Skip to main content
SpringerLink
Log in
Book cover

Melatonin and Melatonergic Drugs in Clinical Practice pp 263–273Cite as

Melatonin and Its Agonists in Sleep Disorders

  • Chapter
  • First Online:

  • 1635 Accesses

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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.

    Article  CAS  PubMed  Google Scholar 

  2. Shochat T, Haimov I, Lavie P. Melatonin: the key to the gate of sleep. Ann Med. 1998;30(1):109–14.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  4. Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin – a sleep-promoting hormone. Sleep. 1997;20:899–907.

    CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  13. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2006;16:93–100.

    Article  CAS  PubMed  Google Scholar 

  14. Llorca PM. The antidepressant agomelatine improves the quality of life of depressed patients: implications for remission. J Psychopharmacol. 2010;24:21–6.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  18. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86(10):4727–30.

    CAS  PubMed  Google Scholar 

  19. Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ. 1994;309:167.

    Article  CAS  PubMed  Google Scholar 

  20. Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep. 1997;20:124–31.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms. 1997;12:657–65.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004;5:523–32.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Saper CB, Lu J, Chou TC, Gooley J. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 2005;28:152–7.

    Article  CAS  PubMed  Google Scholar 

  32. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–63.

    Article  CAS  PubMed  Google Scholar 

  33. Kalsbeek A, Perreau-Lenz S, Buijs RM. A network of (autonomic) clock outputs. Chronobiol Int. 2006;23:521–35.

    Article  CAS  PubMed  Google Scholar 

  34. Reghunandanan V, Reghunandanan R. Neurotransmitters of the suprachiasmatic nuclei. J Circadian Rhythms. 2006;4:2.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  37. Cajochen C. TAK-375 Takeda. Curr Opin Investig Drugs. 2005;6:114–21.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  53. Dobkin RD, Menza M, Bienfait KL, et al. Ramelteon for the treatment of insomnia in menopausal women. Menopause Int. 2009;15:13–8.

    PubMed Central  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  58. Lam RW. Sleep disturbances and depression: a challenge for antidepressants. Int Clin Psychopharmacol. 2006;21(Suppl1):S25–9.

    Article  PubMed  Google Scholar 

  59. Kupfer DJ. Depression and associated sleep disturbances: patient benefits with agomelatine. Eur Neuropsychopharmacol. 2006;16 Suppl 5:S639–43.

    Article  CAS  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  71. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 2007;9:628–35.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  75. Hardeland R, Poeggeler B, Srinivasan V, et al. Melatonergic drugs in clinical practice. Arzneimittelforschung. 2008;58:1–10.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  78. Lankford DA. Tasimelteon for insomnia. Expert Opin Investig Drugs. 2011;20:987–93.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Hadassah Hebrew-University Medical Center, Ein-Kerem, Jerusalem, 91120, Israel

    Amnon Brzezinski MD

Authors
  1. Amnon Brzezinski MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amnon Brzezinski MD .

Editor information

Editors and Affiliations

  1. Sri Sathya Sai Medical Educational and Research Foundation, An International Medical Sciences Research Center, Coimbatore, Tamil Nadu, India

    V. Srinivasan

  2. Department of Obstetrics and Gynecology, Hadassah Hebrew-University Medical Center, Jerusalem, Israel

    Amnon Brzezinski

  3. Department of Physiology, Gulhane Military Medical Academy, Ankara, Turkey

    Sukru Oter

  4. Department of Psychiatry Behavioral Sciences, Mercer University School of Medicine, Macon, Georgia, USA

    Samuel D. Shillcutt

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer India

About this chapter

Cite this chapter

Brzezinski, A. (2014). Melatonin and Its Agonists in Sleep Disorders. In: Srinivasan, V., Brzezinski, A., Oter, S., Shillcutt, S. (eds) Melatonin and Melatonergic Drugs in Clinical Practice. Springer, New Delhi. https://doi.org/10.1007/978-81-322-0825-9_18

Download citation

  • DOI: https://doi.org/10.1007/978-81-322-0825-9_18

  • Published:

  • Publisher Name: Springer, New Delhi

  • Print ISBN: 978-81-322-0824-2

  • Online ISBN: 978-81-322-0825-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation