A structured review study of drug interventions on sleep disorders in patients with autism spectrum disorders (ASD) has not been published to date. This systematic review aimed to investigate drug interventions for the treatment of sleep disorders in children with ASD. The Web of Science, PubMed, and Scopus databases were searched until March 2019. Study quality was assessed using the Delphi checklist. Due to the heterogeneity of the findings, a meta-analysis was not possible. Drug interventions for the treatment of sleep disorders in patients with ASD included melatonin, atomoxetine, and risperidone. Atomoxetine had no effect on sleep disorders in patients with ASD. A total of 10 studies were reviewed. Melatonin appears to be useful for the treatment of sleep problems in patients with ASD, but further studies are needed to determine the effects of other drugs.
Question: What drugs are used to treat sleep disorders in children with ASD?
Finding: Drug interventions for the treatment of sleep disorders in patients with ASD included melatonin, atomoxetine, and risperidone.
Meaning: Melatonin appears to be useful for the treatment of sleep problems in patients with ASD, but further studies are needed to determine the effects of other drugs.
Introduction
Autism spectrum disorders (ASD) are a heterogeneous group and lifelong neurodevelopmental disorders characterized by significantly unnatural or impaired social interaction and participation, difficulty communicating, and restricted behaviors and interests [1,2]. Risk factors for ASD include genetic factors, environmental factors, maternal obesity, maternal smoking, alcohol intake, and pregnancy complications such as preeclampsia and antenatal hemorrhage [3,4]. Pregnancy supplements such as folic acid and vitamins are associated with a 40% reduction in the risk of ASD [4,5].
Sleep disorders are a common problem for children with ASD and often remain untreated. Many hypotheses regarding the cause of sleep problems among ASD patients include anxiety, related brain pathologies, and an inability to regulate the sleep hormone melatonin. Sleep disturbances among children with ASD are associated with inadequate melatonin secretion [6-9]. This problem is an important feature that affects social communication, daily life, daytime functioning and behavior, and quality of life and increases parental sleep disruption and stress. Increased aggression, hyperactivity, and social problems can result from sleep disorder [10].
Parent-directed behavioral interventions for sleep disorders are the first-line treatment for children with ASD [11]. Medication use for sleep disorders is common among children with ASD [12]. Various studies have reported the useful effects of medications such as melatonin for the treatment of sleep disorders among children with ASD [1,6,7]. To date, a structured review study of randomized controlled trials of drug interventions used to treat sleep disorders in patients with ASD. Therefore, the aim of this systematic review was to investigate drug interventions used to treat sleep disorders in children with ASD.
Methods1. Data sources
The present systematic review aimed to identify drugs used to treat sleep disorders among children with ASD. The report based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist was provided of items for reporting systematic reviews and meta-analyses [13]. The Web of Science, PubMed, and Scopus databases were searched for studies published until March 2019.
2. Search strategy
The search strategy used the following terms: (sleep disorder or sleep disturbance or sleep problem) and (drug intervention or drug treatment) and (autism or ASD or autism spectrum disorder) and (clinical trial or controlled trial).
3. Inclusion and exclusion criteria
Inclusion criteria were all full texts that explored drug interventions for sleep disorders among children with ASD based on randomized controlled trials. Exclusion criteria were review studies, letters to the editor, observational studies, case reports, and qualitative studies.
4. Data extraction
Two authors (EJ and SA) independently screened the titles, abstracts, and full texts of the retrieved studies in EndNote X8. Disagreements were resolved by discussion. The included data were: first author, publication year, sample size, child age (range or mean), drug type, drug dose, treatment outcomes, and treatment duration.
5. Quality assessment
Study quality was evaluated using the Delphi checklist [14]. The checklist includes the following: (1) Was a standard randomization performed? (2) Was the interventional allocation concealed? (3) Was the patient blinded? (4) Was the care provider blinded? (5) Was the outcome assessed or blinded? (6) Were the 2 groups similar at baseline? (7) Were the eligibility criteria well-defined? (8) Was the variability of the outcome presented? (9) Was an intention-totreat analysis performed? Accordingly, a maximum score of 9 was allocated to each study.
Results
A total of 671 articles were retrieved in the primary search based on the search strategy to March 2019. We excluded 163 duplicate articles, 487 articles after the title and abstract review, and 8 after the full-text review. A total of 13 articles [1,6,7,9,11,15-19] with 609 participants that met the criteria for inclusion was retrieved in the present systematic review. All articles were published in English. Due to heterogeneity of the findings, a meta-analysis was not possible. A flowchart of the retrieved articles and selection process is shown in Fig. 1.
The present systematic review revealed that atomoxetine had no effect on sleep disorders in patients with ASD (Table 1). It also revealed that melatonin reduced insomnia symptoms, significantly improved sleep latency, improved total sleep time and efficiency, and was a safe long-term treatment option for children with ASD and insomnia. One study reported that risperidone increased the mean sleep time by 29 minutes per day in children with ASD.
