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Diagnosis and Treatment of Non-24-h Sleep–Wake Disorder in the Blind

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Abstract

Non-24-h sleep–wake disorder (non-24) is a circadian rhythm disorder occurring in 55–70% of totally blind individuals (those lacking conscious light perception) in which the 24-h biological clock (central, hypothalamic, circadian pacemaker) is no longer synchronized, or entrained, to the 24-h day. Instead, the overt rhythms controlled by the biological clock gradually shift progressively earlier or later (free run) in accordance with the clock’s near-24-h period, resulting in a recurrent pattern of daytime hypersomnolence and night-time insomnia. Orally administered melatonin and the melatonin agonist tasimelteon have been shown to entrain (synchronize) the circadian clock, resulting in improvements in night-time sleep and daytime alertness. We review the basic principles of circadian rhythms necessary to understand and treat non-24. The time of melatonin or tasimelteon administration must be considered carefully. For most individuals, those with circadian periods longer than 24 h, low-dose melatonin should be administered about 6 h before the desired bedtime, while in a minority, those with circadian periods shorter than 24 h (more commonly female individuals and African–Americans), melatonin should be administered at the desired wake time. Small doses (e.g., 0.5 mg of melatonin) that are not soporific would thus be preferable. Administration of melatonin or tasimelteon at bedtime will entrain individuals with non-24 but at an abnormally late time, resulting in continued problems with sleep and alertness. To date, tasimelteon has only been administered 1 h before the target bedtime in patients with non-24. Issues of cost, dose accuracy, and purity may figure into the decision of whether tasimelteon or melatonin is chosen to treat non-24. However, there are no head-to-head studies comparing efficacy, and studies to date show comparable rates of treatment success (entrainment).

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Fig. 1
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Fig. 3

Graphs reprinted from Lockley et al. [29] with permission

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References

  1. American Academy of Sleep Medicine. The international classification of sleep disorders. Diagnostic and coding manual. 3rd ed. Darien: American Academy of Sleep Medicine; 2014.

    Google Scholar 

  2. Keating GM. Tasimelteon: a review in non-24-hour sleep–wake disorder in totally blind individuals. CNS Drugs. 2016;30:461–8.

    Article  CAS  PubMed  Google Scholar 

  3. Dhillon S, Clarke M. Tasimelteon: first global approval. Drugs. 2014;74(4):505–11.

    Article  CAS  PubMed  Google Scholar 

  4. Buhr ED, Takahashi JS. Molecular components of the mammalian circadian clock. Handb Exp Pharmacol. 2013;217:3–27.

    Article  CAS  Google Scholar 

  5. LeGates TA, Fernandez DC, Hattar S. Light as a central modulator of circadian rhythms, sleep and affect. Nat Rev Neurosci. 2014;15(7):443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Aschoff J, Wever R. The circadian system of man. In: Aschoff J, editor. Handbook of behavioral neurobiology. Biological rhythms, vol. 4. New York: Plenum Press; 1981. p. 311–31.

    Google Scholar 

  7. Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284:2177–81.

    Article  CAS  PubMed  Google Scholar 

  8. Burgess HJ, Eastman CI. Human tau in an ultradian light–dark cycle. J Biol Rhythms. 2008;23(4):374–6.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Duffy JF, Cain SW, Chang AM, et al. Sex difference in the near-24-hour intrinsic period of the human circadian timing system. Proc Natl Acad Sci USA. 2011;108(Suppl 3):15602–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eastman CI, Suh C, Tomaka VA, Crowley SJ. Circadian rhythm phase shifts and endogenous free-running circadian period differ between African–Americans and European–Americans. Sci Rep. 2015;5:8381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eastman CI, Tomaka VA, Crowley SJ. Circadian rhythms of European and African–Americans after a large delay of sleep as in jet lag and night work. Sci Rep. 2016;6:36716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eastman CI, Molina TA, Dziepak ME, Smith MR. Blacks (African Americans) have shorter free-running circadian periods than whites (Caucasian Americans). Chronobiol Int. 2012;29(8):1072–7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lewy AJ, Sack RL. The dim light melatonin onset as a marker for circadian phase position. Chronobiol Int. 1989;6(1):93–102.

    Article  CAS  PubMed  Google Scholar 

  14. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker of circadian phase position. J Biol Rhythms. 1999;14(3):227–36.

    Article  CAS  PubMed  Google Scholar 

  15. 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(2):181–93.

