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

Abstract

Normal circadian rhythms are synchronized to a regular 24 h environmental light–dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep–wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep–wake rhythms seen in CRSDs.

Key Points

  • Circadian rhythm desynchronization is common among patients who present with sleep disorders

  • Circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep–wake rhythm disorder, shift-work sleep disorder and jet lag

  • The hormone melatonin is thought to have an important role in the synchronization of sleep–wake rhythm and rest–activity cycles with the light–dark cycle

  • Exogenous melatonin, sometimes in combination with light therapy, can be beneficial in resynchronizing sleep patterns in patients with CRSDs

  • Well-conducted, large clinical trials are warranted to further assess the efficacy and safety of chronotherapy as a treatment for CRSDs

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References

  1. 1

    Arendt J et al. (1995) Melatonin and adjustment to phase shift. J Sleep Res 4: 74–79

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Atkinson G et al. (2003) The relevance of melatonin to sports medicine and science. Sports Med 33: 809–831

    Article  PubMed  Google Scholar 

  3. 3

    Srinivasan V et al. (2006) Melatonin in mood disorders. World J Biol Psychiatry 7: 138–151

    Article  PubMed  Google Scholar 

  4. 4

    Lockley SW et al. (1997) Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 82: 3763–3770

    CAS  PubMed  Google Scholar 

  5. 5

    Kayumov L et al. (2001) A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med 63: 40–48

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Lewy AJ et al. (2006) Circadian uses of melatonin in humans. Chronobiol Int 23: 403–412

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Arendt J (2003) Importance and relevance of melatonin to human biological rhythms. J Neuroendocrinol 15: 427–431

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Arendt J and Deacon S (1997) Treatment of circadian rhythm disorders—melatonin. Chronobiol Int 14: 185–204

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Kayumov L et al. (2000) Melatonin, sleep, and circadian rhythm disorders. Semin Clin Neuropsychiatry 5: 44–55

    CAS  PubMed  Google Scholar 

  10. 10

    Sack RL et al. (2007) Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders: an American Academy of Sleep Medicine review. Sleep 30: 1460–1483

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Sack RL et al. (2007) Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm: an American Academy of Sleep Medicine review. Sleep 30: 1484–1501

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Morgenthaler TI et al. (2007) Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders: an American Academy of Sleep Medicine report. Sleep 30: 1445–1459

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Ko CH and Takahashi JS (2006) Molecular components of the mammalian circadian clock. Hum Mol Genet 15 (Spec No 2): R271–R277

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Moore RY (1999) A clock for the ages. Science 284: 2102–2103

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Sadun AA et al. (1984) A retinohypothalamic pathway in man: light mediation of circadian rhythms. Brain Res 302: 371–377

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Czeisler CA et al. (1999) Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284: 2177–2181

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Moser M et al. (2006) Cancer and rhythm. Cancer Causes Control 17: 483–487

    Article  PubMed  Google Scholar 

  18. 18

    Ayalon L et al. (2002) Case study of circadian rhythm sleep disorder following haloperidol treatment: reversal by risperidone and melatonin. Chronobiol Int 19: 947–959

    Article  PubMed  Google Scholar 

  19. 19

    Morris M et al. (1990) Sleep-onset insomniacs have delayed temperature rhythms. Sleep 13: 1–14

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Gibertini M et al. (1999) Self-report of circadian type reflects the phase of the melatonin rhythm. Biol Psychol 50: 19–33

    Article  CAS  PubMed  Google Scholar 

  21. 21

    El Ad B (2007) Insomnia in circadian dysrhythmias. Rev Neurol Dis 4: 64–74

    PubMed  Google Scholar 

  22. 22

    Driscoll TR et al. (2007) A systematic review of the neurobehavioural and physiological effects of shiftwork systems. Sleep Med Rev 11: 179–194

    Article  PubMed  Google Scholar 

  23. 23

    Barion A and Zee PC (2007) A clinical approach to circadian rhythm sleep disorders. Sleep Med 8: 566–577

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lack LC and Wright HR (2007) Clinical management of delayed sleep phase disorder. Behav Sleep Med 5: 57–76

    Article  PubMed  Google Scholar 

  25. 25

    Borbely AA (1982) A two process model of sleep regulation. Hum Neurobiol 1: 195–204

