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TREATMENT OF CHRONIC INSOMNIA IN CHILDREN AND ADOLESCENTS WITH NEURODEVELOPMENTAL DISABILITIESSHORT RUNNING TITLE: Treatment of insomnia in NDDAUTHORS: Bruni O, Angriman M, Calisti F, Comandini A, Esposito G, Cortese S, Ferri R.Oliviero Bruni, MDDepartment of Developmental and Social Psychology, Sapienza University Via dei Marsi 78 - 00185 Rome (Italy) email: HYPERLINK "mailto:oliviero.bruni@uniroma1.it" oliviero.bruni@uniroma1.itTel. +39-0633776087.Marco Angriman, MDDepartment of Pediatrics, Child Neurology and Neurorehabilitation Unit, Central Hospital of Bolzano, Bohler Street 5, 39100 Bolzano-ItalyEmail: HYPERLINK "mailto:marco.angriman@" marco.angriman@Tel: +39-0471908868Fabrizio Calisti, MDAngelini, Research Center, S.Palomba - Rome, ItalyEmail: HYPERLINK "mailto:f.calisti@angelini.it" f.calisti@angelini.itTel. +39 06910451Alessandro Comandini, MDAngelini, Research Center, S.Palomba - Rome, ItalyEmail: HYPERLINK "mailto:andini@angelini.it" andini@angelini.itTel. +39 06910451Giovanna EspositoAngelini, Research Center, S.Palomba - Rome, ItalyEmail: HYPERLINK "mailto:g.esposito@angelini.itt" g.esposito@angelini.itTel. +39 06910451Samuele CorteseAcademic Unit of Psychology, Developmental Brain-Behavior Laboratory, University of Southampton, Southampton, UK.New York University Child Study Center, New York, USA.Solent NHS Trust, Southampton, UK.Raffaele FerriSleep Research Centre; Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, ItalyEmail: HYPERLINK "mailto:rferri@oasi.en.it" rferri@oasi.en.itTel. +39-0935936111Address for correspondence: Prof. Oliviero Bruni, Department of Developmental and Social Psychology, Sapienza University, Via dei Marsi 78 - 00185 Rome (Italy)Financial disclosure: O.B. served as a consultant and provided expert testimony for Angelini; M.A. declares no financial disclosure; F.C., A.C. and G.E. were employees of Angelini during the conduct of the study; R.F. declares no financial disclosure.Conflict of interest statement: There are no conflicts of interest to report. No writing assistance was utilized in the production of this manuscript. ABSTRACTSleep disturbances, and especially insomnia, represent a common problem in children with neurodevelopmental disabilities. Effective pharmacologic interventions are needed to improve sleep and quality of life especially when behavioral therapy alone is insufficient. Unfortunately, there are no approved sleep medications by the United States Food and Drug Administration or European Medicines Agency for pediatric insomnia and most of the medications are prescribed off-label. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice. Melatonin is also commonly used and, apparently, is the safest choice for children with developmental disabilities. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Zolpidem, zaleplon, eszopiclone are selective benzodiazepines binding preferentially to GABA type A receptor complexes but only few studies have been carried out in children and adolescents. Alpha-agonists such as clonidine are used in child psychiatry to improve sleep onset latency, especially in ADHD subjects. Tricyclic antidepressants are used in adults with insomnia due to their sedating properties, but are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of the currently prescribed pediatric sleep medicines. KEYWORDS: Sleep disorders; insomnia; neurodevelopmental disorders; drug effectsINTRODUCTIONSleep disorders in children with Neurodevelopmental disabilities (NDDs), represented by difficulty in falling asleep, night awakenings, and reduced sleep duration, are among the most common parental complaints to health care professionals, with prevalence of 86%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1qkklpma15","properties":{"formattedCitation":"(Robinson-Shelton & Malow, 2016)","plainCitation":"(Robinson-Shelton & Malow, 2016)"},"citationItems":[{"id":5835,"uris":[""],"uri":[""],"itemData":{"id":5835,"type":"article-journal","title":"Sleep Disturbances in Neurodevelopmental Disorders","container-title":"Current Psychiatry Reports","page":"6","volume":"18","issue":"1","source":"PubMed","abstract":"Sleep disturbances are extremely prevalent in children with neurodevelopmental disorders compared to typically developing children. The diagnostic criteria for many neurodevelopmental disorders include sleep disturbances. Sleep disturbance in this population is often multifactorial and caused by the interplay of genetic, neurobiological and environmental overlap. These disturbances often present either as insomnia or hypersomnia. Different sleep disorders present with these complaints and based on the clinical history and findings from diagnostic tests, an appropriate diagnosis can be made. This review aims to provide an overview of causes, diagnosis, and treatment of sleep disturbances in neurodevelopmental disorders that present primarily with symptoms of hypersomnia and/or insomnia.","DOI":"10.1007/s11920-015-0638-1","ISSN":"1535-1645","note":"PMID: 26719309","journalAbbreviation":"Curr Psychiatry Rep","language":"eng","author":[{"family":"Robinson-Shelton","given":"Althea"},{"family":"Malow","given":"Beth A."}],"issued":{"date-parts":[["2016",1]]}}}],"schema":""} (Robinson-Shelton & Malow, 2016). In children with NDDs sleep disturbances impact on cognitive and emotional development, aggravating the functional impairment associated with these conditions ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cnuc4qnmp","properties":{"formattedCitation":"(van de Wouw, Evenhuis, & Echteld, 2012)","plainCitation":"(van de Wouw, Evenhuis, & Echteld, 2012)"},"citationItems":[{"id":5169,"uris":[""],"uri":[""],"itemData":{"id":5169,"type":"article-journal","title":"Prevalence, associated factors and treatment of sleep problems in adults with intellectual disability: a systematic review","container-title":"Research in Developmental Disabilities","page":"1310-1332","volume":"33","issue":"4","source":"PubMed","abstract":"In people with intellectual disability (ID), impaired sleep is common. Life expectancy has increased in this group, and it is known that in general population sleep deteriorates with aging. Therefore the aims of this systematic review were to examine how sleep problems are defined in research among adults and older people with ID, and to collect information on the prevalence, associated factors and treatment of sleep problems in this population. PubMed, EMBase, PsycINFO and Web of Science were searched for studies published between January 1990 and August 2011. All empirical studies covering sleep problems in adults with ID were included, and assessed on quality (level of evidence), using a slightly modified version of the SIGN-50 methodology checklist for cohort studies. Of 50 studies that were included for systematic review, one was of high quality, 14 were well conducted, 14 were well conducted but with a high risk of bias, and 21 were non-analytical. The reported estimated prevalence rates of sleep problems in adults with ID ranged from 8.5% to 34.1%. A prevalence of 9.2% was reported for significant sleep problems. Sleep problems were associated with the following factors: challenging behavior; respiratory disease; visual impairment; psychiatric conditions; and using psychotropic, antiepileptic and/or antidepressant medication. Little information was found on older people specifically. Two studies reported treatment effects on sleep problems in larger populations; their findings suggest that non-pharmaceutical interventions are beneficial. Research on the prevalence, associated factors and treatment of sleep problems in adults and older people with ID has mainly focused on subjectively derived data. The definitions used to describe a sleep problem are not uniform, and associations are mainly described as correlations. In order to give recommendations for clinical practice further research is needed, involving objective measurements and multivariate analysis.","DOI":"10.1016/j.ridd.2012.03.003","ISSN":"1873-3379","note":"PMID: 22502859","shortTitle":"Prevalence, associated factors and treatment of sleep problems in adults with intellectual disability","journalAbbreviation":"Res Dev Disabil","language":"eng","author":[{"family":"Wouw","given":"E.","non-dropping-particle":"van de"},{"family":"Evenhuis","given":"H. M."},{"family":"Echteld","given":"M. A."}],"issued":{"date-parts":[["2012",8]]}}}],"schema":""} (van de Wouw, Evenhuis, & Echteld, 2012) but affect also the entire family environment disrupting the siblings and marital relationships and increasing the levels of stress. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ksn78hvus","properties":{"formattedCitation":"(S. E. Goldman, Bichell, Surdyka, & Malow, 2012)","plainCitation":"(S. E. Goldman, Bichell, Surdyka, & Malow, 2012)"},"citationItems":[{"id":5839,"uris":[""],"uri":[""],"itemData":{"id":5839,"type":"article-journal","title":"Sleep in children and adolescents with Angelman syndrome: association with parent sleep and stress","container-title":"Journal of intellectual disability research: JIDR","page":"600-608","volume":"56","issue":"6","source":"PubMed","abstract":"BACKGROUND: Sleep concerns are common in children with Angelman syndrome, with 20-80% of individuals having a decreased sleep need and/or abnormal sleep-wake cycles. The impact of these sleep behaviours on parental sleep and stress is not known.\nMETHOD: Through the use of standardised questionnaires, wrist actigraphy and polysomnography, we defined the sleep behaviours of 15 children/adolescents with Angelman syndrome and the association of the child/adolescents sleep behaviours on parental sleep behaviours and parental stress.\nRESULTS: Both children/adolescents and their parents exhibited over 1?h of wake time after sleep onset and fragmented sleep. Prolonged sleep latency in the child was associated with parent insomnia and daytime sleepiness. Additionally, variability in child total sleep time was associated with parental stress.\nCONCLUSIONS: Poor sleep in children/adolescents with Angelman syndrome was associated with poor parental sleep and higher parental stress. Further work is warranted to identify the underlying causes of the poor sleep, and to relate these findings to daytime functioning, behaviour and the family unit.","DOI":"10.1111/j.1365-2788.2011.01499.x","ISSN":"1365-2788","note":"PMID: 22044653","shortTitle":"Sleep in children and adolescents with Angelman syndrome","journalAbbreviation":"J Intellect Disabil Res","language":"eng","author":[{"family":"Goldman","given":"S. E."},{"family":"Bichell","given":"T. J."},{"family":"Surdyka","given":"K."},{"family":"Malow","given":"B. A."}],"issued":{"date-parts":[["2012",6]]}}}],"schema":""} (S. E. Goldman, Bichell, Surdyka, & Malow, 2012) The pathophysiology of sleep disorders in children with NDDs is multifactorial: in some patients problematic sleep is a phenotypic characteristic of a particular disorder or genetic condition and the knowledge of the distinctive features of sleep disorders in patients with NDDs is crucial for their effective treatment. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1o74dnh9ar","properties":{"formattedCitation":"(Grigg-Damberger & Ralls, 2013)","plainCitation":"(Grigg-Damberger & Ralls, 2013)"},"citationItems":[{"id":731,"uris":[""],"uri":[""],"itemData":{"id":731,"type":"article-journal","title":"Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders.","container-title":"Current opinion in pulmonary medicine","page":"616-625","volume":"19","issue":"6","abstract":"PURPOSE OF REVIEW: This review describes recent research in pediatric behavioral insomnias in neurodevelopmental disorders and their treatment. RECENT FINDINGS: Insomnia in children with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) is typically complex, chronic, and difficult to adequately control. Abnormalities in genetic and/or epigenetic regulation of sleep/wakefulness and its timing predispose patients with NDD to insomnia, although poor sleep hygiene, maladaptive associations, and limit-setting are likely to contribute. Parents are agents for change in problematic sleep behaviors in patients with NDD. We review the benefits of behavioral therapies and melatonin to treat sleep problems in children with NDD. Problematic sleep is so prevalent in some neurodevelopmental syndromes (Rett, Angelman, Williams, and Smith-Magenis) that it is part of their diagnostic criteria. SUMMARY: Children and adolescents with neurological disorders frequently have complex sleep disorders that require treatment. Understanding the basic pathology and treatment strategies provides an opportunity to improve well being and quality of life in those affected by NDD and their families.","DOI":"10.1097/MCP.0b013e328365ab89","note":"PMID: 24055857","journalAbbreviation":"Curr Opin Pulm Med","language":"eng","author":[{"family":"Grigg-Damberger","given":"Madeleine"},{"family":"Ralls","given":"Frank"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} (Grigg-Damberger & Ralls, 2013) In other cases, sleep disorders represent a main comorbidity: a meta-analysis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ctuikq54p","properties":{"formattedCitation":"(Cortese, Faraone, Konofal, & Lecendreux, 2009)","plainCitation":"(Cortese, Faraone, Konofal, & Lecendreux, 2009)"},"citationItems":[{"id":5761,"uris":[""],"uri":[""],"itemData":{"id":5761,"type":"article-journal","title":"Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"894-908","volume":"48","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To perform a meta-analysis of subjective (i.e., based on questionnaires) and objective (i.e., using polysomnography or actigraphy) studies comparing sleep in children with attention-deficit/hyperactivity disorder (ADHD) versus controls.\nMETHOD: We searched for subjective and objective sleep studies (1987-2008) in children with ADHD (diagnosed according to standardized criteria). Studies including subjects pharmacologically treated or with comorbid anxiety/depressive disorders were excluded.\nRESULTS: Sixteen studies, providing 9 subjective and 15 objective parameters and including a total pooled sample of 722 children with ADHD versus 638 controls, were retained. With regard to subjective items, the meta-analysis indicated that children with ADHD had significantly higher bedtime resistance (z = 6.94, p <.001), more sleep onset difficulties (z = 9.38, p <.001), night awakenings (z = 2.15, p =.031), difficulties with morning awakenings (z = 5.19, p <.001), sleep disordered breathing (z = 2.05, p =.040), and daytime sleepiness (z = 1.96, p =.050) compared with the controls. As for objective parameters, sleep onset latency (on actigraphy), the number of stage shifts/hour sleep, and the apnea-hypopnea index were significantly higher in the children with ADHD compared with the controls (z = 3.44, p =.001; z = 2.43, p =.015; z = 3.47, p =.001, respectively). The children with ADHD also had significantly lower sleep efficiency on polysomnography (z = 2.26, p =.024), true sleep time on actigraphy (z = 2.85, p =.004), and average times to fall asleep for the Multiple Sleep Latency Test (z = 6.37, p <.001) than the controls.\nCONCLUSIONS: The children with ADHD are significantly more impaired than the controls in most of the subjective and some of the objective sleep measures. These results lay the groundwork for future evidence-based guidelines on the management of sleep disturbances in children with ADHD.","DOI":"10.1097/CHI.0b013e3181ac09c9","ISSN":"1527-5418","note":"PMID: 19625983","shortTitle":"Sleep in children with attention-deficit/hyperactivity disorder","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Cortese","given":"Samuele"},{"family":"Faraone","given":"Stephen V."},{"family":"Konofal","given":"Eric"},{"family":"Lecendreux","given":"Michel"}],"issued":{"date-parts":[["2009",9]]}}}],"schema":""} (Cortese, Faraone, Konofal, & Lecendreux, 2009) on sleep in ADHD found that children or their parents reported bedtime resistance, sleep-onset difficulties, night awakenings, difficulties with morning awakening, sleep breathing problems, and daytime sleepiness significantly more often than healthy controls. Moreover, sleep disorders might be aggravated by common issues linked to NDDs (such as sensory and motor deficits, psychopathological disturbances, respiratory disorders, epilepsy, and mental retardation) all contributing to the developmental delay. Sleep problems could be specific in different syndromes (i.e. sleep apnea in Down or Prader-Willi syndromes) but the sleep complaints in children with NDDs are mainly represented by difficulty in settling at night (51%) and nocturnal awakenings (67%) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5s4ah2aq6","properties":{"formattedCitation":"(Quine, 1991)","plainCitation":"(Quine, 1991)"},"citationItems":[{"id":5173,"uris":[""],"uri":[""],"itemData":{"id":5173,"type":"article-journal","title":"Sleep problems in children with mental handicap","container-title":"Journal of Mental Deficiency Research","page":"269-290","volume":"35 ( Pt 4)","source":"PubMed","abstract":"This paper reports on a longitudinal study of sleep problems in 200 children with severe mental handicap. Sleep problems were extremely common: 51% of children had settling problems, 67% of children had waking problems, and 32% of parents said they rarely got enough sleep. Sleep problems were also very persistent: between a half and two-thirds of children who exhibited sleep problems at Time 1 still had them 3 years later. Sleep problems were associated with a number of child characteristics: poor communication skills, poor academic skills, poor self-help skills, incontinence, daytime behaviour problems and epilepsy. There were no relationships with family variables such as social class, income, family composition or housing tenure. However, maternal stress, maternal irritability and perceived impact on the family were related to sleep problems. A Sleep Index was constructed, and path analysis was used to trace the main causal pathways of the child, family and social characteristics. Ten variables explained 50% of the variance in the Sleep Problems Index. Communication skills played a pivotal role. The implications of the findings for intervention strategies are discussed.","ISSN":"0022-264X","note":"PMID: 1757978","journalAbbreviation":"J Ment Defic Res","language":"eng","author":[{"family":"Quine","given":"L."}],"issued":{"date-parts":[["1991",8]]}}}],"schema":""} (Quine, 1991) Fragmented sleep throughout the day and night determines daytime sleepiness and irregular sleep schedule that may lead to a free-running rhythm or to a complete reversal of the night-day cycle. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1o67h5ghv","properties":{"formattedCitation":"(Okawa MSH., n.d.)","plainCitation":"(Okawa MSH., n.d.)"},"citationItems":[{"id":5179,"uris":[""],"uri":[""],"itemData":{"id":5179,"type":"chapter","title":"Sleep disorders in mentally retarded and brain- impaired children.","container-title":"Sleep and its Disorders in Children. New York, NY: Raven Press; 1987:","page":"269–290","author":[{"family":"Okawa MSH.","given":""}]}}],"schema":""} (Okawa MSH., n.d.).The are no US Food and Drug Administration (FDA) approved medications to treat insomnia in pediatric patients including those with NDDs, and therefore most of the drugs are prescribed off-label. In this review, we will describe the current clinical evidence for the treatment of chronic insomnia in children and adolescents with NDDs.METHODS:Search strategy and results from each databaseTo ensure high levels of methodological adequacy as recommended by the Cochrane group ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"es2ie444m","properties":{"formattedCitation":"(Higgins JPT & Green S, 2011)","plainCitation":"(Higgins JPT & Green S, 2011)"},"citationItems":[{"id":7758,"uris":[""],"uri":[""],"itemData":{"id":7758,"type":"book","title":"Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0","publisher":"The Cochrane Collaboration","author":[{"family":"Higgins JPT","given":""},{"family":"Green S","given":""}],"issued":{"date-parts":[["2011",3]]}}}],"schema":""} (Higgins JPT & Green S, 2011) and avoid the inevitable bias caused by dependence on investigators agreeing to provide data from unpublished studies, we did not search for unpublished data. We excluded non peer-reviewed references (e.g., conference proceedings) since we considered peer-review process as essential to the quality of the publication. We retained all types of study designs.We searched the following electronic databases: PubMed, Ovid (including PsycINFO, Ovid MEDLINE?, and Embase), Web of Knowledge (Web of Science, Biological abstracts, BIOSIS, FSTA). The specific search terms and syntax for each database are reported in the Supplemental Material. The search was finalized on February 12nd, 2017. No language limitations were applied, to avoid biases due to language restrictions. References list of pertinent reviews/systematic reviews were screened to reduce the likelihood of missing any relevant publication. Two authors (MA and SC) independently and blindly performed the search and screening of papers against eligibility criteria. Any disagreement between the two authors was resolved by consensus. NON-PHARMACOLOGICAL TREATMENT Prevention is the best treatment for insomnia of childhood but, unfortunately, most parents request an evaluation when the disorder has become chronic. Although we will focus on drug treatment, we should emphasize that when there is a decision to start a pharmacologic intervention, behavioral interventions should be always associated. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"16tq80u1ce","properties":{"formattedCitation":"(Jan et al., 2008)","plainCitation":"(Jan et al., 2008)"},"citationItems":[{"id":5841,"uris":[""],"uri":[""],"itemData":{"id":5841,"type":"article-journal","title":"Sleep hygiene for children with neurodevelopmental disabilities","container-title":"Pediatrics","page":"1343-1350","volume":"122","issue":"6","source":"PubMed","abstract":"Sleep disturbances in children with neurodevelopmental disabilities are common and have a profound effect on the quality of life of the child, as well as the entire family. Although interventions for sleep problems in these children often involve a combination of behavioral and pharmacologic strategies, the first line of treatment is the promotion of improved sleep habits or \"hygiene.\" Despite the importance of sleep-hygiene principles, defined as basic optimal environmental, scheduling, sleep-practice, and physiologic sleep-promoting factors, clinicians often lack appropriate knowledge and skills to implement them. In addition, sleep-hygiene practices may need to be modified and adapted for this population of children and are often more challenging to implement compared with their healthy counterparts. This first comprehensive, multidisciplinary review of sleep hygiene for children with disabilities presents the rationale for incorporating these measures in their treatment, outlines both general and specific sleep-promotion practices, and discusses problem-solving strategies for implementing them in a variety of clinical practice settings.","DOI":"10.1542/peds.2007-3308","ISSN":"1098-4275","note":"PMID: 19047255","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Jan","given":"James E."},{"family":"Owens","given":"Judith A."},{"family":"Weiss","given":"Margaret D."},{"family":"Johnson","given":"Kyle P."},{"family":"Wasdell","given":"Michael B."},{"family":"Freeman","given":"Roger D."},{"family":"Ipsiroglu","given":"Osman S."}],"issued":{"date-parts":[["2008",12]]}}}],"schema":""} (Jan et al., 2008); good sleep practices and behavioral interventions are the first recommended treatments for pediatric insomnia in either healthy or NDD children. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uhev00501","properties":{"formattedCitation":"(Honaker & Meltzer, 2014)","plainCitation":"(Honaker & Meltzer, 2014)"},"citationItems":[{"id":624,"uris":[""],"uri":[""],"itemData":{"id":624,"type":"article-journal","title":"Bedtime Problems and Night Wakings in Young Children: An Update of the Evidence.","container-title":"Paediatric respiratory reviews","volume":"15","issue":"4","abstract":"Bedtime problems and night wakings in infants and young children are prevalent, persistent, and associated with a variety of impairments in youth and their families. Assessment strategies include clinical interview, sleep diaries, actigraphy, and subjective measures. A number of treatment approaches with varying degrees of empirical support are available, and several novel strategies have been evaluated in recent years. Appropriate sleep scheduling and a bedtime routine are important components of any treatment program.","DOI":"10.1016/j.prrv.2014.04.011","note":"PMID: 24908611","journalAbbreviation":"Paediatr Respir Rev","language":"ENG","author":[{"family":"Honaker","given":"Sarah Morsbach"},{"family":"Meltzer","given":"Lisa J."}],"issued":{"date-parts":[["2014",12]]}}}],"schema":""} (Honaker & Meltzer, 2014)The first line of treatment is the promotion of better sleep habits that need to be modified and adapted to these children, are often somewhat challenging to implement, and should be associated with other behavioral interventions using a gradual approach (gradual withdrawal, gradual extinction, fading etc.), rather than an abrupt change (e.g. extinction techniques), that may be easier and more acceptable for parents as well as being more appropriate for some children with special needs. The choice of one particular form of behavioral intervention rather than another should be guided by the parent preferences ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"16qkf1jokp","properties":{"formattedCitation":"(Wiggs & France, 2000)","plainCitation":"(Wiggs & France, 2000)"},"citationItems":[{"id":5849,"uris":[""],"uri":[""],"itemData":{"id":5849,"type":"article-journal","title":"Behavioural treatments for sleep problems in children and adolescents with physical illness, psychological problems or intellectual disabilities","container-title":"Sleep Medicine Reviews","page":"299-314","volume":"4","issue":"3","source":"PubMed","abstract":"Young people with physical, psychological or intellectual disabilities or disorders are reported to have more frequent and persistent problems with sleep than their peers without <special needs>. Sleep disorders affecting the quantity or quality of sleep have effects on a child's daytime functioning and the functioning of their families. Many children with special needs have learning and behaviour problems and their parents (particularly mothers) have increased levels of stress and poorer mental health. This relationship between sleep disorders and learning, and behaviour and family functioning makes it particularly important that children with special needs receive appropriate intervention for their sleep disorders. This may be one way of mitigating these other problems. This review considers the case reports and experimental trials which have used behavioural treatments for sleep problems in children and adolescents with special needs. Behavioural treatments for sleep-wake cycle disorders, sleeplessness, parasomnias and excessive sleepiness are reported. These preliminary reports do suggest that behavioural approaches can be rapidly successful for treating sleep problems, even where the sleep problems are long-standing, severe and associated with physical, psychological or intellectual problems. The parent and the clinician should not be deterred from treating the sleep problem in isolation using behavioural treatments. Methodological issues, however, highlight the importance of further and better research. Not all children responded to the behavioural interventions and some needed re-implementation of therapy to maintain improvements; the use of heterogeneous groups make the findings and choice of treatment for individuals difficult to interpret. Finally, there are few studies overall, and the majority are case studies rather than controlled studies using multiple baseline designs or randomization and a control group. Careful studies are required in order to establish the relative efficacy of the behavioural techniques and their suitability with homogeneous subgroups of children with special needs.","DOI":"10.1053/smrv.1999.0094","ISSN":"1532-2955","note":"PMID: 12531171","journalAbbreviation":"Sleep Med Rev","language":"ENG","author":[{"family":"Wiggs","given":"Luci"},{"family":"France","given":"Karyn"}],"issued":{"date-parts":[["2000",6]]}}}],"schema":""} (Wiggs & France, 2000) and like in typically developing children, there is no evidence that one approach is more effective than another. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1q2t8cegio","properties":{"formattedCitation":"(Angriman, Caravale, Novelli, Ferri, & Bruni, 2015)","plainCitation":"(Angriman, Caravale, Novelli, Ferri, & Bruni, 2015)"},"citationItems":[{"id":3526,"uris":[""],"uri":[""],"itemData":{"id":3526,"type":"article-journal","title":"Sleep in children with neurodevelopmental disabilities","container-title":"Neuropediatrics","page":"199-210","volume":"46","issue":"3","source":"PubMed","abstract":"This review describes recent research in pediatric sleep disorders associated with neurodevelopmental disabilities (NDDs) and their treatment. NDDs affect more than 2% of the general population and represent more than 35% of the total cases of children referred to a neuropsychiatric center for sleep problems. Specific clinical and therapeutic aspects of sleep disorders associated with Down syndrome, Fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Rett syndrome, Smith-Magenis syndrome, cerebral palsy, and autism spectrum disorders are described. Furthermore, the drugs commonly used for sleep disorders in children with NDDs are described. The review clearly highlighted that children with NDDs are often affected by sleep disorders that require appropriate clinical and therapeutic approach to improve quality of life in both patients and families.","DOI":"10.1055/s-0035-1550151","ISSN":"1439-1899","note":"PMID: 25918987","journalAbbreviation":"Neuropediatrics","language":"eng","author":[{"family":"Angriman","given":"Marco"},{"family":"Caravale","given":"Barbara"},{"family":"Novelli","given":"Luana"},{"family":"Ferri","given":"Raffaele"},{"family":"Bruni","given":"Oliviero"}],"issued":{"date-parts":[["2015",6]]}}}],"schema":""} (Angriman, Caravale, Novelli, Ferri, & Bruni, 2015) A systematic review of behavioral treatments for insomnia reported that moderate-to-low level of evidence supports behavioral interventions in adolescents and in children with NDDs. This review showed only two studies involving behavioral interventions for sleep problems for children with special needs that met the inclusion criteria. One study included children with autism spectrum disorders ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1jgclfpbsv","properties":{"formattedCitation":"(Adkins et al., 2012)","plainCitation":"(Adkins et al., 2012)"},"citationItems":[{"id":2030,"uris":[""],"uri":[""],"itemData":{"id":2030,"type":"article-journal","title":"Effects of a standardized pamphlet on insomnia in children with autism spectrum disorders.","container-title":"Pediatrics","page":"S139-144","volume":"130 Suppl 2","abstract":"OBJECTIVE: Sleep difficulties are common reasons why parents seek medical intervention in children with autism spectrum disorders (ASDs). We determined whether a pamphlet alone could be used by parents to help their child's insomnia. METHODS: Thirty-six children with ASD, ages 2 to 10 years, were enrolled. All had prolonged sleep latency confirmed by actigraphy showing a mean sleep latency of 30 minutes or more. Parents were randomly assigned to receive the sleep education pamphlet or no intervention. Children wore an actigraphy device to record baseline sleep parameters, with the primary outcome variable being change in sleep latency. Actigraphy data were collected a second time 2 weeks after the parent received the randomization assignment and analyzed by using Student's t test. Parents were also asked a series of questions to gather information about the pamphlet and its usefulness. RESULTS: Although participants randomized to the 2 arms did not differ statistically in age, gender, socioeconomic status, total Children's Sleep Habits Questionnaire score, or actigraphy parameters, some differences may be large enough to affect results. Mean change in sleep-onset latency did not differ between the randomized groups (pamphlet versus no pamphlet). Parents commented that the pamphlet contained good information, but indicated that it would have been more useful to be given specific examples of how to take the information and put it into practice. CONCLUSIONS: A sleep education pamphlet did not appear to improve sleep latency in children with ASDs.","DOI":"10.1542/peds.2012-0900K","note":"PMID: 23118244","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Adkins","given":"Karen W."},{"family":"Molloy","given":"Cindy"},{"family":"Weiss","given":"Shelly K."},{"family":"Reynolds","given":"Ann"},{"family":"Goldman","given":"Suzanne E."},{"family":"Burnette","given":"Courtney"},{"family":"Clemons","given":"Traci"},{"family":"Fawkes","given":"Diane"},{"family":"Malow","given":"Beth A."}],"issued":{"date-parts":[["2012",11]]}}}],"schema":""} (Adkins et al., 2012) whereas the other focused on children with Down syndrome. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1obs6fdae5","properties":{"formattedCitation":"(Stores & Stores, 2004)","plainCitation":"(Stores & Stores, 2004)"},"citationItems":[{"id":5853,"uris":[""],"uri":[""],"itemData":{"id":5853,"type":"article-journal","title":"Evaluation of Brief Group-Administered Instruction for Parents to Prevent or Minimize Sleep Problems in Young Children with Down Syndrome","container-title":"Journal of Applied Research in Intellectual Disabilities","page":"61-70","volume":"17","issue":"2","source":"Wiley Online Library","abstract":"Background? The study concerns the unknown value of group instruction for mothers of young children with Down syndrome (DS) in preventing or minimizing sleep problems. Method?\n* 1Children with DS were randomly allocated to an Instruction group (given basic information about children's sleep) and a Control group for later comparison including objective sleep measures (actometry).\n* 2As a secondary exercise, parental reports of sleep problems and objective sleep measures were compared in children with DS and a small sample of unimpaired children (U group) of comparable age and sex distribution. Results? Instruction (shown to have improved mothers' knowledge) was associated with improvement in behavioural sleep problem ratings at 6-month follow up with no change in sleep-related breathing problem ratings or actometry findings. Sleep-related breathing problem symptoms and actometry abnormalities were significantly more common in the DS group than in the U group at baseline, with no obvious differences for behavioural sleep problems. Conclusions? Group instruction offers some benefit regarding behavioural sleep problems but not for sleep-related breathing problems to which more attention should be paid in children with DS, with a view to precise diagnosis and treatment.","DOI":"10.1111/j.1360-2322.2004.00174.x","ISSN":"1468-3148","language":"en","author":[{"family":"Stores","given":"Rebecca"},{"family":"Stores","given":"Gregory"}],"issued":{"date-parts":[["2004",6,1]]}}}],"schema":""} (Stores & Stores, 2004). An older study showed that bedtime fading resulted successful to advance the bedtimes in a sample of 3 patients with Rett’s syndrome. This treatment resulted in more regular sleep patterns for the girls by increasing appropriate nighttime sleep, reducing inappropriate daytime sleep and reducing problematic nighttime behaviors (e.g., night wakings.) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1k50aravjr","properties":{"formattedCitation":"(Piazza, Fisher, & Moser, 1991)","plainCitation":"(Piazza, Fisher, & Moser, 1991)"},"citationItems":[{"id":7659,"uris":[""],"uri":[""],"itemData":{"id":7659,"type":"article-journal","title":"Behavioral treatment of sleep dysfunction in patients with the Rett syndrome","container-title":"Brain & Development","page":"232-237","volume":"13","issue":"4","source":"PubMed","abstract":"Aberrant sleep patterns are commonly experienced by girls with the Rett syndrome. In this investigation, the problematic sleep of three girls with the Rett syndrome was regulated using a bedtime fading procedure with response cost. The treatment involved systematically delaying the bedtime and utilized a response cost component, removing the child from bed for one hour, when the child did not experience short latency to sleep onset. Daytime sleep was interrupted, except during regularly scheduled naps. A fading procedure was then successfully utilized to advance the bedtimes. This treatment resulted in more regular sleep patterns for the girls by increasing appropriate nighttime sleep, reducing inappropriate daytime sleep and reducing problematic nighttime behaviors (e.g., night wakings). These preliminary findings are important because they suggest that the dysfunctional sleep patterns of girls with the Rett syndrome may be amenable to behavioral treatments.","ISSN":"0387-7604","note":"PMID: 1957971","journalAbbreviation":"Brain Dev.","language":"eng","author":[{"family":"Piazza","given":"C. C."},{"family":"Fisher","given":"W."},{"family":"Moser","given":"H."}],"issued":{"date-parts":[["1991",7]]}}}],"schema":""} (Piazza, Fisher, & Moser, 1991)There were no significant effects for any of the four sleep outcome measures ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"61ror5629","properties":{"formattedCitation":"(Meltzer & Mindell, 2014)","plainCitation":"(Meltzer & Mindell, 2014)"},"citationItems":[{"id":941,"uris":[""],"uri":[""],"itemData":{"id":941,"type":"article-journal","title":"Systematic review and meta-analysis of behavioral interventions for pediatric insomnia.","container-title":"Journal of pediatric psychology","page":"932-948","volume":"39","issue":"8","abstract":"OBJECTIVE: To evaluate and quantify the evidence for behavioral interventions for pediatric insomnia. METHODS: Meta-analysis of 16 controlled trials and qualitative analysis of 12 within-subject studies were conducted (total n = 2,560). RESULTS: Meta-analysis found significant effects for four specified sleep outcomes: sleep-onset latency, number of night wakings, and duration of night wakings, and sleep efficiency, with small to large effect sizes across the controlled clinical trials involving typical children. No significant effects were found for the two studies conducted with special needs populations. Finally, within-subjects studies demonstrated significant effects for all sleep outcomes with large effect sizes. Risk of bias assessment and GRADE ratings of the quality of the evidence are described. CONCLUSION: Moderate-level evidence supports behavioral interventions for pediatric insomnia in young children. However, low evidence for children, adolescents, and those with special needs (due to a lack of studies that met inclusion criteria) highlights the need for future research.","DOI":"10.1093/jpepsy/jsu041","note":"PMID: 24947271","journalAbbreviation":"J Pediatr Psychol","language":"eng","author":[{"family":"Meltzer","given":"Lisa J."},{"family":"Mindell","given":"Jodi A."}],"issued":{"date-parts":[["2014",9]]}}}],"schema":""} (Meltzer & Mindell, 2014) but sleep hygiene education was associated with improvement in daytime behaviors, pediatric quality of life, and sense of competence in parents.More studies are needed to identify factors that may predict treatment success and to tailor behavioral interventions for young children based on the child (e.g., temperament, age), parental, and environmental factors and on the underlying disease. However, the involvement of parents as agents for changing problematic sleep behaviors is fundamental; in this way, the consistent application of cognitive behavioral techniques can be effective in improving quality of life and well-being for patients and caregivers. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"t0WJ4VWh","properties":{"formattedCitation":"(Grigg-Damberger & Ralls, 2013)","plainCitation":"(Grigg-Damberger & Ralls, 2013)"},"citationItems":[{"id":731,"uris":[""],"uri":[""],"itemData":{"id":731,"type":"article-journal","title":"Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders.","container-title":"Current opinion in pulmonary medicine","page":"616-625","volume":"19","issue":"6","abstract":"PURPOSE OF REVIEW: This review describes recent research in pediatric behavioral insomnias in neurodevelopmental disorders and their treatment. RECENT FINDINGS: Insomnia in children with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) is typically complex, chronic, and difficult to adequately control. Abnormalities in genetic and/or epigenetic regulation of sleep/wakefulness and its timing predispose patients with NDD to insomnia, although poor sleep hygiene, maladaptive associations, and limit-setting are likely to contribute. Parents are agents for change in problematic sleep behaviors in patients with NDD. We review the benefits of behavioral therapies and melatonin to treat sleep problems in children with NDD. Problematic sleep is so prevalent in some neurodevelopmental syndromes (Rett, Angelman, Williams, and Smith-Magenis) that it is part of their diagnostic criteria. SUMMARY: Children and adolescents with neurological disorders frequently have complex sleep disorders that require treatment. Understanding the basic pathology and treatment strategies provides an opportunity to improve well being and quality of life in those affected by NDD and their families.","DOI":"10.1097/MCP.0b013e328365ab89","note":"PMID: 24055857","journalAbbreviation":"Curr Opin Pulm Med","language":"eng","author":[{"family":"Grigg-Damberger","given":"Madeleine"},{"family":"Ralls","given":"Frank"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} (Grigg-Damberger & Ralls, 2013) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2fvm8f7jq9","properties":{"formattedCitation":"(Jan et al., 2008)","plainCitation":"(Jan et al., 2008)"},"citationItems":[{"id":5841,"uris":[""],"uri":[""],"itemData":{"id":5841,"type":"article-journal","title":"Sleep hygiene for children with neurodevelopmental disabilities","container-title":"Pediatrics","page":"1343-1350","volume":"122","issue":"6","source":"PubMed","abstract":"Sleep disturbances in children with neurodevelopmental disabilities are common and have a profound effect on the quality of life of the child, as well as the entire family. Although interventions for sleep problems in these children often involve a combination of behavioral and pharmacologic strategies, the first line of treatment is the promotion of improved sleep habits or \"hygiene.\" Despite the importance of sleep-hygiene principles, defined as basic optimal environmental, scheduling, sleep-practice, and physiologic sleep-promoting factors, clinicians often lack appropriate knowledge and skills to implement them. In addition, sleep-hygiene practices may need to be modified and adapted for this population of children and are often more challenging to implement compared with their healthy counterparts. This first comprehensive, multidisciplinary review of sleep hygiene for children with disabilities presents the rationale for incorporating these measures in their treatment, outlines both general and specific sleep-promotion practices, and discusses problem-solving strategies for implementing them in a variety of clinical practice settings.","DOI":"10.1542/peds.2007-3308","ISSN":"1098-4275","note":"PMID: 19047255","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Jan","given":"James E."},{"family":"Owens","given":"Judith A."},{"family":"Weiss","given":"Margaret D."},{"family":"Johnson","given":"Kyle P."},{"family":"Wasdell","given":"Michael B."},{"family":"Freeman","given":"Roger D."},{"family":"Ipsiroglu","given":"Osman S."}],"issued":{"date-parts":[["2008",12]]}}}],"schema":""} (Jan et al., 2008). Allen et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2i9a1omi25","properties":{"formattedCitation":"(Allen, Kuhn, DeHaai, & Wallace, 2013)","plainCitation":"(Allen, Kuhn, DeHaai, & Wallace, 2013)"},"citationItems":[{"id":7759,"uris":[""],"uri":[""],"itemData":{"id":7759,"type":"article-journal","title":"Evaluation of a behavioral treatment package to reduce sleep problems in children with Angelman Syndrome","container-title":"Research in Developmental Disabilities","page":"676-686","volume":"34","issue":"1","source":"PubMed","abstract":"The purpose of this investigation was to evaluate the effectiveness of a behavioral treatment package to reduce chronic sleep problems in children with Angelman Syndrome. Participants were five children, 2-11 years-of-age. Parents maintained sleep diaries to record sleep and disruptive nighttime behaviors. Actigraphy was added to provide independent evaluations of sleep-wake activity. The treatment package targeted the sleep environment, the sleep-wake schedule, and parent-child interactions during sleep times. Treatment was introduced sequentially, across families, and evaluated in an interrupted time series, multiple baseline design. Data show that prior to treatment, baseline rates of nighttime disruptive behavior were stable or increasing and none of the participants were falling to sleep independently. With the introduction of treatment, all participants quickly learned to initiate sleep independently. Gradual reductions were reported in disruptive behaviors and these improvements were sustained over time. Results were replicated with two participants when treatment was withdrawn and reinstated. Changes in disruptive bedtime behaviors and in sleep onset were found to be statistically significant. Parents indicated high satisfaction with the treatment. A behavioral treatment package was found to be effective with five children with long histories of significant sleep-related behavior problems. These results suggest that behavioral treatment may be a reasonable way to address sleep problems in some children with Angelman Syndrome.","DOI":"10.1016/j.ridd.2012.10.001","ISSN":"1873-3379","note":"PMID: 23123881","journalAbbreviation":"Res Dev Disabil","language":"eng","author":[{"family":"Allen","given":"Keith D."},{"family":"Kuhn","given":"Brett R."},{"family":"DeHaai","given":"Kristi A."},{"family":"Wallace","given":"Dustin P."}],"issued":{"date-parts":[["2013",1]]}}}],"schema":""} (Allen, Kuhn, DeHaai, & Wallace, 2013) evaluated the effectiveness of a behavioral treatment package to reduce chronic sleep problems in 5 children (2-11 years of age) affected from Angelman Syndrome. The treatment package targeted the sleep environment, the sleep-wake schedule, and parent-child interactions during sleep times. Changes in disruptive bedtime behaviors and in sleep onset were found to be statistically significant.Training group of parents in behavioural approaches to manage sleep problems represents a novel behavioral approach: the article from Stuttard et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r8kibspkt","properties":{"formattedCitation":"(Stuttard, Beresford, Clarke, Beecham, & Curtis, 2015)","plainCitation":"(Stuttard, Beresford, Clarke, Beecham, & Curtis, 2015)"},"citationItems":[{"id":7669,"uris":[""],"uri":[""],"itemData":{"id":7669,"type":"article-journal","title":"A preliminary investigation into the effectiveness of a group-delivered sleep management intervention for parents of children with intellectual disabilities","container-title":"Journal of intellectual disabilities: JOID","page":"342-355","volume":"19","issue":"4","source":"PubMed","abstract":"Sleep problems are more prevalent and severe among children with intellectual disabilities and autism compared to typically developing children. Training parents in behavioural approaches to manage sleep problems is advocated. However, delivering such interventions via groups is novel. This article reports the findings from a preliminary evaluation of a group-delivered intervention routinely delivered by a Child and Adolescent Mental Health Service Learning Disability team in England. For this purpose, parents (n = 23) of children with intellectual disabilities were recruited. The Children's Sleep Habits Questionnaire, Parents' Sense of Competence Scale and parent-set goals captured outcomes at pre-intervention, post-intervention and 3- and 6-month follow-up. Intervention delivery costs were collected. Take-up was high (86%), and no parent dropped out. Statistically significant improvements in night wakings, parent-set goals and parents' sense of efficacy were observed. The estimated mean cost of delivering each intervention was British (GBP) ?1570. Findings suggest the intervention is a low-cost, acceptable service warranting further evaluation.","DOI":"10.1177/1744629515576610","ISSN":"1744-6309","note":"PMID: 25792540","journalAbbreviation":"J Intellect Disabil","language":"eng","author":[{"family":"Stuttard","given":"Lucy"},{"family":"Beresford","given":"Bryony"},{"family":"Clarke","given":"Sue"},{"family":"Beecham","given":"Jeni"},{"family":"Curtis","given":"Julie"}],"issued":{"date-parts":[["2015",12]]}}}],"schema":""} (Stuttard, Beresford, Clarke, Beecham, & Curtis, 2015) reports the findings from a preliminary evaluation of a group-delivered intervention routinely delivered by a Child and Adolescent Mental Health Service Learning Disability team in England: parents (n = 23) of children with intellectual disabilities were recruited and the follow up was of 6 months. No parent dropped out and statistically significant improvements in night wakings, parent-set goals and parents' sense of efficacy were observed.Table 1 reports non-pharmacological approaches to insomnia in children with NDDs. Table 1. Behavioral strategies for insomnia in children with neurodevelopmental disabilitiesAdjust sleeping environmentDark, quiet, non-stimulating Turn off electronic devicesDevelop a constant bedtime routinePromote self-soothing skills that allow the child to manage nocturnal awakeningsPut to bed and get them up at the same time every dayIn case of difficulties falling asleep:Avoid naps 4 hours before bedtimeApply bedtime fading (delay bedtime closer to the child target bedtime of about 30 minutes; then move bedtime earlier)Favor light exposure when the child gets up and reduce photic stimulation at evening, to reinforce circadian alignment Apply graduated extinction for the child disruptive bedtime behaviorsIn case of frequent nocturnal awakenings:Extinction with parental presence: The parent remains in the room during extinction, acting as a reassurance for the child but providing little interactionGraduate extinction: ignore negative behaviors (i.e., crying) for a given amount of time before checking on the child. The parent gradually increases the amount of time between crying and parental response. Parents provide reassurance through their presence for short durations and with minimal interaction(adapted from ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bib803ke","properties":{"formattedCitation":"(Grigg-Damberger & Ralls, 2013)","plainCitation":"(Grigg-Damberger & Ralls, 2013)"},"citationItems":[{"id":731,"uris":[""],"uri":[""],"itemData":{"id":731,"type":"article-journal","title":"Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders.","container-title":"Current opinion in pulmonary medicine","page":"616-625","volume":"19","issue":"6","abstract":"PURPOSE OF REVIEW: This review describes recent research in pediatric behavioral insomnias in neurodevelopmental disorders and their treatment. RECENT FINDINGS: Insomnia in children with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) is typically complex, chronic, and difficult to adequately control. Abnormalities in genetic and/or epigenetic regulation of sleep/wakefulness and its timing predispose patients with NDD to insomnia, although poor sleep hygiene, maladaptive associations, and limit-setting are likely to contribute. Parents are agents for change in problematic sleep behaviors in patients with NDD. We review the benefits of behavioral therapies and melatonin to treat sleep problems in children with NDD. Problematic sleep is so prevalent in some neurodevelopmental syndromes (Rett, Angelman, Williams, and Smith-Magenis) that it is part of their diagnostic criteria. SUMMARY: Children and adolescents with neurological disorders frequently have complex sleep disorders that require treatment. Understanding the basic pathology and treatment strategies provides an opportunity to improve well being and quality of life in those affected by NDD and their families.","DOI":"10.1097/MCP.0b013e328365ab89","note":"PMID: 24055857","journalAbbreviation":"Curr Opin Pulm Med","language":"eng","author":[{"family":"Grigg-Damberger","given":"Madeleine"},{"family":"Ralls","given":"Frank"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} Grigg-Damberger & Ralls, 2013)An interesting non pharmacological approach refers to bed materials and accessories: Gringras et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"703ge76ed","properties":{"formattedCitation":"(Paul Gringras et al., 2014)","plainCitation":"(Paul Gringras et al., 2014)"},"citationItems":[{"id":1710,"uris":[""],"uri":[""],"itemData":{"id":1710,"type":"article-journal","title":"Weighted blankets and sleep in autistic children--a randomized controlled trial.","container-title":"Pediatrics","volume":"134","issue":"2","abstract":"OBJECTIVE: To assess the effectiveness of a weighted-blanket intervention in treating severe sleep problems in children with autism spectrum disorder (ASD). METHODS: This phase III trial was a randomized, placebo-controlled crossover design. Participants were aged between 5 years and 16 years 10 months, with a confirmed ASD diagnosis and severe sleep problems, refractory to community-based interventions. The interventions were either a commercially available weighted blanket or otherwise identical usual weight blanket (control), introduced at bedtime; each was used for a 2-week period before crossover to the other blanket. Primary outcome was total sleep time (TST) recorded by actigraphy over each","DOI":"10.1542/peds.2013-4285","note":"PMID: 25022743","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Gringras","given":"Paul"},{"family":"Green","given":"Dido"},{"family":"Wright","given":"Barry"},{"family":"Rush","given":"Carla"},{"family":"Sparrowhawk","given":"Masako"},{"family":"Pratt","given":"Karen"},{"family":"Allgar","given":"Victoria"},{"family":"Hooke","given":"Naomi"},{"family":"Moore","given":"Danielle"},{"family":"Zaiwalla","given":"Zenobia"},{"family":"Wiggs","given":"Luci"}],"issued":{"date-parts":[["2014",8]]}}}],"schema":""} (Paul Gringras et al., 2014) assessed the effectiveness of a weighted-blanket intervention in treating severe sleep problems in children with autism spectrum disorder with a randomized, placebo-controlled crossover design; the use of a weighted blanket did not help children with ASD sleep for a longer period of time, fall asleep significantly faster, or wake less often, but resulted well tolerated from the entire family.More recently, Frazier et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2fj1nvdusl","properties":{"formattedCitation":"(Frazier et al., 2017)","plainCitation":"(Frazier et al., 2017)"},"citationItems":[{"id":7673,"uris":[""],"uri":[""],"itemData":{"id":7673,"type":"article-journal","title":"A Randomized, Crossover Trial of a Novel Sound-to-Sleep Mattress Technology in Children with Autism and Sleep Difficulties","container-title":"Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine","page":"95-104","volume":"13","issue":"1","source":"PubMed","abstract":"STUDY OBJECTIVES: This preliminary study investigated the tolerability and efficacy of a novel mattress technology-the Sound-To-Sleep (STS) system-in the treatment of sleep problems in children with autism.\nMETHODS: After screening, 45 children, ages 2.5 to 12.9 years, were randomized to order of mattress technology use (On-Off vs. Off-On). Treatment conditions (On vs. Off) lasted two weeks with immediate crossover. Tolerability, including study discontinuation and parent-report of mattress tolerance and ease of use, was tracked throughout the study. Efficacy assessments were obtained at baseline, prior to crossover, and end of study and included measures of autism traits, other psychopathology symptoms, sensory abnormalities, communication difficulties, quality of life, sleep diary parameters, and single-blinded actigraphy-derived sleep parameters. Statistical analyses evaluated differences in tolerability and efficacy when the STS system was on versus off.\nRESULTS: STS system use was well tolerated (n = 2, 4.4% dropout) and resulted in parent-reported sleep quality improvements (STS off mean = 4.3, 95% CI = 4.05-4.54 vs. on mean = 4.9, 95%CI = 4.67-5.14). The technology was described by parents as very easy to use and child tolerance was rated as good. Parent-diary outcomes indicated improvements in falling asleep and reduced daytime challenging behavior. Actigraphy-derived sleep parameters indicated improved sleep duration and sleep efficiency. Improvements in child and family quality of life were identified on parent questionnaires.\nCONCLUSIONS: A future large sample phase 2 trial of the STS system is warranted and would benefit from extended study duration, an objective primary efficacy outcome, and careful attention to methodological issues that promote compliance with the intervention and study procedures.","DOI":"10.5664/jcsm.6398","ISSN":"1550-9397","note":"PMID: 27784416\nPMCID: PMC5181622","journalAbbreviation":"J Clin Sleep Med","language":"eng","author":[{"family":"Frazier","given":"Thomas W."},{"family":"Krishna","given":"Jyoti"},{"family":"Klingemier","given":"Eric"},{"family":"Beukemann","given":"Mary"},{"family":"Nawabit","given":"Rawan"},{"family":"Ibrahim","given":"Sally"}],"issued":{"date-parts":[["2017",1,15]]}}}],"schema":""} (Frazier et al., 2017) in a preliminary, randomized study investigated the tolerability and the efficacy of a novel mattress technology - the Sound-To-Sleep (STS) system - in the treatment of sleep problems in , 45 children, ages 2.5 to 12.9 years children with autism. A good compliance to this technology was observed and parent-diary outcomes indicated improvements in falling asleep and reduced daytime challenging behavior. Actigraphy-derived sleep parameters indicated improved sleep duration and sleep efficiency.PHARMACOLOGICAL TREATMENTIn children and adolescents with NDDs, behavioral techniques may be difficult to implement and may take weeks or months to show benefits, therefore sleep-promoting agents while continuing behavioral intervention should be recommended. Causes of sleep problems in children with NDDs are often complex and multifactorial: sleep difficulties may be related to co-occurring medical conditions (eg, epilepsy or gastroesophageal reflux) or poor sleep hygiene or behavioral insomnia of childhood that can be challenging to identify in a child with NDDs and be exacerbated by communication challenges. Providers may not have received training, or have the time, to implement behavioral interventions for sleep. Parent-based education and behavioral interventions are the first line of treatment for insomnia, unless symptom severity necessitating early pharmacotherapy is present. Children who do not respond to behavioral interventions could be candidates for pharmacological treatment of insomnia that should always be considered in combination with behavioral treatment. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2l820e3qnn","properties":{"formattedCitation":"(Angriman et al., 2015)","plainCitation":"(Angriman et al., 2015)"},"citationItems":[{"id":3526,"uris":[""],"uri":[""],"itemData":{"id":3526,"type":"article-journal","title":"Sleep in children with neurodevelopmental disabilities","container-title":"Neuropediatrics","page":"199-210","volume":"46","issue":"3","source":"PubMed","abstract":"This review describes recent research in pediatric sleep disorders associated with neurodevelopmental disabilities (NDDs) and their treatment. NDDs affect more than 2% of the general population and represent more than 35% of the total cases of children referred to a neuropsychiatric center for sleep problems. Specific clinical and therapeutic aspects of sleep disorders associated with Down syndrome, Fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Rett syndrome, Smith-Magenis syndrome, cerebral palsy, and autism spectrum disorders are described. Furthermore, the drugs commonly used for sleep disorders in children with NDDs are described. The review clearly highlighted that children with NDDs are often affected by sleep disorders that require appropriate clinical and therapeutic approach to improve quality of life in both patients and families.","DOI":"10.1055/s-0035-1550151","ISSN":"1439-1899","note":"PMID: 25918987","journalAbbreviation":"Neuropediatrics","language":"eng","author":[{"family":"Angriman","given":"Marco"},{"family":"Caravale","given":"Barbara"},{"family":"Novelli","given":"Luana"},{"family":"Ferri","given":"Raffaele"},{"family":"Bruni","given":"Oliviero"}],"issued":{"date-parts":[["2015",6]]}}}],"schema":""} (Angriman et al., 2015) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kjphkps7c","properties":{"formattedCitation":"(Pelayo & Yuen, 2012)","plainCitation":"(Pelayo & Yuen, 2012)"},"citationItems":[{"id":323,"uris":[""],"uri":[""],"itemData":{"id":323,"type":"article-journal","title":"Pediatric sleep pharmacology.","container-title":"Child and adolescent psychiatric clinics of North America","page":"861-883","volume":"21","issue":"4","abstract":"This article reviews common sleep disorders in children and pharmacologic options for them. Discussions of pediatric sleep pharmacology typically focus on treatment of insomnia. Although insomnia is a major concern in this population, other conditions of concern in children are presented, such as narcolepsy, parasomnias, restless legs syndrome, and sleep apnea.","DOI":"10.1016/j.chc.2012.08.001","note":"PMID: 23040905","journalAbbreviation":"Child Adolesc Psychiatr Clin N Am","language":"eng","author":[{"family":"Pelayo","given":"Rafael"},{"family":"Yuen","given":"Kin"}],"issued":{"date-parts":[["2012",10]]}}}],"schema":""} (Pelayo & Yuen, 2012)Due to the lack of controlled studies, there are no sleep medications approved by the FDA or European Medicines Agency (EMA) for pediatric insomnia in general and in children with NDDs. The most used off-label medications are: sedating antihistamines (e.g., diphenhydramine and hydroxyzine), melatonin, benzodiazepines, α-2–receptor agonists (e.g., clonidine), pyrimidine derivatives (e.g., zaleplon and zolpidem), antipsychotics (e.g. risperidone and quetiapine), and sedating antidepressants (e.g., trazodone and mirtazapine). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"22ve6cs7uv","properties":{"formattedCitation":"(Pelayo & Yuen, 2012)","plainCitation":"(Pelayo & Yuen, 2012)"},"citationItems":[{"id":323,"uris":[""],"uri":[""],"itemData":{"id":323,"type":"article-journal","title":"Pediatric sleep pharmacology.","container-title":"Child and adolescent psychiatric clinics of North America","page":"861-883","volume":"21","issue":"4","abstract":"This article reviews common sleep disorders in children and pharmacologic options for them. Discussions of pediatric sleep pharmacology typically focus on treatment of insomnia. Although insomnia is a major concern in this population, other conditions of concern in children are presented, such as narcolepsy, parasomnias, restless legs syndrome, and sleep apnea.","DOI":"10.1016/j.chc.2012.08.001","note":"PMID: 23040905","journalAbbreviation":"Child Adolesc Psychiatr Clin N Am","language":"eng","author":[{"family":"Pelayo","given":"Rafael"},{"family":"Yuen","given":"Kin"}],"issued":{"date-parts":[["2012",10]]}}}],"schema":""} (Pelayo & Yuen, 2012), but little data exist on their efficacy for the treatment of insomnia in children. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2cv73ilqvi","properties":{"formattedCitation":"(Mindell et al., 2006)","plainCitation":"(Mindell et al., 2006)"},"citationItems":[{"id":440,"uris":[""],"uri":[""],"itemData":{"id":440,"type":"article-journal","title":"Pharmacologic management of insomnia in children and adolescents: consensus statement.","container-title":"Pediatrics","page":"e1223-1232","volume":"117","issue":"6","abstract":"OBJECTIVE: The purpose of this work was to develop a consensus statement on the current status and future role for pharmacologic management of insomnia in children and adolescents. METHOD: The National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened expert representatives involved in the study and treatment of pediatric insomnia and conducted a 2-day conference to examine the role of pharmacologic management of pediatric insomnia and to make recommendations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insomnia and its treatment alternatives, workgroups provided recommendations for the evaluation of pharmacologic treatment of insomnia in specific populations of children and adolescents and developed guidelines for the core methodologic issues relevant to the design of clinical trials. The group developed consensus recommendations for clinical trials in this area encompassing: (1) high-priority patient populations for research, (2) inclusion/exclusion criteria, (3) outcome measures, (4) ethical considerations unique to clinical trials involving children and adolescents, and (5) priorities for future research that will enhance the understanding of pediatric insomnia. RESULTS: Conference participants unanimously agreed that there is a need for pharmacologic management of pediatric insomnia. Furthermore, the widespread use of \"hypnotic\" and psychotropic medications for children in the absence of safety and efficacy data indicates a knowledge gap about the best pharmacologic practices for management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of pharmacologic treatment of pediatric insomnia including agreeing on a definition of pediatric insomnia as \"repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.\" It was agreed that priority should be given to insomnia studies in children with attention-deficit/hyperactivity disorder and those with pervasive developmental disorders/autism spectrum disorder. There was also agreement on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate dose levels and to evaluate safety with a wide range of doses. CONCLUSIONS: The treatment of pediatric insomnia is an unmet medical need. Before appropriate pharmacologic management guidelines can be developed, rigorous, large-scale clinical trials of pediatric insomnia treatment are vitally needed to provide information to the clinician on the safety and efficacy of prescription and over-the-counter agents for the management of pediatric insomnia.","DOI":"10.1542/peds.2005-1693","note":"PMID: 16740821","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Mindell","given":"Jodi A."