Current Psychiatry Reports

, Volume 11, Issue 6, pp 488–493 | Cite as

Melatonin, circadian rhythms, and the clock genes in bipolar disorder



Sleep disturbances and dysregulation of circadian rhythms are core elements of bipolar disorder that might be involved in its pathogenesis. It has been proposed that patients with bipolar disorder have an abnormally shifted or arrhythmic circadian system and that the disturbance of circadian rhythms may be caused by an alteration in the circadian clock machinery. Chronotherapeutic strategies based on controlled exposures to environmental stimuli that act on biological rhythms have shown good efficacy in the treatment of illness episodes, thus confirming ex juvantibus the clinical relevance of internal timing in this illness.


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References and Recommended Reading

  1. 1.
    Wirz-Justice A: Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol 2006, 21(Suppl 1):S11–S15.CrossRefPubMedGoogle Scholar
  2. 2.
    Perlis ML, Giles DE, Buysse DJ, et al.: Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord 1997, 42:209–212.CrossRefPubMedGoogle Scholar
  3. 3.
    Bauer M, Grof P, Rasgon N, et al.: Temporal relation between sleep and mood in patients with bipolar disorder. Bipolar Disord 2006, 8:160–167.CrossRefPubMedGoogle Scholar
  4. 4.
    Duncan WC Jr, Pettigrew KD, Gillin JC: REM architecture changes in bipolar and unipolar depression. Am J Psychiatry 1979, 136:1424–1427.PubMedGoogle Scholar
  5. 5.
    Plante DT, Winkelman JW: Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry 2008, 165:830–843.CrossRefPubMedGoogle Scholar
  6. 6.
    Wehr TA, Sack DA, Norman E: Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry 1987, 144:201–204. (Published erratum appears in Am J Psychiatry 1987, 144:542.)PubMedGoogle Scholar
  7. 7.
    Harvey AG: Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry 2008, 165:820–829.CrossRefPubMedGoogle Scholar
  8. 8.
    Wirz-Justice A, Benedetti F, Terman M: Chronotherapeutics for Affective Disorders. A Clinician’s Manual for Light and Wake Therapy. Basel, Switzerland: Karger; 2009.Google Scholar
  9. 9.
    Avery D, Wildschiodtz G, Rafaelsen O: REM latency and temperature in affective disorder before and after treatment. Biol Psychiatry 1982, 17:463–470.PubMedGoogle Scholar
  10. 10.
    Cervantes P, Gelber S, Kin FN, et al.: Circadian secretion of cortisol in bipolar disorder. J Psychiatry Neurosci 2001, 26:411–416.PubMedGoogle Scholar
  11. 11.
    Linkowski P, Van Cauter E, L’Hermite-Baleriaux M, et al.: The 24-hour profile of plasma prolactin in men with major endogenous depressive illness. Arch Gen Psychiatry 1989, 46:813–819.PubMedGoogle Scholar
  12. 12.
    Mendlewicz J, Linkowski P, Kerkhofs M, et al.: Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab 1985, 60:505–512.CrossRefPubMedGoogle Scholar
  13. 13.
    Linkowski P, Mendlewicz J, Leclercq R, et al.: The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Metab 1985, 61:429–438.CrossRefPubMedGoogle Scholar
  14. 14.
    Goodwin F, Jamison K: Manic-Depressive Illness. New York: Oxford University Press; 2007.Google Scholar
  15. 15.
    Wever RA: The Circadian System of Man. New York: Springer; 1979.Google Scholar
  16. 16.
    Wehr TA, Goodwin FK: Biological rhythms in manicdepressive illness. In Circadian Rhythms in Psychiatry. Edited by Wehr TA, Goodwin FK. Pacific Grove, CA: Boxwood; 1983:129–184.Google Scholar
  17. 17.
    Kripke DF: Phase-advance theories for affective illnesses. In Circadian Rhythms in Psychiatry. Edited by Wehr TA, Goodwin FK. Pacific Grove, CA: Boxwood; 1983:41–69.Google Scholar
  18. 18.
    Wehr TA, Wirz-Justice A, Goodwin FK, et al.: Phase advance of the circadian sleep-wake cycle as an antidepressant. Science 1979, 206:710–713.CrossRefPubMedGoogle Scholar
  19. 19.
    Moore RY, Silver R: Suprachiasmatic nucleus organization. Chronobiol Int 1998, 15:475–487.CrossRefPubMedGoogle Scholar
