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Sleep and Vigilance

, Volume 2, Issue 1, pp 23–31 | Cite as

Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man

  • Jaime M. MontiEmail author
  • Pablo Torterolo
  • David Warren Spence
  • Seithikurippu R. Pandi-PerumalEmail author
Review

Abstract

Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.

Keywords

Serotonin 5-HT2A inverse agonist 5-HT2A receptor antagonist N3 sleep NREM sleep REM sleep 

References

  1. 1.
    Iber C, Ancoli-Israel S, Chesson A, Quan SF. Manual for the scoring of sleep and associated events: rules, terminology, and technical specification. Westchester: American Academy of Sleep Medicine; 2007.Google Scholar
  2. 2.
    Monti JM. Sleep laboratory and clinical studies of the effects of triazolam, flunitrazepam and flurazepam in insomniac patients. Methods Find Exp Clin Pharmacol. 1981;3:303–26.PubMedGoogle Scholar
  3. 3.
    Rodríguez JC, Dzierzewski JM, Alessi CA. Sleep problems in the elderly. Med Clin N Am. 2015;99:431–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Ackermann S, Rasch B. Differential effects of non-REM and REM sleep on memory consolidation? Curr Neurol Neurosci Rep. 2014;14:430.CrossRefPubMedGoogle Scholar
  5. 5.
    Wagner U, Degirmenci M, Drosopoulos S, Perras B, Born J. Effects of cortisol suppression on sleep-associated consolidation of neutral and emotional memory. Biol Psychiatry. 2005;58:885–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Rasch B, Born J. About sleep´s role in memory. Physiol Rev. 2013;93:681–766.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Backhaus J, Junghanns K, Born J, Hohaus K, Faasch F, et al. Impaired declarative memory consolidation during sleep in patients with primary insomnia. Influence of sleep architecture and nocturnal cortisol release. Biol Psychiatry. 2006;60:1324–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Cipolli C, Mazzetti M, Plazzi G. Sleep-dependent memory consolidation in patients with sleep disorders. Sleep Med Rev. 2013;17:91–103.CrossRefPubMedGoogle Scholar
  9. 9.
    Griessenberger H, Heib DP, Lechinger J, Luketina N, Petzka M, et al. Susceptibility to declarative memory interference is pronounced in primary insomnia. PLoS One. 2013;8:e57394.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cellini N, de Zambotti M, Covassin N, Sarlo M, Stegagno L. Impaired off-line motor skills consolidation in young primary insomniacs. Neurobiol Learn Mem. 2014;114:141–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Scullin MK. Sleep, memory, and aging: the link between slow-wave sleep and episodic memory changes from younger to older adults. Psychol Aging. 2013;28:105–14.CrossRefPubMedGoogle Scholar
  12. 12.
    American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014.Google Scholar
  13. 13.
    Baglioni C, Regen W, Teghen A, Spiegelhalder K, Feige B, et al. Sleep changes in the disorder of insomnia: a meta-analysis of polysomnographic studies. Sleep Med Rev. 2014;18:195–213.CrossRefPubMedGoogle Scholar
  14. 14.
    Kales A, Kales JD. Evaluation and treatment of insomnia. New York: Oxford University Press; 1984.Google Scholar
  15. 15.
    Monti JM, Pandi-Perumal SR, Langer SZ. Zolpidem: its use in the treatment of sleep disorders. In: Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ, editors. Sleep disorders—diagnosis and therapeutics. London: Informa Healthcare; 2008. p. 295–323.CrossRefGoogle Scholar
  16. 16.
    Monti JM, Pandi-Perumal SR. Eszopiclone: its use in the treatment of insomnia. Neuropsychiatr Dis Treat. 2007;3:441–53.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Walsh JK, Vogel GW, Scharf M, Erman M, William EC, et al. A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of insomnia. Sleep Med. 2000;1:41–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Med. 2014;15:385–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Krystal AD, Lankford A, Durrence HH, Ludington E, Rogowski R, et al. Efficacy and safety of doxepin 3 mg and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep. 2011;34:1433–42.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Norman JL, Anderson SL. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia—critical appraisal of suvorexant. Nat Sci Sleep. 2016;8:239–47.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Stahl SM. Mechanism of action of suvorexant. CNS Spectr. 2016;21:215–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 2012;79:2265–74.CrossRefPubMedGoogle Scholar
  23. 23.
    Dugovic C, Wauquier A. 5-HT2 receptors could be primarily involved in the regulation of slow-wave sleep in the rat. Eur J Pharmacol. 1987;137:145–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Sharpley AL, Solomon RA, Fernando AI, da Roza Davis JM, Cowen PJ. Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans. Psychopharmacology. 1990;101:568–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Monti JM, Jantos H. Effects of the serotonin 5-HT2A/2C receptor agonist DOI and of the selective 5-HT2A or 5-HT2C receptor antagonists EMD 281014 and SB-243213, respectively, on sleep and waking in the rat. Eur J Pharmacol. 2006;553:163–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Popa D, Lena C, Fabre V, Prenat C, Gingrich J, et al. Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci. 2005;25:11231–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Cornea-Hébert V, Riad M, Wu C, Singh SK, Descarries L. Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol. 1999;409:187–209.CrossRefPubMedGoogle Scholar
