Journal of Autism and Developmental Disorders

, Volume 41, Issue 4, pp 427–433 | Cite as

Relation of Melatonin to Sleep Architecture in Children with Autism

  • Roberta M. Leu
  • Liya Beyderman
  • Emmanuel J. Botzolakis
  • Kyla Surdyka
  • Lily Wang
  • Beth A. Malow
Original Paper

Abstract

Children with autism often suffer from sleep disturbances, and compared to age-matched controls, have decreased melatonin levels, as indicated by urine levels of the primary melatonin metabolite, 6-sulfatoxymelatonin (6-SM). We therefore investigated the relationship between 6-SM levels and sleep architecture in children with autism spectrum disorders (ASD). Twenty-three children, aged 4–10 years, completed two nights of polysomnography and one overnight urine collection for measurement of urinary 6-SM excretion rate. Parents completed the Children’s Sleep Habits Questionnaire. We found that higher urinary 6-SM excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime sleepiness. The results warrant further examination to examine the effects of supplemental melatonin on sleep architecture and daytime sleepiness.

Keywords

6-Sulfatoxymelatonin 6-SM Sleep stages Children’s Sleep Habits Questionnaire Parental Concerns Questionnaire Polysomnography 

Notes

Acknowledgments

Support provided by the National Alliance for Autism Research/Autism Speaks Foundation.

