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.
References
- 1
Anton-Tay F, Diaz J L, Fernandez-Guardiola A.
On the effect of melatonin upon human brain. Its possible therapeutic implications.
Life Sci I.
1971;
10
841-850
- 2 Arendt J. Melatonin and the Mammalian Pineal Gland. University Press Cambridge;
1995
- 3
Bes F W, Jobert M, Müller L C, Schulz H.
The diurnal distribution of sleep propensity: experimental data about the interaction
of the propensities for slow-wave sleep and REM sleep.
J Sleep Res.
1996;
5
90-98
- 4
Blau A, Tilmann A, Kunz D.
REM-beta: A new parameter to describe circadian functionality from the hypnogram?.
Sleep.
2001;
24 Suppl
A401
- 5
Boivin D B, Czeisler C A, Dijk D J, Duffy J F, Folkard S, Minors D, Totterdell P,
Waterhouse J.
Complex interaction of the sleep-wake cycle and circadian phase modulates mood in
healthy subjects.
Arch Gen Psychiatry.
1997;
54
45-152
- 6
Borbély A A, Achermann P.
Concepts and models of sleep regulation: an overview.
J Sleep Res.
1992;
1
63-79
- 7 Bruguerolle B. Chronopharmacology. In: Touitou Y, Haus E, eds
Biological Rhythms in Clinical and Laboratory Medicine. Paris; Springer-Verlag 1992: 114-137
- 8
Brzezinski A.
Melatonin in humans.
N Engl J Med.
1997;
336
186-195
- 9
Cagnacci A, Elliott J A, Yen S S.
Melatonin: a major regulator of the circadian rhythm of core temperature in humans.
J Clin Endocrinol Metab.
1992;
75
447-452
- 10
Cajochen C, Krauchi K, Mori D, Graw P, Wirz-Justice A.
Melatonin and S-20 098 increase REM sleep and wake-up propensity without modifying
NREM sleep homeostasis.
Am J Physiol.
1997;
272
R1189-1196
- 11
Cajochen C, Krauchi K, von Arx M A, Mori D, Graw P, Wirz-Justice A.
Daytime melatonin administration enhances sleepiness and theta/alpha activity in the
waking EEG.
Neurosci Lett.
1996;
207
209-213
- 12
Cermakian N, Sassone-Corsi P.
Multilevel regulation of the circadian clock.
Nature Reviews.
2000;
1
59-67
- 13
Cho K, Ennaceur A, Cole J C, Suh C K.
Chronic jet lag produces cognitive deficits.
J Neurosci.
2000;
20
RC66
- 14 Circadian rhythms in psychiatry. Pacific Grove, CA; Boxwood Press 1983
- 15 Czeisler C A, Cajochen C, Turek F W. Melatonin in the regulation of sleep and circadian
rhythms. In: Kryger MH, Roth T, Dement WC, eds
Principles and Practice of Sleep Medicine. 3rd ed Philadelphia; W.B. Saunders 2000: 400-406
- 16
Dawson D, Armstrong S M.
Chronobiotics-drugs that shift rhythms.
Pharmacol Ther.
1996;
69
15-36
- 17
Dawson D, Encel N.
Melatonin and sleep in humans.
J Pineal Res.
1993;
15
1-12
- 18
Dawson D, Rogers N L, van den Heuvel C J, Kennaway D J, Lushington K.
Effect of sustained nocturnal transbuccal melatonin administration on sleep and temperature
in elderly insomniacs.
J Biol Rhythms.
1998;
13
532-538
- 19
Deacon S, Arendt J.
Melatonin-induced temperature suppression and its acute phase-shifting effects correlate
in a dose-dependent manner in humans.
Brain Res.
1995;
688
77-85
- 20
Dijk D J, Cajochen C.
Melatonin and the circadian regulation of sleep initiation, consolidation, structure,
and the sleep EEG.
J Biol Rhythms.
1997;
12
627-635
- 21
Dijk D J, Czeisler C A.
Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity,
sleep structure, electroencephalographic slow waves, and sleep spindle activity in
humans.
J Neurosci.
1995;
15
3526-3538
- 22
Dijk D J, Duffy J F, Riel E, Shanahan T L, Czeisler C A.
Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony
of rest, melatonin and temperature rhythms.
J Physiol.
1999;
516
611-627
- 23
Dijk D J, Roth C, Landolt H P, Werth E, Aeppli M, Achermann P, Borbely A A.