  20. 20.
    Stratmann M, Schibler U: Properties, entrainment, and physiological functions of mammalian peripheral oscillators. J Biol Rhythms 2006, 21:494–506.CrossRefPubMedGoogle Scholar
  21. 21.
    Golombek DA, Pevet P, Cardinali DP: Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Rev 1996, 20:403–412.CrossRefPubMedGoogle Scholar
  22. 22.
    Pandi-Perumal SR, Srinivasan V, Maestroni GJ, et al.: Melatonin: nature’s most versatile biological signal? FEBS J 2006, 273:2813–2838.CrossRefPubMedGoogle Scholar
  23. 23.
    Lowrey PL, Takahashi JS: Genetics of the mammalian circadian system: photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Annu Rev Genet 2000, 34:533–562.CrossRefPubMedGoogle Scholar
  24. 24.
    von Schantz M: Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters. J Genet 2008, 87:513–519.CrossRefGoogle Scholar
  25. 25.
    Mansour HA, Wood J, Logue T, et al.: Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav 2006, 5:150–157.CrossRefPubMedGoogle Scholar
  26. 26.
    Nievergelt CM, Kripke DF, Barrett TB, et al.: Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:234–241.CrossRefPubMedGoogle Scholar
  27. 27.
    Roybal K, Theobold D, Graham A, et al.: Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 2007, 104:6406–6411.CrossRefPubMedGoogle Scholar
  28. 28.
    Benedetti F, Dallaspezia S, Fulgosi MC, et al.: Actimetric evidence that CLOCK 3111 T/C SNP influences depressive insomnia and activity patterns in bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2007, 144B:631–635.CrossRefPubMedGoogle Scholar
  29. 29.
    Katzenberg D, Young T, Finn L, et al.: A CLOCK polymorphism associated with human diurnal preference. Sleep 1998, 21:569–576.PubMedGoogle Scholar
  30. 30.
    Serretti A, Benedetti F, Mandelli L, et al.: Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet 2003, 121B:39–43.CrossRefGoogle Scholar
  31. 31.
    Serretti A, Cusin C, Benedetti F, et al.: Insomnia improvement during antidepressant treatment and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet 2005, 10:10.Google Scholar
  32. 32.
    Benedetti F, Serretti A, Colombo C, et al.: Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet 2003, 123B:23–26.CrossRefPubMedGoogle Scholar
  33. 33.
    Benedetti F, Radaelli D, Bernasconi A, et al.: Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients. Genes Brain Behav 2008, 7:20–25.PubMedGoogle Scholar
  34. 34.
    Martinek S, Inonog S, Manoukian AS, Young MW: A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 2001, 105:769–779.CrossRefPubMedGoogle Scholar
  35. 35.
    Badenhop RF, Moses MJ, Scimone A, et al.: A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. Mol Psychiatry 2002, 7:851–859. (Published erratum appears in Mol Psychiatry 2004, 9:539.)CrossRefPubMedGoogle Scholar
  36. 36.
    Benedetti F, Bernasconi A, Lorenzi C, et al.: A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder. Neurosci Lett 2004, 355:37–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Benedetti F, Serretti A, Colombo C, et al.: A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression. Neurosci Lett 2004, 368:123–126.CrossRefPubMedGoogle Scholar
  38. 38.
    Benedetti F, Serretti A, Pontiggia A, et al.: Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP. Neurosci Lett 2005, 376:51–55.CrossRefPubMedGoogle Scholar
  39. 39.
    Benedetti F, Dallaspezia S, Colombo C, et al.: A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett 2008, 445:184–187.CrossRefPubMedGoogle Scholar
  40. 40.
    Manev H, Uz T: Clock genes: influencing and being influenced by psychoactive drugs. Trends Pharmacol Sci 2006, 27:186–189.CrossRefPubMedGoogle Scholar
  41. 41.
    Ogden CA, Rich ME, Schork NJ, et al.: Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Psychiatry 2004, 9:1007–1029.CrossRefPubMedGoogle Scholar
  42. 42.
    Rowe MK, Wiest C, Chuang DM: GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neurosci Biobehav Rev 2007, 31:920–931.CrossRefPubMedGoogle Scholar
