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Journal of Autism and Developmental Disorders

, Volume 41, Issue 2, pp 175–184 | Cite as

Melatonin Versus Placebo in Children with Autism Spectrum Conditions and Severe Sleep Problems Not Amenable to Behaviour Management Strategies: A Randomised Controlled Crossover Trial

  • Barry Wright
  • David Sims
  • Siobhan Smart
  • Ahmed Alwazeer
  • Ben Alderson-Day
  • Victoria Allgar
  • Clare Whitton
  • Heather Tomlinson
  • Sophie Bennett
  • Jenni Jardine
  • Nicola McCaffrey
  • Charlotte Leyland
  • Christine Jakeman
  • Jeremy Miles
ORIGINAL PAPER

Abstract

Twenty-two children with autism spectrum disorders who had not responded to supported behaviour management strategies for severe dysomnias entered a double blind, randomised, controlled crossover trial involving 3 months of placebo versus 3 months of melatonin to a maximum dose of 10 mg. 17 children completed the study. There were no significant differences between sleep variables at baseline. Melatonin significantly improved sleep latency (by an average of 47 min) and total sleep (by an average of 52 min) compared to placebo, but not number of night wakenings. The side effect profile was low and not significantly different between the two arms.

Keywords

Melatonin Sleep Autism spectrum disorders Dysomnia 

Notes

Acknowldgments

This research was supported by grants from the York Innovations Fund and the London Law Trust. It was given ethical approval by York Research Ethics Committee and sponsored by Selby and York (North Yorkshire and York) PCT.Thanks to Than Lwin, Anne Worrall-Davies, Clare Dover, Helen Pearce and Greg Richardson for their support on the trial steering groups. Thanks also to Clive Nicholson, the trial monitor and to Chris Davey for her support with data entry.

