miércoles, 21 de octubre de 2009
Melatonin, Circadian Rhythms, and Sleep
Disturbances in circadian rhythms often result in disturbances in sleep. Examples include syndromes in which sleep time is delayed or advanced, the sleeping problems associated with jet lag and shift work, and the sleep disorders that occur in totally blind persons with free-running circadian rhythms (i.e., rhythms that are not synchronized to the 24-hour day).1 The hormone melatonin can be used both to characterize and to treat such disorders.
The circadian rhythm of melatonin secretion is generated by the central pacemaker, or "clock," in the suprachiasmatic nuclei of the hypothalamus, and like many other circadian rhythms, it is synchronized to a 24-hour period largely by cues from the light–dark cycle that are received by the suprachiasmatic nuclei. Melatonin secretion is therefore a "hand" of this clock in the sense that it responds to signals from the suprachiasmatic nuclei and in that the timing of the melatonin rhythm indicates the status of the clock, at least in terms of phase (i.e., internal clock time relative to external clock time). It is notable that melatonin can provide feedback to this clock, thus modifying the rhythm of its own production and of other circadian variables.2 In this issue of the Journal, Sack et al.3 take advantage of this action of melatonin to restore a more normal pattern of sleep in totally blind persons with free-running circadian rhythms and associated sleep disorders.
Normally, melatonin is produced during the night. In most species, including humans, its secretion is related to the length of the night: the longer the night, the longer the duration of secretion. In many species, this pattern of production serves as a time cue for seasonal rhythms.2 Whether melatonin has an essential role in mammalian circadian rhythms has been much debated. Certainly, the evening increase in melatonin secretion is associated with an increase in the propensity for sleep.4 Secretion of melatonin during the day, as occurs in diverse pathologic or occupational health situations, is strongly associated with daytime sleepiness or napping,5 and the administration of melatonin during the day induces sleepiness.2 In the early 1980s, the results of two independent studies (one in rats and one in humans) showed that daily timed administration of melatonin could shift the phase of the internal clock and (in rats) entrain it to a normal cycle.2
These observations led directly to the current interest in melatonin and its analogues for the treatment of circadian-rhythm disorders. A sleep–wake cycle that is not synchronized to the 24-hour day is a disorder associated with blindness and may well represent the most important application of melatonin treatment, since in most other circumstances, timed treatment with sufficiently bright light can (at least in theory) reestablish a normal rhythm.6 In studies of many blind people, my colleagues and I have found that the presence of a free-running rhythm is directly related to a greater degree of visual loss.7 In addition, the incidence of this disorder increases with decreases in the perception of light; it occurred in all of our subjects who had no eyes. Treatment with light for synchronization to the 24-hour day is, of course, impossible for persons with no light perception (unless extraocular light proves to be effective). The properties of melatonin thus make it the optimal treatment, if indeed it can entrain free-running circadian rhythms in humans.
Melatonin (in a dose of 5 mg daily, timed to advance the phase of the internal clock) can maintain synchronization of the circadian rhythm to a 24-hour cycle in sighted persons who are living in conditions likely to induce a free-running rhythm, and it appears to synchronize the rhythm in some persons after a short period of free-running.8 In blind persons with free-running rhythms, it has been possible to stabilize, or entrain, the sleep–wake cycle to a 24-hour period, with resulting improvements in sleep and mood.2 However, it has proved difficult to show that the clock itself could be entrained. Two groups have recently reported that complete synchronization can be achieved in some, but not all, blind persons. Sack et al.3 attribute their success to the use of a higher dose of melatonin (10 mg daily, as compared with the 5 mg daily used in most previous studies) and to careful timing of the treatment to start an hour before the preferred bedtime, as the subjects' free-running rhythms approached a normal phase. Previous, unsuccessful studies in which the 5-mg dose was used took this approach to timing, and thus perhaps the use of the higher daily dose was the key to success. However, earlier this year, Lockley et al.9 reported complete synchronization in three totally blind men with only 5 mg of melatonin, timed to advance the phase of the internal clock (as in the current study, but with a more precise definition of phase). Sensitivity to melatonin varies among individual people, as do the pharmacokinetics of the drug.2 This variation may explain the discrepancies among the results of these studies, especially because the number of subjects in whom synchronization has been achieved to date is very small.