Melatonin effect on daytime sleep in men: suppression of EEG low frequency activity
and enhancement of spindle frequency activity.
Neurosci Lett.
1995;
201
13-16
- 24
Dijk D J.
Circadian variation of EEG power spectra in NREM and REM sleep in humans: dissociation
from body temperature.
J Sleep Res.
1999;
8
189-195
- 25
Dolberg O T, Hirschmann S, Grunhaus L.
Melatonin for the treatment of sleep disturbances in major depressive disorder.
Am J Psychiatry.
1998;
155
1119-1121
- 26
Dollins A B, Zhdanova I V, Wurtman R J, Lynch H J, Deng M H.
Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood,
body temperature, and performance.
Proc Natl Acad Sci USA.
1994;
91
1824-1828
- 27
Garfinkel D, Laudon M, Nof D, Zisapel N.
Improvement of sleep quality in elderly people by controlled-release melatonin.
Lancet.
1995;
346
541-544
- 28
Gillette M U, Tischkau S A.
Suprachiasmatic nucleus: the brain's circadian clock.
Recent Prog Horm Res.
1999;
54
33-58
- 29
Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N.
Melatonin replacement therapy of elderly insomniacs.
Sleep.
1995;
18
598-603
- 30
Haimov I, Lavie P.
Circadian characteristics of sleep propensity function in healthy elderly: a comparison
with young adults.
Sleep.
1997;
20
294-300
- 31
Haimov I, Lavie P.
Potential of melatonin replacement therapy in older patients with sleep disorders.
Drugs Aging.
1995;
7
75-78
- 32
Hendricks J C, Sehgal A, Pack A I.
The need for a simple animal model to understand sleep.
Prog Neurobiol.
2000;
61
339-351
- 33
Hughes R J, Badia P.
Sleep-promoting and hypothermic effects of daytime melatonin administration in humans.
Sleep.
1997;
20
124-131
- 34
Hughes R J, Sack R L, Lewy A J.
The role of melatonin and circadian phase in age-related sleep-maintenance insomnia:
assessment in a clinical trial of melatonin replacement.
Sleep.
1998;
21
52-68
- 35
Hunt A E, Al-Ghoul W M, Gillette M U, Dubocovich M L.
Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances
the circadian clock.
Am J Physiol Cell Physiol.
2001;
280
C110-118
- 36
James S P, Sack D A, Rosenthal N E, Mendelson W B.
Melatonin administration in insomnia.
Neuropsychopharmacology.
1990;
3
19-23
- 37
Jewett M E, Kronauer R E, Czeisler C A.
Light-induced suppression of endogenous circadian amplitude in humans.
Nature.
1991;
350
59-62
- 38
Jones B E.
Paradoxical sleep and its chemical/structural substrates in the brain.
Neuroscience.
1991;
40
637-656
- 39
Knutsson A, Akerstedt T, Jonsson B G, Orth-Gomer K.
Increased risk of ischaemic heart disease in shift workers.
Lancet.
1986;
2
89-92
- 40
Krauchi K, Cajochen C, Werth E, Wirz-Justice A.
Warm feet promote the rapid onset of sleep.
Nature.
1999;
401
36-37
- 41
Krause D N, Geary G G, Doolen S, Duckles S P.
Melatonin and cardiovascular function.
Adv Exp Med Biol.
1999;
460
299-310
- 42
Kunz D, Bes F.
Exogenous melatonin in periodic limb movement disorder: an open clinical trial and
a hypothesis.
Sleep.
2001;
24
183-187
- 43
Kunz D, Bes F.
Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot
study on the possible influence of melatonin on REM-sleep regulation.
Mov Disord.
1999;
14
507-511
- 44
Kunz D, Mahlberg R, Müller L C, Tilmann A, Bes F.
Melatonin in patients with reduced REM sleep duration: a randomized clinical trial.
J Clin Endocrinol Metab.
2004;
89
128-134
- 45
Kunz D, Schmitz S, Mahlberg R, Mohr A, Stoter C, Wolf K J, Herrmann W M.
A new concept for melatonin deficit: on pineal calcification and melatonin excretion.
Neuropsychopharmacology.
1999;
21
765-772
- 46
Lavie P.
Ultrashort sleep-waking schedule. III. "Gates" and "forbidden zones" for sleep.