References

  1. Allik, H., Larson, J. O., & Smedje, H. (2006). Sleep patterns of school age children with asperger syndrome or high functioning autism. Journal of Autism and Developmental Disorders, 36, 585–595.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. Armour, D., & Paton, C. (2004). Melatonin in the treatment of insomnia in children and adolescents. Psychiatric Bulletin, 28, 222–224.CrossRefGoogle Scholar
  4. Bramble, D., & Feehan, C. (2005). Psychiatrists’ use of melatonin with children. Child and Adolescent Mental Health, 10(3), 145–149.CrossRefGoogle Scholar
  5. Buscemi, N., Vandermeer, B., Hooton, N., Pandya, R., Tjosvold, L., Hartling, L., et al. (2006). Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. British Medical Journal, 332, 385–388.CrossRefPubMedGoogle Scholar
  6. Camfield, P., Gordon, K., & Dooley, J. (1996). Melatonin appears ineffective in children with intellectual deficits and fragmented sleep: six ‘N of 1’ trials. Journal of Child Neurology, 11, 341–343.CrossRefPubMedGoogle Scholar
  7. Coppola, G., Iervolino, G., Mastrosimone, M., La Torre, G., Ruiu, F., & Pascotto, A. (2004). Melatonin in wake sleep disorders in children, adolescents and young adults with mental retardation with and without epilepsy: A double blind, cross over placebo controlled trial. Brain Development, 26(6), 373–376.CrossRefPubMedGoogle Scholar
  8. Council Directive (EC) 2001/20/EC of the European parliament and of the council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.Google Scholar
  9. DeMuro, R. L., Nafziger, A. N., Blask, D. E., Menhinick, A. M., & Bertino, J. S. (2000). The absolute bioavailability of oral melatonin. The Journal of Clinical Pharmacology, 40, 781–784.CrossRefGoogle Scholar
  10. Dickerson Mayes, S., & Calhoun, S. L. (2009). Variables related to sleep problems in children with autism. Research in Autism Spectrum Disorders, 3(4), 931–941.CrossRefGoogle Scholar
  11. Dodge, N. N., & Wilson, G. A. (2001). Melatonin for treatment of sleep disorders in children with developmental disabilities. Journal of Child Neurology, 16, 581–584.PubMedGoogle Scholar
  12. Doo, S., & Wing, Y. K. (2006). Sleep problems of children with pervasive developmental disorders: Correlation with parental stress. Developmental Medicine and Child Neurology, 48, 650–655.CrossRefPubMedGoogle Scholar
  13. Einfield, S. L., & Tonge, B. J. (1989). The Developmental Behaviour Checklist. Melbourne Australia: Monash University Centre For Developmental Psyhciatry.Google Scholar
  14. Galli-Carminati, G., Deriaz, N., & Bertschy, G. (2009). Melatonin in the treatment of chronic sleep disorders in adults with autism: A retrospective study. Swiss med weekly, 139(19–20), 293–296.Google Scholar
  15. Garstang, J., & Wallis, M. (2006). Randomised controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child: Care, Health and Development, 32, 585–589.CrossRefGoogle Scholar
  16. 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, 741–752.CrossRefPubMedGoogle Scholar
  17. Goldberg, D. (1992). General health questionnaire (GHQ-12). Windsor, UK: Nfer-Nelson.Google Scholar
  18. Gordon, N. (2000). The therapeutics of Melatonin: a paediatric perspective. Brain and Development, 22, 213–217.CrossRefPubMedGoogle Scholar
  19. Hayashi, E. (2000). Effect of melatonin on sleep-wake rhythm: The sleep diary of an autistic male. Psychiatry and Clinical Neurosciences, 54(3), 383.CrossRefPubMedGoogle Scholar
  20. Hayashi, E. (2001). Seasonal changes in sleep and behavioural problems in a prepubescent case with autism. Psychiatry and Clinical Neurosciences, 55, 223–224.CrossRefPubMedGoogle Scholar
  21. Hoshino, Y., Watanabe, H., Yashima, Y., Kaneko, M., & Kumashiro, H. (1984). An investigation on the sleep disturbance of autistic children. Folia Psychiatrica et Neurologica Japonica, 38, 45–51.PubMedGoogle Scholar
  22. Ishizaki, A., et al. (1999). Usefulness of melatonin for developmental sleep and emotional/behavior disorders-studies of melatonin trial on 50 patients with developmental disorders. No To Hattatsu, 31(5), 428–437.PubMedGoogle Scholar
  23. Ivanenko, A., Crabtree, V. M., Tauman, R., et al. (2003). Melatonin in children and adolescents with insomnia: a retrospective study. Clinical Paediatrics, 42, 51–58.CrossRefGoogle Scholar
