Clinical Implications of the Timed Autonomic Nervous System

  • Daniel Pedro Cardinali


There are many reasons for the lack of sleep in our society that operates 24 h a day, 7 days a week, constantly. The main disturbing factor has been the technological advance of being able to light our evenings artificially. This Chapter analyzes the impact of the lack of sleep in the “24/7 Society”, principally the disruption of the three ANS physiological programs. Typical examples of a desynchronized ANS are jet lag, shift work and chronodisruption, the metabolic syndrome and mental illnesses being also examples of a desynchronized ANS. The chronobiological aspects of normal and pathological brain aging and cancer are discussed.


24/7 Society Adjuvant chronobiological treatment Chronodisruption Chronodisruption in cancer Chronodisruption in mental illnesses Chronodisruption in metabolic syndrome Chronodisruption of brain aging Jet lag Light at night Melatonin Shift work 


  1. 1.
    Chang AM, Aeschbach D, Duffy JF, Czeisler CA. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci U S A. 2015;112:1232–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Lavie P. Sleep-wake as a biological rhythm. Annu Rev Psychol. 2001;52:277–303.PubMedCrossRefGoogle Scholar
  3. 3.
    Gringras P, Middleton B, Skene DJ, Revell VL. Bigger, brighter, bluer-better? Current light-emitting devices – adverse sleep properties and preventative strategies. Front Public Health. 2015;3:233.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Covassin N, Singh P. Sleep duration and cardiovascular disease risk: epidemiologic and experimental evidence. Sleep Med Clin. 2016;11:81–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Blanco M, Kriguer N, Pérez Lloret S, Cardinali DP. Attitudes towards treatment among patients suffering from sleep disorders. A Latin American survey. BMC Fam Pract. 2003;4:17.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Wright KP Jr, Bogan RK, Wyatt JK. Shift work and the assessment and management of shift work disorder (SWD). Sleep Med Rev. 2013;17:41–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Singh A, Yeh CJ, Verma N, Das AK. Overview of attention deficit hyperactivity disorder in young children. Health Psychol Res. 2015;3:2115.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Smolensky MH, Hermida RC, Portaluppi F. Circadian mechanisms of 24-hour blood pressure regulation and patterning. Sleep Med Rev. 2017;33:4–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Cardinali DP. Qué es el Sueño. Paidós: Buenos Aires; 2014.Google Scholar
  10. 10.
    Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR. Melatonin and brain inflammaging. Prog Neurobiol. 2015;127-128:46–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Anothaisintawee T, Reutrakul S, Van CE, Thakkinstian A. Sleep disturbances compared to traditional risk factors for diabetes development: systematic review and meta-analysis. Sleep Med Rev. 2016;30:11–24.Google Scholar
  12. 12.
    Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract. 2014;2014:943162.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Reid KJ, Abbott SM. Jet Lag and shift work disorder. Sleep Med Clin. 2015;10:523–35.PubMedCrossRefGoogle Scholar
  14. 14.
    Agorastos A, Linthorst AC. Potential pleiotropic beneficial effects of adjuvant melatonergic treatment in posttraumatic stress disorder. J Pineal Res. 2016;61:3–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Laermans J, Depoortere I. Chronobesity: role of the circadian system in the obesity epidemic. Obes Rev. 2016;17:108–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Oldham MA, Lee HB, Desan PH. Circadian rhythm disruption in the critically ill: an opportunity for improving outcomes. Crit Care Med. 2016;44:207–17.PubMedCrossRefGoogle Scholar
  17. 17.
    Madrid-Navarro CJ, Sanchez-Galvez R, Martinez-Nicolas A, Marina R, Garcia JA, Madrid JA, Rol MA. Disruption of circadian rhythms and delirium, sleep impairment and sepsis in critically ill patients. potential therapeutic implications for increased light-dark contrast and melatonin therapy in an ICU environment. Curr Pharm Des. 2015;21:3453–68.PubMedCrossRefGoogle Scholar
  18. 18.
    Waterhouse J, Reilly T, Atkinson G, Edwards B. Jet lag: trends and coping strategies. Lancet. 2007;369:1117–29.PubMedCrossRefGoogle Scholar
  19. 19.
