REVIEW ARTICLE

CNS Drugs 2001; 15 (4): 311-328 1172-7047/01/0004-0311/$22.00/0 © Adis International Limited. All rights reserved.

Circadian Rhythm Sleep Disorders Pathophysiology and Potential Approaches to Management Nava Zisapel Department of Neurobiochemistry, Tel Aviv University, Tel Aviv, Israel

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Biological Rhythms and the Circadian Control of the Sleep-Wake Cycle . . . . . 2. Circadian Rhythm Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Delayed Sleep Phase Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Advanced Sleep Phase Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Irregular Sleep-Wake Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Non–24-Hour Sleep-Wake Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Jet Lag . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Shift Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Mechanisms of Melatonin-Mediated Sleep-Facilitating and Phase-Shifting Effects 3.1 Effects on Body Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Interaction with GABAA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Effects on Monoamine Neurotransmitters . . . . . . . . . . . . . . . . . . . . . 3.4 Effects on Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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An intrinsic body clock residing in the suprachiasmatic nucleus (SCN) within the brain regulates a complex series of rhythms in humans, including sleep/wakefulness. The individual period of the endogenous clock is usually >24 hours and is normally entrained to match the environmental rhythm. Misalignment of the circadian clock with the environmental cycle may result in sleep disorders. Among these are chronic insomnias associated with an endogenous clock which runs slower or faster than the norm [delayed (DSPS) or advanced (ASPS) sleep phase syndrome, or irregular sleep-wake cycle], periodic insomnias due to disturbances in light perception (non–24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder). Synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland is induced at night, directly regulated by the SCN. Melatonin can relay time-ofday information (signal of darkness) to various organs, including the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light. In addition, melatonin facilitates sleep in humans. In the absence of a light-dark cycle, the timing of the circadian clock, including the timing of melatonin production in the pineal gland, may to some extent be adjusted with properly timed physical exercise.

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Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Under conditions of entrainment to the 24-hour cycle, bright light in the early morning and avoidance of light in the evening should produce a phase advance (for treatment of DSPS), whereas bright light in the evening may be effective in delaying the clock (ASPS). Melatonin, given several hours before its endogenous peak at night, effectively advances sleep time in DSPS and adjusts the sleep-wake cycle to 24 hours in blind individuals. In some blind individuals, melatonin appears to fully entrain the clock. Melatonin and light, when properly timed, may also alleviate jet lag. Because of its sleep-promoting effect, melatonin may improve sleep in night-shift workers trying to sleep during the daytime. Melatonin replacement therapy may also provide a rational approach to the treatment of age-related insomnia in the elderly. However, there is currently no melatonin formulation approved for clinical use, neither are there consensus protocols for light or melatonin therapies. The use of bright light or melatonin for circadian rhythm sleep disorders is thus considered exploratory at this stage.

All living organisms, from single cells to humans, exhibit profound changes in physiological and behavioural (where applicable) conditions between states of high and low activity during the 24-hour day-night cycle.[1] Under conditions of constant darkness or dim light, these cycles are driven by endogenous clocks with a periodicity approximating to 24 hours and are therefore called ‘circadian rhythms’. Under the regular daily light-dark cycles these rhythms are adjusted to the 24-hour periodicity (entrained). In mammals, including humans, the circadian clock governing the adjustment of vital homeostatic functions (sleep, wakefulness, temperature, feeding, neuroendocrine and autonomic rhythms) to the external 24-hour light-dark cycle lies in a paired tiny nucleus in the hypothalamus — the suprachiasmatic nucleus (SCN).[2] The SCN imposes temporal order through generating output signals that relay time-of-day information. The SCN changes its own sensitivity to incoming signals that adjust clock timing, and phase-shifts its activity in response to the incoming signals. Light is the primary stimulus for coordinating the circadian system with the external environment.[2] An output signal generated by the SCN causes the induction of synthesis of the hormone melatonin (N-acetyl-5-methoxytryptamine) at night by the  Adis International Limited. All rights reserved.

pineal gland and its release into the circulation.[3] Light inhibits melatonin synthesis and, thus, plasma melatonin levels are low during the day with a pulse of secretion during the night.[4] Melatonin production is directly regulated by the SCN and melatonin thus serves as a marker of the circadian clock phase; however, it also relays time-of-day and day length information (a signal of darkness) to various organs, including the SCN itself.[5,6] In humans and monkeys, and probably other diurnal species, melatonin facilitates sleep.[7,8] This effect can be demonstrated best when endogenous melatonin levels are low (e.g. during daytime, in pinealectomised patients or in individuals who produce insufficient amounts of melatonin).[9-13] Melatonin production [as evaluated from the amount of the major metabolite 6-sulfatoxy melatonin (6-SMT) excreted in urine] and nocturnal melatonin levels in blood have repeatedly been found to decrease with age in the general population.[14-19] However, we have previously found that, although 6-SMT excretion was lower in healthy elderly individuals than in young adults, it was not significantly lower,[20] suggesting that a decrease in melatonin output may be related to some age-related pathologies rather than to normal aging. This observation was corroborated by a recent finding that in very healthy aged people, circulating melatonin levels do not CNS Drugs 2001; 15 (4)

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differ from those in healthy young people.[21] Notably, healthy individuals with insomnia produced significantly lower amounts of melatonin than those who reported good sleep quality.[20] The term ‘circadian rhythm sleep disorder’ refers to a chronic condition in which an individual’s circadian rhythm of sleep and wakefulness is out of phase with the conventional environmental patterns. Several circadian sleep disorders have been classified: delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), irregular sleep-wake patterns, and non–24-hour sleep-wake syndrome in blind and sighted persons. In all of these, the misalignment with the environmental daynight cycle is persistent, or periodic, and adjustment never seems to occur, or at best is extremely difficult. The pathophysiological process of chronic and periodic circadian rhythm sleep disorders is presumed to be associated with abnormalities occurring in the pacemakers, their coupling to the external cues, or their downstream synchronising mechanisms. Two additional circadian rhythm sleep problems, i.e. those associated with jet lag and shift work, are due to temporary misalignment of the circadian sleep-wake rhythm with environmental patterns. This review focuses on circadian sleep disorders, their characteristics, and the therapeutic potential of light, melatonin and chronotherapeutic (behavioural) treatment. The rationale for using melatonin, light and chronotherapy is based on current knowledge about the entraining effects of exogenous melatonin, light and nonphotic stimuli on circadian rhythms in humans. 1. Biological Rhythms and the Circadian Control of the Sleep-Wake Cycle Recent studies in mutants of fruit flies (Drosophila melanogaster) and mice with disrupted circadian rhythmicity have shown that circadian clocks, including that in the mammalian SCN, are based on a cell autonomous, genetically determined mechanism.[22] Mammalian and Drosophila homologues of a number of genes that encode ele Adis International Limited. All rights reserved.

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ments of the circadian clock have recently been identified. The protein products of these genes interact in a negative feedback loop, establishing a circadian cycle in gene expression. Although a master clock resides in the brain SCN, a functional clock appears to reside in most cells of the body. In all these tissues, at least some output genes are controlled at the transcriptional level directly by clock proteins; others appear to be regulated by cascades of circadian transcription factors or neuronal stimuli.[23,24] Single-unit recording experiments demonstrate elevated electrical activity (output signals) of the ensemble of rat SCN neurons near midday, which persists when the SCN is maintained in vitro in a brain slice from the hypothalamic region. This electrical activity may be phase shifted by incoming signals (e.g. light and melatonin) which adjust clock timing.[23,25,26] Light is the primary stimulus for coordinating the circadian system with the external environmental day-night cycle. Light is perceived by the eyes, resulting in generation of neural signals sent to the visual centres of the brain. A distinct neural pathway, the retino-hypothalamic tract, projects from the retinas into the SCN and other nonvisual regions of the brain.[2] Light acutely affects clock gene expression (e.g. increases expression of the mPER protein) in the nucleus.[27] Since the levels of PER proteins are crucial determinants of the phase position of the clock, light given prior to the endogeneous PER peak (by the end of the subjective night) would presumably lead to an earlier accumulation of PER and thus to a phase advance. In contrast, light given at the descending arm of this peak (early in the subjective night) will delay the disappearance of PER protein and this would translate into phase delays of the clock. Consequently, light will cause delays or advances in the SCN phase position depending on whether the exposure to light occurs at the beginning or end of the dark phase, respectively.[23] One of the most important time signals generated by the SCN occurs via the pineal hormone melatonin. Melatonin, produced by the pineal gland CNS Drugs 2001; 15 (4)

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at night, is the chemical expression of darkness in the organism.[3] Plasma melatonin levels are low during the day, with a pulse of secretion during the night. The hormone is produced and secreted at night into the CSF and general circulation. Recent data obtained from sheep indicate that melatonin levels in the CSF, particularly in the third ventricle, may exceed those in the circulation by severalfold.[28] A similar finding was reported previously in calves.[29] Therefore, some brain regions, particularly those that surround the third ventricle, may be exposed to melatonin levels significantly (6- to 20-fold) higher than those in blood. Melatonin undergoes first pass hepatic metabolism (the half-life in human serum is less than 1 hour),[30] and over 80% is excreted exclusively in the urine as 6-SMT.[31] Therefore, melatonin disappears from the circulation shortly after cessation of its production in the pineal gland, and urinary 6SMT excretion and plasma melatonin levels are highly correlated in humans.[32-34] The neural pathway that extends from the SCN to the pineal gland involves a multisynaptic link via the superior cervical ganglion (SCG).[35] At night, when there is no light, the sympathetic nerve terminals from the SCG release noradrenaline (norepinephrine) in the pineal gland. This stimulates postsynaptic β1-adrenoceptors and, to a lesser extent, α1-adrenoceptors on the surface of the pinealocytes, causing cyclic adenosine monophosphate (cAMP) synthesis.[3] cAMP induces activity of the rate limiting enzyme serotonin-N-acetyl transferase (SNAT) by a process involving RNA and protein synthesis.[36] The effects of noradrenaline released by SCG postganglionic fibres can be blocked by propranolol (a β-adrenergic receptor antagonist). Stimulation of presynaptic α2-adrenoceptors inhibits noradrenline release and thereby melatonin synthesis.[37,38] In addition, drugs such as benzodiazepines, which act on type A receptors of the inhibitory transmitter γ-aminobutyric acid (GABA), also modify melatonin synthesis in the pineal gland.[39] In continuous darkness, melatonin rhythms persist with a circadian periodicity due to an SCN Adis International Limited. All rights reserved.

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driven rhythm in SNAT activity.[3] Light has two effects on pineal melatonin production: light-dark cycles synchronise the rhythm (due to entrainment of the circadian pacemaker) and acute light exposure at night rapidly reduces SNAT activity, thus stopping melatonin production.[40,41] Consequently, melatonin levels in blood and CSF rapidly decrease.[4,41] In all mammals studied to date, the nocturnal increase in pineal melatonin production reflects the environmental light-dark cycle, regardless of the animal being nocturnally or diurnally active.[3] Accumulating evidence suggests that physical exercise may affect melatonin levels, depending on the circadian phase of stimulus presentation. High intensity exercise during the night-time is associated with rapid pronounced elevations of melatonin secretion.[42] In addition, night-time exercise may delay the onset of nocturnal melatonin production the next day by 12 to 24 hours. This late response has been interpreted as evidence that increased physical activity (i.e. nonphotic stimulus) can reset the circadian clock in humans.[43,44] This, however, has not been unequivocally demonstrated, especially since the circadian rhythms of blind people lacking light perception free-run, or cycle at the endogenous rhythm, in the presence of a structured behavioural routine.[45,46] In addition, plasma melatonin levels may be affected by changes in the oxyhaemoglobin/deoxyhaemoglobin ratio,[47] which may be associated with exercise and may thus mask the circadian rhythm of the hormone. The temporal pattern of melatonin production is controlled by the SCN and thus may serve as a marker of the SCN activity phase. In addition, melatonin can acutely suppress electrical activity in the SCN during the daytime,[25] affect gene expression in the SCN and delay or advance the SCN phase on the forthcoming days (depending on whether it is given at the beginning or end of the light phase, respectively).[5,31] It is not yet known whether the acute suppression of SCN electrical activity by melatonin is involved in phase resetting because application of melatonin to SCN from knockout mice in vitro caused phase shift of the electrical CNS Drugs 2001; 15 (4)