    Article  CAS  PubMed  Google Scholar 

  16. Benloucif S, Burgess HJ, Klerman EB, et al. Measuring melatonin in humans. J Clin Sleep Med. 2008;4(1):66–9.

    PubMed  PubMed Central  Google Scholar 

  17. Emens JS, Yuhas K, Rough J, et al. Phase angle of entrainment in morning- and evening-types under naturalistic conditions. Chronobiol Int. 2009;26(3):474–93.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Burgess HJ, Fogg LF. Individual differences in the amount and timing of salivary melatonin secretion. PLoS One. 2008;3(8):e3055.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Martin SK, Eastman CI. Sleep logs of young adults with self-selected sleep times predict the dim light melatonin onset. Chronobiol Int. 2002;19(4):695–707.

    Article  PubMed  Google Scholar 

  20. Burgess HJ, Eastman CI. The dim light melatonin onset following fixed and free sleep schedules. J Sleep Res. 2005;14:229–37.

    Article  PubMed  Google Scholar 

  21. Arendt J, Bojkowski C, Franey C, et al. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab. 1985;60(6):1166–73.

    Article  CAS  PubMed  Google Scholar 

  22. Skene DJ, Lockley SW, James K, Arendt J. Correlation between urinary cortisol and 6-sulphatoxymelatonin rhythms in field studies of blind subjects. Clin Endocrinol. 1999;50:715–9.

    Article  CAS  Google Scholar 

  23. Miles LE, Raynal DM, Wilson MA. Blind man living in normal society has circadian rhythms of 24.9 hours. Science. 1977;198(4315):421–3.

    Article  CAS  PubMed  Google Scholar 

  24. Lewy AJ, Newsome DA. Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab. 1983;56:1103–7.

    Article  CAS  PubMed  Google Scholar 

  25. Sack RL, Lewy AJ, Blood ML, et al. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab. 1992;75:127–34.

    CAS  PubMed  Google Scholar 

  26. Klein T, Martens H, Dijk DJ, et al. Circadian sleep regulation in the absence of light perception: chronic non-24-hour circadian rhythm sleep disorder in a blind man with a regular 24-hour sleep–wake schedule. Sleep. 1993;16:333–43.

    CAS  PubMed  Google Scholar 

  27. Lockley SW, Skene DJ, Arendt J, et al. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab. 1997;82:3763–70.

    CAS  PubMed  Google Scholar 

  28. Klerman EB, Rimmer DW, Dijk DJ, et al. Nonphotic entrainment of the human circadian pacemaker. Am J Physiol. 1998;274:R991–6.

    CAS  PubMed  Google Scholar 

  29. Lockley SW, Dressman MA, Licamele L, et al. Tasimelteon for non-24-hour sleep–wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 2015;386:1754–64.

    Article  CAS  PubMed  Google Scholar 

  30. Emens JS, Laurie AL, Songer JB, Lewy AJ. Non-24-hour disorder in blind individuals revisited: variability and the influence of environmental time cues. Sleep. 2013;36(07):1091–100.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Leger D, Guilleminault C, Santos C, Paillard M. Sleep/wake cycles in the dark: sleep recorded by polysomnography in 26 totally blind subjects compared to controls. Clin Neurophysiol. 2002;113(10):1607–14.

    Article  PubMed  Google Scholar 

  32. Leger D, Guilleminault C, Defrance R, et al. Prevalence of sleep/wake disorders in persons with blindness. Clin Sci. 1999;97:193–9.

    Article  CAS  PubMed  Google Scholar 

  33. Lockley SW, Skene DJ, Butler LJ, Arendt J. Sleep and activity rhythms are related to circadian phase in the blind. Sleep. 1999;22:616–23.

    CAS  PubMed  Google Scholar 

  34. 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(15):1070–7.

    Article  CAS  PubMed  Google Scholar 

  35. Emens JS, Lewy AJ, Lefler BJ, Sack RL. Relative coordination to unknown “weak zeitgebers” in free-running blind individuals. J Biol Rhythms. 2005;20:159–67.

    Article  PubMed  Google Scholar 

  36. Karatsoreos IN, Bhagat S, Bloss EB, et al. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc Natl Acad Sci USA. 2011;108(4):1657–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci USA. 2009;106(11):4453–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. LeGates TA, Altimus CM, Wang H, et al. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature. 2012;491(7425):594–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Emens J, Lewy AJ, Laurie AL, Songer JB. Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods. J Biol Rhythms. 2010;25(5):381–4.