    Cajochen C, Munch M, Knoblauch V, Blatter K, Wirz-Justice A. Age-related changes in the circadian and homeostatic regulation of human sleep. Chronobiol Int. 2006;23:461–74.PubMedCrossRefGoogle Scholar
  20. 20.
    Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP. Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. Adv Ther. 2010;27:796–813.PubMedCrossRefGoogle Scholar
  21. 21.
    Golombek DA, Casiraghi LP, Agostino PV, Paladino N, Duhart JM, Plano SA, Chiesa JJ. The times they’re a-changing: effects of circadian desynchronization on physiology and disease. J Physiol Paris. 2013;107:310–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Ariznavarreta C, Cardinali DP, Villanua M, Granados B, Martin M, Chiesa JJ, Golombek DA, Tresguerres JAF. Circadian rhythms in airline pilots submitted to long-haul transmeridian flights. Aviat Space Environ Med. 2002;73:445–55.PubMedGoogle Scholar
  23. 23.
    Tresguerres J, Ariznavarreta C, Granados B, Martín M, Villanua M, Golombek D, Cardinali DP. Circadian urinary 6-sulphatoxymelatonin, cortisol excretion and locomotor activity in airline pilots during transmeridian flights. J Pineal Res. 2001;31:16–22.PubMedCrossRefGoogle Scholar
  24. 24.
    van DA, Boot CR, Hlobil H, Twisk JW, Smid T, van der Beek AJ. Evaluation of an mHealth intervention aiming to improve health-related behavior and sleep and reduce fatigue among airline pilots. Scand J Work Environ Health. 2014;40:557–68.CrossRefGoogle Scholar
  25. 25.
    McEwen BS. Sleep deprivation as a neurobiologic and physiologic stressor: allostasis and allostatic load. Metabolism. 2006;55:S20–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Coutinho JF, Goncalves OF, Maia L, Fernandes VC, Perrone-McGovern K, Simon-Dack S, Hernandez K, Oliveira-Silva P, Mesquita AR, Sampaio A. Differential activation of the default mode network in jet lagged individuals. Chronobiol Int. 2015;32:143–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Pinheiro SP, Schernhammer ES, Tworoger SS, Michels KB. A prospective study on habitual duration of sleep and incidence of breast cancer in a large cohort of women. Cancer Res. 2006;66:5521–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer. 2005;41:2023–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature. 1997;388:235.PubMedCrossRefGoogle Scholar
  30. 30.
    Diez JJ, Vigo DE, Pérez Lloret S, Ritgers S, Rolé N, Cardinali DP, Pérez-Chada D. Sleep habits, alertness, cortisol levels and cardiac autonomic activity in short distance bus drivers. Differences between morning and afternoon shifts. J Occup Environ Med. 2011;36:806–11.CrossRefGoogle Scholar
  31. 31.
    Diez JJ, Vigo DE, Cardinali DP, Pérez-Chada D. Sleep habits, daytime sleepiness and working conditions in short-distance bus drivers. Int J Workplace Health Manag. 2014;7:202–12.CrossRefGoogle Scholar
  32. 32.
    Eckel RH, Depner CM, Perreault L, Markwald RR, Smith MR, McHill AW, Higgins J, Melanson EL, Wright KP Jr. Morning circadian misalignment during short sleep duration impacts insulin sensitivity. Curr Biol. 2015;25:3004–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Hardeland R. Melatonin and circadian oscillators in aging--a dynamic approach to the multiply connected players. Interdiscip Top Gerontol. 2015;40:128–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Reid KJ, Burgess HJ. Circadian rhythm sleep disorders. Prim Care. 2005;32:449–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Shanahan TL, Czeisler CA. Physiological effects of light on the human circadian pacemaker. Semin Perinatol. 2000;24:299–320.PubMedCrossRefGoogle Scholar
  36. 36.
    Dawson D, Armstrong SM. Chronobiotics--drugs that shift rhythms. Pharmacol Ther. 1996;69:15–36.PubMedCrossRefGoogle Scholar
  37. 37.
    Pandi-Perumal SR, Srinivasan V, Maestroni GJM, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: nature’s most versatile biological signal? FEBS J. 2006;273(13):2813–38.PubMedCrossRefGoogle Scholar
  38. 38.
    Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;CD001520.Google Scholar
  39. 39.
