temporal organization in human and animal physiology. In this paper, we would like to suggest that circadian sleep propensity (CSP) - the endogenously generated 24-hour variation in the drive to wakefulness and sleep - is the product of all circadian rhythms, serving the human brain at night by assisting it in the production of good-quality sleep. If this is indeed the case, developing a CSP index (CSPI) for use in routine polysomnography would be of great value. In addition, we will review current data on melatonin and its relationship to sleep, basing our analysis on the assumption that melatonin is a circadian hormone and a drug with highly time-dependent effects. Because of this special mode of action, future melatonin studies should employ a special chronobiotic protocol that precludes the use of crossover designs and requires outcome measures different from those used in studies on classical hypnotics.     

Treating chronobiological components of chronic insomnia

Circadian rhythms have a strong effect on the ability to sleep across the 24-h period. Maximum sleepiness occurs at the phase of lower endogenous core body temperature. This period is bracketed by two periods of alertness: a "wake-maintenance zone" occurring 6-10h before the time of core temperature minimum, and a "wake-up zone" occurring 4-7h after the minimum. Therefore, if the circadian rhythm drifts earlier with respect to the attempted sleep period, the wake-up zone can impinge on the end of the normal sleep period resulting in premature awakening and the development of early morning awakening insomnia. Similarly, a delay of the circadian rhythm can impose the wake-maintenance zone on the attempted bedtime and lead to sleep onset insomnia. Therefore, these two types of insomnia should be treatable with chronobiologic effects such as bright light and, possibly, melatonin administration. Bright light stimulation at normal wake-up time and melatonin administration 4-8h before normal bedtime can phase advance circadian rhythms to an earlier time. While morning bright light has been efficacious for sleep onset insomnia, evening melatonin administration has yet to be tested. Early morning awakening insomnia has been treated with phase delays imposed by evening bright light but not yet with morning melatonin administration. There is now sufficient evidence to warrant the consideration of chronobiologic manipulations such as bright light therapy for the treatment of chronic sleep onset and early morning awakening insomnia that show evidence of circadian delay or advance, respectively.     

Familial advanced sleep phase syndrome.

BACKGROUND: The circadian rhythms of sleep propensity and melatonin secretion are regulated by a central circadian clock, the suprachiasmatic nucleus of the hypothalamus. The most common types of sleep disorders attributed to an alteration of the circadian clock system are the sleep/wake cycle phase disorders, such as delayed sleep phase syndrome and advanced sleep phase syndrome (ASPS). Advanced sleep phase syndrome is characterized by the complaint of persistent early evening sleep onset and early morning awakening. Although the complaint of awakening earlier than desired is relatively common, particularly in older adults, extreme advance of sleep phase is rare. OBJECTIVE: To phenotypically characterize a familial case of ASPS. METHODS: We identified a large family with ASPS; 32 members of this family gave informed consent to participate in this study. Measures of sleep onset and offset, dim light melatonin onset, the Horne-Ostberg morningness-eveningness questionnaire, and clinical interviews were used to characterize family members as affected or unaffected with ASPS. RESULTS: Affected members rated themselves as "morning types" and had a significant advance in the phase of sleep onset (P<.001) and offset (P =.006) times. The mean sleep onset was 2121 hours for the affected family members and 0025 hours for the unaffected family members. The mean sleep offset was 0507 hours for the affected members and 0828 hours for the unaffected members. (Times are given in military form.) In addition, the phase of the circadian rhythm of melatonin onset for the affected family members was on average 3-1/2 hours earlier than for the unaffected members. CONCLUSIONS: The ASPS trait segregates with an autosomal dominant mode of inheritance. The occurrence of familial ASPS indicates that human circadian rhythms, similar to those in animals, are under genetic regulation. Genetic analysis of familial sleep and circadian rhythm disorders is important for identifying a specific gene(s) responsible for the regulation of sleep and circadian rhythms in humans.     

Melatonin as a hypnotic: con

The physiological roles of melatonin are still unclear despite almost 50 years of research. Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes. This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep. The article "Melatonin as a hypnotic--Pro", also in this issue, presents evidence to support this viewpoint. We do not entirely disagree, but nevertheless feel this is an overly simplistic interpretation of the available data. Our interpretation is that melatonin is primarily a neuroendocrine transducer promoting an increased propensity for 'dark appropriate' behavior. Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome. Evidence supporting this position is drawn primarily from studies of exogenous administration of melatonin and its varied effects on sleep/wake behavior based on dose, time of administration, age and other factors. From this perspective, it will be shown that melatonin can exert hypnotic-like effects but only under limited circumstances.     

Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that, within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is the single most accurate marker for assessing the circadian pacemaker. Additionally, melatonin onset has been used clinically to evaluate problems related to the onset or offset of sleep. DLMO is useful for determining whether an individual is entrained (synchronized) to a 24-h light/dark (LD) cycle or is in a free-running state. DLMO is also useful for assessing phase delays or advances of rhythms in entrained individuals. Additionally, it has become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. More recently, DLMO has also been used to assess the chronobiological features of seasonal affective disorder (SAD). DLMO marker is also useful for identifying optimal application times for therapies such as bright light or exogenous melatonin treatment.     

A clinical approach to circadian rhythm sleep disorders

Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-h social and physical environment. In addition to physiological and environmental factors, maladaptive behaviors often play an important role in the development of many of the circadian rhythm sleep disorders. This review will focus on the clinical approach to the diagnosis and management of the various circadian rhythm sleep disorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type, irregular sleep-wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleep diaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral and environmental factors often are involved in the development of these conditions, a multimodal approach is usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as well as avoidance of bright light at the wrong time of the day and pharmacologic approaches, such as melatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication for the treatment of circadian rhythm sleep disorders.     

Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy

A 9-year-old, blind boy with severe mental retardation with a chronic sleep/wake disturbance had a circadian rhythm of 24.75 hours and an internal desynchronization of the endogenous rhythms. Treatment with oral melatonin given at 6 PM induced a regular sleep/wake pattern. Melatonin, in this patient, convincingly entrained the endogenous rhythm to the appropriate chronological 24-hour day.     

Melatonin receptors: role on sleep and circadian rhythm regulation

The circadian release of the hormone melatonin is regulated by the suprachiasmatic nucleus (SCN), which feeds back into the nucleus to modulate sleep and circadian phase through activation of the MT(1) and/or MT(2) melatonin receptors. Considering the functions of the SCN as a sleep and circadian rhythm regulator, melatonin and melatonin receptor agonists have attracted interest as being possible treatments for sleep and circadian rhythm sleep disorders. Part of this interest has centered on elucidating which melatonin receptors are targets for the regulation of these functions within the SCN. Two G-protein coupled melatonin receptors, the MT(1) and MT(2), inhibit neuronal activity and phase shift circadian firing rhythms in the SCN, respectively. Recent reports have uncovered possible interactions between the two types of receptors in the mammalian SCN, as well as the role of physiological and supraphysiological levels of melatonin on the molecular pharmacology and cellular changes of human and rodent melatonin receptors via desensitization and internalization mechanisms. These data outline the complexity of the interplay between melatonin and its receptors in the SCN and their corresponding roles in sleep and circadian regulation. Although further studies are necessary, a great deal of progress has been made toward understanding how melatonin and its agonists contribute to sleep and circadian phase changes, and how best to develop compounds that can target the functions of the SCN specifically and effectively.     

Late evening brain activation patterns and their relation to the internal biological time, melatonin, and homeostatic sleep debt

Sleep propensity increases sharply at night. Some evidence implicates the pineal hormone melatonin in this process. Using functional magnetic resonance imaging, brain activation during a visual search task was examined at 22:00 h (when endogenous melatonin levels normally increase). The relationships between brain activation, endogenous melatonin (measured in saliva), and self-reported fatigue were assessed. Finally, the effects of exogenous melatonin administered at 22:00 h were studied in a double blind, placebo-controlled crossover manner. We show that brain activation patterns as well as the response to exogenous melatonin significantly differ at night from those seen in afternoon hours. Thus, activation in the rostro-medial and lateral aspects of the occipital cortex and the thalamus diminished at 22:00 h. Activation in the right parietal cortex increased at night and correlated with individual fatigue levels, whereas exogenous melatonin given at 22:00 h reduced activation in this area. The right dorsolateral prefrontal cortex, an area considered to reflect homeostatic sleep debt, demonstrated increased activation at 22:00 h. Surprisingly, this increase correlated with endogenous melatonin. These results demonstrate and partially differentiate circadian effects (whether mediated by melatonin or not) and homeostatic sleep debt modulation of human brain activity associated with everyday fatigue at night.     

The bidirectional phase-shifting effects of melatonin on the arginine vasopressin secretion rhythm in rat suprachiasmatic nuclei in vitro

In vivo melatonin serves as a feedback signal to the circadian pacemaker located in the suprachiasmatic nuclei (SCN) and in vitro it phase advances the circadian rhythm of electrical activity in pacemaker cells. However, the occurrence and nature of phase shifting in secretion by cultured SCN neurons has not yet been established. Here we studied the effects of melatonin on the pattern of spontaneous arginine vasopressin (AVP) release in organotypic SCN slices. This culture mimicked the in vivo circadian AVP secretory rhythm, with low release during the subjective night and with peaks in secretion during the middle of subjective day. The endogenous period of the AVP secretory rhythm in organotypic culture ranged between 23 and 26 h, with the mean period of 24.1 +/- 0.3 h. Melatonin (10 nM) had variable effects on the pattern of AVP secretion depending on time of its application directly to the medium with organotypic SCN slices. When introduced at circadian time 22, 2 and 6 (the times corresponding to the late night and early day), melatonin delayed the AVP secretory rhythm by 1-4 h. When applied at circadian time 10 (late day), however, melatonin advanced the AVP secretory rhythm by about 2 h. At other circadian times, melatonin was ineffective. These results indicate that melatonin exhibits the bidirectional phase-shifting effects on circadian secretory rhythm clock, which depends on the time-window of its application.     

