Table 6.

Melatonin Studies in Children in the European Union (Countries Include Netherlands)

Study	N (age range, yr)	Melatonin Dosage	Duration	Summary/Comments
ADHD
Tjon64	24 (unknown)	3 mg	52 wk	A preliminary open-label study to evaluate the efficacy and safety of melatonin in individuals with ADHD taking methylphenidate. Twenty-four individuals were included, although long-term results (following 3 months of therapy vs 4 weeks) were only available for 13 individuals. Short-term melatonin improved time to falling asleep (n = 24; range: 15–240 min). Following 3 mo of melatonin (n = 13), to falling asleep ranged from 15 to 64 min, and was determined to provide a statistically significant change in onset of sleep (p < 0.01). There was no difference in long-term safety compared with 1 wk of treatment. Limitation: no baseline characteristics were provided.
Van Der Heijden65	105 (6–12)	Weight less than 40 kg = 3 mg. If more than 40 mg, then 6 mg at 1900. Melatonin was provided by Pharma Nord.	5 wk (1-wk baseline 4 wk of tx)	Effect of melatonin on sleep, behavior, and cognition in ADHD and CSOI were evaluated in patients aged 6 to 12 years not taking any medication for ADHD and chronic insomnia were randomly assigned to receive melatonin or placebo. Sleep results were obtained via actigraphy and sleep diaries. When compared with placebo, the melatonin group experienced improved sleep onset (26.9 ± 47.8 when compared with placebo group (10.5 ± 37.4, p < 0.0001). An advance in DLMO 44.4 ± 67.9 min vs a delay in placebo 12.8 ± 60 min, p < 0.001. Total sleep also increased in the melatonin group 19.8 ± 61.9 min compared with placebo, −13.6 ± 50.6, p = 0.01. SEs reported in the melatonin group included headache (5.7%), hyperactivity (5.7%), dizziness (3.8%), abdominal pain (3.8%), and diarrhea (1.9%). No SEs were reported in the placebo group.
Autism
Cortesi66	134 (4–10)	3 mg (1-mg FR, 2-mg CR) at 2100. Titrations were not allowed. Melatonin provided by Armonia Retard 3 mg (Nathura, Montecchio Emilia, Italy)	12 wk	A randomized placebo-controlled trial evaluating the efficacy of melatonin (n = 34), melatonin + CBT (n = 35), CBT (n = 33), or placebo (n = 32) in 134 patients. Sleep latency, total sleep time, wake after sleep onset, and number of awakenings measured by actigraphy, sleep questionnaire, and sleep diary submissions were assessed. Mean total sleep mean time improved on melatonin (17%), melatonin + CBT (22.01%), and CBT (9.31%), but no improvement was noted in the placebo group. All active groups achieve statistical significance in time effect (p < 0.001). Mean sleep onset latency decreased in the melatonin (44.3%), melatonin + CBT (60.75%), and CBT (22.5%) groups, but there was no decrease with placebo. Statistical significance was determined for the time effect (p < 0.001) and time ×group effect (p < 0.001). No SEs were reported.
Paavonen67	15 (5–17)	3 mg daily	14 days of active tx	Effectiveness of melatonin for tx of sleep disturbances in 15 children with Asperger disorder. Evaluations were conducted prior, during, and 3 weeks post tx, and results were evaluated via actigraphy and questionnaires. Sleep latency measured by actigraphy decreased from 40.2 ± 24.09 to 21.82 ± 9.64 (p = 0.002), but sleep duration was unchanged. Behavioral measures significantly improved (p = 0.001), and mild tiredness (n = 2), dizziness (n = 1), and diarrhea (n = 1) were reported.

ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CBT, cognitive-behavioral therapy; CR, controlled release; CSOI, chronic sleep onset insomnia; DLMO, dim light melatonin onset; FR, fast release; IR, immediate release; PR, prolonged release; SE, side effect; tx, treatment