Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders

Kotaro Yuge, Shinichiro Nagamitsu, Yuko Ishikawa, Izumi Hamada, Hiroyuki Takahashi, Hideyuki Sugioka, Osamu Yotsuya, Kazuo Mishima, Masaharu Hayashi, Yushiro Yamashita, Kotaro Yuge, Shinichiro Nagamitsu, Yuko Ishikawa, Izumi Hamada, Hiroyuki Takahashi, Hideyuki Sugioka, Osamu Yotsuya, Kazuo Mishima, Masaharu Hayashi, Yushiro Yamashita

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.

Conclusions: Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being.

Trial registration: ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.

Keywords: Aberrant behaviors; Children; Long-term; Melatonin; Neurodevelopmental disorders; Sleep onset latency; Sleep problems.

Conflict of interest statement

KY reported receiving grant support from Nobelpharma during the conduct of the study. SN reported receiving grant support from Nobelpharma during the conduct of the study. MH reported receiving consulting fees from Nobelpharma during the conduct of the study. KM reported receiving grans from the Japanese Ministry of Health, Labour and Welfare (H29-Seishin-Ippan-001, 19GC1012), the Japanese Ministry of Education, Science, and Technology, and the National Center of Neurology and Psychiatry Intramural Research Grant for Neurological and Psychiatric Disorders, consulting fees from Nobelpharma and Taisho Pharmaceutical, and lecture fees from Eisai, MSD, Takeda Pharmaceutical, Astellas Pharma, and Janssen Pharmaceutical. MF reported receiving grant support from Nobelpharma. HT is an employee of CMIC HOLDINGS. YI, IH, HS, OY are employees of Nobelpharma. YY reported receiving grant support from Nobelpharma.

Figures

Fig. 1
Fig. 1
Subject disposition
Fig. 2
Fig. 2
Changes in sleep onset latency recorded with the electronic sleep diary. *: P <  0.0001 (vs. screening) according to Wilcoxon’s signed rank sum test
Fig. 3
Fig. 3
Changes in the scores of temper upon wakening, refusal to going to bed at prespecified bedtime, and sleepiness intensity after awaking calculated based on the electronic sleep diary. *: P <  0.0001 (vs. screening) according to Wilcoxon’s signed rank sum test
Fig. 4
Fig. 4
Changes in the scores of hyperactivity, irritability, and inappropriate speech calculated based on the ABC-J. *: P <  0.0001 (vs. screening) according to Wilcoxon’s signed rank sum test. ABC-J, the aberrant behavior check list Japanese version

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Source: PubMed

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