The timing of the start of melatonin treatment may be critical. In theory, if melatonin is given daily at the same clock time to a person with a free-running circadian rhythm for a treatment period lasting longer than a complete cycle (i.e., the time taken for the circadian rhythm to become delayed, or very rarely advanced by 24 hours), at some point in the cycle the timing will be optimal for synchronization to occur. This happens in rats,2 but some people treated for years with melatonin continue to have a free-running rhythm,10 albeit with subjective improvement in sleep. These observations underline the importance of assessing the circadian phase before treatment of a circadian-rhythm disorder begins (whether the treatment consists of light, melatonin, or another method). The rhythm of melatonin secretion can be determined by measurements of plasma or salivary melatonin or urinary 6-hydroxymelatonin sulfate (a particularly practical method in field studies).2
The most noteworthy observation in the study by Sack et al.3 is the maintenance of synchronization with a reduction in the dose of melatonin to 0.5 mg daily. Maintenance of synchronization with melatonin at physiologic concentrations supports the view that melatonin is an important component of the human circadian system. Sleep–wake disorders involving a circadian cycle longer than 24 hours are a lifetime problem for blind persons, and it is of the utmost importance that the lowest possible dose of melatonin be used and that long-term safety be evaluated.10
The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits.
Josephine Arendt, Ph.D.
University of Surrey
Guildford, Surrey GU2 7XH, United Kingdom
References
Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 3rd ed. Section 8. Disorders of chronobiology. Philadelphia: W.B. Saunders, 2000:589-614.
Arendt J. Melatonin and the mammalian pineal gland. London: Chapman & Hall, 1995.
Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000;343:1070-1077. [Free Full Text]
Shochat T, Haimov I, Lavie P. Melatonin -- the key to the gate of sleep. Ann Med 1998;30:109-114. [Medline]
Lockley SW, Skene DJ, Tabandeh J, Bird AC, Defrance R, Arendt J. Relationship between napping and melatonin in the blind. J Biol Rhythms 1997;12:16-25. [Free Full Text]
Czeisler CA, Johnson MP, Duffy JF, Brown EN, Ronda JM, Kronauer RE. Exposure to bright light and darkness to treat physiologic maladaptation to night work. N Engl J Med 1990;322:1253-1259. [Abstract]
Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 1997;82:3763-3770. [Free Full Text]
Middleton B, Arendt J, Stone BM. Complex effects of melatonin on human circadian rhythms in constant dim light. J Biol Rhythms 1997;12:467-477.
Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164:R1-R6. [Abstract]
Arendt J. Safety of melatonin in long-term use. J Biol Rhythms 1997;12:673-681.
This article has been cited by other articles:
Prada, C., Udin, S. B., Wiechmann, A. F., Zhdanova, I. V. (2005). Stimulation of Melatonin Receptors Decreases Calcium Levels in Xenopus Tectal Cells by Activating GABAC Receptors. J. Neurophysiol. 94: 968-978 [Abstract] [Full Text]
Rajaratnam, S. M. W, Middleton, B., Stone, B. M, Arendt, J., Dijk, D.-J. (2004). Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans. J. Physiol. 561: 339-351 [Abstract] [Full Text]
Campos, F. L., da Silva-Junior, F. P., de Bruin, V. M. S., de Bruin, P. F. C. (2004). Melatonin Improves Sleep in Asthma: A Randomized, Double-blind, Placebo-controlled Study. Am. J. Respir. Crit. Care Med. 170: 947-951 [Abstract] [Full Text]
Fischer, S., Smolnik, R., Herms, M., Born, J., Fehm, H. L. (2003). Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals. J. Clin. Endocrinol. Metab. 88: 5315-5320 [Abstract] [Full Text]
Mutoh, T., Shibata, S., Korf, H.-W., Okamura, H. (2003). Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice. J. Physiol. 547: 317-332 [Abstract] [Full Text]
Wolfler, A., Abuja, P. M., Linkesch, W., Schauenstein, K., Liebmann, P. M., Vijayalaxmi, , Thomas, C. R. Jr, Reiter, R. J., Herman, T. S. (2002). Questionable Benefit of Melatonin for Antioxidant Pharmacologic Therapy. JCO 20: 4127-4129 [Full Text]
Masana, M. I., Dubocovich, M. L. (2001). Melatonin Receptor Signaling: Finding the Path Through the Dark. Sci Signal 2001: pe39-pe39
The circadian rhythm of melatonin secretion is generated by the central pacemaker, or "clock," in the suprachiasmatic nuclei of the hypothalamus, and like many other circadian rhythms, it is synchronized to a 24-hour period largely by cues from the light–dark cycle that are received by the suprachiasmatic nuclei. Melatonin secretion is therefore a "hand" of this clock in the sense that it responds to signals from the suprachiasmatic nuclei and in that the timing of the melatonin rhythm indicates the status of the clock, at least in terms of phase (i.e., internal clock time relative to external clock time). It is notable that melatonin can provide feedback to this clock, thus modifying the rhythm of its own production and of other circadian variables.2 In this issue of the Journal, Sack et al.3 take advantage of this action of melatonin to restore a more normal pattern of sleep in totally blind persons with free-running circadian rhythms and associated sleep disorders.