In this systematic review, 3 studies were of low quality and 7 were of high quality according to the Delphi checklist (Table 1).
Discussion
To our knowledge, this is the first systematic review to assess drug interventions for the treatment of sleep disorders in patients with ASD.
The results of this systematic review indicated that melatonin reduced insomnia symptoms, significantly improved sleep latency, improved total sleep time and sleep efficiency, and was a safe longterm treatment option for children with ASD and insomnia.
Hollway et al. [6] assessed the effect of atomoxetine on sleep in youth with ASD. There were no significant differences between the atomoxetine group and the manual parent training program, so atomoxetine appeared ineffective.
Rossignol and Frye [2] conducted a meta-analysis of 5 randomized double-blind studies to evaluate the effect of melatonin in children with ASD in 2011. They presented that melatonin use among children with ASD is associated with improved sleep parameters, better daytime behaviors, and a low incidence of side effects.
Different trials reported that melatonin has good efficacy for sleep disturbances among children with ASD. However, the effects of time long require being thoroughly determined. Despite the widespread use of drugs to treat sleep disorders among children with ASD, the US Food and Drug Administration has not approved any for this indication [20].
A meta-analysis was conducted by Braam et al. [21] in 2009 in which the authors searched the PubMed, MEDLINE, and Embase databases for articles published until 2008. The authors evaluated the effects of melatonin on sleep latency, total sleep time, and number of wakes per night and reported that an abnormal melatonin synthesis led to low nocturnal melatonin levels. Increasing a low melatonin level to a more physiological level may lead to less arousal that intervenes with sleep maintenance.
In 2017, Cuomo et al. [22] conducted another meta-analysis to assess the efficacy of sleep-based interventions for children with ASD. The meta-synthesis included 8 published systematic reviews based on 38 original articles assessing the efficacy of sleep interventions among children with ASD. The included reviews determined 5 major groups of sleep interventions for children with ASD: melatonin therapy, pharmacologic treatments other than melatonin, behavioral interventions, parent education programs, and alternative therapies (iron supplementation, multivitamin use, massage therapy, aromatherapy). The findings of this meta-synthesis propose that no single intervention is effective across all sleep disorders in children with ASD. However, melatonin, behavioral interventions, and parent education programs seem the most effective at improving sleep disorders.
Guénolé et al. [23] performed a systematic review in 2011 on melatonin for sleep disorders in children with ASD by searching the PubMed database for studies published through November 2010. They reported evidence of the useful effects of melatonin on sleep disorders among children with ASD with a low incidence of side effects.
None of the included studies in the present systematic review compared the effects of melatonin to those of other sleep drugs. Therefore, the effectiveness of melatonin compared with other sleep drugs was not determined. However, despite this limitation, the present systematic review reviewed 10 studies and demonstrated that melatonin seems effective for the treatment of sleep problems among children with ASD. Further studies are needed to determine the effects of other drugs for these problems among children with ASD.
No potential conflict of interest relevant to this article was reported.
The protocol of this study was confirmed in Hamadan University of Medical Sciences with code 980210789. The authors thank Hamadan University of Medical Sciences for its financial support of this study.
ReferencesMarasASchroderCMMalowBAFindlingRLBreddyJNirTLong-term efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorderJ Child Adolesc Psychopharmacol2018Oct11[Epub]. https://doi.org/10.1089/cap.2018.0020RossignolDAFryeREMelatonin in autism spectrum disorders: a systematic review and meta-analysisDev Med Child Neurol20115378392JenabiEKaramiMKhazaeiSBashirianSThe association between preeclampsia and autism spectrum disorders among children: a metaanalysisKorean J Pediatr20196212630LyallKSchmidtRJHertz-PicciottoIMaternal lifestyle and environmental risk factors for autism spectrum disordersInt J Epidemiol20144344364ChastePLeboyerMAutism risk factors: genes, environment, and gene-environment interactionsDialogues Clin Neurosci20121428192HollwayJAMendoza-BurchamMAndridgeRAmanMGHandenBArnoldLEAtomoxetine, parent training, and their effects on sleep in youth with autism spectrum disorder and attention-deficit/hyperactivity disorderJ Child Adolesc Psychopharmacol2018281305CortesiFGiannottiFSebastianiTPanunziSValenteDControlledrelease melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trialJ Sleep Res2012217009RichdaleALSchreckKASleep