Electroencephalogr Clin Neurophysiol.
1986;
63
414-425
- 47
Lewy A J, Ahmed S, Jackson J M, Sack R L.
Melatonin shifts human circadian rhythms according to a phase-response curve.
Chronobiol Int.
1992;
9
380-392
- 48
Lewy A J, Wehr T A, Goodwin F K, Newsome D A, Markey S P.
Light suppresses melatonin secretion in humans.
Science.
1980;
210
1267-1269
- 49
Liu C, Weaver D R, Jin X, Shearman L P, Pieschl R L, Gribkoff V K, Reppert S M.
Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian
clock.
Neuron.
1997;
19
91-102
- 50
MacFarlane J G, Cleghorn J M, Brown G M, Streiner D L.
The effects of exogenous melatonin on the total sleep time and daytime alertness of
chronic insomniacs: a preliminary study.
Biol Psychiatry.
1991;
30
371-376
- 51
Merica H, Blois R, Bovier P, Gaillard J M.
New variables for defining sleep continuity.
Physiol Behav.
1993;
54
825-831
- 52
Messner M, Hardeland R, Rodenbeck A, Huether G.
Tissue retention and subcellular distribution of continuously infused melatonin in
rats under near physiological conditions.
J Pineal Res.
1998;
25
251-259
- 53
Monk T H, Buysse D J, Carrier J, Kupfer D J.
Inducing jet-lag in older people: Directional asymmetry.
J Sleep Res.
2000;
9
101-116
- 54
Moore-Ede M C, Czeisler C A, Richardson G S.
Circadian timekeeping in health and disease. Part 1. Basic properties of circadian
pacemakers.
N Engl J Med.
1983;
309
469-476
- 55
Nave R, Herer P, Haimov I, Shlitner A, Lavie P.
Hypnotic and hypothermic effects of melatonin on daytime sleep in humans: lack of
antagonism by flumazenil.
Neurosci Lett..
1996;
214
123-126
- 56
Penev P D, Kolker D E, Zee P C, Turek F W.
Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic
heart disease.
Am J Physiol.
1998;
275
H2334-2337
- 57
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M,
Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J,
Maki R, Lammers G J, Bouras C, Kucherlapati R, Nishino S, Mignot E.
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin
peptides in human narcoleptic brains.
Nat Med.
2000;
6
991-997
- 58
Redwine L, Hauger R L, Gillin J C, Irwin M.
Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol,
and melatonin levels in humans.
J Clin Endocrinol Metab.
2000;
85
3597-3603
- 59
Reppert S M, Weaver D R.
Melatonin madness.
Cell.
1995;
83
1059-1062
- 60
Reppert S M.
A clockwork explosion!.
Neuron.
1998;
21
1-4
- 61
Roth T, Richardson G.
Commentary: is melatonin administration an effective hypnotic?.
J Biol Rhythms.
1997;
12
666-669
- 62
Sack R L, Brandes R W, Kendall A R, Lewy A J.
Entrainment of free-running circadian rhythms by melatonin in blind people.
N Engl J Med.
2000;
343
1070-1077
- 63
Samel A, Wegmann H M, Vejvoda M, Maass H, Gundel A, Schutz M.
Influence of melatonin treatment on human circadian rhythmicity before and after a
simulated 9-hr time shift.
J Biol Rhythms.
1991;
6
35-248
- 64
Sharkey K M, Fogg L F, Eastman C I.
Effects of melatonin administration on daytime sleep after simulated night shift work.
J Sleep Res.
2001;
10
181-192
- 65
Shearman L P, Sriram S, Weaver D R, Maywood E S, Chaves I, Zheng B, Kume K, Lee C C,
van der Horst G T, Hastings M H, Reppert S M.
Interacting molecular loops in the mammalian circadian clock.
Science.
2000;
288
1013-1019
- 66
Siegel J M.
Narcolepsy: a key role for hypocretins (orexins).
Cell.
1999;
98
409-412
- 67
Spiegel K, Leproult R, Van Cauter E.
Impact of sleep debt on metabolic and endocrine function.
Lancet.
1999;
354
1435-1439
- 68
Sugden D, McArthur A J, Ajpru S, Duniec K, Piggins H D.
Expression of mt(1) melatonin receptor subtype mRNA in the entrained rat suprachiasmatic
nucleus: a quantitative RT-PCR study across the diurnal cycle.