  24. Jan, M. S., et al. (1994). The treatment of sleep disorders with melatonin. Developmental Medicine and Child Neurology, 36, 97–107.CrossRefPubMedGoogle Scholar
  25. Jan, J. E., Freeman, R. D., & Fast, D. K. (1999). Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Developmental Medicine and Child Neurology, 41, 491–500.CrossRefPubMedGoogle Scholar
  26. Lockley, S. W., Skene, D. J., Arendt, J., Tabandeh, H., Bird, A. C., & Defrance, R. (1997). Relationship between melatonin rhythms and visual loss in the blind. The Journal of Clinical Endocrinology and Metabolism, 82, 3763–3770.CrossRefPubMedGoogle Scholar
  27. Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism diagnostic interview—revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659–685.CrossRefPubMedGoogle Scholar
  28. Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., DiLavore, P. C., et al. (2001). The autism diagnostic observation schedule—generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223.CrossRefGoogle Scholar
  29. Malow, B. A., Marzec, M. L., McGrew, S. G., Wang, L., Henderson, L. M., & Stone, W. L. (2006). Characterising sleep in children with autism spectrum disorders: A multidimensional approach. Sleep, 29, 1563–1571.PubMedGoogle Scholar
  30. McArthur, A. J., & Budden, S. S. (1998). Sleep dysfunction in Rett syndrome: A trial of exogenous melatonin treatment. Developmental Medicine and Child Neurology, 40(3), 186–192.CrossRefPubMedGoogle Scholar
  31. Melke, J., Goubran-Botros, H., Chaste, P., Betancur, C., Nygren, G., Anckarsäter, H., et al. (2008). Abnormal melatonin synthesis in autism spectrum disorders. Molecular Psychiatry, 13(1), 90–98.CrossRefPubMedGoogle Scholar
  32. Minde, K., Faucon, A., & Faulkner, S. (1994). Sleep problems in toddlers, effects of treatment on their daytime behaviour. Journal of American Academy of Child and Adolescent Psychiatry, 33, 1114–1121.CrossRefGoogle Scholar
  33. Miyamoto, A., Oki, J., Takahashi, S., et al. (1999). Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome. Brain and Development, 21, 59–62.CrossRefPubMedGoogle Scholar
  34. Mulchahey, J. J., Goldwater, D. R., & Zemlan, F. P. (2004). A single blind placebo controlled across groups dose escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics of the melatonin analog Beta-methyl-6-chloromelatonin. Life Sciences, 75, 1843–1856.PubMedGoogle Scholar
  35. National Autistic Society (2009, December 15th). Sleep and autism: Helping your child. Retrieved from http://www.nas.org.uk/nas/jsp/polopoly.jsp?d=528&a=3376.
  36. Niederhofer, H., et al. (2003). Brief report: Melatonin facilitates sleep in individuals with mental retardation and insomnia. Journal of Autism and Developmental Disorders, 33(4), 469–472.CrossRefPubMedGoogle Scholar
  37. Nir, I., Meir, D., Zilber, N., Knobler, H., & Hadjez, J. (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, 641–654.CrossRefPubMedGoogle Scholar
  38. Norton, P., & Drew, C. (1994). Autism and potential family stressors. The American Journal of Family Therapy, 22(1), 67–76.CrossRefGoogle Scholar
  39. O’Connell A, Chapparo C (2002) The trouble with sleeping can a waterbed help? Inaugural World Autism Conference.Google Scholar
  40. Patzold, L. M., Richdale, A. L., & Tonge, B. J. (1998). An investigation into the sleep characteristics of children with autism and Asperger’s disorder. Journal of Paediatrics and Child Health, 34, 528–533.CrossRefPubMedGoogle Scholar
  41. Phillips, L., & Appleton, R. (2004). Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Developmental Medicine and Child Neurology, 46(11), 771–775.CrossRefPubMedGoogle Scholar
  42. Quine, L. (1992). Severity of sleep problems in children with severe learning disabilities: Description and correlates. Journal of Community and Applied Social Psychology, 2, 247–268.CrossRefGoogle Scholar
  43. Quine, L. (2001). Sleep problems in primary school children: Comparison between mainstream and special school children care. Health and Development., 37(3), 201–221.CrossRefGoogle Scholar
  44. Ramachandani, P., Wiggs, L., Webb, V., & Stores, G. (2000). A systematic review of treatments for settling problems and night waking in young children. BMJ, 320, 209–213.CrossRefGoogle Scholar
