Loss of response to melatonin treatment is associated with slow melatonin metabolism
Abstract
BACKGROUND: In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism. METHOD: In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose. RESULTS: In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%. CONCLUSION: We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.
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Loss of response after several weeks may suggest a patient's tolerance of melatonin and necessary dose reduction.
“Therefore, loss of response after several weeks may suggest a patient’s tolerance of melatonin and necessary dose reduction.”
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Cites
National Center for Biotechnology Information
Gressner, A. M., & Arndt, T. (2019) · Springer Reference Medizin · doi:10.1007/978-3-662-48986-4_301184 · Cited by 2,610 · see citing works
The basic physiology and pathophysiology of melatonin
Claustrat, B., Brun, J., & Chazot, G. (2004) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2004.08.001 · Cited by 951 · see citing works
Polymorphism of human cytochrome P450 enzymes and its clinical impact
Zhou, S., Liu, J., & Chowbay, B. (2009) · Drug Metabolism Reviews · doi:10.1080/03602530902843483 · Cited by 832 · see citing works
Sachse, C., Brockmöller, J., Bauer, S., & Roots, I. (1999) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1999.00898.x · Cited by 751 · see citing works
Melatonin Shifts Human Orcadian Rhythms According to a Phase-Response Curve
Lewy, A. J., Ahmed, S., Jackson, J. M. L., & Sack, R. L. (1992) · Chronobiology International · doi:10.3109/07420529209064550 · Cited by 693 · see citing works
Dollins, A. B., Zhdanova, I. V., Wurtman, R. J., Lynch, H. J., & Deng, M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.5.1824 · Cited by 578 · see citing works
Butler, M. A., Lang, N. P., Young, J. F., Caporaso, N. E., Vineis, P., Hayes, R. B., Teitel, C. H., Massengill, J., Lawsen, M. F., & Kadlubar, F. F. (1992) · Pharmacogenetics · doi:10.1097/00008571-199206000-00003 · Cited by 419 · see citing works
Pandi-Perumal, S. R., Smits, M. G., Spence, W., Srinivasan, V., Cardinali, D. P., Lowe, A. D., & Kayumov, L. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.06.020 · Cited by 416 · see citing works
Self-citationEffect of Melatonin on Sleep, Behavior, and Cognition in ADHD and Chronic Sleep-Onset Insomnia
VAN der HEIJDEN, K. B., SMITS, M. G., VAN SOMEREN, E. J. W., RIDDERINKHOF, K. R., & GUNNING, W. B. (2007) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000246055.76167.0d · Cited by 378 · see citing works
Self-citationNakajima, M., Yokoi, T., Mizutani, M., Kinoshitah, M., Funayama, M., & Kamataki, T. (1999) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a022352 · Cited by 345 · see citing works
Zhou, S. F., Yang, L.-P., Zhou, Z.-W., Liu, Y., & Chan, E. (2009) · The AAPS Journal · doi:10.1208/s12248-009-9127-y · Cited by 239 · see citing works
Melatonin for Insomnia in Children With Autism Spectrum Disorders
Andersen, I. M., Kaczmarska, J., McGrew, S. G., & Malow, B. A. (2008) · Journal of Child Neurology · doi:10.1177/0883073807309783 · Cited by 228 · see citing works
Zhdanova, I. V. (2004) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2004.04.003 · Cited by 208 · see citing works
Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment
McArthur, A. J., & Budden, S. S. (1998) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1998.tb15445.x · Cited by 207 · see citing works
Smits, M. G., van Stel, H. F., der Heijden, K. V., Meijer, A. M., Coenen, A. M. L., & KERKHOF, G. A. (2003) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000085756.71002.86 · Cited by 184 · see citing works
Self-citationMelatonin: A Sleep-Promoting Hormone
Zhdanova, I. V., Lynch, H. J., & Wurtman, R. J. (1997) · SLEEP · doi:10.1093/sleep/20.10.899 · Cited by 169 · see citing works
Substrate inhibition kinetics for cytochrome P450-catalyzed reactions.
