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Three Part Question

In [children with ADHD] does [melatonin] improve [sleep pattern]?

Clinical Scenario

Adam is an 8-year-old boy with attention deficit hyperactivity disorder (ADHD) who you see with his mother in your paediatric outpatient clinic. She explains that life is being made increasingly stressful for the whole family as Adam is having difficulty getting off to sleep. It often takes him several hours to calm down and go to sleep, and the next day he gets angry and seems to be tired all the time.

Adam’s insomnia is causing him and his mother to become frustrated and exhausted. She is at the end of her tether, but has recently seen on a television programme that melatonin may be effective in improving sleep pattern in children with ADHD. She asks you whether it would work in Adam.

Are the television producers correct? If melatonin is prescribed for Adam, will it be harmful or helpful in improving his sleep?

Search Strategy

MEDLINE (1996 to January week 5 2007) via Ovid: a search was carried out using "Melatonin" [MeSH] AND "Attention deficit and disruptive behaviour disorders" or "Attention deficit with hyperactivity" [MeSH] AND "Sleep" [MeSH]. Two relevant citations were found.

EMBASE (1996 to week 6 2007) via Ovid: a search was carried out using the headings "Melatonin" [MeSH] AND "Attention Deficit Disorder" [MeSH] AND "Sleep" [MeSH]. No further relevant articles were found.


To locate articles that had been published but were still waiting to be indexed (via Ovid MEDLINE In-Process & Other Non-Indexed Citations, February 2007), another search was carried out using the same terms. One abstract due for publication in February 2007 was found. This appeared relevant and was retrieved electronically via the journal website ahead of print.

Cochrane Library: no papers found; BestBETs: no articles found.

Search Outcome

3 articles found

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Weiss et al, 2006, Canada	27 stimulant treated children (6–14 years old) with ADHD with initial insomnia >60 min received sleep hygiene intervention Eligible non-responders (n = 19) were randomised to a 30-day double-blind, placebo-controlled, crossover trial of 5 mg melatonin	Randomised, double-blind, placebo-controlled crossover trial (level 2b)	Time reduction in initial insomnia, measured by somnolog and actigraphy	Sleep hygiene reduced initial insomnia in 5/27 cases (overall effect size 0.67) 17/19 showed a reduction in insomnia of 16 min with melatonin relative to placebo (p<0.01), effect size 0.6 Combined sleep hygiene and melatonin decreased initial insomnia (mean 60 min, effect size 1.7)	Small sample size Randomisation procedure not explained Study sponsored by the melatonin manufacturers
Tjon Pian et al, 2003, The Netherlands	24 children with ADHD (on methylphenidate) and insomnia were treated with 3 mg melatonin	Observational study (level 4)	Reduction in sleep-onset latency, ascertained by clinical interview and psychological test before and after medication	22/24 children had significant improvement in sleep onset, median 135 min (p<0.01) Effect maintained after 3 months No significant adverse events	Small sample size No mention of exclusion criteria No blinding or randomisation Cannot exclude placebo effect
Van der Heijden et al, 2007, The Netherlands	105 medication-free children (6–12 years) with ADHD and chronic sleep onset insomnia were randomly allocated to be given either melatonin (3 mg or 6 mg depending on body weight) or placebo for 4/52	Randomised, double-blind, placebo-controlled trial (level 1b)	Actigraphy derived sleep onset, total time asleep, sleep latency and efficiency, nocturnal restlessness, score on "sleep log" Salivary dim-light melatonin onset Assessments of problem behaviour and emotional symptoms Cognitive assessments of interference control and sustained attention Quality of life score	Sleep onset advanced by 27±48 min with melatonin and delayed by 11±37 min with placebo (p<0.001) Increase in mean total time asleep (20±62 min vs decrease of 14±51 min; p = 0.01) 31% improvement on "sleep log score" (p<0.001) No effect found on behaviour, cognition or quality of life	Well executed study with rigorous methodology Large numbers, well matched for demographic and clinical characteristics Intention to treat analysis completed 2-Year questionnaire follow-up for only 24/107 patients (22%)

Comment(s)

Around 25 to 54% of children with ADHD have a sleep problem (Tjon Pian, Betancourt-Fursow). This difficulty with sleep can be exacerbated by psychostimulant medication used to treat hyperactivity, attention deficit and impulsiveness (Tjon Pian, Sangal). Conversely, it has also been shown that children with persistent sleep onset insomnia can have difficult behavioural or cognitive problems during the day (Sadeh). Therefore, it is important to investigate potential therapies that might help children with ADHD to sleep more soundly in the hope that some improvement in their overall condition may be achieved.

