1. Melatonin in children with an Intellectual Disability
W. Braam
Current role of Melatonin in children: European Consensus Conference

2. Melatonin in children with ID
Melatonin is widely used in children with an intellectual disability.
There are no guidelines on how to prescribe melatonin.
It is considered to be safe without serious side effects.

3. Melatonin in children with ID
However, in our sleep clinic we see more than one patient a month with a severe disturbed sleep wake rhythm caused by the use of melatonin. 3

4. Melatonin in children with ID
Sleep problems are reported to occur in 13 to 86% of individuals with intellectual disabilities depending on study design, participant characteristics, and definition of sleep problems.
Didden R, KorziliusH, van Aperlo B, vanOverloopC, de VriesM. Sleep problems and daytime problembehaviours in children with intellectual disability. J Intellect Disabil Res 2002; 46: 537–47. 4

5. Melatonin in children with ID
Sleep problems in ID are often complex.
They are caused by a combination of biological factors and neurobehavioral deficits. 5

6. Melatonin in children with ID
In ID biological factors are the most important.
Circadian rhythm disturbances (melatonin)
Several somatic disorders, such as gastroesofageal reflux and epilepsy 6

7. Melatonin in children with ID
Management options include behavioural, or pharmacological, or both.
Behavioural treatment is of no use in children with ID in case sleep problems are caused by biological factors. 7

8. Melatonin in specific syndromes
1. Smith Magenis syndrome
Inversed 24h melatonin rhythm
Daytime somnolence
Frequent night waking and early sleep offset
Chik CL et al. Diagnostic utility of daytime salivary melatonin levels in Smith-Magenis syndrome. Am J Med Genet A Jan;152A(1): 8

9. Melatonin in specific syndromes
Melatonin treatment is advised, dose not mentioned
Daytime melatonin release inhibition by acebutolol: 10 mg/kg in a single morning dose
No (controlled) studies
De Leersnyder H. Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab Sep;17(7): Epub 2006 Aug 4. 9

10. Melatonin in specific syndromes
2. Angelman syndrome
Sleep onset and sleep maintenance problems
Melatonin levels are significantly lower than those of the controls
Takaesu Y et al. Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients. Sleep Med. 2012;13(9): 10

11. Melatonin in specific syndromes
Melatonin treatment
Zhadanova (1999):
Open-label trial of 13 children with melatonin 0,3 mg
decreased sleep latency
increased total sleep time
Zhdanova IV et al. Effects of a low dose of melatonin on sleep in children with Angelman syndrome. J Pediatr Endocrinol Metab Jan-Feb;12(1):57-67. 11

12. Melatonin in specific syndromes
Takaesu (2012)
Open-label trial with melatonin 1mg in 6 patients during 3 months
Sleep patterns improved in four cases.
Takaesu Y et al. Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients. Sleep Med. 2012;13(9): 12

13. Melatonin in specific syndromes
Braam double-blind study (2008)
Melatonin 2,5mg (2-6y), 5mg (>6y)
sleep onset advanced by 28 minutes,
sleep latency decreasd by 32 minutes,
total sleep time increased by 56 minutes
number of nights with wakes from 3.1 to 1.6 13

14. Melatonin in specific syndromes
Melatonin levels were extremely high after 4 weeks of treatment
Loss of response after 4 – 8 weeks
Braam et al. Melatonin for Chronic Insomnia in Angelman Syndrome: A Randomized Placebo-Controlled Trial. Journal of Child Neurology 2008; 23: 649–54. 14

15. Melatonin in specific syndromes
3. Rett syndrome
Night wakes with crying, screaming or laughing
Disturbing behaviour
Epilepsy occurs in 50–90% of patients with Rett syndrome, and seizures are more often nocturnal and refractory.
Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. Rett syndrome and epilepsy: an update for child neurologists. Pediatr Neurol 2013; 48:337–345 15

16. Melatonin in specific syndromes
McArthur & Budden (1998)
Double blind placebo controlled study in 9 girls: 4 weeks, 2,5 – 7,5 mg
No melatonin levels were measured . 16

