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Melatonergic Drug: Ramelteon and Its Therapeutic Applications in Insomnia

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Melatonin and Melatonergic Drugs in Clinical Practice

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Abstract

The efficacy of melatonin in promoting and maintaining sleep has been demonstrated in most of the clinical studies. However, because of its short half-life, its sustained effect in improving sleep quality could not be demonstrated uniformly in all the studies that have been undertaken so far. The development of slow-release melatonin preparation Circadin has been found effective in reducing sleep onset time and also for improving sleep quality. This was followed by the introduction of another melatonergic drug ramelteon a melatonin receptor agonist that has high selectivity for MT1 receptors than MT2 receptors and therefore targets sleep onset more specifically than melatonin. Clinical trials undertaken in different countries of European region and Japan have conclusively demonstrated that ramelteon in various doses (from 4 to 32 mg/day) reduced sleep onset latency, increased total sleep time, and sleep efficiency and quality in patients suffering from chronic insomnia. Besides acting as a sedative-hypnotic drug, ramelteon also demonstrated its ability as a drug with chronobiotic properties and has been found useful in resetting the disturbed circadian rhythms. The action of ramelteon in improving sleep efficiency is dose independent and hence acts differently from melatonin. It has a promising value in treating patients with chronic insomnia as it does not have any of the adverse effects like next-day hangover and dependence associated with the usage of other conventional hypnotic drugs.

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References

  1. Lerner AB, Case JD, Takahashi Y, Lee TH, Mori N. Isolation of melatonin a pineal factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587.

    Article  CAS  Google Scholar 

  2. Tricoire H, Moller H, Chemineau P, Malpaux B. Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reprod Suppl. 2003;61:311–21.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Borbely AA. A two process model of sleep regulation. Hum Neurobiol. 1982;1:195–204.

    CAS  PubMed  Google Scholar 

  5. Dijk DJ, Cajochen C. Melatonin and the circadian regulation of sleep initiation, consolidation, structure and sleep EEG. J Biol Rhythms. 1997;12:627–35.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

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

    Article  CAS  PubMed  Google Scholar 

  8. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86:4727–30.

    CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms. 1997;12:604–17.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. 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 

  14. 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 

  15. Srinivasan V, Zakaria R, Othman Z, Brzezinski A, Prasad A, Brown GM. Melatonergic drugs for insomnia and sleep disturbances of mood disorders. CNS Neurol Disord Drug Targets. 2012;11:180–9.

    Article  CAS  PubMed  Google Scholar 

  16. Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc. 2001;49:1185–9.

    Article  CAS  PubMed  Google Scholar 

  17. Bastien CH. Insomnia: neurophysiological and neuropsychological approaches. Neuropsychol Rev. 2011;21:22–40.

    Article  PubMed  Google Scholar 

  18. Van Someren J. Circadian and sleep disturbances in the elderly. Exp Gerontol. 2000;35:1229–37.

    Article  PubMed  Google Scholar 

  19. Montgomery P, Dennis J. A systematic review of non-pharmacological therapies for sleep problems in later life. Sleep Med Rev. 2004;8:47–62.

    Article  PubMed  Google Scholar 

  20. Mendelson WB. Melatonin microinjection into the medial preoptic area increases sleep in the rat. Life Sci. 2002;71:2067–70.

    Article  CAS  PubMed  Google Scholar 

  21. Golombek DA, Pevet P, Cardinali DP. Melatonin effect on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Rev. 1996;20:403–12.

    Article  CAS  PubMed  Google Scholar 

  22. Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, Reppert SM. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997;19:91–102.

    Article  CAS  PubMed  Google Scholar 

  23. Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci U S A. 1994;91:1824–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541–4.

    Article  CAS  PubMed  Google Scholar 

  25. Zhdanova IV, Wurtman RJ, Lynch HJ, Ives JR, Dollins AB, Morabito C, Matheson JK, Schomer DL. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995;57:552–8.

    Article  CAS  PubMed  Google Scholar 

  26. Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2–4 hours before habitual bedtime, on sleep in normal young humans. Sleep. 1996;19:423–31.

    CAS  PubMed  Google Scholar 

  27. Monti JM, Alvarino F, Cardinali D, Savio I, Pintos A. Polysomnographic study of the effect of melatonin on sleep in elderly patients with chronic primary insomnia. Arch Gerontol Geriatr. 1999;28:85–98.

    Article  CAS  PubMed  Google Scholar 

  28. Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9:41–50.

    Article  PubMed  Google Scholar 

  29. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006;332:385–93.

    Article  CAS  PubMed  Google Scholar 

  30. Gorfine T, Assaf Y, Goshen-Gottstein Y, Yeshurun Y, Zisapel N. Sleep-anticipating effects of melatonin in the human brain. Neuroimage. 2006;31:410–8.

    Article  PubMed  Google Scholar 

  31. Mendelson WB. A critical evaluation of the hypnotic efficacy of melatonin. Sleep. 1997;20:916–9.

    CAS  PubMed  Google Scholar 

  32. Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25:48–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry. 2007;68:1723–32.

    Article  CAS  PubMed  Google Scholar 

  34. Wade AG, Crawford G, Ford I, McConnachie A, Nir T, Laudon M, Zisapel N. Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Curr Med Res Opin. 2011;27:87–98.

    Article  CAS  PubMed  Google Scholar 

  35. Gerdin MJ, Masana MI, Rivera-Bermudez MA, Hudson RL, Earnest DJ, Gillette MU, Dubocovich ML. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J. 2004;18:1646–56.

    Article  CAS  PubMed  Google Scholar 

  36. Ying SW, Rusak B, Mocaer B. Chronic exposure to melatonin receptor agonists does not alter their effects on suprachiasmatic nucleus neurons. Eur J Pharmacol. 1998;342:29–37.

    Article  CAS  PubMed  Google Scholar 

  37. Masana MI, Benloucif S, Dubocovich L. Circadian rhythm of MT1 melatonin receptor in the suprachiasmatic nucleus of the C3H/HeN mouse. J Pineal Res. 2000;28:185–92.

    Article  CAS  PubMed  Google Scholar 

  38. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48:301–10.

    Article  CAS  PubMed  Google Scholar 

  39. 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 

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

    CAS  PubMed  Google Scholar 

  41. Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007;47:485–96.

    Article  CAS  PubMed  Google Scholar 

  42. Wu YH, Zhou JN, Balesar R, Unmehopa U, Bao A, Jockers R, Van Heerikhuize J, Swaab DF. Distribution of MT1 melatonin 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 

  43. Reppert SM, Weaver DR, Rivkees SA, Stopa EG. Putative melatonin receptors in a human biological clock. Science. 1988;242(4875):78–81.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  46. 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 

  47. Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21:482–93.

    Article  CAS  PubMed  Google Scholar 

  48. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005;28:303–7.

    PubMed  Google Scholar 

  49. Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7:312–8.

    Article  PubMed  Google Scholar 

  50. 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 

  51. 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 

  52. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007;3:495–504.

    PubMed  Google Scholar 

  53. DeMicco M, Wang-Weigand S, Zhang J. Long-term therapeutic effects of ramelteon treatment in adults with chronic insomnia: a 1 year study. Sleep. 2006;29(Abstract Suppl):A234.

    Google Scholar 

  54. Richardson GS, Wang-Weigand S, Zhang J, DeMicco M. Long-term safety of ramelteon treatment in adults with chronic insomnia: a 1-year study. Sleep. 2006;29(Abstract Suppl):A233.

    Google Scholar 

  55. 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 

  56. Dobkin RD, Menza M, Bienfait KL, Allen LA, Marin H, Gara MA. Ramelteon for the treatment of insomnia in menopausal women. Menopause Int. 2009;15:13–8.