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activity without acutely suppressing the firing rate of SCN neurons.[25] Studies have shown that exogenous melatonin can entrain or phase-shift the endogenous melatonin cycle in vivo.[31,48-51] A phase-response curve for this effect has been reported[50] which appears to be 180° out of phase with that effected by light exposure. Contemporaneous melatonin administration modifies the capability of light to induce circadian phase shifts.[52,53] The synchronisation by melatonin of circadian rhythms may be mediated by the SCN.[26] Sleep is one of the main processes orchestrated by the circadian clock. The timing and propensity of sleep are thought to reflect two interacting processes:[54] (i) an accumulated sleep need (process S), that is manifested by an increase in sleep propensity when sleep is absent and a decrease in sleep propensity in response to excess sleep; and (ii) a circadian process controlled by an endogenous pacemaker (process C), which is basically independent of sleep and waking. Process C is manifested by a tendency to initiate sleep on the falling limb of the endogenous temperature rhythm and termination of sleep on the rising limb. Process S oscillates between upper and lower thresholds which are modulated by process C and which determine the times of onset and termination of sleep, respectively. Whenever the arousal level is reduced (e.g. soporific effect), the upper threshold is lowered, resulting in an increased sleep propensity. The neurons responsible for the onset of sleep are thought to be located in the preoptic area; specifically in the ventrolateral preoptic nucleus.[55] Noradrenalin, acetylcholine and serotonin (5-hydroxytryptamine; 5-HT), all of which are transmitters of wakefulness, inhibit the electrical activity of these neurons. Hence, the upper and lower thresholds for sleep and waking presumably reflect relative inactivity levels of the sleep promoting neurons. Melatonin serves as a darkness signal in the organism and has a major role in the regulation of the sleep-wake cycle. It is still unclear, however, whether process C is mediated by melatonin. Nonetheless, much evidence indicates that melatonin has a ma Adis International Limited. All rights reserved.

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jor role in the facilitation of sleep in humans. Endogenous melatonin levels are positively correlated with sleepiness in sighted persons[56] and with daytime napping in blind individuals.[57] Electrophysiological recordings have demonstrated that the timing of the steepest increase in nocturnal sleepiness (‘sleep gate’) is significantly correlated with the rise of urinary 6-SMT excretion.[58] It has been known for many years that melatonin can induce fatigue and sleep in humans with no undesirable adverse effects[59,60] and that sleep after administration of melatonin has a normal architecture[59-61] with some effects on microstructure.[62] When given during the daytime, the architecture of sleep induced by melatonin resembles to some extent the contribution of the endogenous circadian pacemaker to the spectral composition of the sleep EEG when sleep occurs at night.[63] The ability of melatonin to increase sleep propensity and synchronise the internal clock[64,65] make it a reasonable therapeutic candidate for facilitation of sleep and treatment of circadian rhythm sleep disorders. 2. Circadian Rhythm Sleep Disorders The circadian rhythm sleep disorders are characterised by misalignment between the patient’s sleep pattern and that desired or regarded as the social norm.[66] The common symptom in the majority of the circadian rhythm sleep disorders is that the patient cannot sleep when sleep is desired, needed or expected. The wake episodes can occur at undesired times because sleep is inappropriately aligned with the internal biological clock. Therefore, the patient may experience excessive sleepiness during wake hours, insomnia or sleep deprivation. Circadian rhythm sleep disorders can be persistent (DSPS, ASPS and irregular sleep-wake pattern), periodic (non–24-hour sleep-wake disorder, mostly seen in blind individuals), or transient (jet lag syndrome and shift work). The prevalence of DSPS in the general population is unknown; it is estimated at 7% among adolescents and 5 to 10% among patients with insomnia who are referred to sleep disorder clinics.[67] ASPS appears to be a rare syndrome although ASPS-like CNS Drugs 2001; 15 (4)

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symptoms are frequent among the elderly.[68] Irregular sleep-wake patterns are mostly found in severely demented patients.[69] The non–24-hour sleep phase syndrome is rare in the general population but may occur in 40% of blind individuals, especially those with no light perception.[70] Individuals travelling across multiple time zones frequently experience the jet lag syndrome, and about half of night-shift workers have sleep difficulties. Since 5 to 8% of the population is involved in night-shift work,[71] a prevalence of 2 to 3% of the population may have shift work sleep disorders. 2.1 Delayed Sleep Phase Syndrome

DSPS is a persistent (longer than 6 months) inability to fall asleep and arise at conventional clock times. Sleep onset is often delayed until early morning (0300 to 0600h). When an attempt is not made to conform to the environment, the usual rise time is late morning to early afternoon (1100 to 1400h). Attempts to advance bedtime and sleep onset fail, and the patient experiences sleep onset insomnia, no problems maintaining sleep and severe difficulties in arising and fully awakening. When a conventional rise time is enforced chronically, daytime sleepiness develops because the enforced early rise time reduces total nocturnal sleep time. DSPS differs from a behavioural or lifestyle preference for late bedtime and arising time although the symptom presentation in these two patient groups is similar; patients who have a circadian disorder often fail to adjust to societal schedules and demands despite greater attempts to do so. The traditionally accepted treatment for DSPS is chronotherapy.[72] The assumption is that the pathophysiological basis of DSPS lies in a slower endogenous clock (abnormally long intrinsic circadian periodicity) and thus a delayed phase position of the overt circadian rhythms. Compatible with this hypothesis is the finding that endogenous melatonin secretion is delayed to late night or early morning in DSPS.[73] Moreover, a significant positive correlation between sleep and melatonin phase markers exists in DSPS. Notably, patients with DSPS do seem to be entrained to the 24-hour light Adis International Limited. All rights reserved.

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dark cycle because, albeit delayed, sleep commences at about the same time every day and does not free-run. Thus, their light perception and the entrainment mechanisms appear to be normal. However, the final awakening, relative to melatonin onset, melatonin midpoint and melatonin offset, was significantly longer in patients with DSPS than in control individuals in one study,[74] suggesting that functional disturbance of the sleep-wake cycle and psychosocial constraints also play a major role.[75] Chronotherapy is a behavioural technique in which bedtime is systematically delayed by 3-hour increments each day, thereby establishing a 27hour day. The procedure is maintained until the desired bedtime is reached (i.e. 2300h or midnight), when the conventional 24-hour day is reestablished. This therapy takes advantage of the relative ease of delaying the endogenous clock in DSPS by shifting the sleep phase clockwise until it eventually coincides with the societal schedule. Although the therapy works, it is quite difficult to follow because it calls for regularisation and adherence to a set sleep schedule. The efficacy of chronotherapy may be due in part to the alleged ability of nonphotic stimuli such as physical activity to reset the circadian clock in humans.[43,44] It should, however, be noted that, in some rodents, motor activity has been shown to affect the circadian phase but, in humans, the evidence for such a feedback of activity on the pacemaker is still preliminary.[76] Another approach in DSPS is to treat the patient with bright light or melatonin at the appropriate times so as to phase advance the clock (namely forcing a counter clockwise sleep phase shift). The use of bright light at the subjective dawn and avoidance of light in the subjective evening, or administration of melatonin in the subjective dusk, should produce a phase advance in these patients. Indeed, bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders.[75,77] There is compelling evidence indicating that melatonin effectively adjusts sleep time in individuals with DSPS.[78-80] In these studies, melatonin was given orally, at a 5mg dose once daily for 28 to CNS Drugs 2001; 15 (4)