Normally, melatonin is produced during the night. In most species, including humans, its secretion is related to the length of the night: the longer the night, the longer the duration of secretion. In many species, this pattern of production serves as a time cue for seasonal rhythms.2 Whether melatonin has an essential role in mammalian circadian rhythms has been much debated. Certainly, the evening increase in melatonin secretion is associated with an increase in the propensity for sleep.4 Secretion of melatonin during the day, as occurs in diverse pathologic or occupational health situations, is strongly associated with daytime sleepiness or napping,5 and the administration of melatonin during the day induces sleepiness.2 In the early 1980s, the results of two independent studies (one in rats and one in humans) showed that daily timed administration of melatonin could shift the phase of the internal clock and (in rats) entrain it to a normal cycle.2
These observations led directly to the current interest in melatonin and its analogues for the treatment of circadian-rhythm disorders. A sleep–wake cycle that is not synchronized to the 24-hour day is a disorder associated with blindness and may well represent the most important application of melatonin treatment, since in most other circumstances, timed treatment with sufficiently bright light can (at least in theory) reestablish a normal rhythm.6 In studies of many blind people, my colleagues and I have found that the presence of a free-running rhythm is directly related to a greater degree of visual loss.7 In addition, the incidence of this disorder increases with decreases in the perception of light; it occurred in all of our subjects who had no eyes. Treatment with light for synchronization to the 24-hour day is, of course, impossible for persons with no light perception (unless extraocular light proves to be effective). The properties of melatonin thus make it the optimal treatment, if indeed it can entrain free-running circadian rhythms in humans.
Melatonin (in a dose of 5 mg daily, timed to advance the phase of the internal clock) can maintain synchronization of the circadian rhythm to a 24-hour cycle in sighted persons who are living in conditions likely to induce a free-running rhythm, and it appears to synchronize the rhythm in some persons after a short period of free-running.8 In blind persons with free-running rhythms, it has been possible to stabilize, or entrain, the sleep–wake cycle to a 24-hour period, with resulting improvements in sleep and mood.2 However, it has proved difficult to show that the clock itself could be entrained. Two groups have recently reported that complete synchronization can be achieved in some, but not all, blind persons. Sack et al.3 attribute their success to the use of a higher dose of melatonin (10 mg daily, as compared with the 5 mg daily used in most previous studies) and to careful timing of the treatment to start an hour before the preferred bedtime, as the subjects' free-running rhythms approached a normal phase. Previous, unsuccessful studies in which the 5-mg dose was used took this approach to timing, and thus perhaps the use of the higher daily dose was the key to success. However, earlier this year, Lockley et al.9 reported complete synchronization in three totally blind men with only 5 mg of melatonin, timed to advance the phase of the internal clock (as in the current study, but with a more precise definition of phase). Sensitivity to melatonin varies among individual people, as do the pharmacokinetics of the drug.2 This variation may explain the discrepancies among the results of these studies, especially because the number of subjects in whom synchronization has been achieved to date is very small.
