Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorder
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RESEARCH ARTICLE
Open Access
Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders Kotaro Yuge1*, Shinichiro Nagamitsu1, Yuko Ishikawa2, Izumi Hamada2, Hiroyuki Takahashi3, Hideyuki Sugioka2, Osamu Yotsuya2, Kazuo Mishima4, Masaharu Hayashi5 and Yushiro Yamashita1
Abstract Background: Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. Methods: We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. Results: Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan—74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], − 36.7 ± 46.1 min; 95% confidence interval [CI], − 45.9 to − 27.5; P < 0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P < 0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P < 0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. (Continued on next page)
* Correspondence: [email protected] 1 Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give app
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