Brain Res Mol Brain Res.
1999;
72
176-182
- 69
Turek F W.
Melatonin hype hard to swallow.
Nature.
1996;
379
295-296
- 70
Tzischinsky O, Shlitner A, Lavie P.
The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatonin.
J Biol Rhythms.
1993;
8
199-209
- 71
Utiger R D.
Melatonin-the hormone of darkness.
N Engl J Med.
1992;
327
1377-1379
- 72
Van Cauter E, Plat L, Leproult R, Copinschi G.
Alterations of circadian rhythmicity and sleep in aging: endocrine consequences.
Horm Res.
1998;
49
147-152
- 73
van den Heuvel C J, Kennaway D J, Dawson D.
Effects of daytime melatonin infusion in young adults.
Am J Physiol.
1998;
275
E19-26
- 74
van den Heuvel C J, Kennaway D J, Dawson D.
Thermoregulatory and soporific effects of very low dose melatonin injection.
Am J Physiol.
1999;
276
E249-254
- 75
van den Heuvel C J, Reid K J, Dawson D.
Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological
doses of melatonin.
Physiol Behav.
1997;
61
795-802
- 76
Waterhouse J, Weinert D, Minors D, Folkard S, Owens D, Atkinson G, Macdonald I, Sytnik N,
Tucker P, Reilly T.
A comparison of some different methods for purifying core temperature data from humans.
Chronobiol Int.
2000;
17
539-566
- 77
Wei H G, Riel E, Czeisler C A, Dijk D J.
Attenuated amplitude of circadian and sleep-dependent modulation of electroencephalographic
sleep spindle characteristics in elderly human subjects.
Neurosci Lett.
1999;
260
29-32
- 78 Wever R. Order and disorder in human circadian rhythmicity: possible relations
to mental disorders. In: Kupfer DJ, Monk TH, Barchas JD, eds
Biological Rhythms and Mental Disorders. New York; Guilford 1988: p. 253-346
- 79 Wirz-Justice A. Biological rhythms in mood disorders. In: Bloom FE, Kupfer DJ,
eds
Psychopharmacology: The Fourth Generation of Progress. New York; Raven Press 1995: p. 999-1017
- 80
Wirz-Justice A.
Circadian rhythms in mammalian neurotransmitter receptors.
Prog Neurobiol.
1987;
29
219-259
- 81
Wurts S W, Edgar D M.
Circadian and homeostatic control of rapid eye movement (REM) sleep: promotion of
REM tendency by the suprachiasmatic nucleus.
J Neurosci.
2000;
20
4300-4310
- 82
Wurts S W, Seidel W F, Dement W C, Edgar D M.
Effects of suprachiasmatic nucleus lesions on REM sleep continuity.
Sleep Res.
1997;
26
758
- 83
Wyatt J K, Cecco A R, Czeisler C A, Dijk D J.
Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in
humans living on a 20-h day.
Am J Physiol.
1999;
277
R1152-1163
- 84
Young M W.
Life's 24-hour clock: molecular control of circadian rhythms in animal cells.
Trends Biochem Sci.
2000;
25
601-606
- 85
Zhdanova I V, Lynch H J, Wurtman R J.
Melatonin: a sleep-promoting hormone.
Sleep.
1997;
20
899-907
- 86
Zhdanova I V, Wurtman R J, Lynch H J, Ives J R, Dollins A B, Morabito C, Matheson J K,
Schomer D L.
Sleep-inducing effects of low doses of melatonin ingested in the evening.
Clin Pharmacol Ther.
1995;
57
552-558
- 87
Zhdanova I V, Wurtman R J, Morabito C, Piotrovska V R, Lynch H J.
Effects of low oral doses of melatonin, given 2 - 4 hours before habitual bedtime,
on sleep in normal young humans.
Sleep.
1996;
19
423-431
- 88
Zhdanova I V, Wurtman R J, Regan M M, Taylor J A, Shi J P, Leclair O U.
Melatonin treatment for age-related insomnia.
J Clin Endocrinol Metab.
2001;
86
4727-4730
Dr. D. Kunz
Psychiatrische Universitätsklinik der Charité im St. Hedwig Krankenhaus
Turmstr. 21
10559 Berlin
Germany
Phone: +49-(0)30-2311 2900
Fax: +49-(0)30-2311 2903
Email: dieter.kunz@charite.de