17. Melatonin in specific syndromes
Melatonin significantly decreased sleep-onset latency with 23 minutes (P<0.05) during the first 3 weeks of treatment,
Effect was less in week 4.
McArthur AJ & Budden SS. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol Mar;40(3):186-92 17

18. Melatonin in specific syndromes
4. Williams syndrome
Polysomnography (N=35)
more difficulty falling asleep, with greater restlessness and more arousals from sleep than controls.
No studies on melatonin
Mason TBA et al. Sleep in children with Williams Syndrome. Sleep Medicine 12 (2011) 892–897. 18

19. Randomized trials melatonin in ID
Braam et al. meta analysis (2009)
Nine studies (183 individuals with ID)
decreased sleep latency by 34 minutes (p<0.001)
increased total sleep time by 50 minutes (p<0.001)
decreased the number of wakes / night (p<0.05)
Braam W. et al. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol May;51(5):340-9. 19

20. Randomized trials melatonin in ID
Gringras (2012)
Placebo-controlled study in 146 children
Melatonin (doses ranged from 0.5 to 12mg depending upon response to treatment) for 12 weeks. 20

21. Randomized trials melatonin in ID
Melatonin reduced sleep latency by 38 min
Increased total sleep time by 22 min
Improved wake times in children who fell asleep faster with treatment.
Gringras P, Gamble C, Jones AP, et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ 2012; 345:e6664 21

22. Loss of response to melatonin
Problems with melatonin
In many of our patients the initial good response to melatonin disappears within a few weeks after starting treatment
Response returns after considerable dose reduction. 22

23. Loss of response to melatonin
Melatonin levels 12:00 and 16:00: >50pg/ml
Hypothesis: CYP1A2 poor metaboliser
Braam W et al. Loss of response to melatonin treatment is associated with slow melatonin metabolism. J Intellect Disabil Res Jun;54(6): 23

24. Loss of response to melatonin
Note: melatonin levels 13:00 higher, due to difference in first pass effect 24

25. Loss of response to melatonin
Preliminary data melatonin profiles in
150 patients (excl Smith Magenis syndrome):
In 74 melatonin users at first visit (12:00h)
In 76 melatonin free at first visit (between 17:00 and 19:00h) 25

26. Loss of response to melatonin26

27. Loss of response to melatonin27

28. Loss of response to melatonin
In 40 / 76 non-melatonin users at first visit (52,8%) we found loss of effect and high day time melatonin levels after 4 – 12 weeks of melatonin treatment 28

29. Practical considerations
Start with a low dose of 0.2–0,5 mg fast release melatonin one hour before bedtime; increase by 0,2 - 0,5 mg every 2 weeks as needed (maximum 3 mg) until effect 29

30. Practical considerations
Slow-release melatonin are not useful, except for a few specific cases:
1. When sleep maintenance is better on melatonin fast release, but early waking persists.
2. Smith Magenis syndrome when results on melatonin fast release is poor. 30

31. Practical considerations
Reduce dose if possible to the lowest dose that is effective
Wean slowly 12 weeks after a normal sleep cycle is established. 31

32. Practical considerations
Be aware that loss of efficacy of melatonin treatment most likely is caused by slow melatonin metabolism.
When this happens, dose reduction is strongly advised (one week wash out) instead of dose escalation.
One melatonin-free day a week is an option 32

33. Practical considerations
Be aware of interactions of melatonin with other medication:
Metabolism slower: oral contraceptives, cimetidine, fluvoxamine
Metabolism faster: carbamazepine, esomeprazole, omeprazole, 33

34. Bioavailability is higher
Melatonin dose in slow melatonin metabolisers should be substancially lower because of 2 reasons:
Half life is lower
Bioavailability is higher 34

35. Due to first pass effect bioavailability of melatonin is low:
Males: 8.6 ± 3.9%
Females: 16.8 ± 12.7%
Fourtillan JB et al. Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Biopharm Drug Dispos Jan;21(1):15-22. 35

36. In CYP1A2 polymorphism the mean 1
In CYP1A2 polymorphism the mean 1.5 hr melatonin concentration is 4 times higher than wild type after daytime intake melatonin.
Härtter S et al. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol Dec;56(6): 36