Wednesday, June 18, 2014

Melatonin in autism spectrum disorders: a systematic review and meta-analysis

Aim  The aim of this study was to investigate melatonin-related findings in autism spectrum disorders (ASD), including autistic disorder, Asperger syndrome, Rett syndrome, and pervasive developmental disorders, not otherwise specified.

Method  Comprehensive searches were conducted in the PubMed, Google Scholar, CINAHL, EMBASE, Scopus, and ERIC databases from their inception to October 2010. Two reviewers independently assessed 35 studies that met the inclusion criteria. Of these, meta-analysis was performed on five randomized double-blind, placebo-controlled studies, and the quality of these trials was assessed using the Downs and Black checklist.

Results  Nine studies measured melatonin or melatonin metabolites in ASD and all reported at least one abnormality, including an abnormal melatonin circadian rhythm in four studies, below average physiological levels of melatonin and/or melatonin derivates in seven studies, and a positive correlation between these levels and autistic behaviors in four studies. Five studies reported gene abnormalities that could contribute to decreased melatonin production or adversely affect melatonin receptor function in a small percentage of children with ASD. Six studies reported improved daytime behavior with melatonin use. Eighteen studies on melatonin treatment in ASD were identified; these studies reported improvements in sleep duration, sleep onset latency, and night-time awakenings. Five of these studies were randomized double-blind, placebo-controlled crossover studies; two of the studies contained blended samples of children with ASD and other developmental disorders, but only data for children with ASD were used in the meta-analysis. The meta-analysis found significant improvements with large effect sizes in sleep duration (73min compared with baseline, Hedge’s g 1.97 [95% confidence interval {CI} CI 1.10–2.84], Glass’s Δ 1.54 [95% CI 0.64–2.44]; 44min compared with placebo, Hedge’s g 1.07 [95% CI 0.49–1.65], Glass’s Δ 0.93 [95% CI 0.33–1.53]) and sleep onset latency (66min compared with baseline, Hedge’s g −2.42 [95% CI −1.67 to −3.17], Glass’s Δ −2.18 [95% CI −1.58 to −2.76]; 39min compared with placebo, Hedge’s g −2.46 [95% CI −1.96 to −2.98], Glass’s Δ −1.28 [95% CI −0.67 to −1.89]) but not in night-time awakenings. The effect size varied significantly across studies but funnel plots did not indicate publication bias. The reported side effects of melatonin were minimal to none. Some studies were affected by limitations, including small sample sizes and variability in the protocols that measured changes in sleep parameters.

Interpretation  Melatonin administration in ASD is associated with improved sleep parameters, better daytime behavior, and minimal side effects. Additional studies of melatonin would be helpful to confirm and expand on these findings.

Daniel A. Rossignol and Richard E. Frye
Developmental Medicine & Child Neurology, Volume 53, Issue 9, pages 783–792, September 2011
DOI: 10.1111/j.1469-8749.2011.03980.x

Also look for the upcoming review article: “Melatonin and the Circadian System: Contributions to Successful Female Reproduction” by Russell Reiter et al., Fertility & Sterility, Volume 102, Issue 3, September 2014: “The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. ... The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring exhibit neurobehavioral deficits. Melatonin protects the developing fetus from oxidative stress.” DOI: 10.1016/j.fertnstert.2014.06.014