problems in autism spectrum disorders: prevalence, nature, & possible biopsychosocial aetiologiesSleep Med Rev20091340311WrightBSimsDSmartSAlwazeerAAlderson-DayBAllgarVMelatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trialJ Autism Dev Disord20114117584DevnaniPAHegdeAUAutism and sleep disordersJ Pediatr Neurosci2015103047GringrasPNirTBreddyJFrydman-MaromAFindlingRLEfficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorderJ Am Acad Child Adolesc Psychiatry20175694857e4MalowBAKatzTReynoldsAMShuiACarnoMConnollyHVSleep difficulties and medications in children with autism spectrum disorders: a registry studyPediatrics2016137 Suppl 2S98104PetersJPHooftLGrolmanWStegemanIReporting quality of systematic reviews and meta-analyses of otorhinolaryngologic articles based on the PRISMA statementPLoS One201510e0136540VerhagenAPde VetHCde BieRAKesselsAGBoersMBouterLMThe Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensusJ Clin Epidemiol199851123541WirojananJJacquemontSDiazRBacalmanSAndersTFHagermanRJThe efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndromeJ Clin Sleep Med2009514550WasdellMBJanJEBombenMMFreemanRDRietveldWJTaiJA randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilitiesJ Pineal Res2008445764McArthurAJBuddenSSSleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatmentDev Med Child Neurol19984018692GarstangJWallisMRandomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problemsChild Care Health Dev2006325859AmanMGArnoldLEMcDougleCJVitielloBScahillLDaviesMAcute and long-term safety and tolerability of risperidone in children with autismJ Child Adolesc Psychopharmacol20051586984ReliaSEkambaramVPharmacological approach to sleep disturbances in autism spectrum disorders with psychiatric comorbidities: a literature reviewMed Sci (Basel)2018Oct2564pii: E95. doi: 10.3390/medsci6040095BraamWSmitsMGDiddenRKorziliusHVan GeijlswijkIMCurfsLMExogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysisDev Med Child Neurol2009513409CuomoBMVazSLeeEALThompsonCRogersonJMFalkmerTEffectiveness of sleep-based interventions for children with autism spectrum disorder: a meta-synthesisPharmacotherapy20173755578GuénoléFGodboutRNicolasAFrancoPClaustratBBaleyteJMMelatonin for disordered sleep in individuals with autism spectrum disorders: systematic review and discussionSleep Med Rev20111537987Figure and Table
Flow chart of this systematic review.
Characteristics of the studies included in this systematic review
Study
Target
Drug name
Dose
Outcome
Treatment duration
Age average
Sample size
Study quality
Hollway et al. [6] (2018)
ASD
Atomoxetine
The target dose was 1.2 mg/(kg/day), but if necessary this could be increased to 1.8 mg/(kg/day)
There were no significant differences between treatment groups, ATX appears sleep neutral
10 Weeks
5.0–14.11 Years
54
6
Cortesi et al. [7] (2012)
ASD
Controlled-release melatonin
3 mg
Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive-behavioral therapy had a light positive impact mainly on sleep latency.
12 Weeks
4–10 Years
134
7
Gringras et al. [11] 2017
ASD
Prolonged-Release Melatonin
dose titration: 2–5 mg/day and up to 10 mg/day
PR-M was efficacious and safe for treatment of insomnia in children and adolescents with ASD
13 Weeks
2–17.5 Years
125
7
Maras et al. [1] (2018)
ASD
Prolonged-Release Melatonin
2, 5, or 10 mg
PR-M, shown to be efficacious versus placebo, is an efficacious and safe option for long-term treatment of children with ASD who suffer from insomnia.
13 Weeks
2–17.5 Years
95
7
Wirojanan et al. [15] (2009)
ASD, Fragile X syndrome
Melatonin
3 mg
The results of this study support the efficacy and toler¬ability of melatonin treatment for sleep problems in children with ASD
4 Weeks
2–15.3 Years
12
7
Wright et al. [9] (2011)
ASD
Melatonin
2 mg to a maximum dose of 10 mg/day
Melatonin significantly improved sleep latency (by an average of 47 min) and total sleep (by an average of 52 min) compared to placebo. The side effect profile was low.
3 Months
3–16 Years
17
6
Garstang and Wallis [18] (2006)
ASD
Melatonin
5 mg
This study provided evidence of effectiveness of melatonin in children with sleep difficulties and ASD.
4 Weeks
4 - 16 Years
11
5
Wasdell et al. [16] (2008)
Mixed: neurodevel opmental disabilities, ASD
Controlled-release melatonin
5 mg
The therapy improved the sleep of 47 children and was effective in reducing family stress. Children with neurodevelopmental disabilities, who had treatment resistant chronic delayed sleep phase syndrome and impaired sleep maintenance, showed improvement in melatonin therapy.
10 Days
2–18 Years
51
7
McArthur et al. [17] (1998)
ASD, Rett syndrome
Melatonin
2.5–7.5 mg
Administration of melatonin appeared to improve total sleep time and sleep efficiency. It is a safe treatment as no adverse side effects were detected.
4 Weeks
10.1 Years
9
5
Aman et al. [19] (2005)
Autism
Risperidone
0.5–3.5 mg
Difficulty falling asleep appeared to decline with Risperidone. Increase in sleep time: mean increase of 29 min of sleep per day, after with risperidone therapy.