    Article  PubMed  Google Scholar 

  40. Burgess HJ, Wyatt JK, Park M, Fogg LF. Home circadian phase assessments with measures of compliance yield accurate dim light melatonin onsets. Sleep. 2015;38(6):889–97.

    PubMed  PubMed Central  Google Scholar 

  41. Keijzer H, Smits MG, Duffy JF, Curfs LM. Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders. Sleep Med Rev. 2014;18(4):333–9.

    Article  PubMed  Google Scholar 

  42. Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat: entrainment by melatonin. Science. 1983;219(4588):1089–91.

    Article  CAS  PubMed  Google Scholar 

  43. Reppert SM, Weaver DR, Godson C. Melatonin receptors step into the light: cloning and classification of subtypes. Trends Pharmocol Sci. 1996;17:100–2.

    Article  CAS  Google Scholar 

  44. Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med. 2007;8(Suppl 3):34–42.

    Article  PubMed  Google Scholar 

  45. Attenburrow MEJ, Dowling BA, Sargent PA, et al. Melatonin phase advances circadian rhythm. Psychopharmacol. 1995;121:503–5.

    Article  CAS  Google Scholar 

  46. 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(1–2):77–85.

    Article  CAS  PubMed  Google Scholar 

  47. Mallo C, Zaidan R, Faure A, et al. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol. 1988;119:474–80.

    CAS  PubMed  Google Scholar 

  48. Krauchi K, Cajochen C, Mori D, et al. Early evening melatonin and S-20098 advance circadian phase and nocturnal regulation of core body temperature. Am J Physiol. 1997;272:R1178–88.

    CAS  PubMed  Google Scholar 

  49. Nagtegaal JE, Kerkhof GA, Smits MG, et al. 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. 1998;7(2):135–43.

    Article  CAS  PubMed  Google Scholar 

  50. Samel A, Wegmann HM, Vejvoda M, et al. Influence of melatonin treatment on human circadian rhythmicity before and after a simulated 9-hr time shift. J Biol Rhythms. 1991;6:235–48.

    Article  CAS  PubMed  Google Scholar 

  51. Yang CM, Spielman AJ, D’Ambrosio P, et al. A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern. Sleep. 2001;24:272–81.

    CAS  PubMed  Google Scholar 

  52. Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol. 2002;282:R454–63.

    CAS  Google Scholar 

  53. Wirz-Justice A, Krauchi K, Cajochen C, et al. Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset. J Pineal Res. 2004;36:192–4.

    Article  CAS  PubMed  Google Scholar 

  54. Rajaratnam SMW, Dijk DJ, Middleton B, et al. 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. 2003;88:4303–9.

    Article  CAS  PubMed  Google Scholar 

  55. Paul MA, Miller JC, Gray GW, et al. Melatonin treatment for eastward and westward travel preparation. Psychopharmacol (Berl). 2010;208(3):377–86.

    Article  CAS  Google Scholar 

  56. Paul MA, Gray GW, Lieberman HR, et al. Phase advance with separate and combined melatonin and light treatment. Psychopharmacol (Berl). 2011;214(2):515–23.

    Article  CAS  Google Scholar 

  57. Crowley SJ, Eastman CI. Melatonin in the afternoons of a gradually advancing sleep schedule enhances the circadian rhythm phase advance. Psychopharmacol (Berl). 2013;225(4):825–37.

    Article  CAS  Google Scholar 

  58. Burke TM, Markwald RR, Chinoy ED, et al. Combination of light and melatonin time cues for phase advancing the human circadian clock. Sleep. 2013;36(11):1617–24.

    PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol. 2008;586(2):639–47.

    Article  CAS  PubMed  Google Scholar 

  61. Burgess HJ, Revell VL, Molina TA, Eastman CI. Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. J Clin Endocrinol Metab. 2010;95(7):3325–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lockley SW, Skene DJ, James K, et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol. 2000;164(1):R1–6.

    Article  CAS  PubMed  Google Scholar 

  63. Lewy AJ, Emens JS, Sack RL, et al. Low, but not high, doses of melatonin entrained a free-running blind person with long circadian period. Chronobiol Int. 2002;19(3):649–58.

    Article  CAS  PubMed  Google Scholar 

  64. Lewy AJ, Bauer VK, Hasler BP, et al. Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res. 2001;918:96–100.

    Article  CAS  PubMed  Google Scholar 

  65. Hack LM, Lockley SW, Arendt J, Skene DJ. The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms. 2003;18(5):420–9.