    Czeisler CA, Kronauer RE, Allan JS, Duffy JF, Jewett ME, Brown EN, Ronda JM. Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science. 1989;244:1328–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Cardinali DP, Bortman GP, Liotta G, Perez LS, Albornoz LE, Cutrera RA, Batista J, Ortega GP. 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. 2002;32:41–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Cardinali DP, Furio AM, Reyes MP, Brusco LI. The use of chronobiotics in the resynchronization of the sleep-wake cycle. Cancer Causes Control. 2006;17:601–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Smolensky MH. Circadian rhythms in medicine. CNS Spectr. 2001;6:467–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Crowley SJ, Eastman CI. Phase advancing human circadian rhythms with morning bright light, afternoon melatonin, and gradually shifted sleep: can we reduce morning bright-light duration? Sleep Med. 2015;16:288–97.PubMedCrossRefGoogle Scholar
  44. 44.
    Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8:e63773.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, Britton TC, Crowe C, Dijk DJ, Espie CA, Gringras P, Hajak G, Idzikowski C, Krystal AD, Nash JR, Selsick H, Sharpley AL, Wade AG. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24:1577–601.PubMedCrossRefGoogle Scholar
  46. 46.
    Dinges DF. The state of sleep deprivation: from functional biology to functional consequences. Sleep Med Rev. 2006;10:303–5.PubMedCrossRefGoogle Scholar
  47. 47.
    O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev. 2015;16:1–12.PubMedCrossRefGoogle Scholar
  48. 48.
    Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013:139239.Google Scholar
  49. 49.
    Cardinali DP, Hardeland R. Inflammaging, metabolic syndrome and melatonin: a call for treatment studies. Neuroendocrinology. 2017;104:382–97.PubMedCrossRefGoogle Scholar
  50. 50.
    Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93:359–404.PubMedCrossRefGoogle Scholar
  51. 51.
    Lemche E, Chaban OS, Lemche AV. Neuroendocrine and epigetic mechanisms subserving autonomic imbalance and HPA dysfunction in the metabolic syndrome. Front Neurosci. 2016;10:142.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Pagano ES, Spinedi E, Gagliardino JJ. White adipose tissue and circadian rhythm dysfunctions in obesity pathogenesis and available therapies. Neuroendocrinology. 2017;104:347–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Arora T, Chen MZ, Cooper AR, Andrews RC, Taheri S. The impact of sleep debt on excess adiposity and insulin sensitivity in patients with early type 2 diabetes mellitus. J Clin Sleep Med. 2016;12:673–80.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Arora T, Chen MZ, Omar OM, Cooper AR, Andrews RC, Taheri S. An investigation of the associations among sleep duration and quality, body mass index and insulin resistance in newly diagnosed type 2 diabetes mellitus patients. Ther Adv Endocrinol Metab. 2016;7:3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    McFadden E, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. The relationship between obesity and exposure to light at night: cross-sectional analyses of over 100,000 women in the Breakthrough Generations Study. Am J Epidemiol. 2014;180:245–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Fonken LK, Nelson RJ. The effects of light at night on circadian clocks and metabolism. Endocr Rev. 2014;35:648–670.Google Scholar
  57. 57.
    Karthikeyan R, Marimuthu G, Spence DW, Pandi-Perumal SR, Bahammam AS, Brown GM, Cardinali DP. Should we listen to our clock to prevent type 2 diabetes mellitus? Diabetes Res Clin Pract. 2014;106:182–90.Google Scholar
  58. 58.
    Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466:627–31.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Shi SQ, Ansari TS, McGuinness OP, Wasserman DH, Johnson CH. Circadian disruption leads to insulin resistance and obesity. Curr Biol. 2013;23:372–81.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Gale JE, Cox HI, Qian J, Block GD, Colwell CS, Matveyenko AV. Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction. J Biol Rhythms. 2011;26:423–33.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106:4453–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kelly MA, Rees SD, Hydrie MZ, Shera AS, Bellary S, O’Hare JP, Kumar S, Taheri S, Basit A, Barnett AH. Circadian gene variants and susceptibility to type 2 diabetes: a pilot study. PLoS One. 2012;7:e32670.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, Farrall M, Gauguier D. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A. 2007;104:14412–7.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Karthikeyan R, Marimuthu G, Sooriyakumar M, BaHammam AS, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Per3 length polymorphism in patients with type 2 diabetes mellitus. Horm Mol Biol Clin Invest. 2014;18:145–9.Google Scholar
  65. 65.
