Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: A randomized placebo-controlled trial

Department of Pediatrics and Developmental Neuropsychiatry, Center of Pediatric Sleep Disorders, University of Rome 'La Sapienza', Italy.
Journal of Sleep Research (Impact Factor: 3.35). 05/2012; 21(6). DOI: 10.1111/j.1365-2869.2012.01021.x
Source: PubMed


Although melatonin and cognitive-behavioural therapy have shown efficacy in treating sleep disorders in children with autism spectrum disorders, little is known about their relative or combined efficacy. One hundred and sixty children with autism spectrum disorders, aged 4-10 years, suffering from sleep onset insomnia and impaired sleep maintenance, were assigned randomly to either (1) combination of controlled-release melatonin and cognitive-behavioural therapy; (2) controlled-release melatonin; (3) four sessions of cognitive-behavioural therapy; or (4) placebo drug treatment condition for 12 weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks of treatment. Treatment response was assessed with 1-week actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome measures, derived actigraphically, were sleep latency, total sleep time, wake after sleep onset and number of awakenings. The active treatment groups all resulted in improvements across all outcome measures, with moderate-to-large effect sizes from baseline to a 12-week assessment. Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive-behavioural therapy had a light positive impact mainly on sleep latency, suggesting that some behavioural aspects might play a role in determining initial insomnia. The combination treatment group showed a trend to outperform other active treatment groups, with fewer dropouts and a greater proportion of treatment responders achieving clinically significant changes (63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset latency <30 min). This study demonstrates that adding behavioural intervention to melatonin treatment seems to result in a better treatment response, at least in the short term.

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Available from: Flavia Cortesi, Oct 13, 2014
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    • "Regarding the possible causes, there is a hypothesis that children who are more sensitive to external stimuli can become more vigilant and hyperactive and have some resistance at bedtime, increasing insomnia rates in this population (Hollway and Aman, 2011). Furthermore, this rhythm is known to be modulated by the neurohormone melatonin, the nocturnal production of which is decreased in autism and which is good a candidate for sleep treatment (Cortesi et al., 2012; Tordjman et al., 2015) Regarding the sleep characteristics, subjective data about sleep patterns, such as questionnaires completed by the parents and sleep diaries, as well as objective data (polysomnography and actigraphy) indicate that the most striking feature of sleep in individuals with ASD is the inability to maintain the required latency time; common complaints include difficulty initiating and/or maintaining sleep, reduced total sleep, waking during the night and in the early morning and being unable to stay awake during the day (Elia et al., 2000; Schreck and Mulick, 2000; Miano and Ferri, 2010). As a consequence, the sleep–wake rhythm associated with biological circadian rhythms can be viewed as an adaptation to the day–night cycle, which seems to be important for the rhythmicity and synchrony of motor, emotional, and relational rhythms during the early development of social communication (Tordjman et al., 2015). "
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    Frontiers in Human Neuroscience 06/2015; 9:347. DOI:10.3389/fnhum.2015.00347 · 3.63 Impact Factor
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    • "In addition, a randomized placebo-controlled trial examining insomnia in children with ASD was conducted. In their study, they compared melatonin alone, melatonin combined with cognitive behavioral therapy, cognitive-behavioral therapy and placebo in children with ASD.90 Findings suggested that adding behavioral intervention to melatonin treatment, resulted in better treatment response, at least in the short term. "
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    ABSTRACT: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with both core symptoms and associated symptoms (eg, irritability, aggression, and comorbidities) that affect both the individual and the family/systems around them. There have been recent advances in the understanding of the underlying pathophysiology of ASD pertaining to genetics, epigenetics, neurological, hormonal, and environmental factors that contribute to the difficulties found in individuals with ASD. With this improved understanding, there has been a shift in the application of psychopharmacology in ASD and its related disorders. A literature review was conducted to examine research published in the last 5 years between different classes of psychotropic medications and ASD. The broad scope of the existing literature for the use of conventional medications is summarized and novel medications are discussed.
    Neuropsychiatric Disease and Treatment 02/2014; 10:371-381. DOI:10.2147/NDT.S39516 · 1.74 Impact Factor
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    ABSTRACT: Background: Autism is known to be associated with hyperserotoninemia and, more recently, with decreased blood melatonin level. Melatonin is a neurohormone synthesized from serotonin and involved in circadian rhythms and sleep regulations. Thus, serotonin and melatonin are two ends of a biochemical pathway, and little is known concerning all the steps of this pathway in patients with Autism Spectrum Disorders. Moreover, the clinical relevance of these biochemical endophenotypes remains to be determined. Objectives: Here we explore the serotonin-melatonin pathway in a large cohort of patients with ASD, in order to (i) better characterize the biochemical abnormalities of this pathway in ASD, (ii) determine the clinical correlates of these biochemical abnormalities, and (iii) assess the relevance of these biochemical parameters as biomarkers for ASD diagnosis. Methods: The five parameters related to the serotonin-melatonin pathway, i.e. serotonin, arylalkylamine N-acetyltransferase (AA-NAT) enzyme activity, N-acetylserotonin, acetylserotonin methyltransferase (ASMT) enzyme activity, and melatonin, were measured in the blood of 203 patients with ASD, their unaffected relatives (291 parents and 92 sibs), and age- and sex-matched controls. Biochemical data were correlated with clinical data obtained from ADI-R for 117 patients. Results: Patients with ASD display elevated blood serotonin and N-acetylserotonin levels (p<0,001) compared to controls and unaffected relatives, and decreased ASMT activity and melatonin levels (p<0,001) compared to controls. When confronted to clinical data, melatonin deficiency appears significantly associated with stereotyped behavior (ADI-R axis D, p=0,003). Finally, comparisons between ASD patients, controls and unaffected sibs on the one hand, and between autism and Asperger syndrome on the other hand, reveal that hyperserotoninemia is a relevant biomarker of autism, with good specificity and sensitivity. Conclusions: This study confirms the previously reported major abnormalities of the serotonin-melatonin pathway in ASD. The typical biochemical profile of ASD patients suggests a deficit of the ASMT enzyme, consistent with our previous work. Serotonin and melatonin are both clinically relevant parameters, serotonin as a specific biomarker of autism, and melatonin for behavioral correlates. These results highlight the clinical interest of the serotonin –melatonin pathway in ASD, and its potential role as a susceptibility factor to autism.
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