Current Psychiatry Reports

, 11:459 | Cite as

Circadian misalignment in mood disturbances



Recent refinements in methodology allow chronobiological researchers to answer the following questions: is there circadian misalignment in sleep and mood disturbances, and, if so, is it of the phase-advance or phase-delay type? Measurement of the dim light melatonin onset-to-midsleep interval, or phase-angle difference, in sleep and mood disorders should answer these questions. Although the phase-advance hypothesis of affective disorders was formulated three decades ago, recent studies suggest that many, if not all, mood disturbances have a circadian misalignment component of the phase-delay type, operationally defined as a delay in the dim light melatonin onset relative to the sleep/wake cycle. Phase-delayed disorders can be treated with bright light in the morning and/or low-dose melatonin in the afternoon/evening. Phase-advanced disorders can be treated with bright light in the evening and/or low-dose melatonin in the morning.

References and Recommended Reading

  1. 1.
    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
  2. 2.
    Wehr TA, Wirz-Justice A: Circadian rhythm mechanisms in affective illness and in antidepressant drug action. Pharmacopsychiatry 1982, 15:31–39.CrossRefGoogle Scholar
  3. 3.
    Kripke DF: Phase-advance theories for affective illness. In Circadian Rhythms in Psychiatry. Edited by Wehr TA, Goodwin FK. Pacific Grove, CA: Boxwood Press; 1983:41–69.Google Scholar
  4. 4.
    Emens JS, Lewy AJ, Kinzie MJ, et al.: Circadian misalignment in major depressive disorder. Psychiatry Res 2009, 168:259–261.CrossRefPubMedGoogle Scholar
  5. 5.
    Benloucif S, Burgess HJ, Klerman EB, et al.: Measuring melatonin in humans. J Clin Sleep Med 2008, 4:66–69.PubMedGoogle Scholar
  6. 6.
    Klerman EB, Gershengorn HB, Duffy JF, Kronauer RE: Comparisons of the variability of three markers of the human circadian pacemaker. J Biol Rhythms 2002, 17:181–193.CrossRefPubMedGoogle Scholar
  7. 7.
    Lewy AJ, Sack RL: The dim light melatonin onset (DLMO) as a marker for circadian phase position. Chronobiol Int 1989, 6:93–102.CrossRefPubMedGoogle Scholar
  8. 8.
    Lewy AJ, Cutler NL, Sack RL: The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms 1999, 14:227–236.CrossRefPubMedGoogle Scholar
  9. 9.
    Czeisler CA, Brown EN, Ronda JM, et al.: A clinical method to assess the endogenous circadian phase (ECP) of the deep circadian oscillator in man. Sleep Res 1985, 14:295.Google Scholar
  10. 10.
    Lewy AJ, Wehr TA, Goodwin FK, et al.: Light suppresses melatonin secretion in humans. Science 1980, 210:1267–1269.CrossRefPubMedGoogle Scholar
  11. 11.
    Brainard GC, Hanifin JP, Greeson JM, et al.: Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2001, 21:6405–6412.PubMedGoogle Scholar
  12. 12.
    Lewy A, Emens J, Songer J, et al.: Winter depression: integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model. Sleep Med Clin 2009, 4:285–299.CrossRefGoogle Scholar
  13. 13.
    Kronauer RE, Czeisler CA, Pilato SF, et al.: Mathematical model of the human circadian system with two interacting oscillators. Am J Physiol 1982, 242:R3–R17.PubMedGoogle Scholar
  14. 14.
    Illnerová H, Vanecek J: Two-oscillator structure of the pacemaker controlling the circadian rhythm of N-acetyltransferase in the rat pineal gland. J Comp Physiol A 1982, 145:539–548.CrossRefGoogle Scholar
  15. 15.
    Illnerová H, Vanecek J: Complex control of the circadian rhythm in N-acetyltransferase activity in the rat pineal gland. In Vertebrate Circadian Systems: Structure and Physiology. Edited by Aschoff J, Daan S, Groos G. Berlin: Springer-Verlag; 1982:285–296.Google Scholar
  16. 16.
    Vondrasova-Jelinkova D, Hajek I, Illnerova H: Adjustment of the human melatonin and cortisol rhythms to shortening of the natural summer photoperiod. Brain Res 1999, 816:249–253.CrossRefPubMedGoogle Scholar
  17. 17.
    Lewy AJ, Sack RL, Singer CM: Melatonin, light and chronobiological disorders. In Photoperiodism, Melatonin and the Pineal. Edited by Evered D, Clark S. London: Pitman; 1985:231–252.CrossRefGoogle Scholar
  18. 18.
    Wehr TA, Schwartz PJ, Turner EH, et al.: Bimodal patterns of human melatonin secretion consistent with a two-oscillator model of regulation. Neurosci Lett 1995, 194:105–108.CrossRefPubMedGoogle Scholar
  19. 19.
    Wehr TA, Duncan WC, Sher L, et al.: A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry 2001, 58:1108–1114.CrossRefPubMedGoogle Scholar
  20. 20.
    Kripke DF: Photoperiodic mechanisms for depression and its treatment. In Biological Psychiatry. Edited by Perris C, Struwe G, Jansson B. Amsterdam: Elsevier; 1981:1249–1252.Google Scholar
  21. 21.
    Kripke DF: Critical interval hypothesis for depression. Chronobiol Int 1984, 1:73–80.CrossRefPubMedGoogle Scholar
  22. 22.
    Parry BL, Meliska CJ, Sorenson DL, et al.: Increased melatonin and delayed offset in menopausal depression: role of years past menopause, follicle-stimulating hormone, sleep end time, and body mass index. J Clin Endocrinol Metab 2008, 93:54–60.CrossRefPubMedGoogle Scholar