The timing of the start of melatonin treatment may be critical. In theory, if melatonin is given daily at the same clock time to a person with a free-running circadian rhythm for a treatment period lasting longer than a complete cycle (i.e., the time taken for the circadian rhythm to become delayed, or very rarely advanced by 24 hours), at some point in the cycle the timing will be optimal for synchronization to occur. This happens in rats,2 but some people treated for years with melatonin continue to have a free-running rhythm,10 albeit with subjective improvement in sleep. These observations underline the importance of assessing the circadian phase before treatment of a circadian-rhythm disorder begins (whether the treatment consists of light, melatonin, or another method). The rhythm of melatonin secretion can be determined by measurements of plasma or salivary melatonin or urinary 6-hydroxymelatonin sulfate (a particularly practical method in field studies).2
The most noteworthy observation in the study by Sack et al.3 is the maintenance of synchronization with a reduction in the dose of melatonin to 0.5 mg daily. Maintenance of synchronization with melatonin at physiologic concentrations supports the view that melatonin is an important component of the human circadian system. Sleep–wake disorders involving a circadian cycle longer than 24 hours are a lifetime problem for blind persons, and it is of the utmost importance that the lowest possible dose of melatonin be used and that long-term safety be evaluated.10
The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits.
Josephine Arendt, Ph.D.
University of Surrey
Guildford, Surrey GU2 7XH, United Kingdom
References
Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 3rd ed. Section 8. Disorders of chronobiology. Philadelphia: W.B. Saunders, 2000:589-614.
Arendt J. Melatonin and the mammalian pineal gland. London: Chapman & Hall, 1995.
Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000;343:1070-1077. [Free Full Text]
Shochat T, Haimov I, Lavie P. Melatonin -- the key to the gate of sleep. Ann Med 1998;30:109-114. [Medline]
Lockley SW, Skene DJ, Tabandeh J, Bird AC, Defrance R, Arendt J. Relationship between napping and melatonin in the blind. J Biol Rhythms 1997;12:16-25. [Free Full Text]
Czeisler CA, Johnson MP, Duffy JF, Brown EN, Ronda JM, Kronauer RE. Exposure to bright light and darkness to treat physiologic maladaptation to night work. N Engl J Med 1990;322:1253-1259. [Abstract]
Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 1997;82:3763-3770. [Free Full Text]
Middleton B, Arendt J, Stone BM. Complex effects of melatonin on human circadian rhythms in constant dim light. J Biol Rhythms 1997;12:467-477.
Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164:R1-R6. [Abstract]
Arendt J. Safety of melatonin in long-term use. J Biol Rhythms 1997;12:673-681.
This article has been cited by other articles:
Prada, C., Udin, S. B., Wiechmann, A. F., Zhdanova, I. V. (2005). Stimulation of Melatonin Receptors Decreases Calcium Levels in Xenopus Tectal Cells by Activating GABAC Receptors. J. Neurophysiol. 94: 968-978 [Abstract] [Full Text]
Rajaratnam, S. M. W, Middleton, B., Stone, B. M, Arendt, J., Dijk, D.-J. (2004). Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans. J. Physiol. 561: 339-351 [Abstract] [Full Text]
Campos, F. L., da Silva-Junior, F. P., de Bruin, V. M. S., de Bruin, P. F. C. (2004). Melatonin Improves Sleep in Asthma: A Randomized, Double-blind, Placebo-controlled Study. Am. J. Respir. Crit. Care Med. 170: 947-951 [Abstract] [Full Text]
Fischer, S., Smolnik, R., Herms, M., Born, J., Fehm, H. L. (2003). Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals. J. Clin. Endocrinol. Metab. 88: 5315-5320 [Abstract] [Full Text]
Mutoh, T., Shibata, S., Korf, H.-W., Okamura, H. (2003). Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice. J. Physiol. 547: 317-332 [Abstract] [Full Text]
Wolfler, A., Abuja, P. M., Linkesch, W., Schauenstein, K., Liebmann, P. M., Vijayalaxmi, , Thomas, C. R. Jr, Reiter, R. J., Herman, T. S. (2002). Questionable Benefit of Melatonin for Antioxidant Pharmacologic Therapy. JCO 20: 4127-4129 [Full Text]
Masana, M. I., Dubocovich, M. L. (2001). Melatonin Receptor Signaling: Finding the Path Through the Dark. Sci Signal 2001: pe39-pe39
martes, 20 de octubre de 2009
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