    CAS  PubMed  Google Scholar 

  26. 26

    Lack LC and Wright HR (2007) Chronobiology of sleep in humans. Cell Mol Life Sci 64: 1205–1215

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Dijk DJ and Czeisler CA (1995) 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 15: 3526–3538

    Article  CAS  Google Scholar 

  28. 28

    Czeisler CA et al. (1981) Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep 4: 1–21

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Tobler I et al. (1983) The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions. Neurosci Lett 42: 49–54

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Eastman CI et al. (1984) Suprachiasmatic nuclei lesions eliminate circadian temperature and sleep rhythms in the rat. Physiol Behav 32: 357–368

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Edgar DM et al. (1993) Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 13: 1065–1079

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Wurts SW and Edgar DM (2000) Circadian and homeostatic control of rapid eye movement (REM) sleep: promotion of REM tendency by the suprachiasmatic nucleus. J Neurosci 20: 4300–4310

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Fuller PM et al. (2006) Neurobiology of the sleep–wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 21: 482–493

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Claustrat B et al. (2005) The basic physiology and pathophysiology of melatonin. Sleep Med Rev 9: 11–24

    Article  PubMed  Google Scholar 

  35. 35

    Klein DC and Moore RY (1979) Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus. Brain Res 174: 245–262

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Panda S et al. (2005) Illumination of the melanopsin signaling pathway. Science 307: 600–604

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Thapan K et al. (2001) An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J Physiol 535: 261–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Cardinali DP et al. (1972) Binding of melatonin to human and rat plasma proteins. Endocrinology 91: 1213–1218

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Tricoire H et al. (2003) Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reprod Suppl 61: 311–321

    CAS  PubMed  Google Scholar 

  40. 40

    Nowak R et al. (1987) The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: two non-invasive techniques for monitoring human circadian rhythmicity. Clin Endocrinol (Oxf) 27: 445–452

    Article  CAS  Google Scholar 

  41. 41

    Griefahn B et al. (2003) Excretion of 6-hydroxymelatonin sulfate (6-OHMS) in siblings during childhood and adolescence. Neuroendocrinology 78: 241–243

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Pandi-Perumal SR et al. (2002) Senescence, sleep, and circadian rhythms. Ageing Res Rev 1: 559–604

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Haimov I et al. (1994) Sleep disorders and melatonin rhythms in elderly people. BMJ 309: 167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Kennaway DJ et al. (1999) Urinary 6-sulfatoxymelatonin excretion and aging: new results and a critical review of the literature. J Pineal Res 27: 210–220

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Zisapel N (2007) Sleep and sleep disturbances: biological basis and clinical implications. Cell Mol Life Sci 64: 1174–1186

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Leger D et al. (2004) Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med 116: 91–95

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Dubocovich ML and Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27: 101–110

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Reppert SM (1997) Melatonin receptors: molecular biology of a new family of G protein-coupled receptors. J Biol Rhythms 12: 528–531

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Dubocovich ML et al. (2003) Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 8: d1093–d1108

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Nosjean O et al. (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 275: 31311–31317

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Carlberg C and Wiesenberg I (1995) The orphan receptor family RZR/ROR, melatonin and 5-lipoxygenase: an unexpected relationship. J Pineal Res 18: 171–178

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Benitez-King G (2006) Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 40: 1–9

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Cardinali DP and Freire F (1975) Melatonin effects on brain. Interaction with microtubule protein, inhibition of fast axoplasmic flow and induction of crystaloid and tubular formations in the hypothalamus. Mol Cell Endocrinol 2: 317–330

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Tan DX et al. (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42: 28–42

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Tzischinsky O et al. (1993) The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatonin. J Biol Rhythms 8: 199–209

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Cagnacci A et al. (1992) Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 75: 447–452

    CAS  PubMed  Google Scholar 

  57. 57

    Rajaratnam SM and Arendt J (2001) Health in a 24-h society. Lancet 358: 999–1005

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Pevet P et al. (2002) The chronobiotic properties of melatonin. Cell Tissue Res 309: 183–191

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Arendt J and Skene DJ (2005) Melatonin as a chronobiotic. Sleep Med Rev 9: 25–39