  43. 43.
    Beck-Friis J, Ljunggren JG, Thoren M, et al.: Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test. Psychoneuroendocrinology 1985, 10:173–186.CrossRefPubMedGoogle Scholar
  44. 44.
    Kennedy SH, Kutcher SP, Ralevski E, Brown GM: Nocturnal melatonin and 24-hour 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder. Psychiatry Res 1996, 63:219–222.CrossRefPubMedGoogle Scholar
  45. 45.
    Nurnberger JI Jr, Adkins S, Lahiri DK, et al.: Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatry 2000, 57:572–579.CrossRefPubMedGoogle Scholar
  46. 46.
    Lewy AJ, Wher T, Gold PW, Goodwin FK: Plasma melatonin in manic depressive illness. In Catecholamines: Basic and Clinical Frontiers. Edited by Usdin E, Koping IJ, Barchas JD. Oxford: Pergamon Press; 1979:1173–1175.Google Scholar
  47. 47.
    Kennedy SH, Tighe S, McVey G, Brown GM: Melatonin and cortisol “switches” during mania, depression, and euthymia in a drug-free bipolar patient. J Nerv Ment Dis 1989, 177:300–303.PubMedCrossRefGoogle Scholar
  48. 48.
    Lewy AJ, Wehr TA, Goodwin FK, et al.: Light suppresses melatonin secretion in humans. Science 1980, 210:1267–1269.CrossRefPubMedGoogle Scholar
  49. 49.
    Lewy AJ, Wehr TA, Goodwin FK, et al.: Manic-depressive patients may be supersensitive to light. Lancet 1981, 1:383–384.CrossRefPubMedGoogle Scholar
  50. 50.
    Nathan PJ, Burrows GD, Norman TR: Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology 1999, 21:408–413.CrossRefPubMedGoogle Scholar
  51. 51.
    Lewy AJ, Nurnberger JI Jr, Wehr TA, et al.: Supersensitivity to light: possible trait marker for manic-depressive illness. Am J Psychiatry 1985, 142:725–727.PubMedGoogle Scholar
  52. 52.
    Nurnberger JI Jr, Berrettini W, Tamarkin L, et al.: Supersensitivity to melatonin suppression by light in young people at high risk for affective disorder. A preliminary report. Neuropsychopharmacology 1988, 1:217–223.CrossRefPubMedGoogle Scholar
  53. 53.
    Srinivasan V, Smits M, Spence W, et al.: Melatonin in mood disorders. World J Biol Psychiatry 2006, 7:138–151.CrossRefPubMedGoogle Scholar
  54. 54.
    Hallam KT, Olver JS, Horgan JE, et al.: Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers. Int J Neuropsychopharmacol 2005, 8:255–259.CrossRefPubMedGoogle Scholar
  55. 55.
    Hallam KT, Olver JS, Norman TR: Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers. Neuropsychopharmacology 2005, 30:1400–1404.PubMedGoogle Scholar
  56. 56.
    Bhattacharjee Y: Psychiatric research. Is internal timing key to mental health? Science 2007, 317:1488–1490.CrossRefPubMedGoogle Scholar
  57. 57.
    Benedetti F, Barbini B, Colombo C, Smeraldi E: Chronotherapeutics in a psychiatric ward. Sleep Med Rev 2007, 11:509–522.CrossRefPubMedGoogle Scholar
  58. 58.
    Terman M: Evolving applications of light therapy. Sleep Med Rev 2007, 11:497–507.CrossRefPubMedGoogle Scholar
  59. 59.
    Terman M, Terman JS: Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005, 10:647–663; quiz 672.PubMedGoogle Scholar
  60. 60.
    Lewy AJ, Lefler BJ, Emens JS, Bauer VK: The circadian basis of winter depression. Proc Natl Acad Sci U S A 2006, 103:7414–7419.CrossRefPubMedGoogle Scholar
  61. 61.
    Wehr TA, Sack DA, Norman E: Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep. Biol Psychiatry 1998, 43:822–828.CrossRefPubMedGoogle Scholar
  62. 62.
    Barbini B, Benedetti F, Colombo C, et al.: Dark therapy for mania: a pilot study. Bipolar Disord 2005, 7:98–101.CrossRefPubMedGoogle Scholar
  63. 63.
    Benedetti F, Smeraldi E: Neuroimaging and genetics of antidepressant response to sleep deprivation: implications for drug development. Curr Pharm Des 2009, 15:2637–2649.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Clinical Neurosciences, San Raffaele TurroIstituto Scientifico Ospedale San RaffaeleMilanoItaly

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