  28. 28.
    Monti JM, Jantos H. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Progr Brain Res. 2009;172:625–46.CrossRefGoogle Scholar
  29. 29.
    Idzikowski C, Mills FJ, Glennard R. 5-Hydroxytryptamine-2-antagonist ritanserin increases human slow wave sleep. Brain Res. 1986;378:164–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Idzikowski C, Cowen PJ, Mills FJ. The effect of chronic ritanserin treatment on sleep and the neuroendocrine response to L-tryptophan. Psychopharmacology. 1987;93:416–20.CrossRefPubMedGoogle Scholar
  31. 31.
    Sharpley AL, Elliot JM, Attenburrow MJ, Cowen PJ. Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors. Neuropharmacology. 1994;33:467–71.CrossRefPubMedGoogle Scholar
  32. 32.
    Dijk DJ, Beersma DGM, Daan S, van den Hoofdakker RH. Effects of seganserin, and temazepam on human sleep stages and EEG power spectra. Eur J Pharmacol. 1989;171:207–18.CrossRefPubMedGoogle Scholar
  33. 33.
    Adam K, Oswald I. Effects of repeated ritanserin on middle-aged poor sleepers. Psychopharmacology. 1989;99:219–21.CrossRefPubMedGoogle Scholar
  34. 34.
    Ruiz-Primo E, Haro R, Valencia M. Polysomnographic effects of ritanserin in insomniacs. A crossed double-blind controlled study. Sleep Res. 1989;18:72.Google Scholar
  35. 35.
    Monti JM, Alterwain P, Estévez F, Alvariño F, Giusti M, et al. The effects of ritanserin on mood and sleep in abstinent alcoholic patients. Sleep. 1993;16:647–54.CrossRefPubMedGoogle Scholar
  36. 36.
    da Roza Davis JM, Sharpley AL, Cowen PJ. Slow wave sleep and 5-HT2 receptor sensitivity in generalized anxiety disorder. Psychopharmacology. 1992;108:387–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Paiva T, Arriaga F, Wauquier A, Lara E, Largo R, et al. Effects of ritanserin on sleep disturbances of dysthymic patients. Psychopharmacology. 1988;96:395–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Staner L, Kempenaers C, Simonnet MP, Fransolet L, Mendlewicz J. 5-HT2 receptor antagonism and slow wave sleep in major depression. Acta Psychiatr Scand. 1992;86:133–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Rinaldi-Carmona M, Congy C, Pointeau P, Vidal H, Beliére JC, et al. Identification of binding sites for SR 463449B, a 5-hydroxytryptamine2receptor antagonist, in rodent brain. Life Sci. 1994;54:119–27.CrossRefPubMedGoogle Scholar
  40. 40.
    Francon D, Decobert M, Herve B, Richard A, Griebel G, et al. Eplivanserin promotes sleep maintenance in rats. Sleep Biol Rhythms. 2007;5:A3.Google Scholar
  41. 41.
    Landolt HP, Viola M, Burgess HJ, Finelli LA, Cattelin F, et al. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology. 1999;21:455–66.CrossRefPubMedGoogle Scholar
  42. 42.
    Al-Shamma HA, Anderson C, Chuang F, Luthringer R, Grottick AJ, et al. Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia. J Pharmacol Exp Ther. 2010;322:281–90.CrossRefGoogle Scholar
  43. 43.
    Rosenberg R, Seiden DJ, Hull SG, Erman M, Schwartz H, et al. APD125, a selective serotonin 5-HT2A receptor inverse agonist, significantly improves sleep maintenance in primary insomnia. Sleep. 2008;31:1663–71.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin tartrate, a 5-HT2A receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. 2011;12:134–41.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Morairty SR, Hedely L, Flores J, Martin R, Kilduff TS. Selective 5-HT2A and 5-HT6 receptor antagonists promote sleep in rats. Sleep. 2008;31:34–44.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Vanover KE, Davis RE. Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep. 2010;2:139–50.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Monti JM, Jantos H. Effects of the 5-HT6 receptor antagonists SB-399885 and RO-4368554 and of the 5-HT2A receptor antagonist EMD 281014 on sleep and wakefulness in the rat during both phases of the light-dark cycle. Behav Brain Res. 2011;216:381–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Ivgy-May N, Roth T, Ruwe F, Walsh J. Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a 2-week randomized outpatient trial. Sleep Med. 2015;16:831–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Ivgy-May N, Ruwe F, Krystal A, Roth T. Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory study. Sleep Med. 2015;16:838–44.CrossRefPubMedGoogle Scholar
  50. 50.
    Griebel G, Beeské S, Jacquet A, Laufrais C, Alonso R, et al. Further evidence for the sleep-promoting effects of 5-HT2A receptor antagonists and demonstration of synergistic effects with the hypnotic zolpidem in rats. Neuropharmacology. 2013;70:19–26.CrossRefPubMedGoogle Scholar
  51. 51.
    Chendo I, Ferreira JJ. Pimavanserin for the treatment of Parkinson´s disease psychosis. Expert Opin Pharmacother. 2016;17:2115–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics, School of Medicine Clinics HospitalUniversity of the RepublicMontevideoUruguay
  2. 2.Department of Physiology, School of MedicineUniversity of the RepublicMontevideoUruguay
  3. 3.Dufferin StreetTorontoCanada
  4. 4.Somnogen Canada IncTorontoCanada

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