    Monteleone P, Tortorella A, Docimo L, Maldonato MN, Canestrelli B, De LL, Maj M. Investigation of 3111T/C polymorphism of the CLOCK gene in obese individuals with or without binge eating disorder: association with higher body mass index. Neurosci Lett. 2008;435:30–3.PubMedCrossRefGoogle Scholar
  66. 66.
    Garaulet M, Corbalan MD, Madrid JA, Morales E, Baraza JC, Lee YC, Ordovas JM. CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet. Int J Obes (Lond). 2010;34:516–23.CrossRefGoogle Scholar
  67. 67.
    Ye D, Cai S, Jiang X, Ding Y, Chen K, Fan C, Jin M. Associations of polymorphisms in circadian genes with abdominal obesity in Chinese adult population. Obes Res Clin Pract. 2016;10(Suppl 1):S133–41.PubMedCrossRefGoogle Scholar
  68. 68.
    Yamaguchi M, Uemura H, Arisawa K, Katsuura-Kamano S, Hamajima N, Hishida A, Suma S, Oze I, Nakamura K, Takashima N, Suzuki S, Ibusuki R, Mikami H, Ohnaka K, Kuriyama N, Kubo M, Tanaka H. Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: a cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study. Diabetes Res Clin Pract. 2015;110:301–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Corella D, Asensio EM, Coltell O, Sorli JV, Estruch R, Martinez-Gonzalez MA, Salas-Salvado J, Castaner O, Aros F, Lapetra J, Serra-Majem L, Gomez-Gracia E, Ortega-Azorin C, Fiol M, Espino JD, Diaz-Lopez A, Fito M, Ros E, Ordovas JM. CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial. Cardiovasc Diabetol. 2016;15:4.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Cardinali DP, Cano P, Jimenez-Ortega V, Esquifino AI. Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology. 2011;93:133–42.PubMedCrossRefGoogle Scholar
  71. 71.
    Stamenkovic JA, Olsson AH, Nagorny CL, Malmgren S, Dekker-Nitert M, Ling C, Mulder H. Regulation of core clock genes in human islets. Metabolism. 2012;61:978–85.PubMedCrossRefGoogle Scholar
  72. 72.
    Pivovarova O, Gogebakan O, Sucher S, Groth J, Murahovschi V, Kessler K, Osterhoff M, Rudovich N, Kramer A, Pfeiffer AF. Regulation of the clock gene expression in human adipose tissue by weight loss. Int J Obes (Lond). 2016;40:899–906.CrossRefGoogle Scholar
  73. 73.
    Samblas M, Milagro FI, Gomez-Abellan P, Martinez JA, Garaulet M. Methylation on the circadian gene BMAL1 is associated with the effects of a weight loss intervention on serum lipid levels. J Biol Rhythms. 2016;31:308–17.PubMedCrossRefGoogle Scholar
  74. 74.
    Hardeland R. Melatonin and the pathologies of weakened or dysregulated circadian oscillators. J Pineal Res. 2017;62.Google Scholar
  75. 75.
    Cardinali DP. Ma Vie en Noir. Fifty years with melatonin and the stone of madness. Switzerland: Springer; 2016.Google Scholar
  76. 76.
    Kozirog M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M. Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res. 2011;50:261–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Gonciarz M, Bielanski W, Partyka R, Brzozowski T, Konturek PC, Eszyk J, Celinski K, Reiter RJ, Konturek SJ. Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin. J Pineal Res. 2013;54:154–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, Konturek SJ. The effects of long-term melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study. J Physiol Pharmacol. 2012;63:35–40.PubMedGoogle Scholar
  79. 79.
    Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, Konturek SJ. The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin. J Physiol Pharmacol. 2010;61:705–10.PubMedGoogle Scholar
  80. 80.
    Romo-Nava F, Alvarez-Icaza GD, Fresan-Orellana A, Saracco AR, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga C, Heinze G, Buijs RM. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014;16:410–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, Ashrafi M, Modabbernia MJ. Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res. 2014;53:133–40.PubMedCrossRefGoogle Scholar
  82. 82.
