Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder

Abstract

Objective: A recent 3-month double-blind, placebo-controlled study demonstrated efficacy and safety of pediatric prolonged-release melatonin (PedPRM) for insomnia in children with autism spectrum disorder. This study examined the long-term effects of PedPRM treatment on sleep, growth, body mass index, and pubertal development.

Method: Eighty children and adolescents (2-17.5 years of age; 96% with autism spectrum disorder) who completed the double-blind, placebo-controlled trial were given 2 mg, 5 mg, or 10 mg PedPRM nightly up to 104 weeks, followed by a 2-week placebo period to assess withdrawal effects.

Results: Improvements in child sleep disturbance and caregiver satisfaction with child sleep patterns, quality of sleep, and quality of life were maintained throughout the 104-week treatment period (p < .001 versus baseline for all). During the 2-week withdrawal placebo period, measures declined compared with the treatment period but were still improved compared with baseline. PedPRM was generally safe; the most frequent treatment-related adverse events were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%). Changes in mean weight, height, body mass index, and pubertal status (Tanner staging done by a physician) were within normal ranges for age with no evidence of delay in body mass index or pubertal development.

Conclusion: Nightly PedPRM at optimal dose (2, 5, or 10 mg nightly) is safe and effective for long-term treatment in children and adolescents with autism spectrum disorder and insomnia. There were no observed detrimental effects on children's growth and pubertal development and no withdrawal or safety issues related to the use or discontinuation of the drug.

Clinical trial registration information: Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; https://clinicaltrials.gov/; NCT01906866.

Keywords: autism; melatonin; sleep.

FIGURE 1

Overall Study Design, Patient Disposition, and Dose Breakdown for Participants Note: CSDI = Composite Sleep Disturbance Index; DB = double-blind; OL = open-label; PBO = placebo; PRM = prolonged-release melatonin; SND = sleep and nap diary; TST = total sleep time.

FIGURE 2

Effects of Pediatric Prolonged-Release Melatonin (PedPRM) Treatment on Child and Caregiver Parameters Note: Effects of PedPRM (2, 5, or 10 mg/day) for 28 weeks, 54 weeks, and 106 weeks and placebo withdrawal (2 weeks) on (A) CSDI child sleep disturbance, (B) CSDI caregiver satisfaction, and (C) WHO-5 caregiver quality of life. Data from 106 weeks and 2 weeks withdrawal are mean (SE) change from baseline in the combined PedPRM and placebo population. CSDI = Composite Sleep Disturbance Index; PSQI = Pittsburgh Sleep Quality Index; WHO-5 = 5-item World Health Organization Well-Being Index.

FIGURE 3

Effects of Continuous Pediatric Prolonged-Release Melatonin (PedPRM) Treatment on Pubertal Development Note: Effects of continuous PedPRM treatment (104 weeks PedPRM, 91 weeks placebo) on (A) male and female participant pubic hair growth by age (n = 31), (B) female participant breast development by age (n = 7), and (C) male participant genitalia development by age (n = 24). The individual standard deviation scores (SDS) at baseline (week 2, blue) and end of PedPRM treatment (week 106, red) are depicted. Normal ranges are marked on the right-hand y-axis.