    Article  PubMed  Google Scholar 

  60. 60

    Cardinali DP et al. (2006) The use of chronobiotics in the resynchronization of the sleep/wake cycle. Cancer Causes Control 17: 601–609

    Article  PubMed  Google Scholar 

  61. 61

    Zhdanova IV (2005) Melatonin as a hypnotic: pro. Sleep Med Rev 9: 51–65

    Article  PubMed  Google Scholar 

  62. 62

    Brzezinski A et al. (2005) Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev 9: 41–50

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Buscemi N et al. (2006) Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 332: 385–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    van den Heuvel CJ et al. (1998) Effects of daytime melatonin infusion in young adults. Am J Physiol 275: E19–E26

    CAS  PubMed  Google Scholar 

  65. 65

    van den Heuvel CJ et al. (1999) Thermoregulatory and soporific effects of very low dose melatonin injection. Am J Physiol 276: E249–E254

    CAS  PubMed  Google Scholar 

  66. 66

    Arendt J et al. (1984) The effects of chronic, small doses of melatonin given in the late afternoon on fatigue in man: a preliminary study. Neurosci Lett 45: 317–321

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Deacon S and Arendt J (1995) Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res 688: 77–85

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Cagnacci A et al. (1997) Homeostatic versus circadian effects of melatonin on core body temperature in humans. J Biol Rhythms 12: 509–517

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Rajaratnam SM et al. (2003) Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones. J Clin Endocrinol Metab 88: 4303–4309

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Arendt J et al. (1985) Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab 60: 1166–1173

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Murphy PJ et al. (1996) Nonsteroidal anti-inflammatory drugs alter body temperature and suppress melatonin in humans. Physiol Behav 59: 133–139

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Yamada Y et al. (1995) Prediction of sleep disorders induced by beta-adrenergic receptor blocking agents based on receptor occupancy. J Pharmacokinet Biopharm 23: 131–145

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Scheer FA et al. (2007) Decreased sleep in heart failure: are medications to blame? Arch Intern Med 167: 1098–1099

    PubMed  Google Scholar 

  74. 74

    van den Heuvel CJ et al. (1997) Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav 61: 795–802

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Yazaki M et al. (1999) Demography of sleep disturbances associated with circadian rhythm disorders in Japan. Psychiatry Clin Neurosci 53: 267–268

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Dagan Y and Eisenstein M (1999) Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. Chronobiol Int 16: 213–222

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Quinto C et al. (2000) Posttraumatic delayed sleep phase syndrome. Neurology 54: 250–252

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Ayalon L et al. (2007) Circadian rhythm sleep disorders following mild traumatic brain injury. Neurology 68: 1136–1140

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Nagtegaal JE et al. (1997) Traumatic brain injury-associated delayed sleep phase syndrome. Funct Neurol 12: 345–348

    CAS  PubMed  Google Scholar 

  80. 80

    Watanabe T et al. (2003) Sleep and circadian rhythm disturbances in patients with delayed sleep phase syndrome. Sleep 26: 657–661

    Article  PubMed  Google Scholar 

  81. 81

    Regestein QR and Monk TH (1995) Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry 152: 602–608

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Shirayama M et al. (2003) The psychological aspects of patients with delayed sleep phase syndrome (DSPS). Sleep Med 4: 427–433

    Article  PubMed  Google Scholar 

  83. 83

    Cleare AJ (2003) The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24: 236–252

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Williams G et al. (1996) Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome. Clin Physiol 16: 327–337

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Hermesh H et al. (2001) Circadian rhythm sleep disorders as a possible side effect of fluvoxamine. CNS Spectr 6: 511–513

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Hori M and Asada T (2003) Life-style regularity and core body temperature phase in delayed sleep phase syndrome. Sleep Biol Rhythms 1: 251–252

    Article  Google Scholar 

  87. 87

    American Academy of Sleep Medicine (2001) International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Chicago, IL: American Academy of Sleep Medicine

  88. 88

    Rosenberg R (1991) Case studies in insomnia. In Assessment and Treatment of Delayed Sleep Phase Syndrome, 193–205 (Ed Hauri PJ) New York: Plenum Publishing Corporation