    Tuomi T, Nagorny CL, Singh P, Bennet H, Yu Q, Alenkvist I, Isomaa B, Ostman B, Soderstrom J, Pesonen AK, Martikainen S, Raikkonen K, Forsen T, Hakaste L, Almgren P, Storm P, Asplund O, Shcherbina L, Fex M, Fadista J, Tengholm A, Wierup N, Groop L, Mulder H. Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab. 2016;23:1067–77.PubMedCrossRefGoogle Scholar
  83. 83.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. 2015.Google Scholar
  84. 84.
    Campos CI, Nogueira CH, Fernandes L. Aging, circadian rhythms and depressive disorders: a review. Am J Neurodegener Dis. 2013;2:228–46.Google Scholar
  85. 85.
    Milhiet V, Boudebesse C, Bellivier F, Drouot X, Henry C, Leboyer M, Etain B. Circadian abnormalities as markers of susceptibility in bipolar disorders. Front Biosci (Schol Ed). 2014;6:120–37.Google Scholar
  86. 86.
    Wirz-Justice A. Diurnal variation of depressive symptoms. Dialogues Clin Neurosci. 2008;10:337–43.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Jagannath A, Peirson SN, Foster RG. Sleep and circadian rhythm disruption in neuropsychiatric illness. Curr Opin Neurobiol. 2013;23:888–94.PubMedCrossRefGoogle Scholar
  88. 88.
    Bersani FS, Iannitelli A, Pacitti F, Bersani G. Sleep and biorythm disturbances in schizophrenia, mood and anxiety disorders: a review. Riv Psichiatr. 2012;47:365–75.PubMedGoogle Scholar
  89. 89.
    Lewy AJ, Kern HA, Rosenthal NE, Wehr TA. Bright artificial light treatment of a manic-depressive patient with a seasonal mood cycle. Am J Psychiatry. 1982;139:1496–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Lewy AJ, Nurnberger JI Jr, Wehr TA, Pack D, Becker LE, Powell RL, Newsome DA. Supersensitivity to light: possible trait marker for manic-depressive illness. Am J Psychiatry. 1985;142:725–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Cardinali DP, Pandi-Perumal SR, Brown GM. Sleep and circadian dysregulation in depressive illness. Pharmacological implications. Clin Neuropsychiatry. 2011;8:321–38.Google Scholar
  92. 92.
    Soreca I. Circadian rhythms and sleep in bipolar disorder: implications for pathophysiology and treatment. Curr Opin Psychiatry. 2014;27:467–71.PubMedCrossRefGoogle Scholar
  93. 93.
    Ng TH, Chung KF, Ho FY, Yeung WF, Yung KP, Lam TH. Sleep-wake disturbance in interepisode bipolar disorder and high-risk individuals: a systematic review and meta-analysis. Sleep Med Rev. 2015;20:46–58.PubMedCrossRefGoogle Scholar
  94. 94.
    McCarthy MJ, Welsh DK. Cellular circadian clocks in mood disorders. J Biol Rhythms. 2012;27:339–52.PubMedCrossRefGoogle Scholar
  95. 95.
    Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11:961–70.PubMedCrossRefGoogle Scholar
  96. 96.
    Coogan AN, Thome J. Chronotherapeutics and psychiatry: setting the clock to relieve the symptoms. World J Biol Psychiatry. 2011;12(Suppl 1):40–3.PubMedCrossRefGoogle Scholar
  97. 97.
    Lewy AJ, Emens J, Jackman A, Yuhas K. Circadian uses of melatonin in humans. Chronobiol Int. 2006;23:403–12.PubMedCrossRefGoogle Scholar
  98. 98.
    Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Nilsson LG, Kasper S, Peltonen L, Adolfsson R, Schalling M, Partonen T. Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology. 2003;28:734–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Benedetti F, Dallaspezia S, Colombo C, Pirovano A, Marino E, Smeraldi E. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett. 2008;445:184–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Li SX, Liu LJ, LZ X, Gao L, Wang XF, Zhang JT, Lu L. Diurnal alterations in circadian genes and peptides in major depressive disorder before and after escitalopram treatment. Psychoneuroendocrinology. 2013;38:2789–99.PubMedCrossRefGoogle Scholar
  101. 101.
    Karthikeyan R, Marimuthu G, Ramasubramanian C, Arunachal G, BaHammam AS, Spence DW, Cardinali DP, Brown GM, Pandi-Perumal SR. Association of Per3 length polymorphism with bipolar I disorder and schizophrenia. Neuropsychiatr Dis Treat. 2014;110:2025–30.Google Scholar
  102. 102.