Lin, Y., Lü, P., Tang, C., et al. (2001) · PubMed · Cited by 154 · see citing works
Clinical trials of controlled‐release melatonin in children with sleep–wake cycle disorders
Jan, J. E., Hamilton, D., Seward, N., Fast, D. K., Fréeman, R. D., & Laudon, M. (2000) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2000.290105.x · Cited by 152 · see citing works
Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta‐analysis
Braam, W., Smits, M. G., Didden, R., Korzilius, H. P. L. M., van Geijlswijk, I. M., & Curfs, L. (2009) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2008.03244.x · Cited by 143 · see citing works
Self-citationMelatonin Entrains Free‐running Blind People According to a Physiological Dose‐response Curve
Lewy, A. J., Emens, J. S., Lefler, B. J., Yuhas, K., & Jackman, A. R. (2005) · Chronobiology International · doi:10.1080/07420520500398064 · Cited by 143 · see citing works
Nakajima, M., Yokoi, T., Mizutani, M., Shin, S., Kadlubar, F. F., & Kamataki, T. (1994) · PubMed · Cited by 141 · see citing works
Bioavailability of melatonin in humans after day-time administration of D7 melatonin
Fourtillan, J. B., Brisson, A. M., Gobin, P., Ingrand, I., Decourt, J., & Girault, J. (2000) · Biopharmaceutics & Drug Disposition · doi:10.1002/1099-081x(200001)21:1 · Cited by 119 · see citing works
Melatonin for Chronic Insomnia in Angelman Syndrome: A Randomized Placebo-Controlled Trial
Braam, W., Didden, R., Smits, M. G., & Curfs, L. (2007) · Journal of Child Neurology · doi:10.1177/0883073808314153 · Cited by 104 · see citing works
Self-citationLewy, A. J., Emens, J. S., Sack, R. L., Hasler, B. P., & Bernert, R. A. (2002) · Chronobiology International · doi:10.1081/cbi-120004546 · Cited by 99 · see citing works
Nagtegaal, E., Peeters, T., Swart, W., Smits, M. G., KERKHOF, G. A., & van der Meer, G. (1998) · Therapeutic Drug Monitoring · doi:10.1097/00007691-199804000-00008 · Cited by 82 · see citing works
Self-citationvan der Heijden, K. B., Smits, M. G., Someren, E. J. W. V., & Gunning, W. B. (2005) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2005.00451.x · Cited by 75 · see citing works
Self-citationChevalier, D., Cauffiez, C., Allorge, D., et al. (2001) · Human Mutation · doi:10.1002/humu.49 · Cited by 64 · see citing works
Härtter, S., Ursing, C., Morita, S., Tybring, G., von Bahr, C., Christensen, M., Röjdmark, S., & Bertilsson, L. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2001.116512 · Cited by 57 · see citing works
Miller, G. P., & Guengerich, F. P. (2001) · Biochemistry · doi:10.1021/bi010402z · Cited by 53 · see citing works
Härtter, S., Korhonen, T., Lundgren, S., Rane, A., Tolonen, A., Turpeinen, M., & Laine, K. (2006) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2006.pto_491.x · Cited by 33 · see citing works
Ishizaki, A., Sugama, M., & Takeuchi, N. (1999) · PubMed · Cited by 30 · see citing works
Chevalier, D., Allorge, D., Lo‐Guidice, J., et al. (2001) · Human Mutation · doi:10.1002/humu.48 · Cited by 23 · see citing works
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Maras, A., Schroder, C. M., Malow, B. A., Findling, R. L., Breddy, J., Nir, T., Shahmoon, S., Zisapel, N., & Gringras, P. (2018) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2018.0020 · Cited by 176 · see citing works
Minich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J. (2022) · Nutrients · doi:10.3390/nu14193934 · Cited by 176 · see citing works
Tordjman, S., Najjar, I., Bellissant, E., Anderson, G., Barburoth, M., Cohen, D., Jaafari, N., Schischmanoff, O., Fagard, R., Lagdas, E., et al. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141020508 · Cited by 132 · see citing works
Vural, E. M. S., van Munster, B. C., & de Rooij, S. E. (2014) · Drugs & Aging · doi:10.1007/s40266-014-0178-0 · Cited by 92 · see citing works
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- Authors
- Braam, W., Van Geijlswijk, I., Keijzer, H., Smits, M. G., Didden, R., & Curfs, L. M. G.
- Affiliations
- Maastricht University (NL)
- Ziekenhuis Gelderse Vallei (NL)
- Radboud University Nijmegen (NL)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Braam, W.
- Venue
- Journal of Intellectual Disability Research
- Publisher
- Wiley
- Published
- 2010-05-20
- Volume
- 54
- Issue
- 6
- Pages
- 547-555
- ISSN
- 0964-2633 (ISSN-L)
- 1365-2788
- OpenAlex
- W2157939113
- Cited by
- 94
- References
- 32
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 1 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 11 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 5
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Intellectual Disability Research (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- 's Heeren Loo
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- melatonin, melatonin metabolism, chronic insomnia, intellectual disability, sleep disorders, CYP1A2, cytochrome P450, dose reduction, salivary melatonin
- MeSH terms
- Child, Child, Preschool, Drug Tolerance, Female, Humans, Sleep Initiation and Maintenance Disorders, Male, Melatonin, Intellectual Disability, Metabolic Clearance Rate, Middle Aged, Saliva
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