Advertisement

Melatonin and Its Agonists in Sleep Disorders

  • Amnon BrzezinskiEmail author
Chapter

Abstract

Exogenous melatonin reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age. Daytime administration of exogenous melatonin (when it is not present endogenously) promotes sleep in humans and results in sleeplike brain activity patterns at specific areas such as the precuneus and hippocampus. However, existing studies on the hypnotic efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration.

The inconsistent reports about the effectiveness of exogenous melatonin in the treatment of insomnia brought about the development of more potent melatonin analogs with prolonged effects and the design of slow-release melatonin preparations. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5-HT2C receptor antagonism, reportedly is effective in the treatment of depression-associated insomnia. A review of the currently available evidence regarding the effects of these compounds on sleep quality is presented in this chapter.

Keywords

Melatonin Melatonin agonists Sleep Insomnia Ramelteon Agomelatine 

References

  1. 1.
    Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.PubMedCrossRefGoogle Scholar
  2. 2.
    Shochat T, Haimov I, Lavie P. Melatonin: the key to the gate of sleep. Ann Med. 1998;30(1):109–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18(7):598–603.PubMedGoogle Scholar
  4. 4.
    Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin – a sleep-promoting hormone. Sleep. 1997;20:899–907.PubMedGoogle Scholar
  5. 5.
    Zhdanova IV, Friedman L. Melatonin for treatment of sleep and mood disorders. In: Mischolon D, Rosenbaum J, editors. Natural medications for psychiatric disorders: considering the alternatives. Philadelphia: Williams & Wilkins; 2002. p. 147–74.Google Scholar
  6. 6.
    Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds 3rd CF, Kupfer D. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA. 1997;278(24):2170–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007;16:372–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48:301–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009;15:32–51.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Pandi-Perumal SR, Srinivasan V, Spence DW, et al. Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009;26:613–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine (S20098) is an antagonist at5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003;306:954–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Srinivasan V, Cardinali DP, Pandi-Perumal SR, Brown GM. Melatonin agonists for treatment of sleep and depressive disorders. J Exptl Integ Med. 2011;1:149–58.CrossRefGoogle Scholar
  13. 13.
    Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16:93–100.PubMedCrossRefGoogle Scholar
  14. 14.
    Llorca PM. The antidepressant agomelatine improves the quality of life of depressed patients: implications for remission. J Psychopharmacol. 2010;24:21–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Srinivasan V, Brzezinski A, Spence DW, et al. Sleep, mood disorders and antidepressants: the melatonergic antidepressant agomelatine offers a new strategy for treatment. Psychiatrica Fennica. 2010;41:168–87.Google Scholar
  16. 16.
    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;373:482–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Zemlan FP, Mulchahey JJ, Scharf MB, et al. The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial. J Clin Psychiatry. 2005;66:384–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86(10):4727–30.PubMedGoogle Scholar
  19. 19.
    Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ. 1994;309:167.PubMedCrossRefGoogle Scholar
  20. 20.
    Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep. 1997;20:124–31.PubMedGoogle Scholar
  21. 21.
    Leger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med. 2004;116:91–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Cajochen C, Jewett ME, Dijk DJ. Human circadian melatonin rhythm phase delay during a fixed sleep-wake schedule interspersed with nights of sleep deprivation. J Pineal Res. 2003;35:149–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms. 1997;12:657–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9:41–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Buscemi N, Vandermeer B, Hooten N, et al. The efficacy and safety off exogenous melatonin for primary sleep disorders: a meta-analysis. J Gen Int Med. 2005;20:1151–8.CrossRefGoogle Scholar
