title: 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.
  
  
  METHODS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 's Heeren Loo Zuid-Veluwe, Wekerom, Postbus 75, 6710 BB Ede, The Netherlands. Wiebe.Braam@sheerenloo.nl
authors.forename: W
authors.initials: W
authors.lastname: Braam
authors.forename: I
authors.initials: I
authors.lastname: van Geijlswijk
authors.forename: Henry
authors.initials: H
authors.lastname: Keijzer
authors.forename: Marcel G
authors.initials: MG
authors.lastname: Smits
authors.forename: Robert
authors.initials: R
authors.lastname: Didden
authors.forename: Leopold M G
authors.initials: LM
authors.lastname: Curfs
mesh_terms: D002648:Child; D002675:Child, Preschool; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008550:Melatonin / Q000097:blood* / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D012463:Saliva / Q000737:chemistry; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood* / Q000188:drug therapy*
chemical_list: D008550:Melatonin