},{"family":"Emslie","given":"Graham"},{"family":"Blumer","given":"Jeffrey"},{"family":"Genel","given":"Myron"},{"family":"Glaze","given":"Daniel"},{"family":"Ivanenko","given":"Anna"},{"family":"Johnson","given":"Kyle"},{"family":"Rosen","given":"Carol"},{"family":"Steinberg","given":"Frank"},{"family":"Roth","given":"Thomas"},{"family":"Banas","given":"Bridget"}],"issued":{"date-parts":[["2006",6]]}}}],"schema":""} (Mindell et al., 2006).It should be taken into account that drugs could be initially useful for parent and child relief and in general it is better not to wait a long time to treat insomnia, implementing an immediate brief drug trial rather than act later on a chronic insomnia that has already lasted for several months or years (Pelayo and Dubik, 2008). Especially in infants and children, chronic insomnia can lead to maternal depression, family dysfunction and impaired social functioning but also can affect child’s physical and mental health. Due to these serious implications for both individuals and society, it is essential to treat insomnia either through education of parents, teachers and other caregivers but also with an effective drug treatment, when the insomnia lead to a disruption of family life, child’s and parents’ health.A recent Australian survey on pharmacological management of insomnia in children reported that the most commonly prescribed medications for poor sleep initiation were melatonin (89.1%), clonidine (48%) and antihistamines (29%). Most pediatricians (82%) reported also using behavioral strategies for sleep disturbances, most commonly anxiety relaxation techniques (75%) for poor sleep initiation and graduated extinction (i.e. “controlled crying”, 52%) for disrupted overnight sleep. Paediatricians most commonly prescribed for children with autism (85.2%), developmental delay (76.2%), ADHD (54.5%), behavioral disorders (42.6%), visual impairment (40.6%), and anxiety disorders (25.7%). However, over half of the paediatricians (54.5%) prescribed for typically developing children. (Heussler et al., 2013)In children with NDDs or psychiatric disturbances different surveys confirmed that drugs are commonly prescribed off-label (Bruni et al., 2004)A survey by Owens et al., ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2aaokr5af9","properties":{"formattedCitation":"(Owens, Rosen, Mindell, & Kirchner, 2010)","plainCitation":"(Owens, Rosen, Mindell, & Kirchner, 2010)"},"citationItems":[{"id":1021,"uris":[""],"uri":[""],"itemData":{"id":1021,"type":"article-journal","title":"Use of pharmacotherapy for insomnia in child psychiatry practice: A national survey.","container-title":"Sleep medicine","volume":"11","issue":"7","abstract":"OBJECTIVE: To examine clinical practice patterns regarding non-prescription and prescription medication use for insomnia by child and adolescent psychiatrists. METHODS: Survey mailed to 6018 members of the American Academy of Child and Adolescent Psychiatry. RESULTS: The final sample (N=1273) reported that insomnia was a major problem in almost a third of their school-aged and adolescent patients and endorsed using medication to treat the insomnia in at least a quarter of these patients. Overall, 96% of respondents recommended at least one of the listed prescription medications in a typical month, and 88% recommended an over-the-counter medication. Alpha agonists were the most commonly prescribed insomnia medication for ADHD (81%), significantly higher than in MR/DD (67%), mood (40%), or anxiety disorders (31%). Trazodone was the most commonly prescribed insomnia medication for children with mood (78%) and anxiety disorders (72%). Antidepressants as a class were also commonly used for children in these diagnostic groups. Atypical antipsychotics, anticonvulsants, and short-acting hypnotics were also more likely to be used in children with mood disorders. Melatonin was recommended by more than one-third of respondents. Mitigation of the effects of sleep disruption on daytime functioning was endorsed as an important rationale for the use of sleep medication; concerns about side effects and the lack of empirical support regarding efficacy were cited as significant barriers to their use. CONCLUSIONS: Insomnia is a significant clinical problem in children treated by child psychiatrists for a variety of behavioral, neurodevelopmental, and psychiatric conditions. Management with a broad array of psychotropic medications is common and indicates a highly variable clinical approach to insomnia in this pediatric population.","DOI":"10.1016/j.sleep.2009.11.015","note":"PMID: 20621556","journalAbbreviation":"Sleep Med","language":"eng","author":[{"family":"Owens","given":"Judith A."},{"family":"Rosen","given":"Carol L."},{"family":"Mindell","given":"Jodi A."},{"family":"Kirchner","given":"Hal L."}],"issued":{"date-parts":[["2010",8]]}}}],"schema":""} (Owens, Rosen, Mindell, & Kirchner, 2010) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jc9n0nj8i","properties":{"formattedCitation":"(Oliviero Bruni,Cristiano Violani,Anna Luchetti,Silvia Miano,Elisabetta Verrillo,Carlo Di Donatella Valente, n.d.)","plainCitation":"(Oliviero Bruni,Cristiano Violani,Anna Luchetti,Silvia Miano,Elisabetta Verrillo,Carlo Di Donatella Valente, n.d.)"},"citationItems":[{"id":5857,"uris":[""],"uri":[""],"itemData":{"id":5857,"type":"article-journal","title":"The Sleep Knowledge of Pediatricians and Child Neuropsychiatrists","volume":"Sleep and Hypnosis: A Journal of Clinical Neuroscience and Psychopathology 2004;6(3):130-138","author":[{"family":"Oliviero Bruni,Cristiano Violani,Anna Luchetti,Silvia Miano,Elisabetta Verrillo,Carlo Di Donatella Valente","given":""}]}}],"schema":""} showed that more than one-third of 1,273 child psychiatrists treated insomnia with medication at least half of the time in patients with ADHD, ASD, and with mental retardation/developmental disabilities (MR/DD). Moreover, they reported to treat 17% of preschoolers and at least one-quarter of school-aged and adolescent patients. Overall, 96% of psychiatrists recommended at least one medication in a typical month, and 88% recommended an over-the-counter medication. In general, psychiatrists were more likely to use herbal preparations in children with anxiety or mood disorders than in children with NDDs or ADHD; melatonin was recommended by more than one-third of them (39%) although it is unclear whether it was being used primarily at bedtime for its mild hypnotic effects or as a chronobiotic. The physicians recommended for sleep disorders (mainly insomnia) nonprescription antihistamines in 69% of cases and α agonists in 67% of children with MR/DD. Trazodone was the second most frequently prescribed medication for children with MR/DD (66%) while sedating antidepressants were used in 75.5% of MR cases. Atypical antipsychotics were used by more than half of the psychiatrists in children with MR/DD (52%) and benzodiazepines were used in 21.6% of cases of MR/DD. Tricyclic antidepressants were also used for children in these diagnostic groups (25.5%).We have to consider that this situation could be specific for the USA, however similar results have been replicated also in other countries (Heussler et al. 2013; Bruni et al., 2004)Three recent registry study examined the prescription habits of pediatricians toward sleep disorders in developmental disabilities. Efron et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"n0aru5k8j","properties":{"formattedCitation":"(Efron, Lycett, & Sciberras, 2014)","plainCitation":"(Efron, Lycett, & Sciberras, 2014)"},"citationItems":[{"id":7290,"uris":[""],"uri":[""],"itemData":{"id":7290,"type":"article-journal","title":"Use of sleep medication in children with ADHD","container-title":"Sleep Medicine","page":"472-475","volume":"15","issue":"4","source":"PubMed","abstract":"OBJECTIVE: Sleep problems are common in children with attention-deficit/hyperactivity disorder (ADHD), yet little is known about sleep medication use in this population. The aim of this study was to describe sleep medication use, as well as associated child and family characteristics in school-aged children with ADHD.\nMETHOD: Sleep medication use was ascertained using a prospective parent-completed seven-night sleep and medication log. Exposure variables included socio-demographic characteristics, total sleep problem severity (Children's Sleep Habits Questionnaire), ADHD severity and subtype (ADHD Rating Scale IV), ADHD medication use, internalising and externalising co-morbidities (Anxiety Disorders Interview Schedule for Children/Parent version IV) and parent mental health (Depression Anxiety Stress Scale).\nRESULTS: Two hundred and fifty-seven children with ADHD participated and of these 57 (22%) were taking sleep medication (melatonin 14% and clonidine 9%). Sleep medication use was associated with combined-type ADHD and ADHD medication use. The presence of co-occurring internalising and externalising co-morbidities was also associated with sleep medication use in ad hoc analyses.\nCONCLUSION: Sleep medication use is common in children with ADHD and is associated with combined-type ADHD and use of ADHD medication. Further research is needed on the broad functional benefits and long-term safety of sleep medication in this population.","DOI":"10.1016/j.sleep.2013.10.018","ISSN":"1878-5506","note":"PMID: 24684977","journalAbbreviation":"Sleep Med.","language":"eng","author":[{"family":"Efron","given":"Daryl"},{"family":"Lycett","given":"Kate"},{"family":"Sciberras","given":"Emma"}],"issued":{"date-parts":[["2014",4]]}}}],"schema":""} (Efron, Lycett, & Sciberras, 2014) described sleep medication use in a sample of 257 school-aged children with ADHD and of these 57 (22%) were taking sleep medication (melatonin 14% and clonidine 9%). Sleep medication use was associated with combined-type ADHD and ADHD medication use. The presence of co-occurring internalizing and externalizing co-morbidities was also associated with sleep medication use in ad hoc analyses.A recent study in autism spectrum disorders showed that medications for sleep were prescribed in 46% of 4- to 10-year-olds of children affected from autism and sleep difficulties. The most common medication used for sleep was melatonin followed by α-agonists, with a variety of other medications taken for sleep (anticonvulsants, antidepressants, atypical antipsychotics, and benzodiazepines). Children taking medications for sleep had worse daytime behavior and pediatric quality of life than children not taking sleep medications. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1pmis75s5h","properties":{"formattedCitation":"(Malow et al., 2016)","plainCitation":"(Malow et al., 2016)"},"citationItems":[{"id":7729,"uris":[""],"uri":[""],"itemData":{"id":7729,"type":"article-journal","title":"Sleep Difficulties and Medications in Children With Autism Spectrum Disorders: A Registry Study","container-title":"Pediatrics","page":"S98-S104","volume":"137 Suppl 2","source":"PubMed","abstract":"OBJECTIVES: Sleep difficulties are common in children with autism spectrum disorders, with wide-ranging effects on the child's daytime behavior. We reviewed data within our Autism Speaks Autism Treatment Network Registry to determine the prevalence of sleep difficulties and patterns of medication use.\nMETHODS: Data from 1518 children ages 4 to 10 years were analyzed to determine the number of children documented to have sleep difficulties by parent-completed questionnaires and clinician-completed forms and how these findings related to the use of sleep medications.\nRESULTS: The Children's Sleep Habits Questionnaire total score was ≥41 (associated with clinically significant sleep problems in past research) in 71% of children. The prevalence of sleep diagnoses was less frequent (30% of children aged 4-10 years; P < .0001). Medications for sleep were prescribed in 46% of 4- to 10-year-olds given a sleep diagnosis. The most common medication used for sleep was melatonin followed by α-agonists, with a variety of other medications taken for sleep (anticonvulsants, antidepressants, atypical antipsychotics, and benzodiazepines). Children taking medications for sleep had worse daytime behavior and pediatric quality of life than children not taking sleep medications.\nCONCLUSIONS: Parent concerns about sleep may not be reflected in the information gathered during a clinic visit, supporting the need to develop screening practice pathways for sleep in autism spectrum disorders. Furthermore, many medications taken for sleep have adverse effects, supporting the need for evidence-based interventions in this population.","DOI":"10.1542/peds.2015-2851H","ISSN":"1098-4275","note":"PMID: 26908483","shortTitle":"Sleep Difficulties and Medications in Children With Autism Spectrum Disorders","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Malow","given":"Beth A."},{"family":"Katz","given":"Terry"},{"family":"Reynolds","given":"Ann M."},{"family":"Shui","given":"Amy"},{"family":"Carno","given":"Margaret"},{"family":"Connolly","given":"Heidi V."},{"family":"Coury","given":"Daniel"},{"family":"Bennett","given":"Amanda E."}],"issued":{"date-parts":[["2016",2]]}}}],"schema":""} (Malow et al., 2016) Another recent research ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8isfml5so","properties":{"formattedCitation":"(Bock, Roach-Fox, Seabrook, Rieder, & Matsui, 2016)","plainCitation":"(Bock, Roach-Fox, Seabrook, Rieder, & Matsui, 2016)"},"citationItems":[{"id":6894,"uris":[""],"uri":[""],"itemData":{"id":6894,"type":"article-journal","title":"Sleep-promoting medications in children: physician prescribing habits in Southwestern Ontario, Canada","container-title":"Sleep Medicine","page":"52-56","volume":"17","source":"PubMed","abstract":"BACKGROUND: Research indicates that physicians may frequently use pharmacotherapy to treat pediatric insomnia despite minimal safety data and very limited indications. Canadian data on the subject are lacking. This study aimed to determine physicians' views on and prescribing habits for sleep-promoting over-the-counter medication (OTCM) and prescription (RXM) medications for children.\nMETHODS: A modified 26-item version of the 'Pediatric Sleep Medication Survey', originally developed by Judith Owens and colleagues, was sent to 100 pediatricians and a random sample of 421 family physicians in Southwestern Ontario, Canada.\nRESULTS: A total of 67 returned surveys were sufficiently complete for analysis. Sixty-one respondents indicated their specialty (28 pediatricians, 33 family physicians). In a typical 6-month period, 89% and 66% of respondents have recommended OTCM and RXM, respectively, for children with sleep problems. Only 20% have received any formal training on pediatric sleep disorders. The most common circumstances and sleep problems for which OTCM or RXM were recommended were mood disorders, developmental delay and attention deficit hyperactivity disorder (ADHD) (56, 40, and 39%, respectively), and insomnia, bedtime struggles/delayed sleep onset and circadian rhythm disorders (52, 48, and 28%, respectively). A total of 30% recommended OTCM or RXM to otherwise healthy children with sleep problems. Melatonin (73%), OTC antihistamines (41%), antidepressants (37%), and benzodiazepines (29%) were the most commonly recommended OTCM and RXM, respectively.\nCONCLUSIONS: Respondents in our sample frequently use pharmacotherapy to treat pediatric sleep problems; few have received any training in this area. Our findings indicate the need for evidence-based guidelines and regular physician training in the management of pediatric sleep disorders.","DOI":"10.1016/j.sleep.2015.10.003","ISSN":"1878-5506","note":"PMID: 26847974","shortTitle":"Sleep-promoting medications in children","journalAbbreviation":"Sleep Med.","language":"eng","author":[{"family":"Bock","given":"Dirk E."},{"family":"Roach-Fox","given":"Elizabeth"},{"family":"Seabrook","given":"Jamie A."},{"family":"Rieder","given":"Michael J."},{"family":"Matsui","given":"Doreen"}],"issued":{"date-parts":[["2016",1]]}}}],"schema":""} (Bock, Roach-Fox, Seabrook, Rieder, & Matsui, 2016) found that the most common circumstances and sleep problems for which OTCM or RXM were recommended were mood disorders, developmental delay and attention deficit hyperactivity disorder (ADHD) (56, 40, and 39%, respectively), and insomnia, bedtime struggles/delayed sleep onset and circadian rhythm disorders (52, 48, and 28%, respectively). A total of 30% recommended OTCM or RXM to otherwise healthy children with sleep problems. Melatonin (73%), OTC antihistamines (41%), antidepressants (37%), and benzodiazepines (29%) were the most commonly recommended OTCM and RXM, respectively.Before beginning a drug treatment in children with NDDs, different aspects should be taken into account: commonly these children are taking other drugs (mainly sedatives, antiepileptics, etc.) and the eventual interactions should be considered cautiously, previous sleep medications or homeopathic or OTC preparations, finally the age of the child and his/her clinical history. Treatment goals must be established with the parents and, if possible, with the patient and should be realistic, clearly defined, and measurable. The immediate goal of treatment will usually be to alleviate or improve, rather than to completely eliminate, sleep problems. When a drug has been administered, abrupt discontinuation should be avoided and the treatment should be carefully monitored since there is a natural inclination of the parents to give the lowest dose. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2j6fos9h0a","properties":{"formattedCitation":"(Pelayo & Dubik, 2008)","plainCitation":"(Pelayo & Dubik, 2008)"},"citationItems":[{"id":942,"uris":[""],"uri":[""],"itemData":{"id":942,"type":"article-journal","title":"Pediatric sleep pharmacology.","container-title":"Seminars in pediatric neurology","volume":"15","issue":"2","abstract":"This article reviews the most common pharmacologic options in the treatment of sleep disorders in children. Despite the high prevalence of sleep disorders in children, there is a paucity of education and information available on the pharmacologic management of sleep disorders in children. The principles of sleep physiology and pathophysiology that help provide more rational pharmacologic management are discussed. Medications are typically not Food and Drug Administration (FDA) approved for the pediatric age range or for the specific sleep disorder. Medications have a role for insomnia, narcolepsy, parasomnias, and sleep-related movement disorders. The available choices of hypnotics are reviewed. Medications to increase alertness of narcoleptics and decrease cataplexy are discussed. The use of dopaminergic agents for Restless Legs Syndrome is reviewed. The potential use of medication in sleep apnea is also reviewed. Pharmacologic guidelines need to be developed specifically for sleep disorders in children. Ideally, these guidelines should be FDA approved for the specific sleep disorder and for the pediatric age range. The development of easy to swallow, chewable or liquid forms of these medications are needed. Training programs should play the lead role in enhancing pediatricians' knowledge of the pharmacologic treatment of sleep disorders in children.","DOI":"10.1016/j.spen.2008.03.004","note":"PMID: 18555194","journalAbbreviation":"Semin Pediatr Neurol","language":"eng","author":[{"family":"Pelayo","given":"Rafael"},{"family":"Dubik","given":"Michael"}],"issued":{"date-parts":[["2008",6]]}}}],"schema":""} (Pelayo & Dubik, 2008) The choice of the drug, in view of the lack of scientific evidence, should be guided by an accurate evaluation of the main complaint (i.e. difficulty falling asleep, night awakenings, phase advance or delay, nocturnal hyperactivity, mid-night awakening, etc.) but also a correct family history can be useful. The three greatest unmet clinical needs in the treatment of insomnia are residual daytime sedation, tolerance and addiction potential and improvement in sleep maintenance. Table 2 reports the most commonly used pharmacologic agents for insomnia in children with NDDs. The following section is devoted to describe the drugs and off-label compounds commonly used in chronic insomnia of children with NDDs.Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiotic agent involved in the regulation of the sleep–wake cycle. In older children and adults, its production and secretion begin in the evening and peak during the night between 2:00 and 4:00 AM and are inhibited by light. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2g48h7eear","properties":{"formattedCitation":"(Kennaway, 2000)","plainCitation":"(Kennaway, 2000)"},"citationItems":[{"id":5888,"uris":[""],"uri":[""],"itemData":{"id":5888,"type":"article-journal","title":"Melatonin and development: physiology and pharmacology","container-title":"Seminars in Perinatology","page":"258-266","volume":"24","issue":"4","source":"PubMed","abstract":"This review discusses the development of melatonin rhythmicity in humans and the factors that may alter the appearance of melatonin rhythms. The literature on the possible consequences of disordered melatonin production in relation to Sudden Infant Death Syndrome, fetal origins of adult disease, and scoliosis is critically reviewed. Finally, the emerging use of melatonin to correct sleep disorders in infants and children is reviewed.","ISSN":"0146-0005","note":"PMID: 10975432","shortTitle":"Melatonin and development","journalAbbreviation":"Semin. Perinatol.","language":"eng","author":[{"family":"Kennaway","given":"D. J."}],"issued":{"date-parts":[["2000",8]]}}}],"schema":""} (Kennaway, 2000) A nationwide study showed that hypnotic drug use in 0- to 17-year-old patients increased during the period 2004-2011, from 8.9 to 12.3/1000, mainly owing to the doubling of melatonin use that was dispensed in the highest annual amount among all hypnotic drugs. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u86r5rpv4","properties":{"formattedCitation":"(Hartz, Furu, Bratlid, Handal, & Skurtveit, 2012)","plainCitation":"(Hartz, Furu, Bratlid, Handal, & Skurtveit, 2012)"},"citationItems":[{"id":5902,"uris":[""],"uri":[""],"itemData":{"id":5902,"type":"article-journal","title":"Hypnotic drug use among 0-17 year olds during 2004-2011: a nationwide prescription database study","container-title":"Scandinavian Journal of Public Health","page":"704-711","volume":"40","issue":"8","source":"PubMed","abstract":"AIMS: To (a) describe the prevalence, trend, and amount of hypnotic drug use, (b) determine the prevalence of chronic diseases among hypnotic drug users, and (c) determine levels of recurrent hypnotic drug use (2007-2011), among 0-17 year old Norwegians.\nMETHODS: Data were obtained from the nationwide Norwegian Prescription Database (NorPD) in the period 2004-2011.\nRESULTS: Hypnotic drug use in 0-17 year olds increased during the period, from 8.9 to 12.3 per 1000, mainly owing to doubling of melatonin use. Hypnotic drug use peaked at 15 per 1000 among those aged 1-2 years. Melatonin use increased steadily from 6 to 12 years of age, most pronounced in males. Among females, hypnotic drug use increased threefold from 13 to17 years of age. Melatonin was dispensed in the highest annual amount of all hypnotic drugs; accounting up to a median of 360 defined daily doses in 9-13 year old boys. A total of 62% and 52% of all male and female hypnotic drug users were co-medicated with reimbursable drugs for chronic diseases. Levels of recurrent use (2007-2011) were 12% in boys and 8% in girls, of whom 76-77% were co-medicated with drugs reimbursed for chronic diseases.\nCONCLUSIONS: There is a trend of increasing use of hypnotic drugs among 0-17 year olds, mainly owing to increasing use of melatonin, used in high amounts. Still, melatonin is not recommended in Norway for use in this age group because of insufficient data on safety and efficacy. A threefold increase in hypnotic drugs among females from 13 to 17 years of age warrants attention.","DOI":"10.1177/1403494812464446","ISSN":"1651-1905","note":"PMID: 23108475","shortTitle":"Hypnotic drug use among 0-17 year olds during 2004-2011","journalAbbreviation":"Scand J Public Health","language":"eng","author":[{"family":"Hartz","given":"Ingeborg"},{"family":"Furu","given":"Kari"},{"family":"Bratlid","given":"Trond"},{"family":"Handal","given":"Marte"},{"family":"Skurtveit","given":"Svetlana"}],"issued":{"date-parts":[["2012",12]]}}}],"schema":""} (Hartz, Furu, Bratlid, Handal, & Skurtveit, 2012) Approximately 56% of pediatricians prescribed melatonin for sleep onset insomnia (89.1%), delayed sleep phase (66.3%), and nighttime awakenings (30.7%). It is also prescribed in children with autism (85.2%), NDDs (76.2%), ADHD (54.5%), behavioral disorders (42.6%), visual impairment (40.6%), anxiety disorders (25.7%), and typically developing (54.5%). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jfr995al5","properties":{"formattedCitation":"(Heussler et al., 2013)","plainCitation":"(Heussler et al., 2013)"},"citationItems":[{"id":1102,"uris":[""],"uri":[""],"itemData":{"id":1102,"type":"article-journal","title":"Pharmacological and non-pharmacological management of sleep disturbance in children: an Australian Paediatric Research Network survey.","container-title":"Sleep medicine","page":"189-194","volume":"14","issue":"2","abstract":"BACKGROUND: Australian paediatricians use a wide variety of practices when managing sleep disturbances in children, including use of melatonin and behavioral strategies. However, practice patterns around the use of strategies, dosing, and how the patient populations managed, are unknown. Results could inform guidelines for the management of child sleep disturbances. OBJECTIVE: We aimed to document management practices by Australian general paediatricians for paediatric sleep disturbances through an online survey sent to members of the Australian Paediatric Research Network (APRN) who are recruited from the Royal Australasian College of Physicians. RESULTS: 181 (49%) of 373 eligible paediatricians responded, with 101 prescribing melatonin. The most commonly prescribed medications for poor sleep initiation were melatonin (89.1%), clonidine (48%) and antihistamines (29%). Melatonin doses ranged from 0.5mg to 12mg and duration of treatment was as long as 200weeks. Less than half of the paediatricians were aware of any potential melatonin side effects. Most paediatricians (82%) reported using behavioral strategies for sleep disturbances, most commonly anxiety relaxation techniques (75%) for poor sleep initiation and graduated extinction (i.e. \"controlled crying\", 52%) for disrupted overnight sleep. CONCLUSIONS: Australian paediatricians use both pharmacological and non-pharmacological treatments for paediatric sleep disturbances. Melatonin is the most commonly prescribed medication, but wide variation in its prescribing suggests a lack of knowledge of recommended dosages and effectiveness. Given the prevalence and variation in prescribing, there is an urgent need to develop clear guidance for paediatricians managing children with sleep disturbance.","DOI":"10.1016/j.sleep.2012.09.023","note":"PMID: 23245853","journalAbbreviation":"Sleep Med","language":"eng","author":[{"family":"Heussler","given":"Helen"},{"family":"Chan","given":"Patrick"},{"family":"Price","given":"Anna M. H."},{"family":"Waters","given":"Karen"},{"family":"Davey","given":"Margot J."},{"family":"Hiscock","given":"Harriet"}],"issued":{"date-parts":[["2013",2]]}}}],"schema":""} (Heussler et al., 2013) Systematic reviews and meta-analyses of placebo-controlled, randomized controlled trials (RCTs) in children with NDDs, especially autism, have demonstrated that exogenous melatonin improves sleep, either by reducing the time taken to fall asleep (sleep-onset latency) or by increasing total sleep time, or both. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"13e2liv38r","properties":{"formattedCitation":"(Phillips & Appleton, 2004)","plainCitation":"(Phillips & Appleton, 2004)"},"citationItems":[{"id":5519,"uris":[""],"uri":[""],"itemData":{"id":5519,"type":"article-journal","title":"Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment","container-title":"Developmental Medicine and Child Neurology","page":"771-775","volume":"46","issue":"11","source":"PubMed","abstract":"Sleep disturbances in children with neurodevelopmental disabilities are common and frequently difficult to treat with conventional pharmacological and behavioural methods. Melatonin is a pineal hormone known to be important in the regulation of the circadian rhythm, including the sleep-wake cycle. This systematic review of available evidence from randomized clinical trials assesses whether melatonin plays a beneficial role in these children and, in particular, its effect on total sleep time, time to sleep onset (sleep latency), and number of awakenings. We also looked at a parental view of the effect. Randomized clinical trials were identified where oral melatonin was compared with a placebo in children with any type of neurodevelopmental disability and associated sleep disturbance. Only three studies, reporting a total of 35 children, fulfilled the criteria for inclusion. The two studies that reported time to sleep onset showed a significant decrease (p<0.05) in this specific outcome where melatonin was compared with a placebo. There was no significant effect of melatonin compared with a placebo on the other outcome measures of total sleep time, night-time awakenings, and parental opinions. Despite the extremely limited randomized clinical trial data, melatonin appears to remain a commonly prescribed drug for disturbed sleep in children with neurodevelopmental abnormalities.","ISSN":"0012-1622","note":"PMID: 15540639","journalAbbreviation":"Dev Med Child Neurol","language":"eng","author":[{"family":"Phillips","given":"Louise"},{"family":"Appleton","given":"Richard E."}],"issued":{"date-parts":[["2004",11]]}}}],"schema":""} (Phillips & Appleton, 2004), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"107c1k3qc5","properties":{"formattedCitation":"(Wiebe Braam et al., 2009)","plainCitation":"(Wiebe Braam et al., 2009)"},"citationItems":[{"id":5906,"uris":[""],"uri":[""],"itemData":{"id":5906,"type":"article-journal","title":"Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis","container-title":"Developmental Medicine and Child Neurology","page":"340-349","volume":"51","issue":"5","source":"PubMed","abstract":"Recent meta-analyses on melatonin has raised doubts as to whether melatonin is effective in treating sleep problems in people without intellectual disabilities. This is in contrast to results of several trials on melatonin in treating sleep problems in individuals with intellectual disabilities. To investigate the efficacy of melatonin in treating sleep problems in individuals with intellectual disabilities, we performed a meta-analysis of placebo-controlled randomized trials of melatonin in individuals with intellectual disabilities and sleep problems. Data were selected from articles published on PubMed, Medline, and Embase between January 1990 and July 2008. We examined the influence of melatonin on sleep latency, total sleep time, and number of wakes per night. Quality of trials was assessed using the Downs and Black checklist. Nine studies (including a total of 183 individuals with intellectual disabilities) showed that melatonin treatment decreased sleep latency by a mean of 34 minutes (p<0.001), increased total sleep time by a mean of 50 minutes (p<0.001), and significantly decreased the number of wakes per night (p<0.05). Melatonin decreases sleep latency and number of wakes per night, and increases total sleep time in individuals with intellectual disabilities.","DOI":"10.1111/j.1469-8749.2008.03244.x","ISSN":"1469-8749","note":"PMID: 19379289","shortTitle":"Exogenous melatonin for sleep problems in individuals with intellectual disability","journalAbbreviation":"Dev Med Child Neurol","language":"eng","author":[{"family":"Braam","given":"Wiebe"},{"family":"Smits","given":"Marcel G."},{"family":"Didden","given":"Robert"},{"family":"Korzilius","given":"Hubert"},{"family":"Van Geijlswijk","given":"Ingeborg M."},{"family":"Curfs","given":"Leopold M. G."}],"issued":{"date-parts":[["2009",5]]}}}],"schema":""} (Wiebe Braam et al., 2009) A large clinical trial confirmed the efficacy of melatonin in the treatment of sleep impairment in children with NDDs, using different doses, ranging from 0.5 to 12 mg; the main effects of melatonin were reduced sleep latency (from 102 to 55 minutes in 12 weeks) and increased total sleep time (40 minutes). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mg25olpc7","properties":{"formattedCitation":"(Appleton et al., 2012)","plainCitation":"(Appleton et al., 2012)"},"citationItems":[{"id":5507,"uris":[""],"uri":[""],"itemData":{"id":5507,"type":"article-journal","title":"The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS)","container-title":"Health Technology Assessment (Winchester, England)","page":"i-239","volume":"16","issue":"40","source":"PubMed","abstract":"BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems.\nOBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems.\nDESIGN: Randomised, double-blind, placebo-controlled, parallel study.\nSETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues.\nPARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks.\nINTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose.\nMAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL?), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated.\nRESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant.\nCONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders.\nTRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585.\nFUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.","DOI":"10.3310/hta16400","ISSN":"2046-4924","note":"PMID: 23098680","shortTitle":"The use of MElatonin in children with neurodevelopmental disorders and impaired sleep","journalAbbreviation":"Health Technol Assess","language":"eng","author":[{"family":"Appleton","given":"R. E."},{"family":"Jones","given":"A. P."},{"family":"Gamble","given":"C."},{"family":"Williamson","given":"P. R."},{"family":"Wiggs","given":"L."},{"family":"Montgomery","given":"P."},{"family":"Sutcliffe","given":"A."},{"family":"Barker","given":"C."},{"family":"Gringras","given":"P."}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} (Appleton et al., 2012) A placebo-controlled study in 146 children (age 315 years) with intellectual disability showed similar results. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jjil8fik1","properties":{"formattedCitation":"(P. Gringras et al., 2012)","plainCitation":"(P. Gringras et al., 2012)"},"citationItems":[{"id":5505,"uris":[""],"uri":[""],"itemData":{"id":5505,"type":"article-journal","title":"Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial","container-title":"BMJ (Clinical research ed.)","page":"e6664","volume":"345","source":"PubMed","abstract":"OBJECTIVE: To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.\nDESIGN: 12 week double masked randomised placebo controlled phase III trial.\nSETTING: 19 hospitals across England and Wales.\nPARTICIPANTS: 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours' continuous sleep.\nINTERVENTIONS: Immediate release melatonin or matching placebo capsules administered 45 minutes before the child's bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.\nMAIN OUTCOME MEASURES: Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.\nRESULTS: Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (-15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (-37.5 minutes, -55.3 to -19.7 minutes) and actigraphy (-45.3 minutes, -68.8 to -21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.\nCONCLUSIONS: Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.\nTRIAL REGISTRATION: ISRCT No 05534585.","ISSN":"1756-1833","note":"PMID: 23129488\nPMCID: PMC3489506","shortTitle":"Melatonin for sleep problems in children with neurodevelopmental disorders","journalAbbreviation":"BMJ","language":"eng","author":[{"family":"Gringras","given":"P."},{"family":"Gamble","given":"C."},{"family":"Jones","given":"A. P."},{"family":"Wiggs","given":"L."},{"family":"Williamson","given":"P. R."},{"family":"Sutcliffe","given":"A."},{"family":"Montgomery","given":"P."},{"family":"Whitehouse","given":"W. P."},{"family":"Choonara","given":"I."},{"family":"Allport","given":"T."},{"family":"Edmond","given":"A."},{"family":"Appleton","given":"R."},{"literal":"MENDS Study Group"}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} (P. Gringras et al., 2012)A randomized, placebo-controlled, double-blind, crossover trial of controlled-release melatonin 515 mg 2030 minutes before bedtime in 50 children with NNDs and delayed sleep phase syndrome showed again a great efficacy in decreasing sleep latency (p<0.01) and a non-significant improvement of total nighttime sleep by 31 min. Melatonin was well tolerated but some side effects emerged (seizures, infection, gastrointestinal illness, and agitation). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"n368sfa10","properties":{"formattedCitation":"(Wasdell et al., 2008)","plainCitation":"(Wasdell et al., 2008)"},"citationItems":[{"id":5843,"uris":[""],"uri":[""],"itemData":{"id":5843,"type":"article-journal","title":"A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities","container-title":"Journal of Pineal Research","page":"57-64","volume":"44","issue":"1","source":"PubMed","abstract":"The purpose of this study was to determine the efficacy of controlled-release (CR) melatonin in the treatment of delayed sleep phase syndrome and impaired sleep maintenance of children with neurodevelopmental disabilities including autistic spectrum disorders. A randomized double-blind, placebo-controlled crossover trial of CR melatonin (5 mg) followed by a 3-month open-label study was conducted during which the dose was gradually increased until the therapy showed optimal beneficial effects. Sleep characteristics were measured by caregiver who completed somnologs and wrist actigraphs. Clinician rating of severity of the sleep disorder and improvement from baseline, along with caregiver ratings of global functioning and family stress were also obtained. Fifty-one children (age range 2-18 years) who did not respond to sleep hygiene intervention were enrolled. Fifty patients completed the crossover trial and 47 completed the open-label phase. Recordings of total night-time sleep and sleep latency showed significant improvement of approximately 30 min. Similarly, significant improvement was observed in clinician and parent ratings. There was additional improvement in the open-label somnolog measures of sleep efficiency and the longest sleep episode in the open-label phase. Overall, 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.","DOI":"10.1111/j.1600-079X.2007.00528.x","ISSN":"0742-3098","note":"PMID: 18078449","journalAbbreviation":"J. Pineal Res.","language":"eng","author":[{"family":"Wasdell","given":"Michael B."},{"family":"Jan","given":"James E."},{"family":"Bomben","given":"Melissa M."},{"family":"Freeman","given":"Roger D."},{"family":"Rietveld","given":"Wop J."},{"family":"Tai","given":"Joseph"},{"family":"Hamilton","given":"Donald"},{"family":"Weiss","given":"Margaret D."}],"issued":{"date-parts":[["2008",1]]}}}],"schema":""} (Wasdell et al., 2008) Different studies showed that melatonin (with doses of 1–10 mg given 30–60 min before bedtime) alone or in combination with cognitive-behavioral therapy is effective in insomnia of children with ASD. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mlb9cj604","properties":{"formattedCitation":"(Cortesi, Giannotti, Sebastiani, Panunzi, & Valente, 2012)","plainCitation":"(Cortesi, Giannotti, Sebastiani, Panunzi, & Valente, 2012)"},"citationItems":[{"id":1638,"uris":[""],"uri":[""],"itemData":{"id":1638,"type":"article-journal","title":"Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial.","container-title":"Journal of sleep research","page":"700-709","volume":"21","issue":"6","abstract":"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.","DOI":"10.1111/j.1365-2869.2012.01021.x","note":"PMID: 22616853","journalAbbreviation":"J Sleep Res","language":"eng","author":[{"family":"Cortesi","given":"Flavia"},{"family":"Giannotti","given":"Flavia"},{"family":"Sebastiani","given":"Teresa"},{"family":"Panunzi","given":"Sara"},{"family":"Valente","given":"Donatella"}],"issued":{"date-parts":[["2012",12]]}}}],"schema":""} (Cortesi, Giannotti, Sebastiani, Panunzi, & Valente, 2012), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"16jstpvgsk","properties":{"formattedCitation":"(Suzanne E. Goldman et al., 2014)","plainCitation":"(Suzanne E. Goldman et al., 2014)"},"citationItems":[{"id":435,"uris":[""],"uri":[""],"itemData":{"id":435,"type":"article-journal","title":"Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep.","container-title":"Journal of autism and developmental disorders","page":"2525-2535","volume":"44","issue":"10","abstract":"Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C(max)) and time to peak concentration (T(max)) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin.","DOI":"10.1007/s10803-014-2123-9","note":"PMID: 24752680","journalAbbreviation":"J Autism Dev Disord","language":"eng","author":[{"family":"Goldman","given":"Suzanne E."},{"family":"Adkins","given":"Karen W."},{"family":"Calcutt","given":"M. Wade"},{"family":"Carter","given":"Melissa D."},{"family":"Goodpaster","given":"Robert L."},{"family":"Wang","given":"Lily"},{"family":"Shi","given":"Yaping"},{"family":"Burgess","given":"Helen J."},{"family":"Hachey","given":"David L."},{"family":"Malow","given":"Beth A."}],"issued":{"date-parts":[["2014",10]]}}}],"schema":""} (Suzanne E. Goldman et al., 2014) or with Angelman syndrome. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"19q5etkdjk","properties":{"formattedCitation":"(Wiebe Braam, Didden, Smits, & Curfs, 2008)","plainCitation":"(Wiebe Braam, Didden, Smits, & Curfs, 2008)"},"citationItems":[{"id":5912,"uris":[""],"uri":[""],"itemData":{"id":5912,"type":"article-journal","title":"Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial","container-title":"Journal of Child Neurology","page":"649-654","volume":"23","issue":"6","source":"PubMed","abstract":"Previous studies suggested that melatonin improves sleep in insomniac patients with Angelman syndrome. To assess the efficacy of melatonin, a randomized placebo-controlled study was conducted in 8 children with Angelman syndrome with idiopathic chronic insomnia. After a 1-week baseline period, patients received, depending on age, either melatonin 5 or 2.5 mg, or placebo, followed by 4 weeks of open treatment. Parents recorded lights off time, sleep onset time, wake-up time, and epileptic seizures in a diary. Salivary melatonin levels were measured at baseline and the last evening of the fourth treatment week. Melatonin significantly advanced sleep onset by 28 minutes, decreased sleep latency by 32 minutes, increased total sleep time by 56 minutes, reduced the number of nights with wakes from 3.1 to 1.6 nights a week, and increased endogenous salivary melatonin levels. Parents were satisfied with these results. Indications that melatonin dose in Angelman syndrome patients should be low, are discussed.","DOI":"10.1177/0883073808314153","ISSN":"0883-0738","note":"PMID: 18539989","shortTitle":"Melatonin for chronic insomnia in Angelman syndrome","journalAbbreviation":"J. Child Neurol.","language":"eng","author":[{"family":"Braam","given":"Wiebe"},{"family":"Didden","given":"Robert"},{"family":"Smits","given":"Marcel G."},{"family":"Curfs","given":"Leopold M. G."}],"issued":{"date-parts":[["2008",6]]}}}],"schema":""} (Wiebe Braam, Didden, Smits, & Curfs, 2008) ; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"v9k8nmj8g","properties":{"formattedCitation":"(Andersen, Kaczmarska, McGrew, & Malow, 2008)","plainCitation":"(Andersen, Kaczmarska, McGrew, & Malow, 2008)"},"citationItems":[{"id":7733,"uris":[""],"uri":[""],"itemData":{"id":7733,"type":"article-journal","title":"Melatonin for insomnia in children with autism spectrum disorders","container-title":"Journal of Child Neurology","page":"482-485","volume":"23","issue":"5","source":"PubMed","abstract":"We describe our experience in using melatonin to treat insomnia, a common sleep concern, in children with autism spectrum disorders. One hundred seven children (2-18 years of age) with a confirmed diagnosis of autism spectrum disorders who received melatonin were identified by reviewing the electronic medical records of a single pediatrician. All parents were counseled on sleep hygiene techniques. Clinical response to melatonin, based on parental report, was categorized as (1) sleep no longer a concern, (2) improved sleep but continued parental concerns, (3) sleep continues to be a major concern, and (4) worsened sleep. The melatonin dose varied from 0.75 to 6 mg. After initiation of melatonin, parents of 27 children (25%) no longer reported sleep concerns at follow-up visits. Parents of 64 children (60%) reported improved sleep, although continued to have concerns regarding sleep. Parents of 14 children (13%) continued to report sleep problems as a major concern, with only 1 child having worse sleep after starting melatonin (1%), and 1 child having undetermined response (1%). Only 3 children had mild side-effects after starting melatonin, which included morning sleepiness and increased enuresis. There was no reported increase in seizures after starting melatonin in children with pre-existing epilepsy and no new-onset seizures. The majority of children were taking psychotropic medications. Melatonin appears to be a safe and well-tolerated treatment for insomnia in children with autism spectrum disorders. Controlled trials to determine efficacy appear warranted.","DOI":"10.1177/0883073807309783","ISSN":"0883-0738","note":"PMID: 18182647","journalAbbreviation":"J. Child Neurol.","language":"eng","author":[{"family":"Andersen","given":"Ivy M."},{"family":"Kaczmarska","given":"JoAnna"},{"family":"McGrew","given":"Susan G."},{"family":"Malow","given":"Beth A."}],"issued":{"date-parts":[["2008",5]]}}}],"schema":""} (Andersen, Kaczmarska, McGrew, & Malow, 2008) In nine girls with Rett syndrome (MLT dosage 2.5 to 7.5 mg) the actigraphic evaluation showed that sleep-onset latency was significantly decreased while the number of nighttime awakenings was not affected, and the mean total sleep time increased. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sla48lb6u","properties":{"formattedCitation":"(McArthur & Budden, 1998)","plainCitation":"(McArthur & Budden, 1998)"},"citationItems":[{"id":5914,"uris":[""],"uri":[""],"itemData":{"id":5914,"type":"article-journal","title":"Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment","container-title":"Developmental Medicine and Child Neurology","page":"186-192","volume":"40","issue":"3","source":"PubMed","abstract":"Nine girls with Rett syndrome (mean age, 10.1 years) were monitored 24 hours a day over a period of 10 weeks using wrist actigraphy. Baseline sleep-wake patterns were assessed for 1 week. Subsequently, patients underwent a 4-week melatonin treatment period in a double-blind, placebo-controlled, crossover protocol that employed a 1-week washout between treatment trials. Melatonin doses ranged from 2.5 to 7.5 mg, based upon individual body weight. Baseline sleep quality was poor compared with healthy children. At baseline the group demonstrated a low sleep efficiency (mean [+/- SE], 68.0+/-3.9%), long sleep-onset latency (42.1+/-12.0 minutes), and a short and fragmented total sleep time (7.5+/-0.3 hours; 15+/-2 awakenings per night). Melatonin significantly decreased sleep-onset latency to (mean +/- SE) 19.1+/-5.3 minutes (P<0.05) during the first 3 weeks of treatment. While the variability of individual responsiveness was high, melatonin appeared to improve total sleep time and sleep efficiency in the patients with the worse baseline sleep quality. Finally, a 4-week administration of melatonin appears to be a safe treatment as no adverse side effects were detected, yet long-term effects of chronic melatonin use in pediatric patients are unknown at this time.","ISSN":"0012-1622","note":"PMID: 9566656","shortTitle":"Sleep dysfunction in Rett syndrome","journalAbbreviation":"Dev Med Child Neurol","language":"eng","author":[{"family":"McArthur","given":"A. J."},{"family":"Budden","given":"S. S."}],"issued":{"date-parts":[["1998",3]]}}}],"schema":""} (McArthur & Budden, 1998) A typical syndrome with inverted circadian rhythm of melatonin is the Smith-Magenis syndrome. The most efficacious treatment is a combination of acebutolol, a b1-adrenergic antagonist, given in the morning that decreases daytime plasma melatonin levels during the day and exogenous melatonin at night to replace normal peak endogenous melatonin. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2dovfi4qie","properties":{"formattedCitation":"(De Leersnyder et al., 2001)","plainCitation":"(De Leersnyder et al., 2001)"},"citationItems":[{"id":5916,"uris":[""],"uri":[""],"itemData":{"id":5916,"type":"article-journal","title":"beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome","container-title":"Journal of Medical Genetics","page":"586-590","volume":"38","issue":"9","source":"PubMed","abstract":"Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS.","ISSN":"1468-6244","note":"PMID: 11546826\nPMCID: PMC1734944","journalAbbreviation":"J. Med. Genet.","language":"eng","author":[{"family":"De Leersnyder","given":"H."},{"family":"Blois","given":"M. C.","non-dropping-particle":"de"},{"family":"Vekemans","given":"M."},{"family":"Sidi","given":"D."},{"family":"Villain","given":"E."},{"family":"Kindermans","given":"C."},{"family":"Munnich","given":"A."}],"issued":{"date-parts":[["2001",9]]}}}],"schema":""} (De Leersnyder et al., 2001) Melatonin has been also effective in children with ADHD with delayed sleep phase syndrome (DSPS) and insomnia at a dosage of about 5 mg. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ibij2sqlf","properties":{"formattedCitation":"(Van der Heijden, Smits, Van Someren, & Gunning, 2005)","plainCitation":"(Van der Heijden, Smits, Van Someren, & Gunning, 2005)"},"citationItems":[{"id":870,"uris":[""],"uri":[""],"itemData":{"id":870,"type":"article-journal","title":"Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: a circadian rhythm sleep disorder.","container-title":"Chronobiology international","page":"559-570","volume":"22","issue":"3","abstract":"To investigate whether ADHD-related sleep-onset insomnia (SOI) is a circadian rhythm disorder, we compared actigraphic sleep estimates, the circadian rest-activity rhythm, and dim light melatonin onset (DLMO) in ADHD children having chronic idiopathic SOI with that in ADHD children without sleep problems. Participants were 87 psychotropic-medication-naive children, aged 6 to 12 yrs, with rigorously diagnosed ADHD and SOI (ADHD-SOI) and 33 children with ADHD without SOI (ADHD-noSOI) referred from community mental health institutions and pediatric departments of non-academic hospitals in The Netherlands. Measurements were 1 wk, 24 h actigraphy recordings and salivary DLMO. The mean (+/-SD) sleep onset time was 21:38 +/- 0:54 h in ADHD-SOI, which was significantly (p < 0.001) later than that of 20:49 +/- 0:49 h in ADHD-noSOI. DLMO was significantly later in ADHD-SOI (20:32 +/- 0:55 h), compared with ADHD-noSOI (19:47 +/- 0:49 h; p < 0.001). Wake-up time in ADHD-SOI was later than in ADHD-noSOI (p = 0.002). There were no significant between-group differences in sleep maintenance, as estimated by number of wake bouts and activity level in the least active 5 h period, or inter- and intradaily rhythm variability. We conclude that children with ADHD and chronic idiopathic sleep-onset insomnia show a delayed sleep phase and delayed DLMO, compared with ADHD children without SOI.","DOI":"10.1081/CBI-200062410","note":"PMID: 16076654","journalAbbreviation":"Chronobiol Int","language":"eng","author":[{"family":"Van der Heijden","given":"Kristiaan B."},{"family":"Smits","given":"Marcel G."},{"family":"Van Someren","given":"Eus J. W."},{"family":"Gunning","given":"W. Boudewijn"}],"issued":{"date-parts":[["2005"]]}}}],"schema":""} (Van der Heijden, Smits, Van Someren, & Gunning, 2005), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dQS93C7Y","properties":{"formattedCitation":"(Van der Heijden, Smits, Van Someren, Ridderinkhof, & Gunning, 2007)","plainCitation":"(Van der Heijden, Smits, Van Someren, Ridderinkhof, & Gunning, 2007)"},"citationItems":[{"id":5920,"uris":[""],"uri":[""],"itemData":{"id":5920,"type":"article-journal","title":"Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"233-241","volume":"46","issue":"2","source":"PubMed","abstract":"OBJECTIVE: To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.\nMETHOD: A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.\nRESULTS: Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.\nCONCLUSION: Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.","DOI":"10.1097/01.chi.0000246055.76167.0d","ISSN":"0890-8567","note":"PMID: 17242627","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Van der Heijden","given":"Kristiaan B."},{"family":"Smits","given":"Marcel G."},{"family":"Van Someren","given":"Eus J. W."},{"family":"Ridderinkhof","given":"K. Richard"},{"family":"Gunning","given":"W. Boudewijn"}],"issued":{"date-parts":[["2007",2]]}}}],"schema":""} (Van der Heijden, Smits, Van Someren, Ridderinkhof, & Gunning, 2007), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1na080j3hu","properties":{"formattedCitation":"(Smits et al., 2003)","plainCitation":"(Smits et al., 2003)"},"citationItems":[{"id":5918,"uris":[""],"uri":[""],"itemData":{"id":5918,"type":"article-journal","title":"Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"1286-1293","volume":"42","issue":"11","source":"PubMed","abstract":"OBJECTIVE: To investigate the effect of melatonin treatment on health status and sleep in children with idiopathic sleep-onset insomnia.\nMETHOD: A randomized, double-blind, placebo-controlled trial was conducted in a Dutch sleep center, involving 62 children, 6 to 12 years of age, who suffered more than 1 year from idiopathic chronic sleep-onset insomnia. Patients received either 5 mg melatonin or placebo at 7 pm. The study consisted of a 1-week baseline period, followed by a 4-week treatment. Health status was measured with the RAND General Health Rating Index (RAND-GHRI) and Functional Status II (FS-II) questionnaires. Lights-off time, sleep onset, and wake-up time were recorded in a diary, and endogenous dim light melatonin onset was measured in saliva.\nRESULTS: The total scores of the RAND-GHRI and FS-II improved significantly more during melatonin treatment compared to placebo. The magnitude of change was much higher in the melatonin group than in the placebo group, with standardized response means for the RAND-GHRI of 0.69 versus 0.07 and for the FS-II of 1.61 versus 0.64. Melatonin treatment also significantly advanced sleep onset by 57 minutes, sleep offset by 9 minutes, and melatonin onset by 82 minutes, and decreased sleep latency by 17 minutes. Lights-off time and total sleep time did not change.\nCONCLUSIONS: Melatonin improves health status and advances the sleep-wake rhythm in children with idiopathic chronic sleep-onset insomnia.","DOI":"10.1097/01.chi.0000085756.71002.86","ISSN":"0890-8567","note":"PMID: 14566165","shortTitle":"Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Smits","given":"Marcel G."},{"family":"Stel","given":"Henk F.","non-dropping-particle":"van"},{"family":"Heijden","given":"Kristiaan","non-dropping-particle":"van der"},{"family":"Meijer","given":"Anne Marie"},{"family":"Coenen","given":"Anton M. L."},{"family":"Kerkhof","given":"Gerard A."}],"issued":{"date-parts":[["2003",11]]}}}],"schema":""} (Smits et al., 2003), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tpmpbg88b","properties":{"formattedCitation":"(Weiss, Wasdell, Bomben, Rea, & Freeman, 2006)","plainCitation":"(Weiss, Wasdell, Bomben, Rea, & Freeman, 2006)"},"citationItems":[{"id":5922,"uris":[""],"uri":[""],"itemData":{"id":5922,"type":"article-journal","title":"Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"512-519","volume":"45","issue":"5","source":"PubMed","abstract":"OBJECTIVE: To evaluate the efficacy of sleep hygiene and melatonin treatment for initial insomnia in children with attention-deficit/hyperactivity disorder (ADHD).\nMETHOD: Twenty-seven stimulant-treated children (6-14 years of age) with ADHD and initial insomnia (>60 minutes) received sleep hygiene intervention. Nonresponders were randomized to a 30-day double-blind, placebo-controlled, crossover trial of 5-mg pharmaceutical-grade melatonin provided by the study's sponsor.\nRESULTS: Sleep hygiene reduced initial insomnia to <60 minutes in 5 cases, with an overall effect size in the group as a whole of 0.67. Analysis of the trial data able to be evaluated showed a significant reduction in initial insomnia of 16 minutes with melatonin relative to placebo, with an effect size of 0.6. Adverse events were generally mild and not different from those recorded with placebo treatment. The effect size of the combined sleep hygiene and melatonin intervention from baseline to 90 days' posttrial was 1.7, with a mean decrease in initial insomnia of 60 minutes. Improved sleep had no demonstrable effect on ADHD symptoms.\nCONCLUSION: Combined sleep hygiene and melatonin was a safe and effective treatment for initial insomnia in children with ADHD taking stimulant medication.","DOI":"10.1097/01 chi.0000205706.78818.ef","ISSN":"0890-8567","note":"PMID: 16670647","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Weiss","given":"Margaret D."},{"family":"Wasdell","given":"Michael B."},{"family":"Bomben","given":"Melissa M."},{"family":"Rea","given":"Kathleen J."},{"family":"Freeman","given":"Roger D."}],"issued":{"date-parts":[["2006",5]]}}}],"schema":""} (Weiss, Wasdell, Bomben, Rea, & Freeman, 2006) A systematic review of the literature found that melatonin given in doses 3 to 6 mg/night significantly reduced sleep onset latency and increased total sleep duration, but did not impact on daytime ADHD core symptoms. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1aleujdpd2","properties":{"formattedCitation":"(Cortese et al., 2013)","plainCitation":"(Cortese et al., 2013)"},"citationItems":[{"id":5924,"uris":[""],"uri":[""],"itemData":{"id":5924,"type":"article-journal","title":"Assessment and management of sleep problems in youths with attention-deficit/hyperactivity disorder","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"784-796","volume":"52","issue":"8","source":"PubMed","abstract":"OBJECTIVE: To provide evidence- or consensus-based recommendations concerning the assessment and management of sleep problems in youths with attention-deficit/hyperactivity disorder (ADHD).\nMETHOD: PubMed, Ovid, EMBASE, and Web of Knowledge were searched through October 31, 2012. When no evidence was available, consensus of the authors was achieved. The evidence-level of the recommendations on the management of sleep disturbances was based on the Scottish Intercollegiate Guidelines Network (SIGN) system.\nRESULTS: A total of 139 original articles on sleep and childhood ADHD were retrieved, including 22 on treatment of sleep disturbances. This review focuses on behaviorally based insomnia, circadian rhythm disorder, sleep-disordered breathing, restless legs syndrome/periodic limb movement disorder, and sleep disturbances due to comorbid psychiatric disorders or ADHD medications. Healthy sleep practices are recommended as the foundation of management strategies. Behavioral interventions should be considered as first-line treatment of insomnia, although further evidence from randomized controlled trials (RCTs) is needed to prove their efficacy in ADHD. Among pharmacological treatments, RCTs support the use of melatonin to reduce sleep-onset delay, whereas there is more limited evidence for other medications.\nCONCLUSION: Growing empirical evidence is informing assessment/management strategies of sleep problems in youths with ADHD. However, further RCTs are warranted to support current recommendations.","DOI":"10.1016/j.jaac.2013.06.001","ISSN":"1527-5418","note":"PMID: 23880489","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Cortese","given":"Samuele"},{"family":"Brown","given":"Thomas E."},{"family":"Corkum","given":"Penny"},{"family":"Gruber","given":"Reut"},{"family":"O'Brien","given":"Louise M."},{"family":"Stein","given":"Mark"},{"family":"Weiss","given":"Margaret"},{"family":"Owens","given":"Judith"}],"issued":{"date-parts":[["2013",8]]}}}],"schema":""} (Cortese et al., 2013). A recent randomized controlled trial found a reduction in mean sleep latency in ADHD patients treated with methylphenidate and melatonin 3 to 6 mg. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1l2rn8rae6","properties":{"formattedCitation":"(Mohammadi et al., 2012)","plainCitation":"(Mohammadi et al., 2012)"},"citationItems":[{"id":7735,"uris":[""],"uri":[""],"itemData":{"id":7735,"type":"article-journal","title":"Melatonin effects in methylphenidate treated children with attention deficit hyperactivity disorder: a randomized double blind clinical trial","container-title":"Iranian Journal of Psychiatry","page":"87-92","volume":"7","issue":"2","source":"PubMed","abstract":"OBJECTIVE: The aim of this study was to determine melatonin effects on sleep patterns, symptoms of hyperactivity and attention deficiency in children with attention-deficit hyperactivity disorder (ADHD).\nMETHODS: Children with age range of 7-12 years who had a combined form of ADHD were randomly divided in to 2 groups according to gender blocks. One group took melatonin (3 or 6mg) combined with methylphenidate (Ritalin) (1mg/kg), and the other group took placebo combined with methylphenidate (1mg/kg). ADHD rating scale and sleep patterns questionnaires were completed. Research hypotheses were assessed at the baseline, the second, fourth and eighth weeks after the treatment.\nRESULTS: The mean sleep latency and total sleep disturbance scores were reduced in melatonin group, while the scores increased in the placebo group (p≥0.05). Data analysis, using ANOVA with repeated measures, did not show any statistically significant differences between the two groups in ADHD scores.\nCONCLUSION: Administration of melatonin along with methylphenidate can partially improve symptoms of sleep disturbance. However, it does not seem to reduce attention deficiency and hyperactivity behavior of children with ADHD.","ISSN":"2008-2215","note":"PMID: 22952551\nPMCID: PMC3428643","shortTitle":"Melatonin effects in methylphenidate treated children with attention deficit hyperactivity disorder","journalAbbreviation":"Iran J Psychiatry","language":"eng","author":[{"family":"Mohammadi","given":"Mohammad Reza"},{"family":"Mostafavi","given":"Seyed Ali"},{"family":"Keshavarz","given":"Seyed Ali"},{"family":"Eshraghian","given":"Mohammad Reza"},{"family":"Hosseinzadeh","given":"Payam"},{"family":"Hosseinzadeh-Attar","given":"Mohammad Javad"},{"family":"Kooshesh","given":"Seyed Mohammad Ali"},{"family":"Chamari","given":"Maryam"},{"family":"Akhondzadeh","given":"Shahin"}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} (Mohammadi et al., 2012)In some patients with NDDs, the loss of efficacy of melatonin treatment after an initial good response is a major problem possibly caused by slow metabolism because of decreased activity of the CYP1A2 enzyme. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"13boqhdq0r","properties":{"formattedCitation":"(W. Braam et al., 2013)","plainCitation":"(W. Braam et al., 2013)"},"citationItems":[{"id":5930,"uris":[""],"uri":[""],"itemData":{"id":5930,"type":"article-journal","title":"CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?","container-title":"Journal of intellectual disability research: JIDR","page":"993-1000","volume":"57","issue":"11","source":"PubMed","abstract":"BACKGROUND: In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2.\nMETHOD: In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels.\nRESULTS: In all patients' salivary melatonin levels at noon were >50 or melatonin half time was > 5 h. A SNP was found in eight of 15 patients. The allele 1C was found in two patients and in six patients the 1F allele was found.\nCONCLUSIONS: Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic-type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism.","DOI":"10.1111/j.1365-2788.2012.01595.x","ISSN":"1365-2788","note":"PMID: 22823064","shortTitle":"CYP1A2 polymorphisms in slow melatonin metabolisers","journalAbbreviation":"J Intellect Disabil Res","language":"eng","author":[{"family":"Braam","given":"W."},{"family":"Keijzer","given":"H."},{"family":"Struijker Boudier","given":"H."},{"family":"Didden","given":"R."},{"family":"Smits","given":"M."},{"family":"Curfs","given":"L."}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} (W. Braam et al., 2013) This may result in increasing daily melatonin levels. Consequently, melatonin levels accumulate and after some time the circadian melatonin rhythm is lost. This loss of circadian rhythm might explain why exogenous melatonin loses its effectiveness. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"18pgvvhsb9","properties":{"formattedCitation":"(W. Braam et al., 2010)","plainCitation":"(W. Braam et al., 2010)"},"citationItems":[{"id":5928,"uris":[""],"uri":[""],"itemData":{"id":5928,"type":"article-journal","title":"Loss of response to melatonin treatment is associated with slow melatonin metabolism","container-title":"Journal of intellectual disability research: JIDR","page":"547-555","volume":"54","issue":"6","source":"PubMed","abstract":"BACKGROUND: In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism.\nMETHOD: In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose.\nRESULTS: In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%.\nCONCLUSION: We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.","DOI":"10.1111/j.1365-2788.2010.01283.x","ISSN":"1365-2788","note":"PMID: 20576063","journalAbbreviation":"J Intellect Disabil Res","language":"eng","author":[{"family":"Braam","given":"W."},{"family":"Geijlswijk","given":"I.","non-dropping-particle":"van"},{"family":"Keijzer","given":"Henry"},{"family":"Smits","given":"Marcel G."},{"family":"Didden","given":"Robert"},{"family":"Curfs","given":"Leopold M. G."}],"issued":{"date-parts":[["2010",6]]}}}],"schema":""} (W. Braam et al., 2010).There is now a greater understanding that low doses (0.5 mg) can be effective for some children, with diminishing benefit with doses exceeding 6 mg. Unlike traditional hypnotics such as chloral hydrate and the benzodiazepines, melatonin does not affect sleep architecture. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jvfnqfeiq","properties":{"formattedCitation":"(Bruni et al., 2014)","plainCitation":"(Bruni et al., 2014)"},"citationItems":[{"id":235,"uris":[""],"uri":[""],"itemData":{"id":235,"type":"article-journal","title":"Current role of melatonin in pediatric neurology: Clinical recommendations","container-title":"European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society","source":"NCBI PubMed","abstract":"BACKGROUND/PURPOSE: Melatonin, an indoleamine secreted by the pineal gland, plays a key role in regulating circadian rhythm. It has chronobiotic, antioxidant, anti-inflammatory and free radical scavenging properties.