  26. 26.
    Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol. 2009;51(5):340–9.PubMedCrossRefGoogle Scholar
  27. 27.
    European Food Safety Authority. Scientific Opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (ID 1698, 1790, 4080) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J. 2011;9(6):2241.Google Scholar
  28. 28.
    Wilson SJ, Nutt DJ, Alford C, et al. 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
  29. 29.
    Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004;5:523–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes. 2011;4:307–13.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Saper CB, Lu J, Chou TC, Gooley J. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 2005;28:152–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Kalsbeek A, Perreau-Lenz S, Buijs RM. A network of (autonomic) clock outputs. Chronobiol Int. 2006;23:521–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Reghunandanan V, Reghunandanan R. Neurotransmitters of the suprachiasmatic nuclei. J Circadian Rhythms. 2006;4:2.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13:1177–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Dubocovich ML, Delagrange P, Krause DN, et al. International union of basic and clinical pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein coupled melatonin receptors. Pharmacol Rev. 2010;62:343–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Cajochen C. TAK-375 Takeda. Curr Opin Investig Drugs. 2005;6:114–21.PubMedGoogle Scholar
  38. 38.
    Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptorsMT1 and MT2. J Clin Pharmacol. 2007;47:485–96.PubMedCrossRefGoogle Scholar
  39. 39.
    Stevenson S, Bryson S, Amayke D, Hibberd M. Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects. Clin Pharmacol Ther. 2004;75:P22.Google Scholar
  40. 40.
    Wu YH, Zhou JN, Balesar R, et al. Distribution of MT1melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol. 2006;499:897–910.PubMedCrossRefGoogle Scholar
  41. 41.
    Savaskan E, Olivieri G, Meier F, et al. Increased melatonin1a-receptor immunoreactivity in the hippocampus of Alzheimer’s disease patients. J Pineal Res. 2002;32:59–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Savaskan E, Ayoub MA, Ravid R, et al. Reduced hippocampalMT2 melatonin receptor expression in Alzheimer’s disease. J Pineal Res. 2005;38:10–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Savaskan E, Jockers R, Ayoub M, et al. The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer’s disease. Curr Alzheimer Res. 2007;4:47–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Brunner P, Sozer-Topcular N, Jockers R, et al. Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer’s disease. Eur J Histochem. 2006;50:311–6.PubMedGoogle Scholar
  45. 45.
    Srinivasan V, Pandi-Perumal SR, Trahkt I, et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119:821–46.PubMedCrossRefGoogle Scholar
  46. 46.
    Yukuhiro N, Kimura H, Nishikawa H, et al. Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys. Brain Res. 2004;1027:59–66.PubMedCrossRefGoogle Scholar
  47. 47.
    France CP, Weltman RH, Koek W, Cruz CM, Mcmahon LR. Acute and chronic effects of ramelteon in rhesus monkeys (Macaca mulatta): dependence liability studies. Behav Neurosci. 2006;120:535–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7:312–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose–response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7:17–24.PubMedCrossRefGoogle Scholar
  50. 50.
    Roth T, Seiden D, Wang-Weigand S, Zhang J. A 2-night,3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin. 2007;23:1005–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007;3:495–504.PubMedGoogle Scholar
  52. 52.
    Mini L, Wang-Weigand S, Zhang J. Ramelteon 8 mg/d versus placebo in patients with chronic insomnia: post hoc analysis of a 5-week trial using 50% or greater reduction in latency to persistent sleep as a measure of treatment effect. Clin Ther. 2008;30:1316–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Dobkin RD, Menza M, Bienfait KL, et al. Ramelteon for the treatment of insomnia in menopausal women. Menopause Int. 2009;15:13–8.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Mayer G, Wang-Weigand S, Roth-Schechter B, et al. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep. 2009;32:351–60.PubMedGoogle Scholar
  55. 55.
