Melatonin Benefits in Children with Autism Spectrum Disorder
Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children with Autism Spectrum Disorder
The prevalence of insomnia in children and adolescents with autism spectrum disorder (ASD) is high compared with typically developing peers and estimated at 50% to 80%.1 The most frequent problems are difficulty falling asleep (approximately 40%) and maintaining sleep (approximately 35%).
An accumulating body of evidence demonstrates both short- and long-term negative consequences of poor sleep in children, including inattention, hyperactivity, irritability, poor memory, poorer school performance, anxiety, depression, and poorer cardiometabolic health in early adolescence.
Sleep problems in children with ASD are particularly challenging to their families and associated with increased maternal distress, parental sleep disruption, and poor quality of life of caregivers.8 The improvement of sleep duration and onset in children with ASD is among their families’ priorities for research and treatment development.
Clinical guidelines recommend sleep hygiene and/or behavioral intervention as the first-line treatment, but if this fails, there are no medications approved by the Food and Drug Administration for the treatment of pediatric insomnia.
Melatonin, a hormone produced by the pineal gland during the night, is an endogenous sleep promoter and regulator of the circadian clock in humans. Some evidence suggests impaired regulation of melatonin production in children with ASD. In certain neurogenetic disorders (eg, Smith-Magenis syndrome [SMS]), melatonin production is abnormally shifted to the daytime hours.
Exogenous melatonin has been found to be effective for sleep problems in ASD. Melatonin replacement therapy in ASD and SMS is therefore a rational etiological approach.
Whereas the ongoing need of using melatonin in the treatment of sleep problems in children with ASD is recommended as part of good clinical practice,1 data are needed to support evidence-based clinical recommendations regarding the duration and safety of long-term melatonin use in these children. Pediatric prolonged-release melatonin (PedPRM) is an oral solid preparation of prolonged-release melatonin designed to mimic the physiological secretion profile of melatonin providing sustained plasma levels for 8 to 10 hours. Because the prolonged-release properties of the preparation are lost if crushed, a pediatric-appropriate 3-mm-diameter, film-coated tasteless and odorless prolonged-release melatonin mini-tablet (Slenyto; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) was developed, which can be more easily swallowed and better tolerated by young children. PedPRM has recently been licensed by the European Medicines Agency for use in pediatric populations with ASD and SMS.
A randomized, double-blind (DB), placebo-controlled, parallel-group, multicenter (European Union and United States) study of PedPRM for 13 weeks (2 mg with an optional dose escalation to 5 mg after 3 weeks) in children (N = 25; age range 2–17.5 years) with ASD and SMS with or without ADHD comorbidity demonstrated that PedPRM was efficacious and safe compared with placebo for treatment of insomnia.
The main benefits of PedPRM demonstrated in the DB trial were that total sleep time (TST) increased: participants slept on average 57.5 minutes longer at night with PedPRM compared with 9.14 minutes with placebo (p = .034). Sleep latency also improved, decreasing by 39.6 minutes on average with PedPRM and 12.5 minutes with placebo (p = .011), without causing earlier wakeup time. In addition, externalizing behavior in children and caregivers’ quality of life improved significantly (p = .021 and p = .010, respectively, compared with placebo treatment). Completers of the DB phase entered a prospective 91 weeks of open-label (OL) PedPRM treatment and finally 2 weeks of placebo to evaluate withdrawal effects.
Once all participants in the OL phase completed 39 weeks of follow-up (week 54), the 1-year data were summarized and published,16 while 80 participants continued for an additional 52 weeks of PedPRM treatment and 2 weeks placebo to complete the study. In this article, we report on the benefits and risks of PedPRM treatment (2 mg, 5 mg, or 10 mg daily up to 2 years of continuous use) and discontinuation, including impact of treatment on child sleep, growth, and puberty and caregivers’ sleep and quality of life, thus providing clinicians with evidence-based data relating to PedPRM effectiveness and safety.
Of 119 randomly assigned and treated participants, 95 completed the DB phase (week 15) (51 of the PedPRM-treated and 44 of the placebo-treated groups, mean [SD] age 9 [4.2] years, range 2–17 years, 74.7% male participants). Completers entered the OL phase with PedPRM; 74 completed the treatment (week 106), and 73 completed the run-out phase (70 had ASD [95.9%] and 3 [4.1%] had SMS) (Figure 1B). In the DB phase, significantly more participants discontinued in the placebo group than PedPRM-treated group; the most common reasons for discontinuation were withdrawal of parent consent mainly because of personal reasons (n = 6) and adverse events (n = 6).
Treatment adherence was close to 100% throughout the study. Principal investigators reported that children were able to swallow the mini-tablets without crushing, thus confirming acceptability and suitability of 3-mm-diameter mini-tablets for preschoolers ≥2 years of age.24
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«Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder» Published: January 23, 2020
DOI: https://doi.org/10.1016/j.jaac.2019.12.007