    PubMed Central  PubMed  Google Scholar 

  57. Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep. 2009;32:351–60.

    PubMed  Google Scholar 

  58. Uchimura N, Ogawa A, Hamamura M, Hashimoto T, Nagata H, Uchiyama M. 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 

  59. Uchiyama M, Hamamura M, Kuwano T, Nagata H, Hashimoto T, Ogawa A, Uchimura N. Long-term safety and efficacy of ramelteon in Japanese patients with chronic insomnia. Sleep Med. 2011;12:127–33.

    Article  PubMed  Google Scholar 

  60. Zammit G, Schwartz H, Roth T, Wang-Weigand S. The effects of ramelteon in a first-night model of transient insomnia. Sleep Med. 2009;10(1):55–9.

    Article  PubMed  Google Scholar 

  61. Kohsaka M, Kanemura T, Taniguchi M, Kuwahara H, Mikami A, Kamikawa K, Uno H, Ogawa A, Murasaki M, Sugita Y. Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia. Expert Rev Neurother. 2011;11(10):1389–97.

    Article  PubMed  Google Scholar 

  62. Richardson GS, Zee PC, Wang-Weigand S, Rodriguez L, Peng X. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med. 2008;4:456–61.

    PubMed  Google Scholar 

  63. Srinivasan V, Pandi-Perumal SR, Trahkt I, Spence DW, Poeggeler B, Hardeland R, Cardinali DP. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119:821–46.

    Article  CAS  PubMed  Google Scholar 

  64. McElroy SL, Winstanley EL, Martens B, Patel NC, Mori N, Moeller D, McCoy J, Keck Jr PE. A randomized, placebo-controlled study of adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep disturbance. Int Clin Psychopharmacol. 2011;26(1):48–53.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sri Sathya Sai Medical Educational and Research Foundation, An International Medical Sciences Research Study Center, Prasanthi Nilayam, 40-Kovai Thirunagar Extn, Goldwins, Coimbatore, TN, 641014, India

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  2. National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4, Teramo, Italy

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  3. Department of Neuroscience and Imaging, University “G.D’ Annunzio”, Chieti, 66013, Italy

    Venkataramanujam Srinivasan MSc, PhD, MAMS

  4. Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia

    Rahimah Zakaria MBBS, MSc, PhD (Physiology)

  5. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Mannerheimintie 166, FI-00300, Helsinki, Finland

    Timo Partonen MD, PhD

  6. Department of Psychiatry and Behavioral Sciences, and the Department of Internal Medicine, Neurology Section, Mercer University School of Medicine, 655 First Street, Macon, GA, 31201, USA

    Edward C. Lauterbach MD

  7. Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Preetha Sharone Kuppuswamy MD

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

    Amnon Brzezinski MD

  9. Department of Psychiatry, School of Medical Sciences, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia

    Zahiruddin Othman MD, MMed (Psychiatry)

  10. Department of Neurology, Dr BL Kapur Superspeciality Hospital, Pusa Road, New Delhi, DL, 110005, India

    Atul Prasad MBBS, DM (Neurology)

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  1. Venkataramanujam Srinivasan MSc, PhD, MAMS
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  2. Rahimah Zakaria MBBS, MSc, PhD (Physiology)
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  3. Timo Partonen MD, PhD
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  4. Edward C. Lauterbach MD
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  5. Preetha Sharone Kuppuswamy MD
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  6. Amnon Brzezinski MD
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  7. Zahiruddin Othman MD, MMed (Psychiatry)
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  8. Atul Prasad MBBS, DM (Neurology)
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Correspondence to Venkataramanujam Srinivasan MSc, PhD, MAMS .

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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

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Srinivasan, V. et al. (2014). Melatonergic Drug: Ramelteon and Its Therapeutic Applications in Insomnia. 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_24

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