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30 days. In one study, melatonin was administered to all patients in the evening (2200h)[78] whereas, in the other studies, melatonin was administered 5 hours before the individual melatonin onset time for each patient (measured in dim light).[79,80] In both protocols, melatonin significantly advanced sleep onset and wake times of the individuals with DSPS to earlier hours compared to placebo[78-80] and, in one study, it was shown to improve vigilance and cognitive functions in patients with DSPS.[80] It is not yet known whether the effects of melatonin in DSPS reflect a phase advance of rhythms other than the sleep-wake cycle. The active form of vitamin B12 (methylcobalamin) has been reported to be effective in patients with DSPS.[81] However, a recent trial has not revealed significant improvement with this treatment over that shown by placebo.[82] 2.2 Advanced Sleep Phase Syndrome

ASPS is the reciprocal of DSPS, and is associated with a persistent early evening sleep onset (2000 to 2100h) and early morning awakening (0300 to 0500h) with no sleep maintenance problems. Attempts to delay sleep onset and avoid early awakenings generally fail. When sleep onset is delayed successfully to the conventional bedtime, an early morning awakening still occurs. It has been suggested that the elderly reflect characteristics of ASPS. The evidence suggestive of an age-related phase advance is derived primarily from studies of sleep and wake rhythms in the elderly, which show early bedtimes and awakening times.[83] Additionally, the circadian rhythms of body temperature and cortisol are also phase advanced.[84,85] Contrary to this, older individuals, especially those with insomnia, show an increased lag from sunset to the onset of the melatonin pulse[86] and to the melatonin pulse peak[11] so that the pulse starts later, peaks lower and later, and ends sooner. These age-related changes are associated with sleep disturbances and most probably reflect age-related diminution in output of the circadian pacemaker.[87] In addition, the sleep of the elderly is characterised by increased fragmentation  Adis International Limited. All rights reserved.

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and maintenance problems. These may not be linked to disturbances in the circadian pacemaker.[88] Administration of melatonin at night (0.3 to 2.0mg daily for 1 to 3 weeks) to elderly individuals with insomnia significantly improved their sleep compared with the effects of placebo.[11-13] In a recent study, melatonin (0.5 mg/day) was administered as immediate-release (evening or mid-night administration) or prolonged-release (evening administration) forms to a group of patients with agerelated sleep maintenance insomnia.[89] Melatonin given at all 3 times shortened latencies to persistent sleep, demonstrating that supraphysiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep,[89] perhaps because of the low dose, or the protocol (which included a forced wakeup in the middle of the night). This therapy is aimed at replacement of melatonin produced endogenously without phase shifting the individuals’ circadian pacemaker. Hence, whereas the sleep-wake patterns of the elderly are suggestive of chronobiological change, they can be differentiated from those in patients with ASPS. Chronotherapy in patients with ASPS would involve a systematic advancement of bedtime until the desired bedtime is achieved, a system that may be successful in these patients.[90] This therapy utilises the natural tendency of these patients to have an earlier rather than delayed bedtime. Bright light has also been explored as a potential treatment for patients with ASPS. In healthy individuals, the timing of bright light exposure has a direct effect on the direction and magnitude of the phase shift that can be induced.[91,92] For inducing the phase delay required for patients with ASPS, the light exposure must be presented in the early evening. A successful phase delay (of 6 hours) brought about by early evening bright light exposure (i.e. 4 hours for 7 consecutive days) was reported in an elderly woman.[92] Besides a phaseshifting effect, bright light may also promote arousal in the evening in these patients. No reports exist to date on the use of melatonin for ASPS. In healthy individuals, the timing of CNS Drugs 2001; 15 (4)

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melatonin intake has a direct effect on the direction and magnitude of the phase shift that can be induced.[5] Although the phase-delaying effects of melatonin in humans have not been unequivocally demonstrated, melatonin might presumably be given at the descending arm of the endogenous melatonin peak for inducing a phase delay in patients with ASPS. 2.3 Irregular Sleep-Wake Pattern

The syndrome of irregular sleep-wake pattern consists of temporally disorganised and variable episodes of sleeping and waking behaviour. The frequent short sleep periods show no unusual polysomnographic features apart from their brevity. Body temperature shows apparently random fluctuations, with no discernible circadian rhythmicity.[93] The behavioural disturbance of patients with Alzheimer’s dementia (AD) is characterised, in part, by an irregular sleep-wake pattern. Sleep disruption, nightly restlessness, ‘sundowning’ (i.e. the characteristic late afternoon confusion and agitation of patients with AD) and other circadian disturbances are frequently seen in these patients.[94] Among the factors underlying the circadian changes in patients with AD is the loss of SCN neurons.[95] However the circadian rhythm of core body temperature in patients with AD may remain intact.[96] The decline in melatonin with age is exaggerated in patients with AD[86,97-101] and the mean time of the melatonin peak is shifted to later hours than in healthy elderly individuals.[102] This diminution was evident also in the presenile AD state and even more pronounced in patients with AD who expressed apolipoprotein E-epsilon 4,4 (i.e. who had the genetically determined AD risk factor).[101] The loss of melatonin may have a causal role in the appearance of sleep disruptions, nightly restlessness, sundowning and other circadian disturbances in patients with AD. Some evidence suggests that bright light exposure may be therapeutically effective in improving the sleep-wake disturbance of patients with AD. In a non-blinded clinical trial, evening (1900 to 2100h)  Adis International Limited. All rights reserved.