Melatonin is a hormone secreted by the pineal gland. It is suppressed by daylight but increases with darkness, and regulates the circadian rhythm by promoting the desire to sleep at night. Although several studies have been completed in the past that investigated melatonin administration in adults or children with cognitive disabilities or blindness (Sheldon), little research has been undertaken specifically investigating its use in children with ADHD.

Only three studies were found in this search, all of which were completed within the last 4 years. In all three, sleep onset was promoted by the administration of melatonin. The Weiss et al study showed a reduction in sleep onset insomnia of 16 min with melatonin, but its results should be interpreted with caution as it had no clear inclusion criteria and was sponsored by the manufacturers of melatonin, a source of potential bias.

The second paper by Tjon Pian Gi also showed considerable promotion of sleep onset with melatonin (median 135 min) without significant adverse events but had a relatively poor-quality methodology with no randomisation or blinding to treatment, which means a placebo effect cannot be excluded.

In contrast, the recently published study by Van der Heijden et al looked at a large patient population who had been rigorously diagnosed with ADHD but were medication free. It is the first randomised, double-blind, placebo-controlled trial investigating the use of melatonin in children with ADHD, and potentially provides us with important and relevant clinical information. Outcomes clearly suggest that melatonin was effective in reducing insomnia. Sleep onset advanced by 27±48 min with melatonin compared to a delay of 11±37 min with placebo tablets. There was also a statistically significant increase in total time asleep and sleep efficiency and a decrease in sleep latency and nocturnal restlessness. While no statistically significant improvement was found in problem behaviour, cognitive ability or quality of life score during the 4-week study period, the authors hypothesised that these parameters may improve with time if sleep quality is maintained.

Melatonin appears to be safe and well tolerated in most children with ADHD. The current evidence suggests that it induces clinically relevant advances in sleep onset and increased total time asleep, and could be useful in children with persistent insomnia after simple conservative sleep hygiene measures have been tried. The limited research evidence currently available has not investigated potential long-term effects of melatonin administration and further high quality data from systematic studies are needed.

Clinical Bottom Line

Melatonin administration can be used to advance sleep onset to normal values in children with attention deficit hyperactivity disorder (ADHD) who are not on stimulant medication. (Grade A) Combining sleep hygiene and melatonin may be beneficial in improving sleep pattern in children with ADHD who are on stimulant medication. (Grade C) Melatonin is relatively safe and well-tolerated in children with ADHD and no other underlying neurological problem. (Grade C)

References

1. Weiss MD, Wasdell MB, Bomben MM, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006;45:512–19.
2. Tjon Pian Gi CV, Broeren JP, Starreveld JS, et al. Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Eur J Pediatr 2003;162:554–5.
3. Van der Heijden KB, Smits MG, Van Someren EJ, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry 2007;46:233–41.
4. Betancourt-Fursow de Jimenez YM, Jimenez-Leon JC, Jimenez-Betancourt CS. Attention deficit hyperactivity disorder and sleep disorders. Rev Neurol 2006;42(Suppl 2):S37–S51.
5. Sangal RB, Owens J, Allen AJ, et al. Effects of atomoxetine and methylphenidate on sleep in children with ADHD. Sleep 2006;29:1573–85.
6. Sadeh A, Gruber R, Raviv A. The effects of sleep restriction and extension on school-age children: what a difference an hour makes. Child Dev 2003;74:444–55.
7. Sheldon SH. Proconvulsive effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254–55.