Melatonin, sleep disturbance and cancer risk

The pineal hormone melatonin is involved in the circadian regulation and facilitation of sleep, the inhibition of cancer development and growth, and the enhancement of immune function. Individuals, such as night shift workers, who are exposed to light at night on a regular basis experience biological rhythm (i.e., circadian) disruption including circadian phase shifts, nocturnal melatonin suppression, and sleep disturbances. Additionally, these individuals are not only immune suppressed, but they are also at an increased risk of developing a number of different types of cancer. There is a reciprocal interaction and regulation between sleep and the immune system quite independent of melatonin. Sleep disturbances can lead to immune suppression and a shift to the predominance in cancer-stimulatory cytokines. Some studies suggest that a shortened duration of nocturnal sleep is associated with a higher risk of breast cancer development. The relative individual contributions of sleep disturbance, circadian disruption due to light at night exposure, and related impairments of melatonin production and immune function to the initiation and promotion of cancer in high-risk individuals such as night shift workers are unknown. The mutual reinforcement of interacting circadian rhythms of melatonin production, the sleep/wake cycle and immune function may indicate a new role for undisturbed, high quality sleep, and perhaps even more importantly, uninterrupted darkness, as a previously unappreciated endogenous mechanism of cancer prevention.     

A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm

Abstract Twenty-four-hour profiles of plasma melatonin, cortisol and rectal temperature were measured longitudinally in a sighted man who has been suffering from sleep disorders for more than 10 years. The sleep-wake rhythm of this subject free-ran, despite his routine life, and occasionally showed a sign of internal desyn-chronization, where sleep was lengthened up to 30 h. These states were classified into the non-24-hour sleep-wake syndrome. Plasma melatonin concentrations in the subjective night remained at a low level and showed a damped circadian rhythm. At the same time, robust circadian rhythms were detected in plasma cortisol and rectal temperature, indicating that the circadian pacemaker was intact. The causal relationship between the damping of nocturnal melatonin rise and a failure of entrainment of the sleep-wake cycle is discussed.     

Clinical applications of melatonin in circadian disorders

Chronobiological disorders and syndromes include seasonal affective disorder (SAD), total blindness, advanced and delayed sleep phase syndrome, jet lag, and shift work maladaptation. These disorders are treated by adjusting circadian phase, using appropriately timed bright light exposure and melatonin administration (at doses of 0.5 mg or less). In some cases, it may be necessary to measure internal circadían phase, using the time when endogenous melatonin levels rise.     

Optimization of light and melatonin to phase-shift human circadian rhythms

Both light and melatonin, appropriately timed, have been shown to phase-shift human circadian rhythms. In addition, both light and melatonin have acute physiological and behavioural effects. Depending on the dose, melatonin can reduce core body temperature and induce sleepiness. Conversely, light at night increases body temperature and enhances alertness and performance. The acute and phase-shifting effects of light and melatonin have justified their investigation and use in the treatment of circadian rhythm sleep disorders. Melatonin is the treatment of choice for blind people with non-24 h sleep/wake disorder. Current research is directed towards optimizing these therapies with respect to time of administration, dose and formulation of melatonin, intensity, duration and spectral composition of light. Our studies in totally blind people with non-24 h sleep/wake disorder have shown that, in addition to improving sleep, daily administration of melatonin can entrain their free-running circadian rhythms. The ability of melatonin to entrain free-running rhythms depends, in part, on the time of melatonin administration relative to the subject's circadian phase. Subjects who were entrained by melatonin began their treatment in the phase advance portion (CT 6-18) of the published melatonin phase-response curves (PRCs), whereas those who failed to entrain began their melatonin treatment in the delay portion of the PRC. Whether the effect of light on the human circadian axis can be optimized by altering its spectral composition has been investigated. Recently, it was demonstrated that light-induced melatonin suppression in humans is sensitive to short wavelength light (420-480 nm; lambda(max) approximately 460 nm), a response very different to the classical scotopic and photopic visual systems. Whether other nonvisual light responses (e.g. circadian phase resetting) show a similar spectral sensitivity is currently being studied.