References

  1. Allik, H., Larsson, J. O., & Smedje, H. (2006). Insomnia in school-age children with Asperger syndrome or high-functioning autism. BMC Psychiatry, 6, 18.PubMedCrossRefGoogle Scholar
  2. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders, 4th edition. text revision. Washington, DC: American Psychiatric Association.CrossRefGoogle Scholar
  3. Andersen, I. M., Kaczmarska, J., McGrew, S. G., & Malow, B. A. (2008). Melatonin for insomnia in children with autism spectrum disorders. Journal of Child Neurology, 23(5), 482–485.PubMedCrossRefGoogle Scholar
  4. Autism and Developmental Disabilities Monitoring Network, United States, 2006. (2009). Prevalence of autism spectrum disorders. MMWR Surveillance Summaries, 58(1), 57–66.Google Scholar
  5. Beck-Friis, J., von Rosen, D., Kjellman, B. F., Ljunggren, J. G., & Wetterberg, L. (1984). Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendocrinology, 9(3), 61–277.CrossRefGoogle Scholar
  6. Bojkowski, C. J., & Arendt, J. (1988). Annual changes in 6-sulphatoxymelatonin excretion in man. Acta Endocrinologica, 117(4), 470–476.PubMedGoogle Scholar
  7. Brzezinski, A., Vangel, M. G., Wurtman, R. J., Norrie, G., Zhdanova, I., Ben-Shushan, A., et al. (2005). Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Medicine Reviews, 9(1), 41–50.PubMedCrossRefGoogle Scholar
  8. Cagnacci, A. (1996). Melatonin in relation to physiology in adult humans. Journal of Pineal Research, 21(4), 200–213.PubMedCrossRefGoogle Scholar
  9. Cardinali, D. P., & Pevet, P. (1998). Basic aspects of melatonin action. Sleep Medicine Reviews, 2(3), 175–190.PubMedCrossRefGoogle Scholar
  10. Chamberlain, R. S., & Herman, B. H. (1990). A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biological Psychiatry, 28(9), 773–793.PubMedCrossRefGoogle Scholar
  11. Champier, J., Claustrat, B., Besancon, R., Eymin, C., Killer, C., Jouvet, A., et al. (1997). Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets. Life Sciences, 60(24), 2191–2197.PubMedCrossRefGoogle Scholar
  12. Conti, A., Conconi, S., Hertens, E., Skwarlo-Sonta, K., Markowska, M., & Maestroni, J. M. (2000). Evidence for melatonin synthesis in mouse and human bone marrow cells. Journal of Pineal Research, 28(4), 193–202.PubMedCrossRefGoogle Scholar
  13. Couturier, J. L., Speechley, K. N., Steele, M., Norman, R., Stringer, B., & Nicolson, R. (2005). Parental perception of sleep problems in children of normal intelligence with pervasive developmental disorders: Prevalence, severity, and pattern. Journal of the American Academy of Child and Adolescent Psychiatry, 44(8), 815–822.PubMedCrossRefGoogle Scholar
  14. Garstang, J., & Wallis, M. (2006). Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child: Care, Health and Development, 32(5), 585–589.CrossRefGoogle Scholar
  15. Giannotti, F., Cortesi, F., Cerquiglini, A., & Bernabei, P. (2006). An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. Journal of Autism and Developmental Disorders, 36(6), 741–752.PubMedCrossRefGoogle Scholar
  16. Goldman, S. E., Surdyka, K., Cuevas, R., Adkins, K., Wang, L., & Malow, B. A. (2009). Defining the sleep phenotype in children with autism. Developmental Neuropsychology, 34(5), 560–573.PubMedCrossRefGoogle Scholar
  17. Goodlin-Jones, B. L., Sitnick, S. L., Tang, K., Liu, J., & Anders, T. F. (2008a). The children’s sleep habits questionnaire in toddlers and preschool children. Journal of Developmental and Behavioral Pediatrics, 29(2), 82–88.PubMedCrossRefGoogle Scholar
  18. Goodlin-Jones, B. L., Tang, K., Liu, J., & Anders, T. F. (2008b). Sleep patterns in preschool-age children with autism, developmental delay, and typical development. Journal of the American Academy of Child and Adolescent Psychiatry, 47(8), 930–938.PubMedGoogle Scholar
  19. Graham, C., Cook, M. R., Kavet, R., Sastre, A., & Smith, D. K. (1998). Prediction of nocturnal plasma melatonin from morning urinary measures. Journal of Pineal Research, 24(4), 230–238.PubMedCrossRefGoogle Scholar
  20. Honomichl, R. D., Goodlin-Jones, B. L., Burnham, M., Gaylor, E., & Anders, T. F. (2002). Sleep patterns of children with pervasive developmental disorders. Journal of Autism and Developmental Disorders, 32(6), 553–561.PubMedCrossRefGoogle Scholar
  21. Iber, C., Ancoli-Israel, S., Chesson, A. L., Quan, S. F., & for the American Academy of Sleep Medicine. (2007). The AASM manual for scoring of sleep and associated events: Rules, terminology and technical specification (1st ed.). Westchester, IL: American Academy of Sleep Medicine.Google Scholar
  22. Jan, J. E., Hamilton, D., Seward, N., Fast, D. K., Freeman, R. D., & Laudon, M. (2000). Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. Journal of Pineal Research, 29(1), 34–39.PubMedCrossRefGoogle Scholar
  23. Kauppila, A., Kivela, A., Pakarinen, A., & Vakkuri, O. (1987). Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. The Journal of Clinical Endocrinology and Metabolism, 65(5), 823–828.PubMedCrossRefGoogle Scholar