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bright light (1500 to 2000 lux) reduced night-time locomotor activity and improved the clinical ratings of sleep-wake and sundowning of patients with AD.[103] In another study, bright light exposure in the late morning every day to aged individuals with dementia tended to increase the percentage of time spent asleep in the lights-out period and/or the percentage of time awake in the daytime and to advance sleep onset time.[104] Another study reported that 4 weeks of morning light therapy increased the levels of melatonin, the amplitude of the sleep-wake rhythm, and total and nocturnal sleep time, and decreased daytime sleep and markedly improved behavioural disorders in patients with dementia.[105] Preliminary attempts to apply melatonin administration to patients with AD have recently been reported. In one study in which melatonin was administered to 2 patients with AD, stabilisation of the circadian rest-activity rhythm and some reduction of daytime sleepiness occurred in one patient but the other patient, who had a milder disease, showed no change. The acrophase of rest-activity was delayed for about 1 hour in both patients.[106] Another study has tested the effect of melatonin in monozygotic twins with AD of 8 years’ duration.[107,108] One of the twins was treated with melatonin 6 mg/day for 36 months and eventually had a milder impairment of memory function with an improvement in sleep quality compared with the other twin who was not treated with melatonin. 2.4 Non–24-Hour Sleep-Wake Syndrome

When humans are isolated from all time cues, their circadian rhythms tend to free-run, or cycle at the endogenous rhythm, which in individual and population studies appears to be between 24 and 25 hours.[109-112] Blind individuals may show endogenous melatonin rhythms that are phase-advanced or -delayed with respect to the light-dark or sleepwake cycle or the rhythms may free-run, as occurs with sighted individuals in a constant light environment.[113] Individuals with no conscious light perception have a higher occurrence of and more severe sleep disorders than those with some degree CNS Drugs 2001; 15 (4)

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of light perception because their circadian rhythms tend to free-run.[45] During free-run, the sleep-wake cycle is pushed toward a 24-hour cycle because of social cues, so that the relationship between sleep and other bodily rhythms (e.g. melatonin and cortisol levels and body temperature), which keep free-running, is constantly changing.[71,114-115] Non– 24-hour (or free-running) sleep-wake disorder is characterised by periods of seemingly normal sleep, at times when the circadian system periodically attains a normal phase position with the behaviourally imposed 24-hour sleep-wake cycle. Free-running rhythms in the sleep-wake cycle have been reported in blind individuals and also in some sighted individuals.[116] In sighted persons, non–24-hour sleep-wake disorder is a condition that may benefit from either bright light[116] or melatonin treatment.[117] A 4-week trial of daily melatonin administration (0.5mg at 2100h) to a sighted patient who expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours stabilised the endogenous melatonin and sleep rhythms to a period of 24.1 hours, albeit at a somewhat delayed phase. A 14month follow-up interview revealed that the patient continued to take melatonin 0.5mg daily, and his sleep-wake schedule was stable to near 24 hours with this dosage.[117] Melatonin at a daily dose of 3 to 5mg has also been successfully utilised for adjusting the sleepwake cycle in blind individuals, where the lightdark cycles are ineffective.[45,118-120] For example, melatonin 5 mg/day administered orally to a blind man over 31 days was able to reduce variability in the timing of night sleep onset and to increase sleep duration.[119] Long term melatonin treatment in blind children and young adults improved the sleepwake pattern in all individuals.[120] The effect was maintained during long term therapy of between 1 to 6 years. A blind boy (9 years of age) with severe mental retardation and a chronic sleep-wake disturbance had a circadian rhythm of 24.75 hours and an internal desynchronisation of endogenous rhythms.[121] Treatment with oral melatonin given at 1800h in Adis International Limited. All rights reserved.

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duced a regular sleep-wake pattern and entrained the endogenous rhythms to the appropriate chronological 24-hour day. Melatonin was assessed in an 18-year-old blind man who had chronic sleep disturbances associated with daytime fatigue and excessive daytime somnolence.[122] After 2 unsuccessful treatment regimens with melatonin 5 and 10 mg/day administered at bedtime (2200 to 2230h), a third regimen of melatonin 5 mg/day administered at 2000h for 3 weeks resulted in the successful resolution of his sleep disturbances. In all of these studies an improvement of sleep-wake patterns was found. In a recent crossover study,[65] 7 blind individuals received placebo or melatonin 5mg orally daily at 2100h, according to a single-blind trial design, for a full circadian cycle (35 to 71 days) [although only 5 received placebo for a full circadian cycle]. During melatonin treatment, the cortisol circadian period was shortened in 4 of the 7 freerunning individuals compared with baseline prior to treatment and, in 3 of these, the periods were statistically indistinguishable from entrainment (24-hour). In contrast, the remaining 3 individuals continued to free-run during melatonin treatment. The efficacy of melatonin in entraining the freerunning cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. Melatonin 10 mg/day successfully entrained the rhythm of its own production in 6 of 7 totally blind individuals.[123] It therefore appears that melatonin is able to adjust the sleep-wake cycle to the societal requirement and fully synchronise the circadian system in some free-running blind people,[65,123,124] whereas in other patients temperature and endocrine rhythms might free-run despite apparent synchronisation of the sleep-wake cycle. 2.5 Jet Lag

During the first few days after travelling across several time zones, most travellers experience jet lag. Although the term jet lag refers to disturbances in a variety of symptoms, the most common symptom is loss of sleep and its consequences (e.g. diCNS Drugs 2001; 15 (4)

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urnal sleepiness, depressed mood, decreased efficiency, premature awakening, headaches, reduced cognitive skills, poor psychomotor coordination, moodiness or general malaise). The jet lag syndrome is largely due to the inability of the circadian system to resynchronise rapidly after sudden shifts in the timing of the environmental light-dark cycles. A phase shift toward the new timing of the light-dark cycle gradually resolves the problem. In addition, after transmeridian flight, different rhythms adjust to the new time zone at different rates, some lagging more than others do. As a result, the jet lag that passengers experience is symptomatic of both types of desynchronisation; that is, their rhythms are inappropriately timed for the environment and for each other. The severity of jet lag is directly related to the direction of flight and number of time zones crossed. Eastward flights shorten the day and therefore require a phase advance, meaning that during the days of re-entrainment, the period of the traveller’s circadian rhythms would have to decrease to less than 24 hours so that the phase of the endogenous clock will occur earlier each day until it coincides again with the solar phase at destination. Conversely, westward flights lengthen the day and require a phase delay meaning that during the days of re-entrainment the period would have to increase above 24 hours until external resynchronisation is complete. It has repeatedly been found that individuals’ rhythms readjust faster after westward flights than after eastward flights. Travellers have been found to adjust at the rate of approximately 1.5 hours a day after westward and 1 hour a day after eastward flights. The directional asymmetry occurs irrespective of whether flight is outgoing or homecoming or whether it takes place during the day or night[125] and reflects the relative ease of the biological clock to lengthen its period and difficulty to shorten its period to less than 24 hours. The number of time zones crossed primarily determines the extent of the phase shift; thus, the greater the number of time zones crossed, the more time will be needed to overcome postflight external desynchronisation.  Adis International Limited. All rights reserved.