  45. Richdale, A. L. (1999). Sleep problems in autism: Prevalence, cause and intervention. Developmental Medicine and Child Neurology, 41, 60–66.CrossRefPubMedGoogle Scholar
  46. Sack, R. L., Hughs, R. J., Edgar, D. M., & Lewy, A. J. (1997). Sleep-promoting effects of melatonin. At what dose, in whom, under what circumstances, and by what mechanisms? Sleep, 20, 908–915.PubMedGoogle Scholar
  47. Sheldon, S. (1998). Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet, 351, 1254.CrossRefPubMedGoogle Scholar
  48. Simonds, J. F., & Parraga, H. (1982). Prevalence of sleep disorders and sleep behaviours in children and adolescents. Journal of the American Academy of Child Psychiatry, 21, 383–388.CrossRefPubMedGoogle Scholar
  49. Smits, M. G., Nagtegaal, E. E., Van Der Heijden, R., et al. (2001). Melatonin for chronic onset sleep disorder in children: A randomised placebo-controlled trial. Journal of Child Neurology, 16, 86–92.PubMedGoogle Scholar
  50. Smits, M. G., Van Stel, H. F., Van Der Heijden, R., et al. (2003). Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: A randomised placebo-controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 1286–1293.CrossRefPubMedGoogle Scholar
  51. Stores, G. (2003). Medication for sleep wake disorders. Archives of Disease in Childhood, 88, 899–903.CrossRefPubMedGoogle Scholar
  52. Sutherland, E. R., Martin, R. J., Ellison, M. C., & Kraft, M. (2002). Immunomodulatory effects of melatonin in asthma. American Journal of Respiratory Critical care Medicine, 166, 1055–1061.CrossRefGoogle Scholar
  53. Tuchman, R., & Rapin, I. (2002). Epilepsy in autism. Lancet Neurology, 1(6), 352–358.CrossRefPubMedGoogle Scholar
  54. WHO (1993). The ICD—10 Classification of mental and behavioural disorders:- Diagnostic Criteria for Research: General World Health Organisation.Google Scholar
  55. Wasdell, M. B., Jan, J. E., Bomben, M. M., Freeman, R. D., Rietveld, W. J., Tai, J., et al. (2008). A randomised, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. Journal of Pineal Research, 44, 57–64.PubMedGoogle Scholar
  56. Weiskop, S., Richdale, A., & Matthews, J. (2005). Behavioural treatment to reduce sleep problems in children with autism or fragile X syndrome. Developmental Medicine and Child Neurology, 47, 94–104.CrossRefPubMedGoogle Scholar
  57. Wiggs, L., & Stores, G. (2001). Behavioural treatment for sleep problems in children with severe intellectual disabilities and daytime challenging behaviour: Effect on mothers and fathers. British Journal of Health Psychology, 6(3), 257–269.CrossRefPubMedGoogle Scholar
  58. Wiggs, L., & Stores, G. (2004). Sleep patterns and sleep disorders in children with autism spectrum disorders: Insights using parent report and actigraphy. Developmental Medicine and Child Neurology, 46, 372–380.CrossRefPubMedGoogle Scholar
  59. World Health Organisation (1993). The ICD – 10 Classification of Mental and Behavioural Disorders:- Diagnostic Criteria for Research: General World Health Organisation.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Barry Wright
    • 1
  • David Sims
    • 2
  • Siobhan Smart
    • 3
  • Ahmed Alwazeer
    • 4
  • Ben Alderson-Day
    • 1
  • Victoria Allgar
    • 5
  • Clare Whitton
    • 1
    • 8
  • Heather Tomlinson
    • 1
  • Sophie Bennett
    • 1
  • Jenni Jardine
    • 1
    • 9
  • Nicola McCaffrey
    • 1
    • 10
  • Charlotte Leyland
    • 6
  • Christine Jakeman
    • 7
  • Jeremy Miles
    • 7
    • 11
  1. 1.Lime Trees ChildAdolescent and Family UnitYorkEngland, UK
  2. 2.Hillbrook Child and Family CentreHillbrookKeighleyEngland, UK
  3. 3.Dragon Parade Clinic2 Dragon ParadeHarrogateEngland, UK
  4. 4.Royal Bolton HospitalBoltonEngland, UK
  5. 5.Hull York Medical School, John Hughlings Jackson BuildingUniversity of YorkHeslington, YorkEngland, UK
  6. 6.University of YorkHeslington, YorkEngland, UK
  7. 7.York HospitalYorkEngland, UK
  8. 8.Tees, Esk and Wear Valleys NHS Foundation TrustDarlingtonEngland, UK
  9. 9.Northumberland, Tyne and Wear NHS Foundation TrustNewcastle upon TyneEngland, UK
  10. 10.NHS GrampianAberdeenScotland, UK
  11. 11.RAND CorporationSanta MonicaUSA

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