    Uchimura N, Ogawa A, Hamamura M, et al. Efficacy and safety of ramelteon in Japanese adults with chronic insomnia: a randomized, double-blind, placebo-controlled study. Expert Rev Neurother. 2011;11:215–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Uchiyama M, Hamamura M, Kuwano T, et al. Long-term safety and efficacy of ramelteon in Japanese patients with chronic insomnia. Sleep Med. 2011;12:127–33.PubMedCrossRefGoogle Scholar
  57. 57.
    Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. Nat Clin Pract Neurol. 2007;3:221–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Lam RW. Sleep disturbances and depression: a challenge for antidepressants. Int Clin Psychopharmacol. 2006;21(Suppl1):S25–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Kupfer DJ. Depression and associated sleep disturbances: patient benefits with agomelatine. Eur Neuropsychopharmacol. 2006;16 Suppl 5:S639–43.CrossRefGoogle Scholar
  60. 60.
    Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci. 2004;29:126–33.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Bertaina-Anglade V, La Rochelle CD, Boyer PA, Mocaer E. Antidepressant-like effects of agomelatine(S 20098) in the learned helplessness model. Behav Pharmacol. 2006;17:703–13.PubMedCrossRefGoogle Scholar
  62. 62.
    Fuchs E, Simon M, Schmelting B. Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system. Int Clin Psychopharmacol. 2006;21 Suppl 1:S17–20.PubMedCrossRefGoogle Scholar
  63. 63.
    Millan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther. 2006;110:135–370.PubMedCrossRefGoogle Scholar
  64. 64.
    Landolt HP, Wehrle R. Antagonism of serotonergic5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood? Eur J Neurosci. 2009;29:1795–809.PubMedCrossRefGoogle Scholar
  65. 65.
    Varcoe TJ, Kennaway DJ. Activation of 5-HT2C receptors acutely induces Per1 gene expression in the rat SCN in vitro. Brain Res. 2008;1209:19–28.PubMedCrossRefGoogle Scholar
  66. 66.
    Martin JR, Bos M, Jenck F, et al. 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther. 1998;286:913–24.PubMedGoogle Scholar
  67. 67.
    Detanico BC, Piato AL, Freitas JJ, et al. Antidepressant like effects of melatonin in the mouse chronic mild stress model. Eur J Pharmacol. 2009;607:121–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Mcelroy SL, Winstanley EL, Martens B, et al. A randomized, placebo-controlled study of adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep disturbance. Int Clin Psychopharmacol. 2010;26:48–53.CrossRefGoogle Scholar
  69. 69.
    Crupi R, Mazzon E, Marino A, et al. Melatonin treatment mimics the antidepressant action in chronic corticosterone treated mice. J Pineal Res. 2010;49:123–9.PubMedGoogle Scholar
  70. 70.
    Loo H, Hale A, Dhaenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2Cantagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17:239–47.PubMedCrossRefGoogle Scholar
  71. 71.
    Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 2007;9:628–35.PubMedCrossRefGoogle Scholar
  72. 72.
    Di Giannantonio M, Di Iorio G, Guglielmo R, et al. Major depressive disorder, anhedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents. 2011;25:109–14.PubMedGoogle Scholar
  73. 73.
    Lopes MC, Quera-Salva MA, Guilleminault C. Cycling alternating pattern in the NREM sleep of patients within major depressive disorder: baseline results and change overtime with a new antidepressant. Sleep Med. 2005;6(Suppl2):87–8.Google Scholar
  74. 74.
    Lopes MC, Quera-Salva MA, Guilleminault C. Non-REM sleep instability in patients with major depressive disorder: subjective improvement and improvement of non-REM sleep instability with treatment (Agomelatine). Sleep Med. 2007;9:33–41.PubMedCrossRefGoogle Scholar
  75. 75.
    Hardeland R, Poeggeler B, Srinivasan V, et al. Melatonergic drugs in clinical practice. Arzneimittelforschung. 2008;58:1–10.PubMedGoogle Scholar
  76. 76.
    Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71:109–20.PubMedCrossRefGoogle Scholar
  77. 77.
    Vachharajani NN, Yeleswaram K, Boulton DW. Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist. J Pharm Sci. 2003;92:760–72.PubMedCrossRefGoogle Scholar
  78. 78.
    Lankford DA. Tasimelteon for insomnia. Expert Opin Investig Drugs. 2011;20:987–93.PubMedCrossRefGoogle Scholar
  79. 79.
    Mulchahey JJ, Goldwater DR, Zemlan FP. A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin. Life Sci. 2004;75:1843–56.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyHadassah Hebrew-University Medical CenterJerusalemIsrael

Personalised recommendations