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Melatonin was proposed as a treatment for jet lag[51,126] because of its ability to shift bodily circadian rhythms.[31,125] Melatonin phase shifts its production according to a phase-response curve that is nearly opposite to that of light exposure.[5,50] As indicated from the studies cited below, there is evidence for improvement of sleep by melatonin in individuals with jet lag. Melatonin treatment is less effective with regard to resynchronisation of endogenous melatonin, cortisol and core temperature rhythms although enhanced resynchronisation of some, but not all, hormone and electrolyte excretion rates has been noted.[127] Melatonin 5 mg/day given at 1800h for 3 days before travelling and at local bedtime for 4 days after arrival apparently improved self-reported jet lag symptoms in individuals travelling eastward across 8 time zones.[51,125] Those who received melatonin treatment also showed shorter sleep latency, improved sleep quality and more rapid synchronisation of melatonin and cortisol with the new time zone.[13,128] Later studies[129,130] indicated a beneficial effect of melatonin treatment in alleviating sleep problems in jet-lagged individuals after trans-meridian flights compared with placebo treatment. In a simulated jet lag situation in an isolation facility, 8 healthy men underwent a 9-hour advance during 2 periods each of 15 days’ duration. In a double-blind, crossover design, they took either melatonin or placebo at 1800h local time for 3 days before the time shift and at 1400h for 4 days afterwards. Melatonin treatment enhanced the resynchronisation speed of some, but not all, hormone and electrolyte excretion rates for several days after the time shift.[127] On the other hand, Wever,[109] also using a dosage of 5 mg/day, found no significant effect on re-entrainment of circadian rhythms after shifting under controlled laboratory circumstances. In another study, individuals took either melatonin 8 mg/day or placebo on the day of the eastward flight and for 3 consecutive days thereafter at 2200h local time. On day 8, self ratings significantly discriminated between melatonin and placebo for global treatment efficacy, morning fatigue and evening CNS Drugs 2001; 15 (4)

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sleepiness.[131] Oral melatonin 5 mg/day taken at bedtime on the day of arrival and for 5 days afterwards, reduced jet lag and sleep disturbances, or enhanced recovery from these symptoms in flight crew members after round-trip overseas flights, compared with placebo.[132] However, crew members who started the melatonin 3 days before the day of arrival reported a poorer overall recovery than the placebo group. One study showed air crew who were administered melatonin on a long transmeridian mission had improved sleep patterns and fewer errors on a choice reaction task after arrival.[133] Beneficial effects of low doses (0.5 to 5.0mg) of melatonin on jet lag have recently been reported.[134] Melatonin 5mg significantly improved the self-rated sleep quality, shortened sleep latency, and reduced fatigue and daytime sleepiness after an intercontinental flight.[134] Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5mg dose. In contrast, 3 alternative regimens of melatonin (5.0mg at bedtime, 0.5mg at bedtime and 0.5mg taken on a shifting schedule) did not improve jet lag severity or sleep quality in 257 Norwegian physicians travelling on a 6-hour eastward flight.[135] Exposure to bright light at destination during daytime may, if appropriately timed with respect to the subjective circadian phase, improve jet lag– related fatigue, perhaps by inhibiting the rise in endogenous melatonin production which would occur at this time in the country of origin. It may also improve subsequent responsiveness to melatonin given at night for improving sleep at the destination zone.[136,137] It seems, therefore, that exogenous melatonin has some beneficial effects on the symptoms of jet lag, although the optimal dose and timing of ingestion have yet to be determined. It is also unclear whether the effectiveness of melatonin in jet lag is primarily due to its sleep-inducing effects, or if it indeed advances resynchronisation of the circadian rhythm. In this respect it is notable that administration of a regular release formulation appears to be more effective than a controlled release formu Adis International Limited. All rights reserved.

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lation in phase shifting the circadian clock.[134,138] This might be because melatonin can have opposite effects on the phase of the circadian clock depending on the time of administration. A robust, short increase in melatonin may thus provide a better signal for phase shifting than a signal with prolonged duration that could theoretically provoke phase advances and delays the same night. On the other hand, if the effect of melatonin on jet lag is primarily due to its sleep promoting effect, then ingestion of melatonin (0.5 to 5.0mg) in the evening at destination zone and exposure to light during the day may be a practical way to ease jet lag phenomena. 2.6 Shift Work

Night workers frequently complain of sleepiness, reduced performance and disturbed sleep due to lack of adjustment of the circadian rhythm. Physicians are increasingly confronted with patients whose conditions may be exacerbated by a failure to cope with the repeated changes in schedule that shift work requires. Coping problems stem from factors relating to circadian rhythm desynchronisation, sleep disorders, and social and domestic issues. Commonly, the night worker is trying to sleep when the endogenous clock is promoting wakefulness and to maintain good performance when the clock is promoting sleep. As in the jet lag situation, the process is a slow one, with more than a week elapsing before complete circadian realignment occurs. The process of circadian realignment for the night worker is difficult to achieve and easily switched to diurnal orientation because of the social and domestic demands of the individual weekend breaks which require daytime wakefulness.[139] As with jet lag, the circadian system will tend to delay rather than advance its phase position. Therefore, shift rotation in a forward direction (nights, mornings, evenings) usually results in faster circadian realignment than a backward one (evenings, mornings, nights). In addition, individuals with longer natural free-running periods (evening types) often find shift work easier to cope with than indiCNS Drugs 2001; 15 (4)

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viduals with shorter natural free-running periods (morning types), perhaps because they can cope more easily with forward shift rotations, or can sleep well during the morning.[140] Multiple surveys in both Europe and the US have indicated that night workers get about 5 to 7 hours less sleep per week than their day-working counterparts do.[141] This sleep loss is sometimes partially recouped on days off but does represent a chronic state of partial sleep deprivation that undoubtedly affects the mood and performance abilities of the shift worker. Very bright (>7000 lux) levels of nocturnal work place illumination coupled with complete darkness for the 8-hour day sleep period at home has been shown to phase shift the circadian systems of young volunteers within a week.[142] The effects of bright light treatment on the adaptation to 14 days of consecutive night work were studied at an oil platform in the North Sea, and the subsequent re-adaptation to day life at home. Bright light treatment of 30 minutes per exposure was applied during the first 4 nights of the night-shift period and the first 4 days at home following the shift period and scheduled individually to phase-delay the circadian rhythm. Bright light treatment modestly facilitated the subjective adaptation to night work, but enhanced the subsequent re-adaptation to day life.[143] Single dose administration of triazolam (0.5mg) could improve the quality and duration of day sleeps in rotating shift workers[144] with no significant phase resetting effects. Thus, hypnosedatives may ameliorate the sleep disturbance related to the night shift work. However, the use of hypnosedatives is inadvisable for shift workers, because problems of tolerance and dependence are too likely to occur. Melatonin has sleep-promoting and phase-shifting effects, which are best manifested during the daytime hours. Because night-shift workers sleep during the day, they could benefit from melatonin treatment. Whether phase shifting is at all desirable is still unclear and the conclusion is very much affected by work schedules. On a rapidly rotating shift it may be better to maintain a diurnal phase  Adis International Limited. All rights reserved.