    Vollmer LL, Strawn JR, Sah R. Acid-base dysregulation and chemosensory mechanisms in panic disorder: a translational update. Transl Psychiatry. 2015;5:e572.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Huang F, Yang Z, Li CQ. The melatonergic system in anxiety disorders and the role of melatonin in conditional fear. Vitam Horm. 2017;103:281–94.PubMedCrossRefGoogle Scholar
  104. 104.
    Cardinali DP, Vidal MF, Vigo DE. Agomelatine: Its role in the management of major depressive disorder. Clin Med Insights Psychiatry. 2012;4:1–23.CrossRefGoogle Scholar
  105. 105.
    Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol. 2016;56:361–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Monti JM, BaHammam AS, Pandi-Perumal SR, Bromundt V, Spence DW, Cardinali DP, Brown GM. Sleep and circadian rhythm dysregulation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:209–16.PubMedCrossRefGoogle Scholar
  107. 107.
    Mansour HA, Wood J, Logue T, Chowdari KV, Dayal M, Kupfer DJ, Monk TH, Devlin B, Nimgaonkar VL. Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav. 2006;5:150–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Lane JM, Vlasac I, Anderson SG, Kyle SD, Dixon WG, Bechtold DA, Gill S, Little MA, Luik A, Loudon A, Emsley R, Scheer FA, Lawlor DA, Redline S, Ray DW, Rutter MK, Saxena R. Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. Nat Commun. 2016;7:10889.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Benson KL. Sleep in schizophrenia: pathology and treatment. Sleep Med Clin. 2015;10:49–55.PubMedCrossRefGoogle Scholar
  110. 110.
    Gerbaldo H, Demisch L, Cardinali DP. Light exposure patterns in schizophrenia. Acta Psychiatr Scand. 1992;85:94–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Ju P, Cui D. The involvement of N-methyl-D-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia. Acta Biochim Biophys Sin (Shanghai). 2016;48:209–19.CrossRefGoogle Scholar
  112. 112.
    Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry. 2012;200:308–16.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Pasternak O, Westin CF, Dahlben B, Bouix S, Kubicki M. The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophr Res. 2015;161:113–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Morera-Fumero AL, Abreu-Gonzalez P. Role of melatonin in schizophrenia. Int J Mol Sci. 2013;14:9037–50.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Aston C, Jiang L, Sokolov BP. Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res. 2004;77:858–66.PubMedCrossRefGoogle Scholar
  116. 116.
    Zorn JV, Schur RR, Boks MP, Kahn RS, Joels M, Vinkers CH. Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis. Psychoneuroendocrinology. 2016;77:25–36.PubMedCrossRefGoogle Scholar
  117. 117.
    Tang Q, Song P, Xu L. The government’s role in regulating, coordinating, and standardizing the response to Alzheimer’s disease: anticipated international cooperation in the area of intractable and rare diseases. Intractable Rare Dis Res. 2016;5:238–43.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Zdanys KF, Steffens DC. Sleep disturbances in the elderly. Psychiatr Clin North Am. 2015;38:723–41.PubMedCrossRefGoogle Scholar
  119. 119.
    Duffy JF, Zitting KM, Chinoy ED. Aging and circadian rhythms. Sleep Med Clin. 2015;10:423–34.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    American Geriatrics Society 2015. Updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63:2227–46.CrossRefGoogle Scholar
  121. 121.
    Cardinali DP, Golombek DA, Rosenstein RE, Brusco LI, Vigo DE. Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse. Pharmacol Res. 2016;109:12–23.PubMedCrossRefGoogle Scholar
  122. 122.
    Baandrup L, Fasmer OB, Glenthoj BY, Jennum PJ. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial. BMC Psychiatry. 2016;16:348.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Clay E, Falissard B, Moore N, Toumi M. Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries. Eur J Clin Pharmacol. 2013;69:1–10.PubMedCrossRefGoogle Scholar
  124. 124.
    Zeppenfeld DM, Simon M, Haswell JD, D’Abreo D, Murchison C, Quinn JF, Grafe MR, Woltjer RL, Kaye J, Iliff JJ. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 2017;74:91–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Venkat P, Chopp M, Chen J. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain. Croat Med J. 2016;57:223–8.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    MacLeod R, Hillert EK, Cameron RT, Baillie GS. The role and therapeutic targeting of alpha-, beta- and gamma-secretase in Alzheimer’s disease. Future Sci OA. 2015;1:FSO11.Google Scholar
  127. 127.