    Google Scholar 

  89. 89

    Shibui K et al. (2003) Melatonin, cortisol and thyroid-stimulating hormone rhythms are delayed in patients with delayed sleep phase syndrome. Sleep Biol Rhythms 1: 209–214

    Article  Google Scholar 

  90. 90

    Wittmann M et al. (2006) Social jetlag: misalignment of biological and social time. Chronobiol Int 23: 497–509

    Article  PubMed  Google Scholar 

  91. 91

    Lewy AJ et al. (1998) The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int 15: 71–83

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Shibui K et al. (1999) Melatonin rhythms in delayed sleep phase syndrome. J Biol Rhythms 14: 72–76

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Archer SN et al. (2003) A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 26: 413–415

    Article  PubMed  Google Scholar 

  94. 94

    Cermakian N and Boivin DB (2003) A molecular perspective of human circadian rhythm disorders. Brain Res Brain Res Rev 42: 204–220

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Ebisawa T et al. (2001) Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep 2: 342–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Ebisawa T (2007) Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes. J Pharmacol Sci 103: 150–154

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Weitzman ED et al. (1981) Delayed sleep phase syndrome: a chronobiological disorder with sleep-onset insomnia. Arch Gen Psychiatry 38: 737–746

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Lewy AJ and Sack RL (1986) Light therapy and psychiatry. Proc Soc Exp Biol Med 183: 11–18

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Smits MG and Pandi-Perumal SR (2006) Delayed phase sleep syndrome: a melatonin onset disorder. In Melatonin: Biological Basis of its Function in Health and Disease, 263–272 (Eds Pandi-Perumal SR and Cardinali DP) Georgetown, TX: Landes Bioscience

    Google Scholar 

  100. 100

    Voultsios A et al. (1997) Salivary melatonin as a circadian phase marker: validation and comparison to plasma melatonin. J Biol Rhythms 12: 457–466

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Pandi-Perumal SR et al. (2007) Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuropsychopharmacol Biol Psychiatry 31: 1–11

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Rosenthal NE et al. (1990) Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome. Sleep 13: 354–361

    CAS  PubMed  Google Scholar 

  103. 103

    Zisapel N (2001) Circadian rhythm sleep disorders: pathophysiology and potential approaches to management. CNS Drugs 15: 311–328

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Dahlitz M et al. (1991) Delayed sleep phase syndrome response to melatonin. Lancet 337: 1121–1124

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Okawa M et al. (1990) Vitamin B12 treatment for sleep-wake rhythm disorders. Sleep 13: 15–23

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Yamadera H et al. (1996) A multicenter study of sleep-wake rhythm disorders: therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics. Psychiatry Clin Neurosci 50: 203–209

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Okawa M et al. (1997) Vitamin B12 treatment for delayed sleep phase syndrome: a multi-center double-blind study. Psychiatry Clin Neurosci 51: 275–279

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Alvarez B et al. (1992) The delayed sleep phase syndrome: clinical and investigative findings in 14 subjects. J Neurol Neurosurg Psychiatry 55: 665–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Lewy AJ et al. (1992) Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 9: 380–392

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Nagtegaal JE et al. (1998) Delayed sleep phase syndrome: a placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset. J Sleep Res 7: 135–143

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Mundey K et al. (2005) Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep 28: 1271–1278

    Article  PubMed  Google Scholar 

  112. 112

    Smits MG et al. (2001) Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol 16: 86–92

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Smits MG et al. (2003) Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 42: 1286–1293

    Article  PubMed  Google Scholar 

  114. 114

    Reid KJ et al. (2001) Familial advanced sleep phase syndrome. Arch Neurol 58: 1089–1094

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Ando K et al. (2002) Delayed and advanced sleep phase symptoms. Isr J Psychiatry Relat Sci 39: 11–18

    PubMed  Google Scholar 

  116. 116

    Czeisler CA et al. (1987) Biologic rhythm disorders, depression, and phototherapy: a new hypothesis. Psychiatr Clin North Am 10: 687–709

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Arendt J (2006) Melatonin and human rhythms. Chronobiol Int 23: 21–37

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Zucconi M (2002) Article reviewed: familial advanced sleep phase syndrome. Sleep Med 3: 177–178