  23. 23.
    Klerman EB, Zeitzer JM, Duffy JF, et al.: Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects. J Clin Endocrinol Metab 2001, 86:3166–3170.CrossRefPubMedGoogle Scholar
  24. 24.
    Duffy JF, Dijk D, Hall EF, Czeisler CA: Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young or older people. J Investig Med 1999, 47:141–150.PubMedGoogle Scholar
  25. 25.
    Lewy AJ, Ahmed S, Jackson JML, Sack RL: Melatonin shifts circadian rhythms according to a phase-response curve. Chronobiol Int 1992, 9:380–392.CrossRefPubMedGoogle Scholar
  26. 26.
    Lewy AJ, Bauer VK, Ahmed S, et al.: The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int 1998, 15:71–83.CrossRefPubMedGoogle Scholar
  27. 27.
    Burgess HJ, Revell VL, Eastman CL: A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol 2008, 586:639–647.CrossRefPubMedGoogle Scholar
  28. 28.
    Roenneberg T, Aschoff J: Annual rhythm of human reproduction: II. Environmental correlations. J Biol Rhythms 1990, 5:217–239.CrossRefPubMedGoogle Scholar
  29. 29.
    Davis FC, Mannion J: Entrainment of hamster pup circadian rhythms by prenatal melatonin injections to the mother. Am J Physiol 1988, 255:R439–R448.PubMedGoogle Scholar
  30. 30.
    Richter CP: Biological Clocks in Medicine and Psychiatry. Springfield, IL: Charles C. Thomas; 1965.Google Scholar
  31. 31.
    Halberg F: Physiologic considerations underlying rhythmometry with special reference to emotional illness. In Cycles Biologiques et Psychiatrie. Edited by deAjuriaguerra J. Paris: Masson et Cie; 1968:73.Google Scholar
  32. 32.
    Kripke DF, Mullaney DJ, Atkinson M, Wolf S: Circadian rhythm disorders in manic-depressives. Biol Psychiatry 1978, 13:335–351.PubMedGoogle Scholar
  33. 33.
    Lewy AJ, Newsome DA: Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab 1983, 56:1103–1107.CrossRefPubMedGoogle Scholar
  34. 34.
    Lockley SW, Skene DJ, James K, et al.: Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000, 164:R1–R6.CrossRefPubMedGoogle Scholar
  35. 35.
    Emens JS, Lewy AJ, Lefler BJ, Sack RL: Relative coordination to unknown “weak zeitgebers” in free-running blind individuals. J Biol Rhythms 2005, 20:159–167.CrossRefPubMedGoogle Scholar
  36. 36.
    Lewy AJ, Emens JS, Bernert RA, Lefler BJ: Eventual entrainment of the human circadian pacemaker by melatonin is independent of the circadian phase of treatment initiation: clinical implications. J Biol Rhythms 2004, 19:68–75.CrossRefPubMedGoogle Scholar
  37. 37.
    Lewy AJ, Emens JS, Lefler BJ, et al.: Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 2005, 22:1093–1106.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    Emens J, Lewy AJ, Yuhas K, et al.: Melatonin entrains free-running blind individuals with circadian periods less than 24 hours [abstract]. Sleep 2006, 29:A62.Google Scholar
  40. 40.
    Klerman EB: Non-photic effects on the circadian system: results from experiments in blind and sighted individuals. In Zeitgebers, Entrainment and Masking of the Circadian System. Edited by Honma K, Honma S. Sapporo, Japan: Hokkaido University Press; 2001:155–169.Google Scholar
  41. 41.
    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
  42. 42.
    Gronfier C, Wright KP, Kronauer RE, Czeisler CA: Entrainment of the human circadian pacemaker to longer-than-24-h days. Proc Natl Acad Sci U S A 2007, 104:9081–9086.CrossRefPubMedGoogle Scholar
  43. 43.
    Lewy AJ: Melatonin and human chronobiology. Cold Spring Harbor Symp Quant Biol 2007, 72:626–636.CrossRefGoogle Scholar
  44. 44.
    James SP, Wehr TA, Sack DA, et al.: Treatment of seasonal affective disorder with light in the evening. Br J Psychiatry 1985, 147:424–428.CrossRefPubMedGoogle Scholar
  45. 45.
    Lewy AJ, Sack RL, Miller S, Hoban TM: Antidepressant and circadian phase-shifting effects of light. Science 1987, 235:352–354.CrossRefPubMedGoogle Scholar
  46. 46.
    Eastman CI, Young MA, Fogg LF, et al.: Bright light treatment of winter depression: a placebo-controlled trial. Arch Gen Psychiatry 1998, 55:883–889.CrossRefPubMedGoogle Scholar
  47. 47.
    Lewy AJ, Bauer VK, Cutler NL, et al.: Morning versus evening light treatment of patients with winter depression. Arch Gen Psychiatry 1998, 55:890–896.CrossRefPubMedGoogle Scholar
  48. 48.
    Terman M, Terman JS, Ross DC: A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Arch Gen Psychiatry 1998, 55:875–882.CrossRefPubMedGoogle Scholar
  49. 49.
    Emens JS, Lewy AJ, Rough JN, Songer JB: Sub-clinical dysphoria correlates with phase-delayed circadian misalignment in healthy individuals [abstract]. Sleep 2009, 32:A355–A356.Google Scholar
  50. 50.
    Lewy AJ: Depressive disorders may more commonly be related to circadian phase delays rather than advances: time will tell. Sleep Med 2009 (in press).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Oregon Health & Science UniversityPortlandUSA

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