    Hurtado-Alvarado G, Dominguez-Salazar E, Pavon L, Velazquez-Moctezuma J, Gomez-Gonzalez B. Blood-brain barrier disruption induced by chronic sleep loss: low-grade inflammation may be the link. J Immunol Res. 2016;2016:4576012.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Collins O, Dillon S, Finucane C, Lawlor B, Kenny RA. Parasympathetic autonomic dysfunction is common in mild cognitive impairment. Neurobiol Aging. 2012;33:2324–33.PubMedCrossRefGoogle Scholar
  129. 129.
    Ooms S, Ju YE. Treatment of sleep disorders in dementia. Curr Treat Options Neurol. 2016;18:40.PubMedCrossRefGoogle Scholar
  130. 130.
    Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008;299:2642–55.Google Scholar
  131. 131.
    Sirin FB, Kumbul DD, Vural H, Eren I, Inanli I, Sutcu R, Delibas N. Plasma 8-isoPGF2alpha and serum melatonin levels in patients with minimal cognitive impairment and Alzheimer disease. Turk J Med Sci. 2015;45:1073–7.PubMedCrossRefGoogle Scholar
  132. 132.
    Allan CL, Behrman S, Ebmeier KP, Valkanova V. Diagnosing early cognitive decline-When, how and for whom? Maturitas. 2017;96:103–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Daulatzai MA. Pharmacotherpy and Alzheimer’s disease: the M-Drugs (melatonin, minocycline, modafinil, and memantine) approach. Curr Pharm Des. 2016;22:2411–30.PubMedCrossRefGoogle Scholar
  134. 134.
    Martino Adami PV, Galeano P, Wallinger ML, Quijano C, Rabossi A, Pagano ES, Olivar N, Reyes Toso C, Cardinali DP, Brusco LI, DoCarmo S, Radi R, Gevorkian G, Castaño EM, Cuello AC, Morelli L. Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer’s disease is associated to neurotoxic Aβ species and independent of neuroinflammation. Biochim Biophys Acta. 2017;1863:731–43.PubMedCrossRefGoogle Scholar
  135. 135.
    Monti D, Ostan R, Borelli V, Castellani G, Franceschi C. Inflammaging and omics in human longevity. Mech Ageing Dev. 2016.Google Scholar
  136. 136.
    Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz). 2016;64:111–26.CrossRefGoogle Scholar
  137. 137.
    Ralph MR, Lehman MN. Transplantation: a new tool in the analysis of the mammalian hypothalamic circadian pacemaker. Trends Neurosci. 1991;14:362–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Carrillo-Vico A, Lardone PJ, Alvarez-Sanchez N, Rodriguez-Rodriguez A, Guerrero JM. Melatonin: buffering the immune system. Int J Mol Sci. 2013;14:8638–83.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.PubMedCrossRefGoogle Scholar
  140. 140.
    Stevens RG, Zhu Y. Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem? Philos Trans R Soc Lond B Biol Sci. 2015;370.Google Scholar
  141. 141.
    Straif K, Baan R, Grosse Y, Secretan B, El GF, Bouvard V, Altieri A, Benbrahim-Tallaa L, Cogliano V. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8:1065–6.CrossRefGoogle Scholar
  142. 142.
    Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer. 2015;22:R183–204.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Lin X, Chen W, Wei F, Ying M, Wei W, Xie X. Night-shift work increases morbidity of breast cancer and all-cause mortality: a meta-analysis of 16 prospective cohort studies. Sleep Med. 2015;16:1381–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Valenzuela FJ, Vera J, Venegas C, Munoz S, Oyarce S, Munoz K, Lagunas C. Evidences of polymorphism associated with circadian system and risk of pathologies: a review of the literature. Int J Endocrinol. 2016;2016:2746909.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Altman BJ. Cancer clocks out for lunch: disruption of circadian rhythm and metabolic oscillation in cancer. Front Cell Dev Biol. 2016;4:62.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Cardinali DP, Escames G, Acuña-Castroviejo D, Ortiz F, Fernández-Gil B, Guerra Librero A, García-López S, Shen Y, Florido J. Melatonin-induced oncostasis. Mechanisms and clinical relevance. Integr Oncol. 2016;S1:006. doi: 10.4172/2329-6771.S1-006.Google Scholar
  147. 147.
    Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC. Growth and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal melatonin suppression. Breast Cancer Res Treat. 2003;79:313–20.PubMedCrossRefGoogle Scholar
  148. 148.
    Blask DE, Brainard GC, Dauchy RT, Hanifin JP, Davidson LK, Krause JA, Sauer LA, Rivera-Bermudez MA, Dubocovich ML, Jasser SA, Lynch DT, Rollag MD, Zalatan F. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005;65:11174–84.PubMedCrossRefGoogle Scholar
  149. 149.
    Dauchy RT, Hoffman AE, Wren-Dail MA, Hanifin JP, Warfield B, Brainard GC, Xiang S, Yuan L, Hill SM, Belancio VP, Dauchy EM, Smith K, Blask DE. Daytime blue light enhances the nighttime circadian melatonin inhibition of human prostate cancer growth. Comp Med. 2015;65:473–85.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Wang X, Ji A, Zhu Y, Liang Z, Wu J, Li S, Meng S, Zheng X, Xie L. A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer. Oncotarget. 2015;6:25046–60.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Ma Z, Yang Y, Fan C, Han J, Wang D, Di S, Hu W, Liu D, Li X, Reiter RJ, Yan X. Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Oncotarget. 2016;7:46768–84.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Howell D, Oliver TK, Keller-Olaman S, Davidson JR, Garland S, Samuels C, Savard J, Harris C, Aubin M, Olson K, Sussman J, MacFarlane J, Taylor C. Sleep disturbance in adults with cancer: a systematic review of evidence for best practices in assessment and management for clinical practice. Ann Oncol. 2014;25:791–800.PubMedCrossRefGoogle Scholar
  153. 153.
    Dahiya S, Ahluwalia MS, Walia HK. Sleep disturbances in cancer patients: underrecognized and undertreated. Cleve Clin J Med. 2013;80:722–32.PubMedCrossRefGoogle Scholar
  154. 154.
    Chen WY, Giobbie-Hurder A, Gantman K, Savoie J, Scheib R, Parker LM, Schernhammer ES. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 2014;145:381–8.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Dickerson SS, Connors LM, Fayad A, Dean GE. Sleep-wake disturbances in cancer patients: narrative review of literature focusing on improving quality of life outcomes. Nat Sci Sleep. 2014;6:85–100.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Harris B, Ross J, Sanchez-Reilly S. Sleeping in the arms of cancer: a review of sleeping disorders among patients with cancer. Cancer J. 2014;20:299–305.PubMedCrossRefGoogle Scholar
  157. 157.
    Palesh OG, Roscoe JA, Mustian KM, Roth T, Savard J, Ancoli-Israel S, Heckler C, Purnell JQ, Janelsins MC, Morrow GR. Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. J Clin Oncol. 2010;28:292–8.PubMedCrossRefGoogle Scholar
  158. 158.
    Jia Y, Lu Y, Wu K, Lin Q, Shen W, Zhu M, Huang S, Chen J. Does night work increase the risk of breast cancer? A systematic review and meta-analysis of epidemiological studies. Cancer Epidemiol. 2013;37:197–206.PubMedCrossRefGoogle Scholar
  159. 159.
    Armstrong TS, Shade MY, Breton G, Gilbert MR, Mahajan A, Scheurer ME, Vera E, Berger AM. Sleep-wake disturbance in patients with brain tumors. Neuro Oncol. 2017;19:323–35.PubMedGoogle Scholar
  160. 160.
    Casault L, Savard J, Ivers H, Savard MH, Simard S. Utilization of hypnotic medication in the context of cancer: predictors and frequency of use. Support Care Cancer. 2012;20:1203–10.PubMedCrossRefGoogle Scholar
  161. 161.
    Thekdi SM, Trinidad A, Roth A. Psychopharmacology in cancer. Curr Psychiatry Rep. 2015;17:529.PubMedCrossRefGoogle Scholar
  162. 162.
    Dallmann R, Okyar A, Levi F. Dosing-time makes the poison: circadian regulation and pharmacotherapy. Trends Mol Med. 2016;22:430–45.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Daniel Pedro Cardinali
    • 1
  1. 1.Facultad de Ciencias MédicasPontificia Universidad Católica ArgentinaBuenos AiresArgentina

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