    Article  PubMed  Google Scholar 

  119. 119

    Liu RY et al. (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-ε4/4 genotype. J Clin Endocrinol Metab 84: 323–327

    CAS  PubMed  Google Scholar 

  120. 120

    Wu YH and Swaab DF (2007) Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. Sleep Med 8: 623–636

    Article  PubMed  Google Scholar 

  121. 121

    Toh KL et al. (2001) An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291: 1040–1043

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Jones CR et al. (1999) Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 5: 1062–1065

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Satoh K et al. (2003) Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 26: 416–417

    Article  PubMed  Google Scholar 

  124. 124

    Brusco LI et al. (1998) Monozygotic twins with Alzheimer's disease treated with melatonin: case report. J Pineal Res 25: 260–263

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Brusco LI et al. (1998) Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer's disease. Neuro Endocrinol Lett 19: 111–115

    CAS  Google Scholar 

  126. 126

    Cardinali DP et al. (2002) The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett 23 (Suppl 1): S20–S23

    Google Scholar 

  127. 127

    Furio AM et al. (2007) Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. J Pineal Res 43: 404–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Cohen-Mansfield J et al. (2000) Melatonin for treatment of sundowning in elderly persons with dementia—a preliminary study. Arch Gerontol Geriatr 31: 65–76

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Mahlberg R et al. (2004) Melatonin treatment of day-night rhythm disturbances and sundowning in Alzheimer disease: an open-label pilot study using actigraphy. J Clin Psychopharmacol 24: 456–459

    Article  PubMed  Google Scholar 

  130. 130

    Asayama K et al. (2003) Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 70: 334–341

    Article  PubMed  Google Scholar 

  131. 131

    Waterhouse J et al. (2007) Jet lag: trends and coping strategies. Lancet 369: 1117–1129

    Article  PubMed  Google Scholar 

  132. 132

    Arendt J (1997) Jet lag/night shift, blindness and melatonin. Trans Med Soc Lond 114: 7–9

    PubMed  Google Scholar 

  133. 133

    Oxenkrug GF and Requintina PJ (2003) Melatonin and jet lag syndrome: experimental model and clinical implications. CNS Spectr 8: 139–148

    Article  PubMed  Google Scholar 

  134. 134

    Herxheimer A (2005) Jet lag. Clin Evid Jun: 2178–2183

    Google Scholar 

  135. 135

    Cardinali DP et al. (2002) A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes. J Pineal Res 32: 41–46

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Takahashi T et al. (2002) Melatonin alleviates jet lag symptoms caused by an 11-hour eastward flight. Psychiatry Clin Neurosci 56: 301–302

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Srinivasan V et al. (2008) Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. Travel Med Infect Dis 6: 17–28

    Article  PubMed  Google Scholar 

  138. 138

    Reid KJ and Burgess HJ (2005) Circadian rhythm sleep disorders. Prim Care 32: 449–473

    Article  PubMed  Google Scholar 

  139. 139

    Reilly T et al. (1997) Travel fatigue and jet-lag. J Sports Sci 15: 365–369

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Daan S and Lewy AJ (1984) Scheduled exposure to daylight: a potential strategy to reduce “jet lag” following transmeridian flight. Psychopharmacol Bull 20: 566–568

    CAS  PubMed  Google Scholar 

  141. 141

    Akerstedt T (2005) Shift work and sleep disorders. Sleep 28: 9–11

    PubMed  Google Scholar 

  142. 142

    Akerstedt T (2007) Altered sleep/wake patterns and mental performance. Physiol Behav 90: 209–218

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Akerstedt T and Kecklund G (2001) Age, gender and early morning highway accidents. J Sleep Res 10: 105–110

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Czeisler CA et al. (1990) Exposure to bright light and darkness to treat physiologic maladaptation to night work. N Engl J Med 322: 1253–1259

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Folkard S et al. (1993) Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int 10: 315–320

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Sack RL and Lewy AJ (1997) Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind. J Biol Rhythms 12: 595–603

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Quera-Salva MA et al. (1997) Rapid shift in peak melatonin secretion associated with improved performance in short shift work schedule. Sleep 20: 1145–1150