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position; however, when long periods of night work are required, facilitating circadian adaptation may be desired. Melatonin 5 mg/day taken at the desired bedtime improved problems related to sleep and increased alertness during working hours in police officers working spans of 7 successive night-shifts compared with placebo.[145] Administration of melatonin in multiple daily doses (2mg at 0800h then 1mg at 1100 and 1400h) significantly improved sleep quality but was unable to improve cognitive psychomotor performance and phase-shift the circadian system to night shift.[138] This is most probably because of the administration of multiple doses, since both phase-advances and phase-delays were likely to have occurred. The effects of triazolam and melatonin on cardiac autonomic function and sleep structure have been compared.[146] Triazolam was associated with a higher heart rate during sleep, presumably due to the reduction of parasympathetic tone via interaction of triazolam at GABA receptors, since melatonin does not interfere with autonomic activity. Melatonin, unlike the benzodiazepines, does not appear to suppress rapid eye-movement sleep.[62,146] The sleep-facilitating effects of melatonin were augmented in the presence of benzodiazepines.[62,146,147] While it is difficult to draw definite conclusions based on the few data that exist, it appears that whether melatonin will produce a circadian effect in addition to the sleep-facilitating effect at all may depend on the formulation. As with jet lag, a fast release formulation may be more potent in phase shifting whereas administration of melatonin in multiple doses or a sustained release formulation may improve daytime sleep in night-shift workers. 3. Mechanisms of MelatoninMediated Sleep-Facilitating and Phase-Shifting Effects The mechanisms underlying the sleep-facilitating action of melatonin are not entirely clear. Nevertheless, several hypothetical mechanisms may be CNS Drugs 2001; 15 (4)

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proposed, based on evidence from human and animal studies. 3.1 Effects on Body Temperature

Melatonin exerts its soporific effect through lowering core body temperature, thereby reducing arousal and increasing sleep-propensity.[51] However, physiological sleep-promoting doses of melatonin do not have any effect on body temperature and the temperature-lowering effects of melatonin seem to occur later than sleep induction and may therefore not be the cause for the sleep-promoting effects of melatonin.[58] A recent work has revealed that selective vasodilation of distal skin regions (and hence heat loss) promotes the rapid onset of sleep.[148] Melatonin caused warming of distal skin, which may enhance sleep onset.[149] 3.2 Interaction with GABAA Receptors

The sleep effects of melatonin and its analogues are not mediated by direct binding to benzodiazepine or cannabinoid receptors[150] and are not inhibited by flumazenil, a GABAA receptor antagonist.[151] However, melatonin facilitates the hypnotic effects of benzodiazepines. Melatonin augments the sleep induction by benzodiazepine hypnosedatives[62,146,147] in humans and facilitates phenobarbital-induced sleep in rats.[150] It has been shown that melatonin MEL1A (mt1) receptors facilitate the inhibitory activity of GABAA receptors, whereas melatonin MEL1B (MT2) receptors inhibit GABAA receptor activity.[152] In rats, MEL1A receptors are expressed in the SCN whereas MEL1B receptors have been found in the SCN as well as the hippocampus.[152] Because of its lipid solubility, melatonin might be accessible at all brain structures that are directly involved in sleep initiation and maintenance. Hence, the sleep-facilitating effects of melatonin might hypothetically be in part due to interaction between MEL1A and GABAA receptors in the SCN and other brain structures where these receptors co-exist.  Adis International Limited. All rights reserved.

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3.3 Effects on Monoamine Neurotransmitters

Melatonin might modify the release of monoamine neurotransmitters involved in sleep or arousal, thereby initiating a cascade of events culminating in the activation of sleep mechanisms. The activity of the sleep promoting neurons found in the preoptic area may be inhibited by serotonin and other neurotransmitters of wakefulness.[55] In the rat, melatonin has been shown to inhibit the stimulated release of dopamine[153,154] and facilitate the release of serotonin (unpublished observations) from the hypothalamus, primarily the preoptic area.[153,154] Specific low affinity melatonin binding sites in the rat hypothalamus and medullapons were correlated with the inhibitory effects of melatonin on dopamine release from the hypothalamus and medulla-pons in vitro.[155] It should be noted that rats, being nocturnal animals, are awake at night when melatonin levels peak in their blood. It is tempting to suggest that the melatonin-mediated facilitation of serotonin release and thus inhibition of the sleep promoting neurons supports arousal in the rat. It is yet to be studied whether melatonin inhibits the release of the neurotransmitters associated with waking in the brain, thus facilitating sleep. 3.4 Effects on Glutamate

Melatonin may inhibit the release of glutamate, the major excitatory neurotransmitter in the brain, at centres involved in sleep or arousal. In rats, melatonin has been found to inhibit the amphetaminestimulated release of glutamate from the hypothalamus in vivo.[156] The relevance of this effect to the regulation of the sleep-wake cycle in the rat has not yet been explored. 3.5 Other Effects

An acute suppression of SCN activity by melatonin via MEL1A receptors located at the nucleus might also contribute to the sleep promoting effect of the hormone.[25] The chronobiotic effects of melatonin are not yet understood. They may theoretically represent CNS Drugs 2001; 15 (4)

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facilitation of GABAA receptor–mediated synchronising activity in the SCN.[152] Transgenic mice lacking mt1 receptors were still responsive to the phase-shifting effects of melatonin.[25] Based on pharmacological data on the effects of selective MEL1B receptor antagonists, it has been proposed that MEL1B receptors present in the SCN may be involved in the phase-shifting activity of melatonin.[157] Since melatonin receptors of the MEL1B type reportedly inhibit GABAergic activity,[152] the phase-shifting effects of melatonin may involve inhibition rather than facilitation of GABAergic activity at the SCN. Alternatively, melatonin may interfere with the phase-shifting effects of glutamate at the SCN, or with its release. The phase-shifting effects of light on SCN activity are mediated via glutamate Nmethyl-D-aspartate receptors at the SCN cells.[158] Light and glutamate cause phase delays early in the night, by acting through elevation of intracellular Ca2+. Late in the night, light and glutamate utilise a cyclic guanosine monophosphate–mediated mechanism to induce phase advances.[23] Inhibition by melatonin of the release of glutamate[156] at the SCN may inhibit phase shifts induced by light. Recent evidence indicates that light affects transcription of mammalian clock proteins.[159] Melatonin may also affect clock gene expression, thus phaseresetting the clock. The interplay between melatonin, glutamate, serotonin and GABA in the regulation by melatonin of sleep and the sleep-wake cycle warrants further investigation. 4. Conclusion Chronotherapy, bright light and melatonin, a hormone produced by the pineal gland at night, appear to help regulate the sleep-wake cycle. Because of the relative ease of use, with further study and clinical experience, melatonin may become an accepted therapy for sleep disorders related to permanent, periodic or transient misalignment of the sleep-wake cycle with the environmental day-night pattern and insomnia in the elderly. Although melatonin preparations are available without prescription in health food stores and pharmacies in the US,  Adis International Limited. All rights reserved.