    Article  CAS  PubMed  Google Scholar 

  66. 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(6):1093–106.

    Article  CAS  PubMed  Google Scholar 

  67. Sack RL, Lewy AJ, Blood ML, et al. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms. 1991;6(3):249–61.

    Article  CAS  PubMed  Google Scholar 

  68. 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(1):68–75.

    Article  CAS  PubMed  Google Scholar 

  69. Emens J, Lewy A, Yuhas K, et al. Melatonin entrains free-running blind individuals with circadian periods less than 24 hours. Sleep. 2006;29:A62.

    Google Scholar 

  70. Revell VL, Burgess HJ, Gazda CJ, et al. Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light. J Clin Endocrinol Metab. 2006;91(1):54–9.

    Article  CAS  PubMed  Google Scholar 

  71. Suhner A, Schlagenhauf P, Tschopp A, et al. Impact of melatonin on driving performance. J Travel Med. 1998;5(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  72. Auger RR, Burgess HJ, Emens JS, et al. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep–wake disorders: advanced sleep–wake phase disorder (ASWPD), delayed sleep–wake phase disorder (DSWPD), non-24-hour sleep–wake rhythm disorder (N24SWD), and irregular sleep–wake rhythm disorder (ISWRD): an update for 2015. An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2015;11(10):1199–236.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. I. The stability and lability of spontaneous frequency. J Comp Physiol. 1976;106:223–52.

    Article  Google Scholar 

  74. Kripke DF, Elliott JA, Youngstedt SD, Rex KM. Circadian phase response curves to light in older and young women and men. J Circadian Rhythms. 2007;5(1):4.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Gunn PJ, Middleton B, Davies SK, et al. Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions. Chronobiol Int. 2016;33(1):39–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rajaratnam SM, Polymeropoulos MH, Fisher DM, et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet. 2009;373(9662):482–91.

    Article  CAS  PubMed  Google Scholar 

  77. Blask DE. Melatonin, sleep disturbance and cancer risk. Sleep Med Rev. 2009;13(4):257–64.

    Article  PubMed  Google Scholar 

  78. Reiter RJ, Tan DX, Erren TC, et al. Light-mediated perturbations of circadian timing and cancer risk: a mechanistic analysis. Integr Cancer Ther. 2009;8(4):354–60.

    Article  CAS  PubMed  Google Scholar 

  79. Goncalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87(10):1127–32.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Tasimelteon (Hetlioz) for non-24-hour sleep–wake disorder. Med Lett Drugs Ther. 2014;56(1441):34–5.

  81. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002. doi:10.1002/14651858.CD001520.

  82. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders: a meta-analysis. J Gen Intern Med. 2005;20:1151–8.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Rubio-Sastre P, Scheer FA, Gomez-Abellan P, et al. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014;37(10):1715–9.

    PubMed  PubMed Central  Google Scholar 

  84. Garaulet M, Gomez-Abellan P, Rubio-Sastre P, et al. Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism. 2015;64(12):1650–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Hospital and Specialty Medicine, VA Portland Health Care System, 3710 SW US Veterans Hospital Road, P3-PULM, Portland, OR, 97239, USA

    Jonathan S. Emens

  2. Departments of Psychiatry and Medicine, Oregon Health and Science University, VA Portland Health Care System, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA

    Jonathan S. Emens

  3. Biological Rhythms Research Laboratory, Department of Behavioral Sciences, Rush University Medical Center, Chicago, 60612, IL, USA

    Charmane I. Eastman

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Correspondence to Jonathan S. Emens.

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No funding supported the writing of this review. National Institutes of Health Grants R01HL086934 and R01NR007677 to Charmane Eastman provided support for the studies that generated the phase response curves (Fig. 1).

Conflict of interest

Jonathan Emens has consulted regarding the drug tasimelteon but permanently severed all consulting relationships as required by the FDA to serve as an advisor for the Endocrinology and Metabolic Drugs Advisory Committee meeting on 12 January, 2015. Charmane Eastman served as an advisor to the FDA Peripheral and Central Nervous System Drugs Advisory Committee that recommended approval for tasimelteon for the treatment of non-24-h sleep–wake disorder in the totally blind on 14 November, 2013.

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Emens, J.S., Eastman, C.I. Diagnosis and Treatment of Non-24-h Sleep–Wake Disorder in the Blind. Drugs 77, 637–650 (2017). https://doi.org/10.1007/s40265-017-0707-3

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