    CAS  PubMed  Google Scholar 

  148. 148

    Nakagawa H et al. (1992) Sleep propensity free-runs with the temperature, melatonin and cortisol rhythms in a totally blind person. Sleep 15: 330–336

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Tabandeh H et al. (1998) Disturbance of sleep in blindness. Am J Ophthalmol 126: 707–712

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Skene DJ and Arendt J (2007) Circadian rhythm sleep disorders in the blind and their treatment with melatonin. Sleep Med 8: 651–655

    Article  PubMed  Google Scholar 

  151. 151

    Shibui K et al. (1998) Continuous measurement of temperature in non-24 hour sleep-wake syndrome. Psychiatry Clin Neurosci 52: 236–237

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Kamei Y et al. (1998) Clinical characteristics of circadian rhythm sleep disorders. Psychiatry Clin Neurosci 52: 234–235

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Eliott AL et al. (1971) A man with too long a day. J Physiol 212: 30P–31P

    CAS  PubMed  Google Scholar 

  154. 154

    Hoban TM et al. (1989) Entrainment of a free-running human with bright light? Chronobiol Int 6: 347–353

    Article  CAS  PubMed  Google Scholar 

  155. 155

    McArthur AJ et al. (1996) Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment. Sleep 19: 544–553

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Oren DA et al. (1997) Restoration of detectable melatonin after entrainment to a 24-hour schedule in a 'free-running' man. Psychoneuroendocrinology 22: 39–52

    Article  CAS  PubMed  Google Scholar 

  157. 157

    Dagan Y and Ayalon L (2005) Case study: psychiatric misdiagnosis of non-24-hours sleep–wake schedule disorder resolved by melatonin. J Am Acad Child Adolesc Psychiatry 44: 1271–1275

    Article  PubMed  Google Scholar 

  158. 158

    Lockley SW et al. (2000) Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 164: R1–R6

    Article  CAS  PubMed  Google Scholar 

  159. 159

    Hack LM et al. (2003) The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms 18: 420–429

    Article  CAS  PubMed  Google Scholar 

  160. 160

    Lewy AJ et al. (2004) Eventual entrainment of the human circadian pacemaker by melatonin is independent of the circadian phase of treatment initiation: clinical implications. J Biol Rhythms 19: 68–75

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Sack RL et al. (2000) Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 343: 1070–1077

    Article  CAS  PubMed  Google Scholar 

  162. 162

    Horne JA and Ostberg O (1976) A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 4: 97–110

    CAS  PubMed  Google Scholar 

  163. 163

    Zavada A et al. (2005) Comparison of the Munich chronotype questionnaire with the Horne–Ostberg's morningness–eveningness Score. Chronobiol Int 22: 267–278

    Article  PubMed  Google Scholar 

  164. 164

    Mongrain V et al. (2006) Circadian and homeostatic sleep regulation in morningness–eveningness. J Sleep Res 15: 162–166

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Katzenberg D et al. (1998) A CLOCK polymorphism associated with human diurnal preference. Sleep 21: 569–576

    Article  CAS  PubMed  Google Scholar 

  166. 166

    Pereira DS et al. (2005) Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep 28: 29–32

    PubMed  Google Scholar 

  167. 167

    Mishima K et al. (2005) The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet 133: 101–104

    Article  Google Scholar 

  168. 168

    Carpen JD et al. (2005) A single-nucleotide polymorphism in the 5′-untranslated region of the hPER2 gene is associated with diurnal preference. J Sleep Res 14: 293–297

    Article  PubMed  Google Scholar 

  169. 169

    Mansour HA et al. (2005) Circadian genes and bipolar disorder. Ann Med 37: 196–205

    Article  CAS  PubMed  Google Scholar 

  170. 170

    Bauer M et al. (2006) Temporal relation between sleep and mood in patients with bipolar disorder. Bipolar Disord 8: 160–167

    Article  PubMed  Google Scholar 

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Correspondence to Seithikurippu R Pandi-Perumal.

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SP Pandi-Perumal is a stockholder and the President and Chief Executive Officer of Somnogen, Inc.. The other authors declared no competing interests.

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Pandi-Perumal, S., Trakht, I., Spence, D. et al. The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders. Nat Rev Neurol 4, 436–447 (2008). https://doi.org/10.1038/ncpneuro0847

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