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their potency, purity, tolerability and effectiveness cannot be assured. Until large clinical trials provide further information about the efficacy of melatonin, its adverse effects, associated drug interactions and effects on various disease states, melatonin products should be used with the understanding that many questions about their safety are yet to be answered. References 1. Hastings M. The brain, circadian rhythms, and clock genes. BMJ 1998; 317 (7174): 1704-7 2. Klein DC, Moore RY, Reppert SM. Suprachiasmatic nucleus: the mind’s clock, 1991 ed. New York (NY): Oxford University Press, 1991 3. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991; 12 (2): 151-80 4. Lewy AJ, Wehr TA, Goodwin FK, et al. Light suppresses melatonin secretion in humans. Science 1980; 210 (4475): 1267-9 5. Lewy AJ, Ahmed S, Jackson JM, et al. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9 (5): 380-92 6. Bartness TJ, Goldman BD. Mammalian pineal melatonin: a clock for all seasons. Experientia 1989; 45 (10): 939-45 7. Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin: a sleeppromoting hormone. Sleep 1997; 20 (10): 899-907 8. Zhdanova IV SA, Leclair OU, Rosene DL, et al. Effects of melatonin on sleep in Macaca Nemestrina and Macaca Mulatta: dose dependency. Sleep 2000; 23 Suppl. 2: 161A-2A 9. Dollins AB, Zhdanova IV, Wurtman RJ, et al. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci U S A 1994; 91 (5): 1824-8 10. Petterborg LJ, Thalen BE, Kjellman BF, et al. Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin. Brain Res Bull 1991; 27 (2): 181-5 11. Garfinkel D, Laudon M, Nof D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin [see comments]. Lancet 1995; 346 (8974): 541-4 12. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995; 18 (7): 598-603 13. Wurtman RJ, Zhdanova I. Improvement of sleep quality by melatonin [letter]. Lancet 1995; 346 (8988): 1491 14. Iguchi H, Kato KI, Ibayashi H. Melatonin serum levels and metabolic clearance rate in patients with liver cirrhosis. J Clin Endocrinol Metab 1982; 54 (5): 1025-7 15. Pierpaoli W, Maestroni GJM. Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects. Immunol Lett 1987; 16: 355-61 16. Waldhauser F, Weiszenbacher G, Tatzer E, et al. Alternations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988; 66: 648-52 17. Sharma M, Palacios-Bois J, Schwartz G, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 1989; 25: 305-19 18. van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol 1991; 260 (4 Pt 1): E651-61

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41. Gastel JA, Roseboom PH, Rinaldi PA, et al. Melatonin production: proteasomal proteolysis in serotonin N-acetyltransferase regulation. Science 1998; 279 (5355): 1358-60 42. Buxton OM, L’Hermite-Baleriaux M, Hirschfeld U, et al. Acute and delayed effects of exercise on human melatonin secretion. J Biol Rhythms 1997; 12 (6): 568-74 43. Buxton OM, Frank SA, L’Hermite-Baleriaux M, et al. Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms. Am J Physiol 1997; 273 (3 Pt 1): E536-42 44. Van Reeth O, Sturis J, Byrne MM, et al. Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men. Am J Physiol 1994; 266 (6 Pt 1): E964-74 45. Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biol Signals Recept 1999; 8 (1-2): 90-5 46. Sack RL, Lewy AJ, Blood ML, et al. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 1992; 75 (1): 127-34 47. Gilad E, Zisapel N. High-affinity binding of melatonin to hemoglobin. Biochem Mol Biol Int 1995; 56: 1-6 48. Armstrong SM, Cassone VM, Chesworth MJ, et al. Synchronization of mammalian circadian rhythms by melatonin. J Neural Transm Suppl 1986; 21: 375-94 49. Mallo C, Zaidan R, Faure A, et al. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol (Copenh) 1988; 119 (4): 474-80 50. Lewy AJ, Sack RL. The role of melatonin and light in the human circadian system. Prog Brain Res 1996; 111: 205-16 51. Arendt J, Skene DJ, Middleton B, et al. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 1997; 12 (6): 604-17 52. Deacon S, Arendt J. Adapting to phase shifts. II. Effects of melatonin and conflicting light treatment. Physiol Behav 1996; 59 (4-5): 675-82 53. Cagnacci A, Soldani R, Yen SS. Contemporaneous melatonin administration modifies the circadian response to nocturnal bright light stimuli. Am J Physiol 1997; 272 (2 Pt 2): R482-6 54. Borbely A, Ascherman, P. Sleep regulation in humans: conceptual advances and novel approaches. Tokyo: Academic Press, 1997 55. Gallopin T FP, Eggermann E, Caull B, et al. Identification of sleep promoting neurons in vitro. Nature 2000 Apr 27; 404: 992-5 56. Akerstedt T, Gillberg M, Wetterberg L. The circadian covariation of fatigue and urinary melatonin. Biol Psychiatry 1982; 17 (5): 547-54 57. Lockley SW, Skene DJ, Arendt J, et al. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 1997; 82 (11): 3763-70 58. Shochat T, Luboshitzky R, Lavie P. Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 1997; 273 (1 Pt 2): R364-70 59. Young SN. Melatonin, sleep, aging, and the health protection branch [editorial]. J Psychiatry Neurosci 1996; 21 (3): 161-4 60. Cajochen C, Krauchi K, von Arx MA, et al. Daytime melatonin administration enhances sleepiness and theta/alpha activity in the waking EEG. Neurosci Lett 1996; 207 (3): 209-13 61. James SP, Mendelson WB, Sack DA, et al. The effect of melatonin on normal sleep. Neuropsychopharmacology 1987; 1 (1): 41-4

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Correspondence and offprints: Dr Nava Zisapel, Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: [email protected]

CNS Drugs 2001; 15 (4)