  24. Kulman, G., Lissoni, P., Rovelli, F., Roselli, M. G., Brivio, F., & Sequeri, P. (2000). Evidence of pineal endocrine hypofunction in autistic children. Neuroendocrinology Letters, 21(1), 31–34.PubMedGoogle Scholar
  25. Luboshitzky, R., Yanai, D., Shen-Orr, Z., Israeli, E., Herer, P., & Lavie, P. (1998). Daily and seasonal variations in the concentration of melatonin in the human pineal gland. Brain Research Bulletin, 47(3), 271–276.PubMedCrossRefGoogle Scholar
  26. Malow, B. A. (2004). Sleep disorders, epilepsy, and autism. Mental Retardation and Developmental Disabilities Research Reviews, 10(2), 122–125.PubMedCrossRefGoogle Scholar
  27. Malow, B. A., Marzec, M. L., McGrew, S. G., Wang, L., Henderson, L. M., & Stone, W. L. (2006). Characterizing sleep in children with autism spectrum disorders: A multidimensional approach. Sleep, 29(12), 1563–1571.PubMedGoogle Scholar
  28. McGrew, S., Malow, B. A., Henderson, L., Wang, L., Song, Y., & Stone, W. L. (2007). Developmental and behavioral questionnaire for autism spectrum disorders. Pediatric Neurology, 37(2), 108–116.PubMedCrossRefGoogle Scholar
  29. Melke, J., Goubran Botros, H., Chaste, P., Betancur, C., Nygren, G., Anckarsater, H., et al. (2008). Abnormal melatonin synthesis in autism spectrum disorders. Molecular Psychiatry, 13(1), 90–98.PubMedCrossRefGoogle Scholar
  30. Nir, I., Meir, D., Zilber, N., Knobler, H., Hadjez, J., & Lerner, Y. (1995). Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism. Journal of Autism and Developmental Disorders, 25(6), 641–654.PubMedCrossRefGoogle Scholar
  31. Nowak, R., McMillen, I. C., Redman, J., & Short, R. V. (1987). The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: Two non-invasive techniques for monitoring human circadian rhythmicity. Clinical Endocrinology (Oxford), 27(4), 445–452.CrossRefGoogle Scholar
  32. Owens, J. A., Spirito, A., & McGuinn, M. (2000). The children’s sleep habits questionnaire (CSHQ): Psychometric properties of a survey instrument for school-aged children. Sleep, 23(8), 1043–1051.PubMedGoogle Scholar
  33. Paavonen, E. J., Nieminen-von Wendt, T., Vanhala, R., Aronen, E. T., & von Wendt, L. (2003). Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. Journal of Child and Adolescent Psychopharmacology, 13(1), 83–95.PubMedCrossRefGoogle Scholar
  34. Richdale, A. L. (1999). Sleep problems in autism: Prevalence, cause, and intervention. Developmental Medicine and Child Neurology, 41(1), 60–66.PubMedCrossRefGoogle Scholar
  35. Ronnberg, L., Kauppila, A., Leppaluoto, J., Martikainen, H., & Vakkuri, O. (1990). Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. The Journal of Clinical Endocrinology and Metabolism, 71(2), 492–496.PubMedCrossRefGoogle Scholar
  36. Schreck, K. A., Mulick, J. A., & Smith, A. F. (2004). Sleep problems as possible predictors of intensified symptoms of autism. Research in Developmental Disabilities, 25(1), 57–66.PubMedCrossRefGoogle Scholar
  37. Sivan, Y., Laudon, M., Tauman, R., & Zisapel, N. (2001). Melatonin production in healthy infants: Evidence for seasonal variations. Pediatric Research, 49(1), 63–68.PubMedCrossRefGoogle Scholar
  38. Slominski, A., Tobin, D. J., Zmijewski, M. A., Wortsman, J., & Paus, R. (2008). Melatonin in the skin: Synthesis, metabolism and functions. Trends in Endocrinology and Metabolism, 19(1), 17–24.PubMedCrossRefGoogle Scholar
  39. Tordjman, S., Anderson, G. M., Pichard, N., Charbuy, H., & Touitou, Y. (2005). Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biological Psychiatry, 57(2), 134–138.PubMedCrossRefGoogle Scholar
  40. Wiggs, L., & Stores, G. (2004). Sleep patterns and sleep disorders in children with autistic spectrum disorders: Insights using parent report and actigraphy. Developmental Medicine and Child Neurology, 46(6), 372–380.PubMedCrossRefGoogle Scholar
  41. Williams, P. G., Sears, L. L., & Allard, A. (2004). Sleep problems in children with autism. Journal of Sleep Research, 13, 265–268.CrossRefGoogle Scholar
  42. Wirojanan, J., Jacquemont, S., Diaz, R., Bacalman, S., Anders, T. F., Hagerman, R. J., et al. (2009). The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. Journal of Clinical Sleep Medicine, 5(2), 145–150.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Roberta M. Leu
    • 1
  • Liya Beyderman
    • 1
  • Emmanuel J. Botzolakis
    • 4
  • Kyla Surdyka
    • 1
  • Lily Wang
    • 2
  • Beth A. Malow
    • 1
    • 3
  1. 1.Sleep Disorders Division, Department of NeurologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of BiostatisticsVanderbilt University School of MedicineNashvilleUSA
  3. 3.Vanderbilt Kennedy Center for Human DevelopmentVanderbilt UniversityNashvilleUSA
  4. 4.Medical Scientist Training ProgramVanderbilt University School of MedicineNashvilleUSA

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