\nMETHODS: A conference in Rome in 2014 aimed to establish consensus on the roles of melatonin in children and on treatment guidelines.\nRESULTS AND CONCLUSION: The best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5?h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified.","DOI":"10.1016/j.ejpn.2014.12.007","ISSN":"1532-2130","note":"PMID: 25553845","shortTitle":"Current role of melatonin in pediatric neurology","journalAbbreviation":"Eur. J. Paediatr. Neurol.","language":"ENG","author":[{"family":"Bruni","given":"Oliviero"},{"family":"Alonso-Alconada","given":"Daniel"},{"family":"Besag","given":"Frank"},{"family":"Biran","given":"Valerie"},{"family":"Braam","given":"Wiebe"},{"family":"Cortese","given":"Samuele"},{"family":"Moavero","given":"Romina"},{"family":"Parisi","given":"Pasquale"},{"family":"Smits","given":"Marcel"},{"family":"Van der Heijden","given":"Kristiaan"},{"family":"Curatolo","given":"Paolo"}],"issued":{"date-parts":[["2014",12,17]]}}}],"schema":""} (Bruni et al., 2014) A single study reported that melatonin for treatment of chronic sleep onset insomnia in children is effective in a dosage of 0.05 mg/kg given at least 1 to 2 h before desired bedtime. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"146j6co111","properties":{"formattedCitation":"(van Geijlswijk, van der Heijden, Egberts, Korzilius, & Smits, 2010)","plainCitation":"(van Geijlswijk, van der Heijden, Egberts, Korzilius, & Smits, 2010)"},"citationItems":[{"id":5934,"uris":[""],"uri":[""],"itemData":{"id":5934,"type":"article-journal","title":"Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT","container-title":"Psychopharmacology","page":"379-391","volume":"212","issue":"3","source":"PubMed","abstract":"RATIONALE: Pharmacokinetics of melatonin in children might differ from that in adults.\nOBJECTIVES: This study aims to establish a dose-response relationship for melatonin in advancing dim light melatonin onset (DLMO), sleep onset (SO), and reducing sleep onset latency (SOL) in children between 6 and 12?years with chronic sleep onset insomnia (CSOI).\nMETHODS: The method used for this study is the randomized, placebo-controlled double-blind trial. Children with CSOI (n?=?72) received either melatonin 0.05, 0.1, and 0.15?mg/kg or placebo during 1?week. Sleep was assessed with log and actigraphy during this week and the week before. Outcomes were the shifts in DLMO, SO, and SOL.\nRESULTS: Treatment with melatonin significantly advanced SO and DLMO by approximately 1?h and decreased SOL by 35?min. Within the three melatonin groups, effect size was not different, but the circadian time of administration (TOA) correlated significantly with treatment effect on DLMO (r (s)?=?-0.33, p?=?0.022) and SO (r (s)?=?-0.38, p?=?0.004), whereas clock TOA was correlated with SO shift (r?=?-0.35, p?=?0.006) and not with DLMO shift.\nCONCLUSIONS: No dose-response relationship of melatonin with SO, SOL, and DLMO is found within a dosage range of 0.05-0.15?mg/kg. The effect of exogenous melatonin on SO, SOL, and DLMO increases with an earlier circadian TOA. The soporific effects of melatonin enhance the SO shift. This study demonstrates that melatonin for treatment of CSOI in children is effective in a dosage of 0.05?mg/kg given at least 1 to 2?h before DLMO and before desired bedtime.","DOI":"10.1007/s00213-010-1962-0","ISSN":"1432-2072","note":"PMID: 20668840\nPMCID: PMC2952772","shortTitle":"Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia","journalAbbreviation":"Psychopharmacology (Berl.)","language":"eng","author":[{"family":"Geijlswijk","given":"Ingeborg M.","non-dropping-particle":"van"},{"family":"Heijden","given":"Kristiaan B.","non-dropping-particle":"van der"},{"family":"Egberts","given":"A. C. G."},{"family":"Korzilius","given":"Hubert P. L. M."},{"family":"Smits","given":"Marcel G."}],"issued":{"date-parts":[["2010",10]]}}}],"schema":""} (van Geijlswijk, van der Heijden, Egberts, Korzilius, & Smits, 2010) Headaches, confusion, dizziness, cough and rashes have been reported, but these common symptoms are likely to be coincidental or caused by impurities in the unregulated formulations of melatonin. Previous reports of poor seizure control, poor asthma control and adverse endocrinological problems during puberty have not been confirmed. Both systematic reviews and meta-analyses of RCTs suggest that there are no significant adverse side effects associated with the use of melatonin. Unanswered clinical questions include whether slow-release preparations are superior to immediate-release in increasing total sleep time, and whether a more rational and optimal prescription of melatonin might be achieved by measuring salivary melatonin before its use.RamelteonRamelteon is a synthetic melatonin receptor agonist with high affinity for the MT1 and MT2 receptors, is approved by the FDA for use in adults. Only few case reports have been published in children with NDDs reporting in general a low level of efficacy on night awakenings. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2frs6hsq09","properties":{"formattedCitation":"(Stigler, Posey, & McDougle, 2006)","plainCitation":"(Stigler, Posey, & McDougle, 2006)"},"citationItems":[{"id":5940,"uris":[""],"uri":[""],"itemData":{"id":5940,"type":"article-journal","title":"Ramelteon for insomnia in two youths with autistic disorder","container-title":"Journal of Child and Adolescent Psychopharmacology","page":"631-636","volume":"16","issue":"5","source":"PubMed","abstract":"OBJECTIVE: The aim of this study was to report preliminary data on the effectiveness and tolerability of ramelteon for the treatment of insomnia in youth with autistic disorder (autism).\nMETHOD: Two youths, ages 7 and 18 years, with autism and significant insomnia characterized by problems with sleep onset and maintenance received an open-label trial of ramelteon (4-8 mg) over a duration of 16-18 weeks.\nRESULTS: Target symptoms of delayed sleep onset and/or frequent nocturnal awakening improved significantly, as determined by Clinical Global Impressions-Improvement (CGI-I) scale ratings of either \"much improved\" or \"very much improved.\" Ramelteon was well tolerated. No daytime sedation was reported.\nCONCLUSIONS: This case report illustrates the potential effectiveness and tolerability of ramelteon for sleep disturbances in 2 patients with autism. Further research is needed to verify its safety, tolerability, and efficacy in children and adolescents with autism.","DOI":"10.1089/cap.2006.16.631","ISSN":"1044-5463","note":"PMID: 17069551","journalAbbreviation":"J Child Adolesc Psychopharmacol","language":"eng","author":[{"family":"Stigler","given":"Kimberly A."},{"family":"Posey","given":"David J."},{"family":"McDougle","given":"Christopher J."}],"issued":{"date-parts":[["2006",10]]}}}],"schema":""} (Stigler, Posey, & McDougle, 2006), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4h7fnh5nq","properties":{"formattedCitation":"(Asano, Ishitobi, Kosaka, Hiratani, & Wada, 2014)","plainCitation":"(Asano, Ishitobi, Kosaka, Hiratani, & Wada, 2014)"},"citationItems":[{"id":5942,"uris":[""],"uri":[""],"itemData":{"id":5942,"type":"article-journal","title":"Ramelteon monotherapy for insomnia and impulsive behavior in high-functioning autistic disorder","container-title":"Journal of Clinical Psychopharmacology","page":"402-403","volume":"34","issue":"3","source":"PubMed","DOI":"10.1097/JCP.0000000000000137","ISSN":"1533-712X","note":"PMID: 24717259","journalAbbreviation":"J Clin Psychopharmacol","language":"eng","author":[{"family":"Asano","given":"Mizuki"},{"family":"Ishitobi","given":"Makoto"},{"family":"Kosaka","given":"Hirotaka"},{"family":"Hiratani","given":"Michio"},{"family":"Wada","given":"Yuji"}],"issued":{"date-parts":[["2014",6]]}}}],"schema":""} (Asano, Ishitobi, Kosaka, Hiratani, & Wada, 2014), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1qm4ssm42l","properties":{"formattedCitation":"(Miyamoto et al., 2013)","plainCitation":"(Miyamoto et al., 2013)"},"citationItems":[{"id":664,"uris":[""],"uri":[""],"itemData":{"id":664,"type":"article-journal","title":"[Treatment with ramelteon for sleep disturbance in severely disabled children and young adults].","container-title":"No to hattatsu. Brain and development","page":"440-444","volume":"45","issue":"6","abstract":"OBJECTIVE: The aim of this study was to determine the efficacy and safety of ramelteon for severely disabled children and young adults who had already been treated for sleep disturbance with melatonin at a dose of 3 mg. METHODS: Eleven patients, who were aged between 3-25 years and included 4 patients with cerebral palsy, -took 3-8 mg of ramelteon at bedtime, after a one-week of washout period. Sleep states were evaluated using sleep diaries recorded by caregivers or using actigraphs. RESULTS: Ramelteon was effective in 8 out of the 11 patients. Ramelteon was tolerated well except for mild daytime sleepiness in three patients. CONCLUSIONS: This preliminary study showed the efficacy and safety of ramelteon for sleep disturbance in severely disabled children and young adults. Further trials are necessary to determine optimal dosage and safety of ramelteon in children.","note":"PMID: 24313003","journalAbbreviation":"No To Hattatsu","language":"jpn","author":[{"family":"Miyamoto","given":"Akie"},{"family":"Fukuda","given":"Ikue"},{"family":"Tanaka","given":"Hajime"},{"family":"Oka","given":"Ryuuji"},{"family":"Araki","given":"Akiko"},{"family":"Cho","given":"Kazuhiko"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} (Miyamoto et al., 2013) AntihistaminesHistamine is a wake-promoting neurotransmitter, and inactivation or suppression in various animal models has led to sedation and disrupted wakefulness patterns. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2kt60tfl40","properties":{"formattedCitation":"(Mignot, Taheri, & Nishino, 2002)","plainCitation":"(Mignot, Taheri, & Nishino, 2002)"},"citationItems":[{"id":5487,"uris":[""],"uri":[""],"itemData":{"id":5487,"type":"article-journal","title":"Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders","container-title":"Nature Neuroscience","page":"1071-1075","volume":"5 Suppl","source":"PubMed","abstract":"Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy--molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.","DOI":"10.1038/nn944","ISSN":"1097-6256","note":"PMID: 12403989","shortTitle":"Sleeping with the hypothalamus","journalAbbreviation":"Nat. Neurosci.","language":"eng","author":[{"family":"Mignot","given":"Emmanuel"},{"family":"Taheri","given":"Shahrad"},{"family":"Nishino","given":"Seiji"}],"issued":{"date-parts":[["2002",11]]}}}],"schema":""} (Mignot, Taheri, & Nishino, 2002)First generation antihistamines are lipid soluble and pass through the blood-brain-barrier; they bind to H1 receptors in the CNS and have minimal effects on sleep architecture. Ethanolamines (such as diphenhydramine) have potent sedative effects as do piperazine derivatives (such as hydroxyzine).Diphenhydramine is the most commonly used and is a competitive H1-histamine receptor blocker. Peak blood and tissue levels are achieved within 2 h of ingestion. The recommended dosage for adults is 25 to 50 mg, whereas in children the effective dose is 0.5 mg/kg up to 25 mg. Hydroxyzine is effective at 0.5 mg/kg in children.12 Although antihistamines are the most prescribed or obtained over-the-counter agents for pediatric insomnia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"26e6tk9rm5","properties":{"formattedCitation":"(Schnoes, Kuhn, Workman, & Ellis, 2006)","plainCitation":"(Schnoes, Kuhn, Workman, & Ellis, 2006)"},"citationItems":[{"id":5721,"uris":[""],"uri":[""],"itemData":{"id":5721,"type":"article-journal","title":"Pediatric prescribing practices for clonidine and other pharmacologic agents for children with sleep disturbance","container-title":"Clinical Pediatrics","page":"229-238","volume":"45","issue":"3","source":"PubMed","abstract":"The prescription rates of clonidine have risen dramatically and the extent to which these increases can be attributed to treatment of sleep disturbance is unknown. Surveys were mailed to 800 pediatricians across four geographically diverse states to assess prescribing practices specific to sleep disturbance. Ninety-six percent of the respondents treated sleep disturbance. More than one third of the sample reported using clonidine specifically for sleep disturbance including sleep onset, sleep schedule, nighttime awakening, and early morning awakening problems and parasomnias. Clonidine ranked second only to antihistamines as the most commonly used medication for treating sleep disturbance.","ISSN":"0009-9228","note":"PMID: 16708135","journalAbbreviation":"Clin Pediatr (Phila)","language":"eng","author":[{"family":"Schnoes","given":"Connie J."},{"family":"Kuhn","given":"Brett R."},{"family":"Workman","given":"Elizabeth F."},{"family":"Ellis","given":"Cynthia R."}],"issued":{"date-parts":[["2006",4]]}}}],"schema":""} (Schnoes, Kuhn, Workman, & Ellis, 2006) randomized controlled data in children are lacking. A study showed a significant decrease in sleep latency time and number of awakenings ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1qcrfj14n6","properties":{"formattedCitation":"(Russo, Gururaj, & Allen, 1976)","plainCitation":"(Russo, Gururaj, & Allen, 1976)"},"citationItems":[{"id":5982,"uris":[""],"uri":[""],"itemData":{"id":5982,"type":"article-journal","title":"The effectiveness of diphenhydramine HCI in pediatric sleep disorders","container-title":"Journal of Clinical Pharmacology","page":"284-288","volume":"16","issue":"5-6","source":"PubMed","abstract":"Fifty children with a variety of sleep disorders were studied in a placebo-controlled, double-blind clinical trial of diphenydramine elixir given in a dosage of 1.0 mg/kg at bedtime. Sleep records measuring latency time, number of awakenings, and duration of sleep were compiled by the patient's parent. A global assessment as to the severity of sleep disturbance and the therapeutic effect of the medication and placebo was made on a weekly basis. Diphenhydramine was significantly better than placebo in reducing sleep latency time and the number of awakenings per night, while sleep duration was marginally increased. There were no essential differences between diphenhydramine and placebo in the other study parameters, i.e., restlessness, nightmares, and difficulty awakening. Diphenhydramine was judged to be more effective than placebo on the weekly global assessment. The results indicate that diphenhydramine is a safe, effective bedtime sleep aid for pediatric patients.","ISSN":"0091-2700","note":"PMID: 770511","journalAbbreviation":"J Clin Pharmacol","language":"eng","author":[{"family":"Russo","given":"R. M."},{"family":"Gururaj","given":"V. J."},{"family":"Allen","given":"J. E."}],"issued":{"date-parts":[["1976",6]]}}}],"schema":""} (Russo, Gururaj, & Allen, 1976) while another study in infants showed inefficacy compared to placebo. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1q2bene9og","properties":{"formattedCitation":"(Merenstein, Diener-West, Halbower, Krist, & Rubin, 2006)","plainCitation":"(Merenstein, Diener-West, Halbower, Krist, & Rubin, 2006)"},"citationItems":[{"id":5493,"uris":[""],"uri":[""],"itemData":{"id":5493,"type":"article-journal","title":"The trial of infant response to diphenhydramine: the TIRED study--a randomized, controlled, patient-oriented trial","container-title":"Archives of Pediatrics & Adolescent Medicine","page":"707-712","volume":"160","issue":"7","source":"PubMed","abstract":"OBJECTIVE: To determine if infants aged 6 to 15 months with frequent parent-reported nighttime awakenings require reduced parental aid during a week of diphenhydramine hydrochloride treatment and 2 and 4 weeks after its discontinuation.\nDESIGN: Double-blind, randomized, controlled clinical trial.\nSETTING: The study was conducted from May 1, 2004, through May 1, 2005; patients were recruited nationally.\nPARTICIPANTS: Forty-four participants aged 6 to 15 months.\nINTERVENTIONS: Placebo or diphenhydramine was administered in infants 30 minutes before anticipated bedtime.\nMAIN OUTCOME MEASURES: The primary outcome was dichotomous: a parental report of improvement in the number of night awakenings requiring parental assistance during the intervention week, which ended on day 14. Secondary outcomes were improved sleep during the 2 weeks before days 29 and 43, parental overall happiness with sleep, and improved sleep latency.\nRESULTS: On June 6, 2005, the data safety monitoring board voted unanimously to stop the trial early because of lack of effectiveness of diphenhydramine over placebo. Only 1 of 22 children receiving diphenhydramine showed improvement compared with 3 of 22 receiving placebo. To reach the a priori determined sample size and have a positive outcome (ie, rejecting the null hypothesis), the trial would have needed to enroll 16 more participants in each arm, with 15 of the 16 in the diphenhydramine group and 0 of 16 in the placebo group improving.\nCONCLUSION: During 1 week of therapy and at follow-up 2 and 4 weeks later, diphenhydramine was no more effective than placebo in reducing nighttime awakening or improving overall parental happiness with sleep for infants.","DOI":"10.1001/archpedi.160.7.707","ISSN":"1072-4710","note":"PMID: 16818836","shortTitle":"The trial of infant response to diphenhydramine","journalAbbreviation":"Arch Pediatr Adolesc Med","language":"eng","author":[{"family":"Merenstein","given":"Dan"},{"family":"Diener-West","given":"Marie"},{"family":"Halbower","given":"Ann C."},{"family":"Krist","given":"Alex"},{"family":"Rubin","given":"Haya R."}],"issued":{"date-parts":[["2006",7]]}}}],"schema":""} (Merenstein, Diener-West, Halbower, Krist, & Rubin, 2006) Other antihistaminines have been used: trimeprazine was used in 22 children with night awakenings showing a moderate improvement; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pk73t8i2e","properties":{"formattedCitation":"(France, Blampied, & Wilkinson, 1999)","plainCitation":"(France, Blampied, & Wilkinson, 1999)"},"citationItems":[{"id":5495,"uris":[""],"uri":[""],"itemData":{"id":5495,"type":"article-journal","title":"A multiple-baseline, double-blind evaluation of the effects of trimeprazine tartrate on infant sleep disturbance","container-title":"Experimental and Clinical Psychopharmacology","page":"502-513","volume":"7","issue":"4","source":"PubMed","abstract":"Infant sleep disturbance involving chronic night waking and resistance to settling to sleep or returning to sleep is a common problem for families with children 6-27 months old. Prescription and nonprescription sedatives are frequently administered without clear evidence that they are effective as either long-term or short-term palliatives. Trimeprazine tartrate, administered either 15 mg/5 mL or 30 mg/5 mL, was compared with both baseline and placebo in a multiple-baseline-across participants, double-blind study. No clinically significant effects of the low dose were detected, whereas the effects of the high dose were not consistently replicated across nor within participants. During active drug treatment, only 2 of 12 children achieved Sleep Behaviour Scale scores indicative of nonproblem sleep. Trimeprazine tartrate is not recommended as a pharmacological treatment for infant sleep disturbance unless as an adjunct to a behavioral therapy program.","ISSN":"1064-1297","note":"PMID: 10609985","journalAbbreviation":"Exp Clin Psychopharmacol","language":"eng","author":[{"family":"France","given":"K. G."},{"family":"Blampied","given":"N. M."},{"family":"Wilkinson","given":"P."}],"issued":{"date-parts":[["1999",11]]}}}],"schema":""} (France, Blampied, & Wilkinson, 1999) niaprazine (1 mg/kg in a single dose at bedtime) showed a decrease of sleep onset latency and an increase of sleep duration ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"13k7qplhrd","properties":{"formattedCitation":"(Ottaviano, Giannotti, & Cortesi, 1991)","plainCitation":"(Ottaviano, Giannotti, & Cortesi, 1991)"},"citationItems":[{"id":5497,"uris":[""],"uri":[""],"itemData":{"id":5497,"type":"article-journal","title":"The effect of niaprazine on some common sleep disorders in children. A double-blind clinical trial by means of continuous home-videorecorded sleep","container-title":"Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery","page":"332-335","volume":"7","issue":"6","source":"PubMed","abstract":"A placebo-controlled double-blind clinical trial on the effect of niaprazine on children with some common sleep disorders was carried out. Niaprazine at a daily dosage of 1 mg/kg body weight or placebo at random was administered to a selected group of 36 children (aged from 6 months to 6 years) suffering from frequent nighttime waking or inability to fall asleep. The effect of niaprazine (or placebo) on sleep disorders was studied by means of continuous home-videorecorded sleep before and after the trial. A reliable positive effect of niaprazine on the sleep disorders considered was found. No adverse side effects were observed. We conclude that niaprazine seems to represent an effective and safe drug for the therapy of frequent nighttime waking and inability to fall asleep.","ISSN":"0256-7040","note":"PMID: 1837245","journalAbbreviation":"Childs Nerv Syst","language":"eng","author":[{"family":"Ottaviano","given":"S."},{"family":"Giannotti","given":"F."},{"family":"Cortesi","given":"F."}],"issued":{"date-parts":[["1991",10]]}}}],"schema":""} (Ottaviano, Giannotti, & Cortesi, 1991) even if compared with benzodiazepines. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fr08hsrf1","properties":{"formattedCitation":"(Montanari, Schiaulini, Covre, Steffan, & Furlanut, 1992)","plainCitation":"(Montanari, Schiaulini, Covre, Steffan, & Furlanut, 1992)"},"citationItems":[{"id":5499,"uris":[""],"uri":[""],"itemData":{"id":5499,"type":"article-journal","title":"Niaprazine vs chlordesmethyldiazepam in sleep disturbances in pediatric outpatients","container-title":"Pharmacological Research","page":"83-84","volume":"25 Suppl 1","source":"PubMed","ISSN":"1043-6618","note":"PMID: 1354861","journalAbbreviation":"Pharmacol. Res.","language":"eng","author":[{"family":"Montanari","given":"G."},{"family":"Schiaulini","given":"P."},{"family":"Covre","given":"A."},{"family":"Steffan","given":"A."},{"family":"Furlanut","given":"M."}],"issued":{"date-parts":[["1992",3]]}}}],"schema":""} (Montanari, Schiaulini, Covre, Steffan, & Furlanut, 1992)No studies are available on the efficacy of antihistamines in children with NDDs.The most common adverse reaction to antihistamines at therapeutic doses is impaired consciousness. With overdose, adverse effects are predominately anticholinergic, including fever, mydriasis, blurred vision, dry mouth, constipation, urinary retention, tachycardia, dystonia, and confusion. There are some reports on toxicity of diphenhydramine with catatonic stupor, anxiety, visual hallucinations and, more rarely, respiratory insufficiency and seizures, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1k9c57a74b","properties":{"formattedCitation":"(Dinndorf, McCabe, & Frierdich, 1998)","plainCitation":"(Dinndorf, McCabe, & Frierdich, 1998)"},"citationItems":[{"id":5992,"uris":[""],"uri":[""],"itemData":{"id":5992,"type":"article-journal","title":"Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses","container-title":"The Journal of Pediatrics","page":"293-295","volume":"133","issue":"2","source":"PubMed","abstract":"Diphenhydramine is generally considered an innocuous drug with a minimal risk for abuse and untoward side effects. We describe children and adolescents with chronic hematologic and oncologic diseases who exhibited drug-seeking behavior or anticholinergic symptoms with the use of diphenhydramine. These cases illustrate that the assumption that this drugs is without significant adverse effects may be unwarranted, especially for children and adolescents with chronic diseases.","ISSN":"0022-3476","note":"PMID: 9709726","journalAbbreviation":"J. Pediatr.","language":"eng","author":[{"family":"Dinndorf","given":"P. A."},{"family":"McCabe","given":"M. A."},{"family":"Frierdich","given":"S."}],"issued":{"date-parts":[["1998",8]]}}}],"schema":""} (Dinndorf, McCabe, & Frierdich, 1998) with fatal toxicity in 5 infants 6-12 weeks old. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rukuhfa2f","properties":{"formattedCitation":"(Baker et al., 2003)","plainCitation":"(Baker et al., 2003)"},"citationItems":[{"id":5994,"uris":[""],"uri":[""],"itemData":{"id":5994,"type":"article-journal","title":"Fatal diphenhydramine intoxication in infants","container-title":"Journal of Forensic Sciences","page":"425-428","volume":"48","issue":"2","source":"PubMed","abstract":"Diphenhydramine is an antihistamine available in numerous over-the-counter preparations. Often used for its sedative effects in adults, it can cause paradoxical central nervous system stimulation in children, with effects ranging from excitation to seizures and death. Reports of fatal intoxications in young children are rare. We present five cases of fatal intoxication in infants 6, 8, 9, 12, and 12 weeks old. Postmortem blood diphenhydramine levels in the cases were 1.6, 1.5, 1.6, 1.1 and 1.1 mg/L, respectively. Anatomic findings in each case were normal. In one case the child's father admitted giving the infant diphenhydramine in an attempt to induce the infant to sleep; in another case, a daycare provider admitted putting diphenhydramine in a baby bottle. Two cases remain unsolved; one case remains under investigation. The postmortem drug levels in these cases are lower than seen in adult fatalities. We review the literature on diphenhydramine toxicity, particularly as it pertains to small children, and discuss the rationale for treating these cases as fatal intoxications.","ISSN":"0022-1198","note":"PMID: 12665005","journalAbbreviation":"J. Forensic Sci.","language":"eng","author":[{"family":"Baker","given":"Andrew M."},{"family":"Johnson","given":"Deborah G."},{"family":"Levisky","given":"Joseph A."},{"family":"Hearn","given":"William L."},{"family":"Moore","given":"Karla A."},{"family":"Levine","given":"Barry"},{"family":"Nelson","given":"Stephen J."}],"issued":{"date-parts":[["2003",3]]}}}],"schema":""} (Baker et al., 2003) Hydroxyzine seems to be safer and no fatal cases have been reported. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lnii85hbu","properties":{"formattedCitation":"(Magera, Betlach, Sweatt, & Derrick, 1981)","plainCitation":"(Magera, Betlach, Sweatt, & Derrick, 1981)"},"citationItems":[{"id":5996,"uris":[""],"uri":[""],"itemData":{"id":5996,"type":"article-journal","title":"Hydroxyzine intoxication in a 13-month-old child","container-title":"Pediatrics","page":"280-283","volume":"67","issue":"2","source":"PubMed","abstract":"A case of hydroxyzine toxicity following accidental ingestion in a 13-month old female infant has been presented. A plasma hydroxyzine concentration 8.5 hours after the acute ingestion was 102.7 micrograms/ml and toxicity was manifested primarily by generalized seizures and sinus tachycardia. General supportive care and seizure control with physostigmine resulted in complete recovery within 72 hours. This case represents the first documented report of hydroxyzine toxicity following acute ingestion in a child.","ISSN":"0031-4005","note":"PMID: 7243454","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Magera","given":"B. E."},{"family":"Betlach","given":"C. J."},{"family":"Sweatt","given":"A. P."},{"family":"Derrick","given":"C. W."}],"issued":{"date-parts":[["1981",2]]}}}],"schema":""} (Magera, Betlach, Sweatt, & Derrick, 1981)Finally, tolerance can develop quickly and some children can experience dramatic and paradoxical overarousal. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qdft9bgfe","properties":{"formattedCitation":"(P. Gringras, 2008)","plainCitation":"(P. Gringras, 2008)"},"citationItems":[{"id":95,"uris":[""],"uri":[""],"itemData":{"id":95,"type":"article-journal","title":"When to use drugs to help sleep.","container-title":"Archives of disease in childhood","page":"976-981","volume":"93","issue":"11","abstract":"Paediatric sleep medicine is a relatively new but important and rapidly growing field. It is increasingly recognised that many \"adult\" sleep disorders begin in childhood where the consequences of missed diagnoses can be devastating. Adequate training of all health care professionals and careful eliciting of symptoms remains the first step in ensuring accurate and timely diagnoses. Although behavioural approaches play a huge role in paediatric sleep medicine, at times severe sleep disorders also require pharmacological treatments. However, the evidence base for these is weak, and currently treatments of conditions including insomnia, narcolepsy and restless legs syndrome in childhood still rely on hopeful extrapolation from adult data. A growth in randomised controlled trials over the last 5 years is encouraging; trial methodologies are also improving. International working groups and multicentre trials will increasingly be needed to evaluate the new technologies and pharmacological treatments that are emerging.","DOI":"10.1136/adc.2007.128728","ISSN":"1468-2044 0003-9888","note":"PMID: 18676436","journalAbbreviation":"Arch Dis Child","language":"eng","author":[{"family":"Gringras","given":"P."}],"issued":{"date-parts":[["2008",11]]}}}],"schema":""} (P. Gringras, 2008)ClonidineClonidine is a central and peripheral α-adrenergic agonist that acts on presynaptic neurons and inhibits noradrenergic release and transmission, approved by the FDA for the treatment of hypertension. Due to its sedative effects, clonidine is commonly prescribed as a sleep aid in children, but there are no well-controlled studies available. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tptd4fhi2","properties":{"formattedCitation":"(Nguyen, Tharani, Rahmani, & Shapiro, 2014)","plainCitation":"(Nguyen, Tharani, Rahmani, & Shapiro, 2014)"},"citationItems":[{"id":5563,"uris":[""],"uri":[""],"itemData":{"id":5563,"type":"article-journal","title":"A review of the use of clonidine as a sleep aid in the child and adolescent population","container-title":"Clinical Pediatrics","page":"211-216","volume":"53","issue":"3","source":"PubMed","DOI":"10.1177/0009922813502123","ISSN":"1938-2707","note":"PMID: 24027233","journalAbbreviation":"Clin Pediatr (Phila)","language":"eng","author":[{"family":"Nguyen","given":"Mathew"},{"family":"Tharani","given":"Shalini"},{"family":"Rahmani","given":"Mariam"},{"family":"Shapiro","given":"Michael"}],"issued":{"date-parts":[["2014",3]]}}}],"schema":""} (Nguyen, Tharani, Rahmani, & Shapiro, 2014) It is hypothesized that clonidine produces sedation via decrease in norepinephrine via negative feedback by agonism of the α2-adrenergic receptors at the level of the locus coeruleus, which would increase REM sleep. Administration of low doses of clonidine (range 0.025–0.05 mg) has little effect on sleep and can either increase or decrease the duration of REM sleep. At medium-to-high doses (0.1–0.3 mg), clonidine appears to have postsynaptic activity on the α2-adrenergic receptors, which results in decrease of acetylcholine, increasing REM latency, stage 2 sleep, and slow-wave sleep. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"96sufrm8k","properties":{"formattedCitation":"(Delbarre & Schmitt, 1971)","plainCitation":"(Delbarre & Schmitt, 1971)"},"citationItems":[{"id":5599,"uris":[""],"uri":[""],"itemData":{"id":5599,"type":"article-journal","title":"Sedative effects of alpha-sympathomimetic drugs and their antagonism by adrenergic and cholinergic blocking drugs","container-title":"European Journal of Pharmacology","page":"356-363","volume":"13","issue":"3","source":"PubMed","ISSN":"0014-2999","note":"PMID: 4397033","journalAbbreviation":"Eur. J. Pharmacol.","language":"eng","author":[{"family":"Delbarre","given":"B."},{"family":"Schmitt","given":"H."}],"issued":{"date-parts":[["1971"]]}}}],"schema":""} (Delbarre & Schmitt, 1971) The most commonly reported side effects of clonidine include drowsiness, transient sedation, headache, dizziness, fatigue, somnolence, insomnia, hypotension, and bradycardia. Ingrassia and Turk, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1lp0cm5vi1","properties":{"formattedCitation":"(Ingrassia & Turk, 2005)","plainCitation":"(Ingrassia & Turk, 2005)"},"citationItems":[{"id":5609,"uris":[""],"uri":[""],"itemData":{"id":5609,"type":"article-journal","title":"The use of clonidine for severe and intractable sleep problems in children with neurodevelopmental disorders--a case series","container-title":"European Child & Adolescent Psychiatry","page":"34-40","volume":"14","issue":"1","source":"PubMed","abstract":"This paper reports on the use of clonidine for the treatment of severe sleep problems associated with behavioural difficulties in children with neurodevelopmental disabilities. Data were obtained from reviewing the case notes of a series of six children with neurodevelopmental disorders of different nature and severity, presenting with problematic sleep. All children in this group showed maintained improvements in their sleep pattern following the use of clonidine with only mild side-effects reported.","DOI":"10.1007/s00787-005-0424-4","ISSN":"1018-8827","note":"PMID: 15756514","journalAbbreviation":"Eur Child Adolesc Psychiatry","language":"eng","author":[{"family":"Ingrassia","given":"Antonina"},{"family":"Turk","given":"Jeremy"}],"issued":{"date-parts":[["2005",2]]}}}],"schema":""} (Ingrassia & Turk, 2005) in a retrospective chart review found clonidine to be an effective therapeutic intervention for alleviating sleep disturbances in six children with NDDs, aged 6-14 years a t a dose of 0.05 – 0.1 mg at bedtime. No relevant side effects were reported. In a retrospective review, 19 children with ASD were treated with oral clonidine at 50 g with a slow titration up to 100 g, 30 minutes before bedtime, reporting reduced sleep latency and nocturnal awakenings. Adverse effects were skin irritation with transdermal administration, and daytime drowsiness with administration of tablets. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"83as4u08f","properties":{"formattedCitation":"(Ming, Gordon, Kang, & Wagner, 2008)","plainCitation":"(Ming, Gordon, Kang, & Wagner, 2008)"},"citationItems":[{"id":1663,"uris":[""],"uri":[""],"itemData":{"id":1663,"type":"article-journal","title":"Use of clonidine in children with autism spectrum disorders.","container-title":"Brain & development","page":"454-460","volume":"30","issue":"7","abstract":"Children with autism spectrum disorders (ASD) often exhibit sleep and behavioral disorders. Treatment of sleep disorders can be difficult in these children. Clonidine, an alpha2-adrenergic receptor agonist, has been shown to be effective in reducing impulsivity, inattention, and hyperactivity, as well as in serving as a sedative for medial procedures. An open labeled retrospective study of clonidine in treatment of insomnia, and/or hyperactivity, inattention, mood disorder, and aggressive behaviors was conducted using parent reports of sleep initiation and maintenance, as well as behaviors prior and during clonidine treatment. Clonidine was effective in reducing sleep initiation latency and night awakening, to a less degree in improving attention deficits hyperactivity, mood instability and aggressiveness in this cohort of 19 children with ASD. The side effects were largely tolerable. Further evaluation with placebo-controlled double-blind clinical trial of clonidine use in ASD will provide more insight into the clinical efficacy and safety of the medicine in ASD.","DOI":"10.1016/j.braindev.2007.12.007","note":"PMID: 18280681","journalAbbreviation":"Brain Dev","language":"eng","author":[{"family":"Ming","given":"Xue"},{"family":"Gordon","given":"Emily"},{"family":"Kang","given":"Ning"},{"family":"Wagner","given":"George C."}],"issued":{"date-parts":[["2008",8]]}}}],"schema":""} (Ming, Gordon, Kang, & Wagner, 2008) Moreover, Hollway et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2cqumobfe9","properties":{"formattedCitation":"(Hollway & Aman, 2011)","plainCitation":"(Hollway & Aman, 2011)"},"citationItems":[{"id":5627,"uris":[""],"uri":[""],"itemData":{"id":5627,"type":"article-journal","title":"Pharmacological treatment of sleep disturbance in developmental disabilities: a review of the literature","container-title":"Research in Developmental Disabilities","page":"939-962","volume":"32","issue":"3","source":"PubMed","abstract":"Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study.","DOI":"10.1016/j.ridd.2010.12.035","ISSN":"1873-3379","note":"PMID: 21296553","shortTitle":"Pharmacological treatment of sleep disturbance in developmental disabilities","journalAbbreviation":"Res Dev Disabil","language":"eng","author":[{"family":"Hollway","given":"Jill A."},{"family":"Aman","given":"Michael G."}],"issued":{"date-parts":[["2011",6]]}}}],"schema":""} (Hollway & Aman, 2011) in a comprehensive literature search, showed that clonidine was effective on sleep disturbances in children with comorbid ASD and other NDDs at doses ranging from 0.05 to 0.225 mg/day. In children who are taking concomitant CNS-depressing agents and in individuals with hemodynamic instability or cardiac pathology, the use of clonidine should be accurately monitored. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2a0cvb41nh","properties":{"formattedCitation":"(Spiller et al., 2005)","plainCitation":"(Spiller et al., 2005)"},"citationItems":[{"id":5635,"uris":[""],"uri":[""],"itemData":{"id":5635,"type":"article-journal","title":"Toxic clonidine ingestion in children","container-title":"The Journal of Pediatrics","page":"263-266","volume":"146","issue":"2","source":"PubMed","abstract":"OBJECTIVES: We performed a prospective case series to seek dosage or clinical parameters to better identify patients who need direct medical evaluation.\nSTUDY DESIGN: All clonidine ingestions in children younger than 12 years of age reported to 6 poison centers were followed for a minimum of 24 hours. Exclusion criterion was polydrug ingestion.\nRESULTS: The study included 113 patients, of whom 63 were male. Mean age was 3.8 years (+/-2.4 SD). Clinical effects were common, but severe adverse effects occurred in <10% of patients. The dose ingested was reported for 90 patients (80%); 61 (68%) children ingested <0.3 mg and none had coma, respiratory depression, or hypotension. The lowest dose ingested by history with coma and respiratory depression was 0.3 mg (0.015 mg/kg). Prior clonidine therapy did not affect outcome. Onset of full clinical effects in all cases was complete within 4 hours of ingestion.\nCONCLUSIONS: We recommend direct medical evaluation for (1) all children 4 years of age and younger with unintentional clonidine ingestion of >or=0.1 mg, (2) ingestion of >0.2 mg in children 5 to 8 years of age, and (3) ingestion of >or=0.4 mg in children older than 8 years of age. Observation for 4 hours may be sufficient to detect patients who will develop severe effects.","DOI":"10.1016/j.jpeds.2004.09.027","ISSN":"0022-3476","note":"PMID: 15689921","journalAbbreviation":"J. Pediatr.","language":"eng","author":[{"family":"Spiller","given":"Henry A."},{"family":"Klein-Schwartz","given":"Wendy"},{"family":"Colvin","given":"Jonathan M."},{"family":"Villalobos","given":"Danny"},{"family":"Johnson","given":"Paul B."},{"family":"Anderson","given":"Deborah L."}],"issued":{"date-parts":[["2005",2]]}}}],"schema":""} (Spiller et al., 2005) Benzodiazepines: ClonazepamBenzodiazepines bind to the benzodiazepine subunit of the GABA chloride receptor complex, facilitating the action of the inhibitory neurotransmitter GABA. These hypnotics have long been the first choice treatment for insomnia in adults, but they raise concerns about cognitive impairment, rebound insomnia, and the potential risk for dependence. These concerns and little evidence-based data availability in the pediatric population, contribute to limit their use in children. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"288gk75vf","properties":{"formattedCitation":"(Owens, 2011)","plainCitation":"(Owens, 2011)"},"citationItems":[{"id":737,"uris":[""],"uri":[""],"itemData":{"id":737,"type":"article-journal","title":"Update in pediatric sleep medicine.","container-title":"Current opinion in pulmonary medicine","page":"425-430","volume":"17","issue":"6","abstract":"PURPOSE OF REVIEW: To summarize the most important recent scientific developments in the field of clinical pediatric sleep medicine, specifically as relates to sleep disorders and sleep in special pediatric populations. RECENT FINDINGS: The major themes covered in this review include sleep-disordered breathing; narcolepsy; restless legs syndrome/periodic limb movement disorder; insomnia; sleep in children with medical conditions; and sleep in children with neurodevelopmental and psychiatric disorders. SUMMARY: An expanded understanding of the pathophysiology, epidemiology, clinical evaluation methods, sequelae, and empirically supported treatment options of common pediatric sleep disorders, especially in high-risk populations, is key to a rational approach to diagnosis and management of these children in clinical settings.","DOI":"10.1097/MCP.0b013e32834ba901","note":"PMID: 21921795","journalAbbreviation":"Curr Opin Pulm Med","language":"eng","author":[{"family":"Owens","given":"Judith A."}],"issued":{"date-parts":[["2011",11]]}}}],"schema":""} (Owens, 2011) Short term or as-needed administration is the most frequent suggested treatment.In 5 children aged 1.5 to 10 years with Williams syndrome, clonazepam 0.25–0.75 mg at bedtime, determined an immediate improvement in nighttime awakenings and daytime behaviors in four of the five patients that persisted at 3-6 months follow-up. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"29sqavvi90","properties":{"formattedCitation":"(Arens et al., 1998)","plainCitation":"(Arens et al., 1998)"},"citationItems":[{"id":2384,"uris":[""],"uri":[""],"itemData":{"id":2384,"type":"article-journal","title":"Periodic limb movement in sleep in children with Williams syndrome","container-title":"The Journal of Pediatrics","page":"670-674","volume":"133","issue":"5","source":"PubMed","abstract":"OBJECTIVE: Williams syndrome (WS) is associated with neurobehavioral abnormalities that include irritability and attention-deficit/hyperactivity disorder. Parents often report children having difficulties initiating and maintaining sleep because of restlessness and arousals. Therefore we evaluated a group of children with WS for the presence of a movement arousal sleep disorder.\nMETHODS: Twenty-eight families of children with WS participated in a telephone survey aimed to screen for a movement arousal disorder. Of the 16 children identified as having such a disorder, 7 (mean age, 3.9 +/- 2.2 years) underwent polysomnography. Their studies were compared with those of 10 matched control subjects (mean age, 5.3 +/- 2.0 years).\nRESULTS: The 7 subjects with WS who were screened by the survey had sleep latency, total sleep time, arousals, and awakenings that were similar to those of control subjects. However, they presented with a disorder of periodic limb movement in sleep (PLMS). The PLMS index in the subjects with WS was 14.9 +/- 6.2 versus 2.8 +/- 1.9 in control subjects (P < .0001). In addition, arousal and awakening in subjects with WS were strongly associated with PLMS. Moreover, children with WS spend more time awake during sleep periods than control subjects (10.0% +/- 7.0% vs 4.4% +/- 4.7%; P < .05). Five children were treated with clonazepam, and in 4 a significant clinical response was noted.\nCONCLUSION: We report an association between WS and PLMS. Clonazepam may reduce the clinical symptoms of PLMS in some of these children.","ISSN":"0022-3476","note":"PMID: 9821427","journalAbbreviation":"J. Pediatr.","language":"eng","author":[{"family":"Arens","given":"R."},{"family":"Wright","given":"B."},{"family":"Elliott","given":"J."},{"family":"Zhao","given":"H."},{"family":"Wang","given":"P. P."},{"family":"Brown","given":"L. W."},{"family":"Namey","given":"T."},{"family":"Kaplan","given":"P."}],"issued":{"date-parts":[["1998",11]]}}}],"schema":""} (Arens et al., 1998) An effect on REM sleep behavior disorder in a child with autism has been reported. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"12tq24cpi3","properties":{"formattedCitation":"(Thirumalai, Shubin, & Robinson, 2002)","plainCitation":"(Thirumalai, Shubin, & Robinson, 2002)"},"citationItems":[{"id":5649,"uris":[""],"uri":[""],"itemData":{"id":5649,"type":"article-journal","title":"Rapid eye movement sleep behavior disorder in children with autism","container-title":"Journal of Child Neurology","page":"173-178","volume":"17","issue":"3","source":"PubMed","abstract":"We performed nocturnal polysomnography on 11 children with autism who had symptoms of disrupted sleep and nocturnal awakenings. We identified rapid eye movement (REM) sleep behavior disorder in 5 of these 11 patients. Since REM sleep behavior disorder typically affects elderly males with neurodegenerative diseases, the identification of this phenomenon in autistic children could have profound implications for our understanding of the neurochemical and neurophysiologic bases of autism. Further, accurate diagnosis of REM sleep behavior disorder would enable specific treatment with clonazepam and help the family and the child consolidate sleep and improve daytime performance.","ISSN":"0883-0738","note":"PMID: 12026231","journalAbbreviation":"J. Child Neurol.","language":"eng","author":[{"family":"Thirumalai","given":"Shanti S."},{"family":"Shubin","given":"Richard A."},{"family":"Robinson","given":"Ricki"}],"issued":{"date-parts":[["2002",3]]}}}],"schema":""} (Thirumalai, Shubin, & Robinson, 2002) From the available data, clonazepam may represent a treatment option in children with arousal disorders (parasomnias) or PLMD/RLS, but future trials focused on objective sleep measures and safety issues are needed.Non-benzodiazepine sedative-hypnoticsThey represent non-benzodiazepine receptor agonists (NBzRAs) that binds preferentially to GABAA receptor complexes containing α1 subunits; they have minimal effects on sleep architecture with a slight increase slow-wave sleep. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ujf47ilu","properties":{"formattedCitation":"(Zisapel, 2012)","plainCitation":"(Zisapel, 2012)"},"citationItems":[{"id":5385,"uris":[""],"uri":[""],"itemData":{"id":5385,"type":"article-journal","title":"Drugs for insomnia","container-title":"Expert Opinion on Emerging Drugs","page":"299-317","volume":"17","issue":"3","source":"PubMed","abstract":"INTRODUCTION: Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on \"hypnotic\" or specific drug names and \"Insomnia\").\nAREAS COVERED: GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future.\nEXPERT OPINION: Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.","DOI":"10.1517/14728214.2012.690735","ISSN":"1744-7623","note":"PMID: 22681198","journalAbbreviation":"Expert Opin Emerg Drugs","language":"eng","author":[{"family":"Zisapel","given":"Nava"}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} (Zisapel, 2012) There are very few studies conducted in children. One study reported children with ADHD and insomnia aged 6-11 years or 12-17 years receiving treatment with zolpidem at 0.25 mg/kg per day (max 10 mg/day) vs. placebo reported a mean change in latency to persistent sleep at week 4 that did not differ between zolpidem and placebo groups. No next-day residual effects of treatment and no rebound phenomena occurred after treatment discontinuation. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28vt85b93m","properties":{"formattedCitation":"(Blumer, Findling, Shih, Soubrane, & Reed, 2009)","plainCitation":"(Blumer, Findling, Shih, Soubrane, & Reed, 2009)"},"citationItems":[{"id":1895,"uris":[""],"uri":[""],"itemData":{"id":1895,"type":"article-journal","title":"Controlled clinical trial of zolpidem for the treatment of insomnia associated with attention-deficit/ hyperactivity disorder in children 6 to 17 years of age.","container-title":"Pediatrics","page":"e770-776","volume":"123","issue":"5","abstract":"OBJECTIVE: The goal was to evaluate the hypnotic efficacy of zolpidem at 0.25 mg/kg per day (maximum of 10 mg/day), compared with placebo, in children 6 through 17 years of age who were experiencing insomnia associated with attention-deficit/hyperactivity disorder. METHODS: An 8-week, North American, multicenter, double-blind, placebo-controlled, parallel-group study was conducted. Patients underwent stratification according to age (6-11 years [N = 111] or 12-17 years [N = 90]) and were assigned randomly to receive treatment with the study drug or placebo (in a 2:1 ratio). The primary efficacy variable was latency to persistent sleep between weeks 3 and 6. Secondary efficacy variables also were assessed, and behavioral and cognitive components of attention-deficit/hyperactivity disorder were monitored. Safety was assessed on the basis of reports of adverse events, abnormal laboratory data, vital signs, and physical examination findings. The potential for next-day residual effects also was assessed. RESULTS: The baseline-adjusted mean change in latency to persistent sleep at week 4 did not differ significantly between the zolpidem and placebo groups (-20.28 vs -21.27 minutes). However, differences favoring zolpidem were observed for the older age group in Clinical Global Impression scores at weeks 4 and 8. No next-day residual effects of treatment were associated with zolpidem, and no rebound phenomena occurred after treatment discontinuation. Central nervous system and psychiatric disorders were the most-frequent treatment-emergent adverse events (>5%) that were observed more frequently with zolpidem than with placebo; these included dizziness, headache, and hallucinations. Ten (7.4%) patients discontinued zolpidem treatment because of adverse events. CONCLUSION: Zolpidem at a dose of 0.25 mg/kg per day to a maximum of 10 mg failed to reduce the latency to persistent sleep on polysomnographic recordings after 4 weeks of treatment in children and adolescents 6 through 17 years of age who had attention-deficit/hyperactivity disorder-associated insomnia.","DOI":"10.1542/peds.2008-2945","note":"PMID: 19403468","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Blumer","given":"Jeffrey L."},{"family":"Findling","given":"Robert L."},{"family":"Shih","given":"Weichung Joe"},{"family":"Soubrane","given":"Christina"},{"family":"Reed","given":"Michael D."}],"issued":{"date-parts":[["2009",5]]}}}],"schema":""} (Blumer, Findling, Shih, Soubrane, & Reed, 2009) Eszopiclone has been administered in 371 children aged 6–17 years with a diagnosis of ADHD and sleep disturbances but failed to show a benefit over placebo; dose-dependent adverse events were reported in 46–61% of patients. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1i485fajdn","properties":{"formattedCitation":"(Sangal, Blumer, Lankford, Grinnell, & Huang, 2014)","plainCitation":"(Sangal, Blumer, Lankford, Grinnell, & Huang, 2014)"},"citationItems":[{"id":1986,"uris":[""],"uri":[""],"itemData":{"id":1986,"type":"article-journal","title":"Eszopiclone for insomnia associated with attention-deficit/hyperactivity disorder.","container-title":"Pediatrics","page":"e1095-1103","volume":"134","issue":"4","abstract":"OBJECTIVE: To evaluate efficacy and safety of eszopiclone compared with placebo in children and adolescents with insomnia associated with attention-deficit/hyperactivity disorder (ADHD). METHODS: A 12-week, randomized, double-blind, placebo-controlled trial evaluated efficacy and safety of high- or low-dose eszopiclone (1 or 2 mg in children aged 6-11 years, 2 or 3 mg in children ages 12-17 years), given every evening, in 486 patients with","DOI":"10.1542/peds.2013-4221","note":"PMID: 25266438","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Sangal","given":"R. Bart"},{"family":"Blumer","given":"Jeffrey L."},{"family":"Lankford","given":"D. Alan"},{"family":"Grinnell","given":"Todd A."},{"family":"Huang","given":"Holly"}],"issued":{"date-parts":[["2014",10]]}}}],"schema":""} (Sangal, Blumer, Lankford, Grinnell, & Huang, 2014) The most frequent adverse events (>5%) were dizziness and headache68 but also disinhibition and hallucinations have been reported. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1pl9hfbq97","properties":{"formattedCitation":"(Liskow & Pikalov, 2004)","plainCitation":"(Liskow & Pikalov, 2004)"},"citationItems":[{"id":5677,"uris":[""],"uri":[""],"itemData":{"id":5677,"type":"article-journal","title":"Zaleplon overdose associated with sleepwalking and complex behavior","container-title":"Journal of the American Academy of Child and Adolescent Psychiatry","page":"927-928","volume":"43","issue":"8","source":"PubMed","DOI":"10.1097/01.chi.0000129219.66563.aa","ISSN":"0890-8567","note":"PMID: 15266187","journalAbbreviation":"J Am Acad Child Adolesc Psychiatry","language":"eng","author":[{"family":"Liskow","given":"Barry"},{"family":"Pikalov","given":"Andrei"}],"issued":{"date-parts":[["2004",8]]}}}],"schema":""} (Liskow & Pikalov, 2004)GabapentinFDA approved gabapentin for treatment of partial seizures in 1993. It was originally designed as a precursor of γ-amino butyric acid (GABA) that easily enters the blood–brain barrier, and increases brain synaptic GABA. It has been approved for the treatment of neuropathic pain and RLS in addition to its original purpose as an anticonvulsant medication. However, its precise pharmacological mechanism in humans remains unknown. In addition to its demonstrated efficacy in these indications, patient-reported sleep assessments among a variety of clinical conditions suggest that gabapentin has beneficial effects on sleep. The improvement of sleep might be mediated by the increase in slow-wave sleep and the decrease of WASO. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"v9k1t5f24","properties":{"formattedCitation":"(Rosenberg et al., 2014)","plainCitation":"(Rosenberg et al., 2014)"},"citationItems":[{"id":362,"uris":[""],"uri":[""],"itemData":{"id":362,"type":"article-journal","title":"A Randomized, Double-Blind, Single-Dose, Placebo-Controlled, Multicenter, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance","container-title":"Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine","page":"1093-1100","volume":"10","issue":"10","source":"PubMed Central","abstract":"Study Objectives:\nTo evaluate the effects of single doses of gabapentin 250 and 500 mg on polysomnographic (PSG) and participant-reported sleep measures in a 5-h phase advance insomnia model.\n\nMethods:\nAdults reporting occasional disturbed sleep received gabapentin 500 mg (n = 125), 250 mg (n = 125), or placebo (n = 127) 30 min prior to bedtime and were in bed from 17:00 to 01:00, ～5 h before their habitual bedtime. Sleep was assessed by PSG, post-sleep questionnaire, and the Karolinska Sleep Diary (KSD). Next-day residual effects (Digit Symbol Substitution Test [DSST] and Stanford Sleepiness Scale [SSS]) and tolerability were assessed.\n\nResults:\nDemographics were comparable among groups. Among PSG endpoints, wake after sleep onset (primary endpoint) (135.7 [placebo], 100.7 [250 mg], and 73.2 [500 mg] min) was significantly lower and total sleep time (TST) (311.4, 356.5, and 378.7 min) significantly greater in both gabapentin groups versus placebo. Latency to persistent sleep was not significantly different among groups. Percent slow wave sleep (12.6%, 15.4%, and 17.0%, respectively) was significantly greater and percent stage 1 (15.1%, 11.8%, and 10.8%, respectively) significantly lower relative to placebo. Gabapentin was associated with significantly higher values of KSD Sleep Quality Index and reported TST versus placebo; no other reported outcomes were significant. Neither gabapentin dose produced evidence of next-day residual effects as measured by DSST and SSS. Adverse events were infrequent (< 5%).\n\nConclusion:\nParticipants with occasional disturbed sleep treated with gabapentin showed significantly longer sleep duration and greater depth (versus placebo) in response to a phase advance manipulation known to disrupt sleep maintenance.\n\nCitation:\nRosenberg RP, Hull SG, Lankford DA, Mayleben DW, Seiden DJ, Furey SA, Jayawardena S, Roth T. A randomized, double-blind, single-dose, placebo-controlled, multicenter, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. J Clin Sleep Med 2014;10(10):1093-1100.","DOI":"10.5664/jcsm.4108","ISSN":"1550-9389","note":"PMID: 25317090\nPMCID: PMC4173087","journalAbbreviation":"J Clin Sleep Med","author":[{"family":"Rosenberg","given":"Russell P."},{"family":"Hull","given":"Steven G."},{"family":"Lankford","given":"D. Alan"},{"family":"Mayleben","given":"David W."},{"family":"Seiden","given":"David J."},{"family":"Furey","given":"Sandy A."},{"family":"Jayawardena","given":"Shyamalie"},{"family":"Roth","given":"Thomas"}],"issued":{"date-parts":[["2014",10,15]]}}}],"schema":""} (Rosenberg et al., 2014)In a recent case series, gabapentin was found to be a safe and a well-tolerated treatment for sleep-onset and sleep maintenance insomnia in 23 children, 87% of whom had NDDs. With gabapentin initiated at an average dose of 5 mg/kg (range 3–7.5 mg/kg) 30–45 minutes before bedtime, with titration to a maximum dose of 15 mg/kg (range 6–15 mg/ kg), 78% of children showed improvement in sleep (as reported by parents). Furthermore, this beneficial response was noted at doses of 5 to 15 mg/kg orally at bedtime, much lower than the recommended dose to treat epileptic seizures (40 mg/kg divided three times daily). Side effects in a few cases included agitated nighttime awakenings and difficulty falling asleep. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mlmc6e3ve","properties":{"formattedCitation":"(Robinson & Malow, 2013)","plainCitation":"(Robinson & Malow, 2013)"},"citationItems":[{"id":1340,"uris":[""],"uri":[""],"itemData":{"id":1340,"type":"article-journal","title":"Gabapentin shows promise in treating refractory insomnia in children.","container-title":"Journal of child neurology","page":"1618-1621","volume":"28","issue":"12","abstract":"Insomnia is prevalent in pediatrics, particularly in those with neurodevelopmental disorders. Gabapentin has shown promise in treating insomnia in adults. The purpose of our study was to review our experience with using gabapentin to treat insomnia in children. We identified 23 children, seen by the authors in our Pediatric Sleep Clinic from January 2009 to March 2012. The mean age was 7.2 years and 70% were male. The majority (87%) had been given diagnoses of neurodevelopmental or neuropsychiatric disorders. All parents received education in sleep behavioral interventions. The majority of children (70%) had both sleep-onset and sleep maintenance insomnia. The average starting dose of gabapentin was 5 mg/kg every bedtime and the maximal dose was 15 mg/kg every bedtime. At follow-up, improved sleep was noted in 78% of children. Adverse effects were noted in 6 children.","DOI":"10.1177/0883073812463069","note":"PMID: 23112238","journalAbbreviation":"J Child Neurol","language":"eng","author":[{"family":"Robinson","given":"Althea A."},{"family":"Malow","given":"Beth A."}],"issued":{"date-parts":[["2013",12]]}}}],"schema":""} (Robinson & Malow, 2013)Antidepressants Tricyclic and atypical antidepressants (mirtazapine, nefazodone, and trazodone), are used in clinical practice to treat insomnia in adult and pediatric populations. Their effects on sleep is mediated by an action on different neurotransmitters, such as serotonin, histamine and acetylcholine, involved in sleep regulation. Tricyclic antidepressantsTricyclic antidepressants (amitriptyline, trimipramine, and doxepin) determine a reduction of REM and slow-wave sleep and have been used to treat insomnia. Either amitriptyline or trimipramine have been demonstrated to have sedative effects in adults. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6fcqet8ep","properties":{"formattedCitation":"(Holmberg, 1988)","plainCitation":"(Holmberg, 1988)"},"citationItems":[{"id":6038,"uris":[""],"uri":[""],"itemData":{"id":6038,"type":"article-journal","title":"Sedative effects of maprotiline and amitriptyline","container-title":"Acta Psychiatrica Scandinavica","page":"584-586","volume":"77","issue":"5","source":"PubMed","abstract":"By means of critical flicker fusion measurements and subjective estimation of drowsiness, experiments with 12 healthy subjects over periods of 8 h showed that maprotiline caused less than half the amount of sedation compared to amitriptyline, both drugs given in single doses of 50 mg. The experiments were blind, randomized and placebo controlled. Implications for clinical use are discussed.","ISSN":"0001-690X","note":"PMID: 3044007","journalAbbreviation":"Acta Psychiatr Scand","language":"eng","author":[{"family":"Holmberg","given":"G."}],"issued":{"date-parts":[["1988",5]]}}}],"schema":""} (Holmberg, 1988), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"26c7qab141","properties":{"formattedCitation":"(Ware, Brown, Moorad, Pittard, & Cobert, 1989)","plainCitation":"(Ware, Brown, Moorad, Pittard, & Cobert, 1989)"},"citationItems":[{"id":6040,"uris":[""],"uri":[""],"itemData":{"id":6040,"type":"article-journal","title":"Effects on sleep: a double-blind study comparing trimipramine to imipramine in depressed insomniac patients","container-title":"Sleep","page":"537-549","volume":"12","issue":"6","source":"PubMed","abstract":"Trimipramine, a sedating tricyclic antidepressant, and imipramine were compared on polysomnographic parameters during a 4-week double-blind trial in depressed patients with insomnia and anxiety. Trimipramine eliminated objective evidence of sleep disturbance. This was not the case with imipramine, although depression improved similarly in both groups. Subjects' sleep appeared unchanged or more disturbed at the end of the treatment with imipramine. For trimipramine, the major changes in sleep parameters occurred during the first week of drug administration and did not parallel the gradual changes seen in the measures of depression. Additionally, trimipramine did not suppress REM sleep even in a subgroup of six trimipramine patients who had short rapid-eye-movement (REM) sleep latencies during the placebo baseline period, even though their depression was alleviated. The data demonstrate that (a) antidepressants may vary in their effects on sleep, even though they have similar effects on depression; (b) REM sleep suppression does not necessarily accompany improvement in depression; and (c) reports of improved sleep by patients undergoing antidepressant therapy may not reflect improvement on objective measures of sleep. The different sleep effects suggest the possibility of different antidepressant pathways.","ISSN":"0161-8105","note":"PMID: 2688037","shortTitle":"Effects on sleep","journalAbbreviation":"Sleep","language":"eng","author":[{"family":"Ware","given":"J. C."},{"family":"Brown","given":"F. W."},{"family":"Moorad","given":"P. J."},{"family":"Pittard","given":"J. T."},{"family":"Cobert","given":"B."}],"issued":{"date-parts":[["1989",12]]}}}],"schema":""} (Ware, Brown, Moorad, Pittard, & Cobert, 1989), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1nknejjumd","properties":{"formattedCitation":"(Riemann et al., 2002)","plainCitation":"(Riemann et al., 2002)"},"citationItems":[{"id":6042,"uris":[""],"uri":[""],"itemData":{"id":6042,"type":"article-journal","title":"Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study","container-title":"Pharmacopsychiatry","page":"165-174","volume":"35","issue":"5","source":"PubMed","abstract":"In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.","DOI":"10.1055/s-2002-34119","ISSN":"0176-3679","note":"PMID: 12237787","shortTitle":"Trimipramine in primary insomnia","journalAbbreviation":"Pharmacopsychiatry","language":"eng","author":[{"family":"Riemann","given":"D."},{"family":"Voderholzer","given":"U."},{"family":"Cohrs","given":"S."},{"family":"Rodenbeck","given":"A."},{"family":"Hajak","given":"G."},{"family":"Rüther","given":"E."},{"family":"Wiegand","given":"M. H."},{"family":"Laakmann","given":"G."},{"family":"Baghai","given":"T."},{"family":"Fischer","given":"W."},{"family":"Hoffmann","given":"M."},{"family":"Hohagen","given":"F."},{"family":"Mayer","given":"G."},{"family":"Berger","given":"M."}],"issued":{"date-parts":[["2002",9]]}}}],"schema":""} (Riemann et al., 2002) There are no data supporting the use of amitriptyline or trimipramine in children with NDDs; however, amitriptyline is commonly used in children with NDDs beginning with a very low dose (5 mg) and then increasing it until the desired effect is achieved, but it should not exceed 50 mg. Doxepin in adults (3-6 mg), determines improvements in sleep maintenance and early morning awakenings; when used in children with pruritus, it determined central nervous system depression. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"yWvlII9u","properties":{"formattedCitation":"(Zell-Kanter, Toerne, Spiegel, & Negrusz, 2000)","plainCitation":"(Zell-Kanter, Toerne, Spiegel, & Negrusz, 2000)"},"citationItems":[{"id":6044,"uris":[""],"uri":[""],"itemData":{"id":6044,"type":"article-journal","title":"Doxepin toxicity in a child following topical administration","container-title":"The Annals of Pharmacotherapy","page":"328-329","volume":"34","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To describe a case of a child with altered mental status following the topical administration of doxepin.\nCASE SUMMARY: A five-year-old Hispanic girl was brought to the emergency department because she was difficult to arouse at school. She had recently developed a generalized eczematous rash for which she was prescribed doxepin hydrochloride 5% cream. An entire tube (30 g) of doxepin cream was applied in the 24 hours prior to presentation. The patient was responsive only to noxious stimuli, with no focal neurologic abnormalities. She was decontaminated and observed in a pediatric intensive care unit. By 18 hours after presentation, she had fully recovered and was discharged.\nCONCLUSIONS: Topical doxepin, available as a 5% cream, is indicated for the treatment of pruritus secondary to eczematous dermatoses in adults. Diminished skin integrity and the application of a massive quantity of doxepin 5% cream to a large body surface area contributed to the toxicity in this child. Since the safety and efficacy of doxepin cream has not been established in children younger than 12 years, it should be used with caution in this population.","ISSN":"1060-0280","note":"PMID: 10917379","journalAbbreviation":"Ann Pharmacother","language":"eng","author":[{"family":"Zell-Kanter","given":"M."},{"family":"Toerne","given":"T. S."},{"family":"Spiegel","given":"K."},{"family":"Negrusz","given":"A."}],"issued":{"date-parts":[["2000",3]]}}}],"schema":""} (Zell-Kanter, Toerne, Spiegel, & Negrusz, 2000) Side effects of tricyclics include anxiety and agitation, anticholinergic effects (e.g., blurred vision, dry mouth, urinary retention, orthostatic hypotension), cardiotoxicity and worsening of RLS symptoms.MirtazapineMirtazapine is an α2-adrenergic, 5-HT receptor agonist with a high degree of sedation at low doses. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"v8pqa08pc","properties":{"formattedCitation":"(Younus & Labellarte, 2002)","plainCitation":"(Younus & Labellarte, 2002)"},"citationItems":[{"id":1158,"uris":[""],"uri":[""],"itemData":{"id":1158,"type":"article-journal","title":"Insomnia in children: when are hypnotics indicated?","container-title":"Paediatric drugs","volume":"4","issue":"6","abstract":"Insomnia in children is a nonspecific impairing symptom that may be the result of normal developmental changes, psychosocial duress, a sleep disorder, a psychiatric disorder, other medical disorders, substance misuse, or an adverse effect of medication. Careful clinical assessment of insomnia in children may include the use of symptom rating scales, laboratory testing, or other medical assessment. Short- and long-term treatment of insomnia in children involves management of etiological factors and associated syndromes. Controlled treatment studies of pediatric insomnia are limited to <10 published studies of psychosocial and/or psychopharmacological treatment in young children. Directive parent education and behavior modification techniques have been effective in short-term treatment of insomnia in young children, and may be the preferred treatment of extrinsic insomnia, as well as an important adjunctive treatment of any insomnia symptoms. Two benzodiazepines [flurazepam and delorazepam (chlordesmethyldiazepam)], one antihistamine (niaprazine) and one phenothiazine [alimemazine (trimeprazine)] have been shown to be effective in the short-term treatment of insomnia in young children, although none of these agents have US Food and Drug Administration approval for pediatric insomnia. Short-acting benzodiazepines may have a role in the brief treatment of pediatric insomnia associated with an anxiety or mood disorder, psychosis, aggression, medication- induced activation, or anticipatory anxiety associated with a medical procedure. However, tachyphylaxis and risk of misuse preclude the long-term use of benzodiazepines for the treatment of insomnia in children. Newer hypnotics, which appear better tolerated than the benzodiazepines in studies of adults, may have a role when combined with psychosocial treatments of pediatric insomnia. Treatment of intrinsic pediatric insomnia may additionally involve chronotherapy or medical management.","note":"PMID: 12038875","journalAbbreviation":"Paediatr Drugs","language":"eng","author":[{"family":"Younus","given":"Mohammed"},{"family":"Labellarte","given":"Michael J."}],"issued":{"date-parts":[["2002"]]}}}],"schema":""} (Younus & Labellarte, 2002) It has been shown to decrease sleep-onset latency, increase sleep duration, and reduce wake after sleep onset (WASO), with relatively little effect on REM sleep. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cbej6v6sc","properties":{"formattedCitation":"(Wichniak, Wierzbicka, & Jernajczyk, 2012)","plainCitation":"(Wichniak, Wierzbicka, & Jernajczyk, 2012)"},"citationItems":[{"id":5681,"uris":[""],"uri":[""],"itemData":{"id":5681,"type":"article-journal","title":"Sleep and antidepressant treatment","container-title":"Current Pharmaceutical Design","page":"5802-5817","volume":"18","issue":"36","source":"PubMed","abstract":"The aim of this review was to describe the sleep anomalies in depression, the effects of antidepressants on sleep, the usefulness of antidepressants in the treatment of primary insomnia and insomnia in other psychiatric disorders. Depression is associated with abnormalities in the sleep pattern that include disturbances of sleep continuity, diminished slow-wave sleep (SWS) and altered rapid eye movement (REM) sleep parameters. Although none of the reported changes in sleep are specific to depression, many of them, for example increased REM density and reduced amount of SWS in the first sleep cycle, are used as biological markers for research on depression and in the development of antidepressant drugs. An antidepressant should reverse abnormalities in the sleep pattern. However, many antidepressants can worsen sleep. Because of the activating effects of some drugs, for example imipramine, desipramine, fluoxetine, paroxetine, venlafaxine, reboxetine and bupropion, many patients who take them have to be co-prescribed with sleep-promoting agents to improve sleep. Even in maintenance treatment with activating antidepressants as many as 30-40% of patients may still suffer from insomnia. Antidepressants with sleep-promoting effects include sedative antidepressants, for example doxepin, mirtazapine, trazodone, trimipramine, and agomelatine which promotes sleep not through a sedative action but through resynchronization of the circadian rhythm. Sedative antidepressants are frequently used in the treatment of primary insomnia, although not many double-blind studies have been provided to support such an approach to insomnia treatment. One exception is doxepin, which has been approved for the treatment of insomnia characterized by difficulties in maintaining sleep.","ISSN":"1873-4286","note":"PMID: 22681161","journalAbbreviation":"Curr. Pharm. Des.","language":"eng","author":[{"family":"Wichniak","given":"Adam"},{"family":"Wierzbicka","given":"Aleksandra"},{"family":"Jernajczyk","given":"Wojciech"}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} (Wichniak, Wierzbicka, & Jernajczyk, 2012) There is a single open-label study in autistic children and children with other forms of pervasive developmental disorders, which suggests some efficacy for insomnia. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mvncbl5hm","properties":{"formattedCitation":"(Posey, Guenin, Kohn, Swiezy, & McDougle, 2001)","plainCitation":"(Posey, Guenin, Kohn, Swiezy, & McDougle, 2001)"},"citationItems":[{"id":6052,"uris":[""],"uri":[""],"itemData":{"id":6052,"type":"article-journal","title":"A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders","container-title":"Journal of Child and Adolescent Psychopharmacology","page":"267-277","volume":"11","issue":"3","source":"PubMed","abstract":"OBJECTIVE: The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs).\nMETHODS: Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist.\nRESULTS: Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders (\"much improved\" or \"very much improved\" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation.\nCONCLUSIONS: Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.","DOI":"10.1089/10445460152595586","ISSN":"1044-5463","note":"PMID: 11642476","journalAbbreviation":"J Child Adolesc Psychopharmacol","language":"eng","author":[{"family":"Posey","given":"D. J."},{"family":"Guenin","given":"K. D."},{"family":"Kohn","given":"A. E."},{"family":"Swiezy","given":"N. B."},{"family":"McDougle","given":"C. J."}],"issued":{"date-parts":[["2001"]]}}}],"schema":""} (Posey, Guenin, Kohn, Swiezy, & McDougle, 2001)Trazodone Trazodone is one of the most sedating antidepressants and the most widely studied of antidepressants in terms of sleep in adults. It is the most commonly prescribed insomnia medication for children with mood and anxiety disorders in a survey of child and adolescent psychiatrists ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"27e98iu1rb","properties":{"formattedCitation":"(Owens et al., 2010)","plainCitation":"(Owens et al., 2010)"},"citationItems":[{"id":1021,"uris":[""],"uri":[""],"itemData":{"id":1021,"type":"article-journal","title":"Use of pharmacotherapy for insomnia in child psychiatry practice: A national survey.","container-title":"Sleep medicine","volume":"11","issue":"7","abstract":"OBJECTIVE: To examine clinical practice patterns regarding non-prescription and prescription medication use for insomnia by child and adolescent psychiatrists. METHODS: Survey mailed to 6018 members of the American Academy of Child and Adolescent Psychiatry. RESULTS: The final sample (N=1273) reported that insomnia was a major problem in almost a third of their school-aged and adolescent patients and endorsed using medication to treat the insomnia in at least a quarter of these patients. Overall, 96% of respondents recommended at least one of the listed prescription medications in a typical month, and 88% recommended an over-the-counter medication. Alpha agonists were the most commonly prescribed insomnia medication for ADHD (81%), significantly higher than in MR/DD (67%), mood (40%), or anxiety disorders (31%). Trazodone was the most commonly prescribed insomnia medication for children with mood (78%) and anxiety disorders (72%). Antidepressants as a class were also commonly used for children in these diagnostic groups. Atypical antipsychotics, anticonvulsants, and short-acting hypnotics were also more likely to be used in children with mood disorders. Melatonin was recommended by more than one-third of respondents. Mitigation of the effects of sleep disruption on daytime functioning was endorsed as an important rationale for the use of sleep medication; concerns about side effects and the lack of empirical support regarding efficacy were cited as significant barriers to their use. CONCLUSIONS: Insomnia is a significant clinical problem in children treated by child psychiatrists for a variety of behavioral, neurodevelopmental, and psychiatric conditions. Management with a broad array of psychotropic medications is common and indicates a highly variable clinical approach to insomnia in this pediatric population.","DOI":"10.1016/j.sleep.2009.11.015","note":"PMID: 20621556","journalAbbreviation":"Sleep Med","language":"eng","author":[{"family":"Owens","given":"Judith A."},{"family":"Rosen","given":"Carol L."},{"family":"Mindell","given":"Jodi A."},{"family":"Kirchner","given":"Hal L."}],"issued":{"date-parts":[["2010",8]]}}}],"schema":""} (Owens et al., 2010) Its action is mediated by the 5-HT2A/C antagonism and inhibition of postsynaptic binding of serotonin and blocking of histamine receptors. Recent empirical evidence suggest that trazodone may interact with the melatonin system: Giannaccini et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"i2mvtococ","properties":{"formattedCitation":"(Giannaccini et al., 2016)","plainCitation":"(Giannaccini et al., 2016)"},"citationItems":[{"id":6167,"uris":[""],"uri":[""],"itemData":{"id":6167,"type":"article-journal","title":"Melatonin and pro-hypnotic effectiveness of the antidepressant Trazodone: A preliminary evaluation in insomniac mood-disorder patients","container-title":"Clinical Biochemistry","source":"PubMed","DOI":"10.1016/j.clinbiochem.2016.06.014","ISSN":"1873-2933","note":"PMID: 27374436","shortTitle":"Melatonin and pro-hypnotic effectiveness of the antidepressant Trazodone","journalAbbreviation":"Clin. Biochem.","language":"ENG","author":[{"family":"Giannaccini","given":"Gino"},{"family":"Masala","given":"Irene"},{"family":"Palego","given":"Lionella"},{"family":"Betti","given":"Laura"},{"family":"Pacciardi","given":"Bruno"},{"family":"Palagini","given":"Laura"},{"family":"Luchini","given":"Federica"},{"family":"Belli","given":"Simone"},{"family":"Lucacchini","given":"Antonio"},{"family":"Mauri","given":"Mauro"}],"issued":{"date-parts":[["2016",6,30]]}}}],"schema":""} (Giannaccini et al., 2016) measured clinical and melatonin parameters before and after 1 month of therapy with trazodone in insomniac mood-depressed patients. Patients with refractory depressed-mood and insomnia improved after treatment and responsive patients excreted more urinary 6-hydroxy-melatonin sulfate than before treatment, reflecting an enhanced nighttime production of the pineal hormone in these subjects and suggesting an interaction between trazodone and melatonin system. Based on this data, the Authors support the role of melatonin as a biological indicator of pro-hypnotic and antidepressant benefits of trazodone.Trazodone suppresses REM sleep and increases slow-wave sleep, which may prove to have beneficial effects in memory function of children who are challenged intellectually and who struggle to generalize and maintain adaptive skills of daily living.As reported above, it is commonly used to manage insomnia in clinical practice. However, only very few studies have been conducted in children and adolescents. Anecdotal reports show the efficacy of trazodone mainly in mid-night and terminal insomnia.Trazodone has been used for insomnia in 17 children with opsoclonus-myoclonus syndrome. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"184esjo348","properties":{"formattedCitation":"(Pranzatelli et al., 2005)","plainCitation":"(Pranzatelli et al., 2005)"},"citationItems":[{"id":6054,"uris":[""],"uri":[""],"itemData":{"id":6054,"type":"article-journal","title":"Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone","container-title":"The Journal of Pediatrics","page":"372-378","volume":"147","issue":"3","source":"PubMed","abstract":"OBJECTIVES: Parents of children with opsoclonus-myoclonus syndrome (OMS) frequently describe poor sleep and rage attacks. We hypothesized that these manifestations are related and could result from underlying monoaminergic dysfunction.\nSTUDY DESIGN: We clinically characterized the sleep and behavioral characteristics of 51 young children with OMS; 19 of those with the most disruptive sleep patterns were treated with trazodone, a soporific serotonergic agent.\nRESULTS: Sleep disturbances, including prolonged sleep latency, fragmented sleep, reduced quantity of sleep, snoring, and non-restorative sleep, were reported in 32 children, and frequent rage attacks were reported in 25. In 59% of the poor sleepers, parents felt that the problem was severe enough to warrant treatment. Children sleeping <10 hours/night had a higher rage frequency than those who slept more. Of the children who required trazodone, 84% were receiving corticosteroids or adrenocorticotropic hormone (corticotrophin), compared with 37% in the subgroup with normal sleep. Trazodone (3.0 +/- 0.4 mg/kg/day) improved sleep and behavior in 95% of the children, significantly increasing total sleep time by 72%, decreasing the number of awakenings by 76%, and reducing rage attacks by 33%.\nCONCLUSIONS: Children with OMS exhibited multiple types of sleep disturbances, which contributed to rage attacks. Trazodone was effective in improving sleep and decreasing rage attacks and was well tolerated, even in toddlers.","DOI":"10.1016/j.jpeds.2005.05.016","ISSN":"0022-3476","note":"PMID: 16182678","shortTitle":"Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome","journalAbbreviation":"J. Pediatr.","language":"eng","author":[{"family":"Pranzatelli","given":"Michael R."},{"family":"Tate","given":"Elizabeth D."},{"family":"Dukart","given":"William S."},{"family":"Flint","given":"Mary Jo"},{"family":"Hoffman","given":"Michael T."},{"family":"Oksa","given":"Amy E."}],"issued":{"date-parts":[["2005",9]]}}}],"schema":""} (Pranzatelli et al., 2005) The starting dose of 25 mg was increased to a maximum of 100 or 150 mg depending on age. The effects on sleep were not dose dependent and low dosages were effective for insomnia.The most commonly reported side effects are dry mouth, nausea, vomiting, drowsiness, dizziness/light-headedness, headache, and morning hangover. Less common or rare side effects are hypotension, tachycardia, serotonin syndrome and priapism. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ciqb0cgmq","properties":{"formattedCitation":"(Bossini et al., 2015)","plainCitation":"(Bossini et al., 2015)"},"citationItems":[{"id":6162,"uris":[""],"uri":[""],"itemData":{"id":6162,"type":"article-journal","title":"Off-Label Trazodone Prescription: Evidence, Benefits and Risks","container-title":"Current Pharmaceutical Design","page":"3343-3351","volume":"21","issue":"23","source":"PubMed","abstract":"Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction. Despite the favorable clinical experience and the encouraging results from the studies that have tested the efficacy of trazodone for some of its off-label indications, it is paramount that large, randomized and controlled clinical trials be conducted in the near future to evaluate which of the many off-label indications are supported by a strong scientific evidence.","ISSN":"1873-4286","note":"PMID: 26088119","shortTitle":"Off-Label Trazodone Prescription","journalAbbreviation":"Curr. Pharm. Des.","language":"eng","author":[{"family":"Bossini","given":"Letizia"},{"family":"Coluccia","given":"Anna"},{"family":"Casolaro","given":"Ilaria"},{"family":"Benbow","given":"Jim"},{"family":"Amodeo","given":"Giovanni"},{"family":"De Giorgi","given":"Riccardo"},{"family":"Fagiolini","given":"Andrea"}],"issued":{"date-parts":[["2015"]]}}}],"schema":""} (Bossini et al., 2015) It is not commonly indicated in Rett syndrome for the risk of QT interval prolongation. It should be noted that, since the doses of trazodone for insomnia are lower than those used for depression, the incidence of side effects is also lower.Chloral hydrate Chloral hydrate is indicated for nighttime sedation in children since it was initially considered a safe agent in infants and young children at dosages of 25–100 mg/kg/day. However, respiratory depression and hepatotoxicity have been reported after administration of chloral hydrate. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5TuV3Skw","properties":{"formattedCitation":"(Biban, Baraldi, Pettennazzo, Filippone, & Zacchello, 1993)","plainCitation":"(Biban, Baraldi, Pettennazzo, Filippone, & Zacchello, 1993)"},"citationItems":[{"id":6140,"uris":[""],"uri":[""],"itemData":{"id":6140,"type":"article-journal","title":"Adverse effect of chloral hydrate in two young children with obstructive sleep apnea","container-title":"Pediatrics","page":"461-463","volume":"92","issue":"3","source":"PubMed","ISSN":"0031-4005","note":"PMID: 8361806","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Biban","given":"P."},{"family":"Baraldi","given":"E."},{"family":"Pettennazzo","given":"A."},{"family":"Filippone","given":"M."},{"family":"Zacchello","given":"F."}],"issued":{"date-parts":[["1993",9]]}}}],"schema":""} (Biban, Baraldi, Pettennazzo, Filippone, & Zacchello, 1993)For these reasons it should be avoided or at least carefully controlled in children with NDDs at risk for OSA. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"F6bQBSRW","properties":{"formattedCitation":"(Sheldon, 2001)","plainCitation":"(Sheldon, 2001)"},"citationItems":[{"id":1715,"uris":[""],"uri":[""],"itemData":{"id":1715,"type":"article-journal","title":"Insomnia in Children.","container-title":"Current treatment options in neurology","volume":"3","issue":"1","abstract":"Insomnia in the pediatric populations is very different than insomnia in the adult population. Although both involve sleeplessness, the causes vary significantly. Sleeplessness during early infancy is normal, and the developing sleep-wake pattern of an infant is inconsistent with the normal sleep-wake pattern of parents. Asynchrony of parental and infant sleep patterns can lead to specific complaints of sleeplessness in infants. Parental response to the infant's developing sleep-wake pattern may be a factor that determines the presence (or absence) of problem sleeplessness as the child matures. Problem sleeplessness in children may result from behavioral, circadian, or biologic or medical abnormalities. Therefore, evaluation of the sleepless child should not be limited to only behavioral etiologies.","note":"PMID: 11123857","journalAbbreviation":"Curr Treat Options Neurol","language":"ENG","author":[{"family":"Sheldon","given":""}],"issued":{"date-parts":[["2001",1]]}}}],"schema":""} (Sheldon, 2001) It may cause gastric distress, nausea, and vomiting, drowsiness, dizziness, malaise, and fatigue. Children may experience idiosyncratic reactions characterized by confusion, disorientation, and paranoia. Used chronically, chloral hydrate is habit forming and associated with tolerance. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"deiq48stm","properties":{"formattedCitation":"(Glaze, 2004)","plainCitation":"(Glaze, 2004)"},"citationItems":[{"id":477,"uris":[""],"uri":[""],"itemData":{"id":477,"type":"article-journal","title":"Childhood insomnia: why Chris can't sleep.","container-title":"Pediatric clinics of North America","volume":"51","issue":"1","abstract":"Children of all ages experience difficulty initiating and maintaining sleep, which is known as childhood insomnia. Insomnia is a symptom that may be caused by a primary sleep disorder or is associated with other sleep, medical, and psychiatric disorders. The sleep disturbance causes significant impairment in daytime functioning and impacts negatively on family life. This problem is managed primarily by behavioral or cognitive-behavioral approaches. Medications are frequently prescribed, but there is a lack of data from controlled studies to support the use of pharmacologic agents in the management of childhood insomnia.","note":"PMID: 15008581","journalAbbreviation":"Pediatr Clin North Am","language":"eng","author":[{"family":"Glaze","given":"Daniel G."}],"issued":{"date-parts":[["2004",2]]}}}],"schema":""} (Glaze, 2004) Atypical antipsychoticsAtypical antipsychotics such as risperidone, quetiapine, aripiprazole, and olanzapine are typically used off-label in children with psychiatric or developmental disorders. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1bk6m82dsl","properties":{"formattedCitation":"(Masi et al., 2009)","plainCitation":"(Masi et al., 2009)"},"citationItems":[{"id":5713,"uris":[""],"uri":[""],"itemData":{"id":5713,"type":"article-journal","title":"Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders: a retrospective study","container-title":"CNS drugs","page":"511-521","volume":"23","issue":"6","source":"PubMed","abstract":"BACKGROUND: Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterized by impairment in social interactions, in verbal and non-verbal communication, and by restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. The appropriate use of pharmacotherapy can improve some aberrant symptoms and behaviours and increase the person's response to non-pharmacological interventions.\nOBJECTIVE: To describe clinical outcomes, or symptom changes, and adverse effects during naturalistic treatment with aripiprazole monotherapy in children with PDDs and severe behavioural disorders (such as aggression against self and/or others, hostility, hyperactivity, severe impulsiveness).\nMETHOD: This retrospective naturalistic study included 34 patients (23 males and 11 females, age range 4.5-15 years, mean age 10.2 +/- 3.3 years), admitted during 2006-2007, diagnosed according to DSM-IV criteria and followed up for 4-12 months (mean 7.0 +/- 3.6 months). Outcome measures were three global measures of clinical and functional impairment and improvement from baseline: the Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales; the Children's Global Assessment Scale (C-GAS); and the Childhood Autism Rating Scale (CARS), a specific measure of PDD symptoms.\nRESULTS: The mean baseline CGI-S was 5.7 +/- 0.8 (markedly ill/severely ill). The mean final dosage of aripiprazole was 8.1 +/- 4.9 mg/day. At the endpoint, 11 patients (32.4%) were 'much improved' or 'very much improved' (CGI-I score of 1 or 2), 12 patients (35.3%) were 'minimally improved' (CGI-I score of 3) and 10 (29.4%) were 'unchanged' or 'worsened' (CGI-I score of 4 or 5). C-GAS and CARS scores significantly improved (p < 0.0001, effect sizes 0.59 and 0.62, respectively). Nine patients (26.5%) experienced moderate to severe agitation, which was associated with self-injurious behaviours in five of these patients, and five patients presented with sleep disorders. Twelve patients (35.3%) discontinued medication during the follow-up because of lack of efficacy or adverse effects.\nCONCLUSIONS: In these severely impaired children with PDDs, aripiprazole monotherapy was associated with a significant improvement in maladaptive behaviours in one-third of patients. Agitation and insomnia were the most frequent adverse effects. Further controlled studies in larger samples to explore possible predictors of efficacy are warranted.","DOI":"10.2165/00023210-200923060-00005","ISSN":"1172-7047","note":"PMID: 19480469","shortTitle":"Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders","journalAbbreviation":"CNS Drugs","language":"eng","author":[{"family":"Masi","given":"Gabriele"},{"family":"Cosenza","given":"Angela"},{"family":"Millepiedi","given":"Stefania"},{"family":"Muratori","given":"Filippo"},{"family":"Pari","given":"Cinzia"},{"family":"Salvadori","given":"Francesco"}],"issued":{"date-parts":[["2009"]]}}}],"schema":""} (Masi et al., 2009), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1msl10jrd4","properties":{"formattedCitation":"(Capone, Goyal, Grados, Smith, & Kammann, 2008)","plainCitation":"(Capone, Goyal, Grados, Smith, & Kammann, 2008)"},"citationItems":[{"id":5711,"uris":[""],"uri":[""],"itemData":{"id":5711,"type":"article-journal","title":"Risperidone use in children with Down syndrome, severe intellectual disability, and comorbid autistic spectrum disorders: a naturalistic study","container-title":"Journal of developmental and behavioral pediatrics: JDBP","page":"106-116","volume":"29","issue":"2","source":"PubMed","abstract":"OBJECTIVE: We report on an open-label, naturalistic study using risperidone to treat disruptive behaviors and self-injury in children with Down syndrome, severe intellectual disability, and comorbid autism spectrum disorders (DS+ASDs). We hypothesized that hyperactivity and disruptive behaviors would improve in response to risperidone treatment consistent with previous studies of children with ASD.\nMETHODS: Subjects were children (mean age, 7.8 +/- 2.6 years), consisting of 20 males and three females identified through our outpatient Down Syndrome Clinic between 2000 and 2004.\nRESULTS: Using the Aberrant Behavior Checklist as the primary outcome measure, all five subscales showed significant improvement following risperidone treatment. The mean duration of treatment was 95.8 +/- 16.8 days, and mean total daily dose was 0.66 +/- 0.28 mg/day. The Hyperactivity, Stereotypy, and Lethargy subscale scores showed the most significant reduction (p < .001), followed by Irritability (p < .02), and Inappropriate Speech (p < .04). Children with disruptive behavior and self-injury showed the greatest improvement. Sleep quality improved for 88% of subjects with preexisting sleep disturbance. Subjects for whom a follow-up weight was available showed a mean weight increase of 2.8 +/- 1.5 kg during the treatment period.\nCONCLUSIONS: These findings support our clinical impression of improvement on important target behaviors such as aggression, disruptiveness, self-injury, stereotypy, and social withdrawal. Low-dose risperidone appears to be well tolerated in children with DS+ASD, although concerns about weight gain and metabolic alterations may limit its usefulness over the long term in some children.","DOI":"10.1097/DBP.0b013e318165c100","ISSN":"0196-206X","note":"PMID: 18349709","shortTitle":"Risperidone use in children with Down syndrome, severe intellectual disability, and comorbid autistic spectrum disorders","journalAbbreviation":"J Dev Behav Pediatr","language":"eng","author":[{"family":"Capone","given":"George T."},{"family":"Goyal","given":"Parag"},{"family":"Grados","given":"Marco"},{"family":"Smith","given":"Brandon"},{"family":"Kammann","given":"Heather"}],"issued":{"date-parts":[["2008",4]]}}}],"schema":""} (Capone, Goyal, Grados, Smith, & Kammann, 2008) Risperidone and olanzapine have been prescribed for sleep disturbances in children, but no studies are available evaluating their safety and effectiveness. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"29t9rjao2s","properties":{"formattedCitation":"(Schnoes et al., 2006)","plainCitation":"(Schnoes et al., 2006)"},"citationItems":[{"id":5721,"uris":[""],"uri":[""],"itemData":{"id":5721,"type":"article-journal","title":"Pediatric prescribing practices for clonidine and other pharmacologic agents for children with sleep disturbance","container-title":"Clinical Pediatrics","page":"229-238","volume":"45","issue":"3","source":"PubMed","abstract":"The prescription rates of clonidine have risen dramatically and the extent to which these increases can be attributed to treatment of sleep disturbance is unknown. Surveys were mailed to 800 pediatricians across four geographically diverse states to assess prescribing practices specific to sleep disturbance. Ninety-six percent of the respondents treated sleep disturbance. More than one third of the sample reported using clonidine specifically for sleep disturbance including sleep onset, sleep schedule, nighttime awakening, and early morning awakening problems and parasomnias. Clonidine ranked second only to antihistamines as the most commonly used medication for treating sleep disturbance.","ISSN":"0009-9228","note":"PMID: 16708135","journalAbbreviation":"Clin Pediatr (Phila)","language":"eng","author":[{"family":"Schnoes","given":"Connie J."},{"family":"Kuhn","given":"Brett R."},{"family":"Workman","given":"Elizabeth F."},{"family":"Ellis","given":"Cynthia R."}],"issued":{"date-parts":[["2006",4]]}}}],"schema":""} (Schnoes et al., 2006), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tu4m0vudb","properties":{"formattedCitation":"(Hollway & Aman, 2011)","plainCitation":"(Hollway & Aman, 2011)"},"citationItems":[{"id":5627,"uris":[""],"uri":[""],"itemData":{"id":5627,"type":"article-journal","title":"Pharmacological treatment of sleep disturbance in developmental disabilities: a review of the literature","container-title":"Research in Developmental Disabilities","page":"939-962","volume":"32","issue":"3","source":"PubMed","abstract":"Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study.","DOI":"10.1016/j.ridd.2010.12.035","ISSN":"1873-3379","note":"PMID: 21296553","shortTitle":"Pharmacological treatment of sleep disturbance in developmental disabilities","journalAbbreviation":"Res Dev Disabil","language":"eng","author":[{"family":"Hollway","given":"Jill A."},{"family":"Aman","given":"Michael G."}],"issued":{"date-parts":[["2011",6]]}}}],"schema":""} (Hollway & Aman, 2011), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"252og7polv","properties":{"formattedCitation":"(Meltzer, Mindell, Owens, & Byars, 2007)","plainCitation":"(Meltzer, Mindell, Owens, & Byars, 2007)"},"citationItems":[{"id":5719,"uris":[""],"uri":[""],"itemData":{"id":5719,"type":"article-journal","title":"Use of sleep medications in hospitalized pediatric patients","container-title":"Pediatrics","page":"1047-1055","volume":"119","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Little is known about the medications prescribed for sleep in hospitalized children. The aims of this study were to (1) determine the percentage of hospitalized children who receive medication for sleep disturbances, (2) determine what medications are prescribed for sleep difficulties, and (3) examine medical and demographic variables related to medications prescribed during hospitalization.\nPATIENTS AND METHODS: A chart review was conducted for all inpatients at 3 pediatric hospitals across 26 randomly selected days in 2004. Demographic, medical, and medication data were collected on 9440 patients. The sample was 54.5% male, had a mean age of 7.0 years, and was 63% white. Almost 19% of the patients had at least 1 psychiatric diagnosis.\nRESULTS: Overall, 6.0% of all hospitalized children (3% of all medically hospitalized children, excluding children with a psychiatric diagnosis) were prescribed medications for sleep, with antihistamines the most frequently prescribed medication (36.6%), followed by benzodiazepines (19.4%); hypnotic agents were the least frequently prescribed (2.2%). Significant differences were found in both the frequency of sleep-medication prescriptions and the types of medications used across hospitals, as well as for age, length of hospitalization, and service that the child was discharged from. Children with a psychiatric diagnosis were more likely to receive a sleep medication, with 22% of children on a psychiatric service receiving a sleep-related medication.\nCONCLUSIONS: Approximately 3% to 6% of children are treated pharmacologically with a broad array of sleep medications in hospital settings. Prescription practices vary by hospital, medical service, child age, and diagnosis. The results from this study indicate that medications are being prescribed for sleep in hospitalized children, especially in children with psychiatric diagnoses. However, given that there are neither Food and Drug Administration-approved sleep medications for children nor clinical consensus guidelines regarding their use, clinical trials, practice guidelines, and additional research are clearly needed.","DOI":"10.1542/peds.2006-2773","ISSN":"1098-4275","note":"PMID: 17545369","journalAbbreviation":"Pediatrics","language":"eng","author":[{"family":"Meltzer","given":"Lisa J."},{"family":"Mindell","given":"Jodi A."},{"family":"Owens","given":"Judith A."},{"family":"Byars","given":"Kelly C."}],"issued":{"date-parts":[["2007",6]]}}}],"schema":""} (Meltzer, Mindell, Owens, & Byars, 2007) Tolerability profile of these medications can be tricky: excessive weight gain may exacerbate any sleep-disordered breathing present in the child; metabolic effects like hyperglycemia or hyperprolactinemia may be unsafe in certain clinical conditions (i.e. Down Syndrome or Prader-Willy Syndrome).Atypical antipsychotics (e.g., risperidone, aripiprazole) should be considered to treat a comorbid condition (i.e. aggressive, self-injurious behaviors in children with ASD) and they might help to relief from insomnia when dosed at bedtime.A small randomized, and placebo-controlled study of quetiapine (25 mg — a relatively low dose) in adults, showed a statistically non-significant trend toward improvement in total sleep time and reduced sleep latency. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"h5ij1a0pf","properties":{"formattedCitation":"(Tassniyom, Paholpak, Tassniyom, & Kiewyoo, 2010)","plainCitation":"(Tassniyom, Paholpak, Tassniyom, & Kiewyoo, 2010)"},"citationItems":[{"id":6068,"uris":[""],"uri":[""],"itemData":{"id":6068,"type":"article-journal","title":"Quetiapine for primary insomnia: a double blind, randomized controlled trial","container-title":"Journal of the Medical Association of Thailand = Chotmaihet Thangphaet","page":"729-734","volume":"93","issue":"6","source":"PubMed","abstract":"OBJECTIVE: To evaluate the clinical efficacy of Quetiapine 25 mg for the treatment of primary insomnia.\nMATERIAL AND METHOD: A randomized, double-blind, placebo-controlled clinical trial was conducted. Patients with DSM-IV-TR defined primary insomnia were asked to record a sleep diary one week prior to treatment, followed by 2 weeks of nightly treatment with either Quetiapine 25 mg or placebo. The primary outcomes were total sleep time (TST), sleep latency (SL), daytime alertness and functioning and sleep satisfaction; side effects were recorded as secondary outcome. Data were collected between January 2007 and December 2007, at Srinagarind Hospital of Khon Kaen University.\nRESULTS: Thirteen patients completed the present study (mean age 45.95 years old; range 25-62). Quetiapine group increased mean TST by 124.92 minutes and 72.24 minutes in the placebo group. Mean SL was reduced by 96.16 minutes in the Quetiapine group and 23.72 minutes in the placebo group. Statistical significance was not reached between both groups. In the Quetiapine group two patients reported side effects of dry lips, dry tongue and morning drowsiness.\nCONCLUSION: The present study is the first study to evaluate the effect of Quetiapine in primary insomnia in a randomized controlled trial. Quetiapine at 25 mg at night did show a trend for improvement of TST and reduced SL in primary insomnia with few side effects but not reaching statistical significance. A study with a larger sample size is needed to demonstrate its efficacy.","ISSN":"0125-2208","note":"PMID: 20572379","shortTitle":"Quetiapine for primary insomnia","journalAbbreviation":"J Med Assoc Thai","language":"eng","author":[{"family":"Tassniyom","given":"Kanida"},{"family":"Paholpak","given":"Suchat"},{"family":"Tassniyom","given":"Sompon"},{"family":"Kiewyoo","given":"Jiraporn"}],"issued":{"date-parts":[["2010",6]]}}}],"schema":""} (Tassniyom, Paholpak, Tassniyom, & Kiewyoo, 2010) There is a single open-label trial involving 11 children with ASD who did demonstrate a reduction in sleep disturbance. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10md39n41f","properties":{"formattedCitation":"(Golubchik, Sever, & Weizman, 2011)","plainCitation":"(Golubchik, Sever, & Weizman, 2011)"},"citationItems":[{"id":6070,"uris":[""],"uri":[""],"itemData":{"id":6070,"type":"article-journal","title":"Low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior: open-label trial","container-title":"Clinical Neuropharmacology","page":"216-219","volume":"34","issue":"6","source":"PubMed","abstract":"BACKGROUND: Atypical antipsychotics may be useful in treating aggression associated with autistic spectrum disorder (ASD). We evaluated the effectiveness of low-dose quetiapine treatment in ASD adolescent patients with aggressive behavior.\nMETHOD: Eleven adolescent patients (8 boys and 3 girls) diagnosed with ASD, aged 13 to 17 years, were treated with quetiapine in an open-label study over an 8-week period. The severity of ASD, aggressive behavior, and sleep disturbances were assessed using the Clinical Global Impression-Severity (CGI-S), Overt Aggression Scale, and Child Sleep Habits Questionnaire, respectively.\nRESULTS: Nonsignificant changes were obtained in autistic behavior after quetiapine treatment (CGI-S: 4.0 ± 0.6 vs CGI-S after: 3.1 ± 1.1; 2-tailed paired t = 1.93; df = 10; P = 0.08). Severity of aggressive behavior decreased significantly after quetiapine treatment (Overt Aggression Scale: 2.1 ± 0.94 vs 1.3 ± 0.64, respectively; 2-tailed paired t = 2.37; df =10; P = 0.028). Sleep disturbances improved significantly (Child Sleep Habits Questionnaire: 49.0 ± 12 vs 44.1 ± 9.6; 2-tailed paired t = 2.98; df =10; P = 0.014) and a positive correlation was found between the improvements in aggression and sleep (Spearman correlation: r = 0.43; N = 11; P = 0.013). Quetiapine was well tolerated.\nCONCLUSION: Short-term low-dose quetiapine treatment may reduce aggression levels and improve sleep quality in adolescents with ASD.","DOI":"10.1097/WNF.0b013e31823349ac","ISSN":"1537-162X","note":"PMID: 21996644","shortTitle":"Low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior","journalAbbreviation":"Clin Neuropharmacol","language":"eng","author":[{"family":"Golubchik","given":"Pavel"},{"family":"Sever","given":"Jonathan"},{"family":"Weizman","given":"Abraham"}],"issued":{"date-parts":[["2011",12]]}}}],"schema":""} (Golubchik, Sever, & Weizman, 2011) Without more definitive data, the use of neuroleptics for insomnia in children is generally not recommended.Tryptophan / 5-hydroxytryptophan (5-HTP)Tryptophan is a precursor of serotonin and melatonin widely used in the 80s for the treatment of sleep disorders and headache prophylaxis. It does not have opioid-like effects and does not limit cognitive performance or inhibit arousal from sleep. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"f3gcf6imf","properties":{"formattedCitation":"(Lieberman, Kane, & Reife, 1985)","plainCitation":"(Lieberman, Kane, & Reife, 1985)"},"citationItems":[{"id":4936,"uris":[""],"uri":[""],"itemData":{"id":4936,"type":"article-journal","title":"Neuromuscular effects of monoamine oxidase inhibitors","container-title":"Journal of Clinical Psychopharmacology","page":"221-228","volume":"5","issue":"4","source":"PubMed","abstract":"The MAOI drugs produce neuromuscular effects at therapeutic and toxic doses when given alone or in combination with other drugs. These effects range from muscle tension and twitches to forceful myoclonic jerks. These effects may also be a part of a more pervasive toxic syndrome that includes autonomic and mental symptoms as well. There is some evidence that serotonergic mechanisms play a role in mediating the neuromuscular effects of MAOIs. The authors have hypothesized that MAOIs produce a condition of heightened neuromuscular excitability due to a combination of increased serotonergic tone and central disinhibition of alpha-motoneuron mediated spinal activity. Further study is needed in which objective pharmacologic and neurophysiologic measures are used.","ISSN":"0271-0749","note":"PMID: 3874888","journalAbbreviation":"J Clin Psychopharmacol","language":"eng","author":[{"family":"Lieberman","given":"J. A."},{"family":"Kane","given":"J. M."},{"family":"Reife","given":"R."}],"issued":{"date-parts":[["1985",8]]}}}],"schema":""} (Lieberman, Kane, & Reife, 1985) In the literature, several positive effects on sleep have been reported: improvement of sleep latency and decrease of arousals. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1lko90deo5","properties":{"formattedCitation":"(Schneider-Helmert & Spinweber, 1986)","plainCitation":"(Schneider-Helmert & Spinweber, 1986)"},"citationItems":[{"id":5389,"uris":[""],"uri":[""],"itemData":{"id":5389,"type":"article-journal","title":"Evaluation of L-tryptophan for treatment of insomnia: a review","container-title":"Psychopharmacology","page":"1-7","volume":"89","issue":"1","source":"PubMed","abstract":"Sleep laboratory and outpatient studies of the hypnotic efficacy of the amino acid L-tryptophan are reviewed, with particular emphasis on evaluation of therapeutic effectiveness in the treatment of insomnia. In younger situational insomniacs, whose sleep problem consists solely of longer than usual sleep latencies, L-tryptophan is effective in reducing sleep onset time on the first night of administration in doses ranging from 1 to 15 g. In more chronic, well-established sleep-onset insomnia or in more severe insomnias characterized by both sleep onset and sleep maintenance problems, repeated administration of low doses of L-tryptophan over time may be required for therapeutic improvement. In these patients, hypnotic effects appear late in the treatment period or, as shown in some studies, even after discontinuation of treatment. The improvement in sleep measures post-treatment has given rise to use of a treatment regimen known as \"interval therapy\", in which L-tryptophan treatment alternates with an L-tryptophan-free interval until improvement occurs. The absence of side effects and lack of development of tolerance in long-term use are important factors in the decision to embark upon a trial of L-tryptophan treatment. In addition, L-tryptophan administration is not associated with impairment of visuomotor, cognitive, or memory performance, nor does it elevate threshold for arousal from sleep.","ISSN":"0033-3158","note":"PMID: 3090582","shortTitle":"Evaluation of L-tryptophan for treatment of insomnia","journalAbbreviation":"Psychopharmacology (Berl.)","language":"eng","author":[{"family":"Schneider-Helmert","given":"D."},{"family":"Spinweber","given":"C. L."}],"issued":{"date-parts":[["1986"]]}}}],"schema":""} (Schneider-Helmert & Spinweber, 1986), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1fsitp48dg","properties":{"formattedCitation":"(Hartmann & Spinweber, 1979)","plainCitation":"(Hartmann & Spinweber, 1979)"},"citationItems":[{"id":5399,"uris":[""],"uri":[""],"itemData":{"id":5399,"type":"article-journal","title":"Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake","container-title":"The Journal of Nervous and Mental Disease","page":"497-499","volume":"167","issue":"8","source":"PubMed","abstract":"Previous results have demonstrated sleep-inducing effects of L-tryptophan in doses of 1 to 15 g at bedtime. The present laboratory study extends the dose-response curve downward, comparing doses of 1/4 g, 1/2 g, and 1 g of L-tryptophan with placebo, in 15 mild insomniacs (subjects who reported sleep latencies of over 30 minutes). One gram of L-tryptophan significantly reduced sleep latency: the lower doses produced a trend in the same direction. Stage IV sleep was significantly increased by 1/4 g of L-tryptophan. These results at low doses have interesting implications since the normal dietary intake of L-tryptophan is 1/2 g to 2 g per day.","ISSN":"0022-3018","note":"PMID: 469515","journalAbbreviation":"J. Nerv. Ment. Dis.","language":"eng","author":[{"family":"Hartmann","given":"E."},{"family":"Spinweber","given":"C. L."}],"issued":{"date-parts":[["1979",8]]}}}],"schema":""} (Hartmann & Spinweber, 1979) One study with L-Tryptophan at different dosages (250 mg, 1 g and 3 g) in adults showed improvement in sleep latency, a reduction in WASO, with a moderate effect on quality of sleep. None of the papers reported systematic information regarding adverse effects associated with tryptophan. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"h2iq2ncc0","properties":{"formattedCitation":"(Hudson, Hudson, Hecht, & MacKenzie, 2005)","plainCitation":"(Hudson, Hudson, Hecht, & MacKenzie, 2005)"},"citationItems":[{"id":6080,"uris":[""],"uri":[""],"itemData":{"id":6080,"type":"article-journal","title":"Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia","container-title":"Nutritional Neuroscience","page":"121-127","volume":"8","issue":"2","source":"PubMed","abstract":"BACKGROUND: Intact protein rich in tryptophan was not seen as an alternative to pharmaceutical grade tryptophan since protein also contains large neutral amino acids (LNAAs) that compete for transport sites across the blood-brain barrier (BBB). Deoiled gourd seed (an extremely rich source of tryptophan-22 mg tryptophan/1 g protein) was combined with glucose, a carbohydrate that reduces serum levels of competing LNAAs which was then compared to pharmaceutical grade tryptophan with carbohydrate as well as carbohydrate alone.\nMETHOD: Objective and subjective measures of sleep were employed to measure changes in sleep as part of a double blind placebo controlled study where subjects were randomly assigned to one of three conditions: (1) Protein source tryptophan (deoiled gourd seed) in combination with carbohydrate; (2) pharmaceutical grade tryptophan in combination with carbohydrate; (3) carbohydrate alone.\nSUBJECTS: Out of 57 subjects 49 of those who began the study completed the three week protocol.\nRESULTS: Protein source tryptophan with carbohydrate and pharmaceutical grade tryptophan, but not carbohydrate alone, resulted in significant improvement on subjective and objective measures of insomnia. Protein source tryptophan with carbohydrate alone proved effective in significantly reducing time awake during the night.\nCONCLUSION: Protein source tryptophan is comparable to pharmaceutical grade tryptophan for the treatment of insomnia.","DOI":"10.1080/10284150500069561","ISSN":"1028-415X","note":"PMID: 16053244","journalAbbreviation":"Nutr Neurosci","language":"eng","author":[{"family":"Hudson","given":"Craig"},{"family":"Hudson","given":"Susan Patricia"},{"family":"Hecht","given":"Tracy"},{"family":"MacKenzie","given":"Joan"}],"issued":{"date-parts":[["2005",4]]}}}],"schema":""} (Hudson, Hudson, Hecht, & MacKenzie, 2005), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"b36f0ioeg","properties":{"formattedCitation":"(Hartmann, Lindsley, & Spinweber, 1983)","plainCitation":"(Hartmann, Lindsley, & Spinweber, 1983)"},"citationItems":[{"id":5395,"uris":[""],"uri":[""],"itemData":{"id":5395,"type":"article-journal","title":"Chronic insomnia: effects of tryptophan, flurazepam, secobarbital, and placebo","container-title":"Psychopharmacology","page":"138-142","volume":"80","issue":"2","source":"PubMed","abstract":"This study compared the effects of l-tryptophan (1 g), secobarbital (100 mg), flurazepam (30 mg), and placebo on sleep in 96 serious insomniacs. Each treatment was given nightly for 7 nights in a separate-group design. Outcome measures were subjective estimates by subjects of a number of sleep parameters during the week of treatment and for 1 week after, and an overall evaluation made by subjects and investigators at the end of the 2 weeks. During the treatment week, flurazepam produced significant improvement on several sleep measures compared to placebo, while tryptophan and secobarbital did not. Flurazepam and secobarbital produced withdrawal symptoms during the post-treatment week, while tryptophan and placebo did not. Sleep latency was not significantly improved by tryptophan during the treatment week, but continued to improve during the post-treatment week, resulting in a significant difference between tryptophan and baseline in week 2.","ISSN":"0033-3158","note":"PMID: 6410442","shortTitle":"Chronic insomnia","journalAbbreviation":"Psychopharmacology (Berl.)","language":"eng","author":[{"family":"Hartmann","given":"E."},{"family":"Lindsley","given":"J. G."},{"family":"Spinweber","given":"C."}],"issued":{"date-parts":[["1983"]]}}}],"schema":""} (Hartmann, Lindsley, & Spinweber, 1983), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ktr2crtjj","properties":{"formattedCitation":"(Spinweber, 1986)","plainCitation":"(Spinweber, 1986)"},"citationItems":[{"id":5387,"uris":[""],"uri":[""],"itemData":{"id":5387,"type":"article-journal","title":"L-tryptophan administered to chronic sleep-onset insomniacs: late-appearing reduction of sleep latency","container-title":"Psychopharmacology","page":"151-155","volume":"90","issue":"2","source":"PubMed","abstract":"The effects of 3 g L-tryptophan on sleep, performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 male, chronic sleep-onset insomniacs (mean age 20.3 +/- 2.4 years). Following a sleep laboratory screening night, all subjects received placebo for 3 consecutive nights (single-blind), ten subjects received L-tryptophan, and ten received placebo for 6 nights (double-blind). All subjects received placebo on 2 withdrawal nights (single-blind). There was no effect of L-tryptophan on sleep latency during the first 3 nights of administration. On nights 4-6 of administration, sleep latency was significantly reduced. Unlike benzodiazepine hypnotics, L-tryptophan did not alter sleep stages, impair performance, elevate arousal threshold, or alter brain electrical activity during sleep.","ISSN":"0033-3158","note":"PMID: 3097693","shortTitle":"L-tryptophan administered to chronic sleep-onset insomniacs","journalAbbreviation":"Psychopharmacology (Berl.)","language":"eng","author":[{"family":"Spinweber","given":"C. L."}],"issued":{"date-parts":[["1986"]]}}}],"schema":""} (Spinweber, 1986) 5-HTP is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. The effects of 5-HTP on sleep structure are conflicting: increase or decrease of REM and increase of SWS. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ce5i9pq9a","properties":{"formattedCitation":"(Meolie et al., 2005)","plainCitation":"(Meolie et al., 2005)"},"citationItems":[{"id":1363,"uris":[""],"uri":[""],"itemData":{"id":1363,"type":"article-journal","title":"Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence.","container-title":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","page":"173-187","volume":"1","issue":"2","abstract":"PURPOSE: To evaluate the level of evidence regarding the safety and efficacy of nonprescription therapies used for insomnia. REVIEWERS: Members of the American Academy of Sleep Medicine's Clinical Practice Review Committee. METHODS: A search of the World Wide Web was conducted using the terms insomnia, herbal remedies, and alternative treatments to develop a list of therapies. Therapies in this review include passionflower, valerian, Jamaican dogwood, hops, California poppy, chamomile, lemon balm, St. John's wort, kava kava, wild lettuce, scullcap, Patrinia root, first-generation histamine-1-receptor antagonists, alcohol, calcium, vitamin A, nicotinamide, magnesium, vitamin B12, I-tryptophan,","note":"PMID: 17561634","journalAbbreviation":"J Clin Sleep Med","language":"eng","author":[{"family":"Meolie","given":"Amy Lynn"},{"family":"Rosen","given":"Carol"},{"family":"Kristo","given":"David"},{"family":"Kohrman","given":"Michael"},{"family":"Gooneratne","given":"Nalaka"},{"family":"Aguillard","given":"Robert Neal"},{"family":"Fayle","given":"Robert"},{"family":"Troell","given":"Robert"},{"family":"Townsend","given":"Don"},{"family":"Claman","given":"David"},{"family":"Hoban","given":"Timothy"},{"family":"Mahowald","given":"Mark"}],"issued":{"date-parts":[["2005",4,15]]}}}],"schema":""} (Meolie et al., 2005) The exact mechanism of action of the sedative effects of 5-HTP is not completely clear and it is not sure that it is mediated only by conversion in serotonin. Serotonin (5-HT) should not be considered either wake-promoting or SWS-promoting, the effect of 5-HT on sleep-wake behavior would depend upon the activation of the serotonergic system (systemic administration of low vs. high doses of the precursor 5-HTP), and the time at which the activation occurs (light vs. dark period of the light-dark cycle). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2lmuuk3a5q","properties":{"formattedCitation":"(Imeri, Mancia, Bianchi, & Opp, 2000)","plainCitation":"(Imeri, Mancia, Bianchi, & Opp, 2000)"},"citationItems":[{"id":6090,"uris":[""],"uri":[""],"itemData":{"id":6090,"type":"article-journal","title":"5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in rats","container-title":"Neuroscience","page":"445-452","volume":"95","issue":"2","source":"PubMed","abstract":"The precise role of serotonin (5-hydroxytryptamine) in the regulation of sleep is not fully understood. To further clarify this role for 5-hydroxytryptamine, the 5-hydroxytryptamine precursors L-tryptophan (40 and 80 mg/kg) and L-5-hydroxytryptophan (25-, 50-, 75-, 100 mg/kg) were injected intraperitoneally into freely behaving rats 15 min prior to dark onset, and subsequent effects on sleep-wake activity and cortical brain temperature were determined. L-5-hydroxytryptophan, but not L-tryptophan, induced dose-dependent changes in sleep-wake activity. During the 12-h dark period, non-rapid eye movement sleep was inhibited in post-injection hours 1-2 by the two lowest L-5-hydroxytryptophan doses tested, while the two highest doses induced a delayed increase in non-rapid eye movement sleep in post-injection hours 3-12. These highest doses inhibited non-rapid eye movement sleep during the subsequent 12-h light period. The finding that L-5-hydroxytryptophan, but not L-tryptophan, induced a dose-dependent and long-lasting decrease in cortical brain temperature regardless of whether or not non-rapid eye movement sleep was suppressed or enhanced contributes to a growing list of conditions showing that sleep-wake activity and thermoregulation, although normally tightly coupled, may be dissociated. The initial non-rapid eye movement sleep inhibition observed following low doses of L-5-hydroxytryptophan may be attributable to increased serotonergic activity since 5-hydroxytryptamine may promote wakefulness per se, whereas the delayed non-rapid eye movement sleep enhancement after higher doses may be due to the induction by 5-hydroxytryptamine of sleep-inducing factor(s), as previously hypothesized. The period of non-rapid eye movement sleep inhibition beginning 12 h after administration of L-5-hydroxytryptophan doses that increase non-rapid eye movement sleep is characteristic of physiological manipulations in which non-rapid eye movement sleep is enhanced. The results of the present study suggest that the complex effects of 5-HT on sleep depend on the degree and time course of activation of the serotonergic system such that 5-HT may directly inhibit sleep, yet induce a cascade of physiological processes that enhance subsequent sleep.","ISSN":"0306-4522","note":"PMID: 10658624","journalAbbreviation":"Neuroscience","language":"eng","author":[{"family":"Imeri","given":"L."},{"family":"Mancia","given":"M."},{"family":"Bianchi","given":"S."},{"family":"Opp","given":"M. R."}],"issued":{"date-parts":[["2000"]]}}}],"schema":""} (Imeri, Mancia, Bianchi, & Opp, 2000) It has been hypothesized that the 5-hydroxytryptophan-related increase of SWS during the dark period depends upon the synthesis or release of as yet to be identified sleep-promoting factors. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hvaepin1l","properties":{"formattedCitation":"(Monti, 2011)","plainCitation":"(Monti, 2011)"},"citationItems":[{"id":6092,"uris":[""],"uri":[""],"itemData":{"id":6092,"type":"article-journal","title":"Serotonin control of sleep-wake behavior","container-title":"Sleep Medicine Reviews","page":"269-281","volume":"15","issue":"4","source":"PubMed","abstract":"Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT(1-7). The 5-HT(1A) and 5-HT(1B) receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT(3) receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT(6) and 5-HT(7) receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT(2A) and 5-HT(2C) receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT(7) receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT(1A) receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT(1B) (CP-94253), 5-HT(2A/2C) (DOI), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94235), 5-HT(2C) (RO 60-0175), 5-HT(2A/2C) (DOI, DOM), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT(2A/2C) receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT(2A) receptor antagonists volinanserin and pruvanserin and of the 5-HT(2A) receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT(2A) receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT(2A) antagonists or 5-HT(2A) inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.","DOI":"10.1016/j.smrv.2010.11.003","ISSN":"1532-2955","note":"PMID: 21459634","journalAbbreviation":"Sleep Med Rev","language":"eng","author":[{"family":"Monti","given":"Jaime M."}],"issued":{"date-parts":[["2011",8]]}}}],"schema":""} (Monti, 2011) Very limited data are available on the effects of 5-HTP on insomnia symptoms and none in children with NDDs.IronIron is a co-factor for tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dopamine. Iron deficiency anemia in infancy was reported to be associated with higher motor activity during sleep, shorter night sleep duration and higher frequency of night waking ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"219s9vd770","properties":{"formattedCitation":"(Kordas et al., 2008)","plainCitation":"(Kordas et al., 2008)"},"citationItems":[{"id":5447,"uris":[""],"uri":[""],"itemData":{"id":5447,"type":"article-journal","title":"Maternal reports of sleep in 6-18 month-old infants from Nepal and Zanzibar: association with iron deficiency anemia and stunting","container-title":"Early Human Development","page":"389-398","volume":"84","issue":"6","source":"PubMed","abstract":"BACKGROUND: Infants with iron deficiency anemia (IDA) and stunting explore and interact less with their environment. They may also be fatigued more often, suggesting their sleep may be affected. It is unclear whether fatigue in these infants is due to poor nighttime sleep or if it is compensated for with frequent naps or longer sleep.\nAIMS: In 2 studies from Pemba Island, Zanzibar and 1 from Nepal we investigated the relationship between IDA, stunting, and maternal reports of sleep in 6-18 mo old infants.\nMETHODS: Parents reported on the number and duration of naps, hours of nighttime sleep, and frequency of night waking. Anemia was defined as Hb<10 g/dL, iron deficiency as zinc protoporphyrin (ZPP > or = 90 micromol/mol heme), stunting as HAZ<-2 SD, and IDA as Hb<10 g/dL and ZPP > or = 90 micromol/mol heme.\nRESULTS: The prevalence of IDA and stunting was 34-84% and 22-37%, respectively. Most infants napped during the day and took approximately 1.5 naps (mean nap duration 1.4-1.7 h). Mean nighttime sleep duration was 8.3-9.7 h and infants awoke 2.1-2.5 times per night. Both IDA and stunting were associated with differences in reported sleep characterized by shorter night sleep duration and higher frequency of night waking; stunting was also related to shorter nap duration.\nCONCLUSIONS: We found reduced sleep duration and increased night waking among infants with IDA and stunting. Because sleep plays an essential role in infant development, our findings indicate a clear need for further research into these relationships.","DOI":"10.1016/j.earlhumdev.2007.10.007","ISSN":"0378-3782","note":"PMID: 18022771","shortTitle":"Maternal reports of sleep in 6-18 month-old infants from Nepal and Zanzibar","journalAbbreviation":"Early Hum. Dev.","language":"eng","author":[{"family":"Kordas","given":"Katarzyna"},{"family":"Siegel","given":"Emily H."},{"family":"Olney","given":"Deanna K."},{"family":"Katz","given":"Joanne"},{"family":"Tielsch","given":"James M."},{"family":"Chwaya","given":"Hababu M."},{"family":"Kariger","given":"Patricia K."},{"family":"Leclerq","given":"Steven C."},{"family":"Khatry","given":"Subarna K."},{"family":"Stoltzfus","given":"Rebecca J."}],"issued":{"date-parts":[["2008",6]]}}}],"schema":""} (Kordas et al., 2008) and supplemental iron was associated with longer sleep duration. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1606h3eept","properties":{"formattedCitation":"(Kordas et al., 2009)","plainCitation":"(Kordas et al., 2009)"},"citationItems":[{"id":5441,"uris":[""],"uri":[""],"itemData":{"id":5441,"type":"article-journal","title":"The effects of iron and/or zinc supplementation on maternal reports of sleep in infants from Nepal and Zanzibar","container-title":"Journal of developmental and behavioral pediatrics: JDBP","page":"131-139","volume":"30","issue":"2","source":"PubMed","abstract":"BACKGROUND: There is some evidence that sleep patterns may be affected by iron deficiency anemia but the role of iron in sleep has not been tested in a randomized iron supplementation trial.\nOBJECTIVE: We investigated the effect of iron supplementation on maternal reports of sleep in infants in 2 randomized, placebo-controlled trials from Pemba Island, Zanzibar, and Nepal.\nDESIGN: In both studies, which had parallel designs and were carried out in years 2002 to 2003, infants received iron-folic acid with or without zinc daily for 12 months, and assessments of development were made every 3 months for the duration of the study. Eight hundred seventy-seven Pemban (12.5 +/- 4.0 months old) and 567 Nepali (10.8 +/- 4.0 months) infants participated. Maternal reports of sleep patterns (napping frequency and duration, nighttime sleep duration, frequency of night waking) were collected.\nRESULTS: Mean Hb concentration was 9.2 +/- 1.1 for Pemban and 10.1 +/- 1.2 g/dL for Nepali infants. Approximately, one-third of the children were stunted. Supplemental iron was consistently associated with longer night and total sleep duration. The effects of zinc supplementation also included longer sleep duration.\nCONCLUSIONS: Micronutrient supplementation in infants at high risk for iron deficiency and iron deficiency anemia was related to increased night sleep duration and less night waking.","DOI":"10.1097/DBP.0b013e31819e6a48","ISSN":"1536-7312","note":"PMID: 19322104\nPMCID: PMC2771202","journalAbbreviation":"J Dev Behav Pediatr","language":"eng","author":[{"family":"Kordas","given":"Katarzyna"},{"family":"Siegel","given":"Emily H."},{"family":"Olney","given":"Deanna K."},{"family":"Katz","given":"Joanne"},{"family":"Tielsch","given":"James M."},{"family":"Kariger","given":"Patricia K."},{"family":"Khalfan","given":"Sabra S."},{"family":"LeClerq","given":"Steven C."},{"family":"Khatry","given":"Subarna K."},{"family":"Stoltzfus","given":"Rebecca J."}],"issued":{"date-parts":[["2009",4]]}}}],"schema":""} (Kordas et al., 2009) In some cases, night awakenings starting in the first year of life might be an early sign of restless leg syndrome. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"27hljto8rs","properties":{"formattedCitation":"(Kotagal & Silber, 2004)","plainCitation":"(Kotagal & Silber, 2004)"},"citationItems":[{"id":141,"uris":[""],"uri":[""],"itemData":{"id":141,"type":"article-journal","title":"Childhood-onset restless legs syndrome.","container-title":"Annals of neurology","page":"803-807","volume":"56","issue":"6","abstract":"The clinical characteristics of childhood-onset restless legs syndrome are described. Thirty-two of 538 subjects (5.9%) examined in our sleep disorders center received diagnoses of restless legs syndrome. They were classified based on published criteria into probable (n = 9/32 or 28%) and definite (n = 23/32 or 78%) categories. Apart from an earlier age of diagnosis of the probable group, no differences were found between the two categories. Sleep onset or sleep maintenance insomnia was the most common symptoms, being present in 28 of 32 subjects (87.5%). Inattentiveness was seen in 8 of 32 subjects (25%). Serum ferritin levels were measured in 24 of 32 subjects and were below 50 microg/L in 20 of 24 subjects (83%). A family history of restless legs syndrome was present in 23 of 32 (72%) subjects, with mothers almost three times more likely to be affected than fathers (p = 0.02). We conclude that iron deficiency and a strong family history are characteristic of childhood-onset restless legs syndrome.","DOI":"10.1002/ana.20292","ISSN":"0364-5134 0364-5134","note":"PMID: 15505786","journalAbbreviation":"Ann Neurol","language":"eng","author":[{"family":"Kotagal","given":"Suresh"},{"family":"Silber","given":"Michael H."}],"issued":{"date-parts":[["2004",12]]}}}],"schema":""} (Kotagal & Silber, 2004), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"c56mcglof","properties":{"formattedCitation":"(Picchietti & Stevens, 2008)","plainCitation":"(Picchietti & Stevens, 2008)"},"citationItems":[{"id":318,"uris":[""],"uri":[""],"itemData":{"id":318,"type":"article-journal","title":"Early manifestations of restless legs syndrome in childhood and adolescence.","container-title":"Sleep medicine","page":"770-781","volume":"9","issue":"7","abstract":"OBJECTIVE: To describe the symptomatology reported by a series of children and adolescents who at initial consultation did not meet full diagnostic criteria for pediatric restless legs syndrome (RLS) but subsequently did so over the course of clinical follow-up. METHODS: Retrospective assessment of all patients with pediatric RLS receiving ongoing care in a pediatric sleep/neurology practice at a large multispecialty clinic (n=50). Eighteen children and adolescents who met inclusion and exclusion criteria were identified by chart review. All but one had undergone polysomnography. RESULTS: Detailed sleep histories were available for 10 girls and 8 boys, all of whom presented initially with clinical sleep disturbance. Mean age at the initial sleep evaluation was 10.3 years and mean age at RLS diagnosis was 14.7 years. Detailed descriptions of the sensory RLS symptoms were recorded. Retrospective age of onset for chronic clinical sleep disturbance was a mean of 3.1 years, with 10 families reporting onset in infancy. Of the 18, 16 reported chronic sleep-onset problems and eight sleep-maintenance problems at the time of initial evaluation. Ten had a history of growing pains. Thirteen were found to have a family history of RLS. Eleven of 17 had periodic leg movements in sleep (PLMS) > or = 5 per hour. Comorbidities included parasomnias (7), attention-deficit/hyperactivity disorder (ADHD) (13), oppositional defiant disorder (ODD) (4), anxiety disorders (6), and depression (5). Serum ferritin levels of <50ng/mL were found in 16 of 18. CONCLUSIONS: In this group of 18 children and adolescents, clinical sleep disturbance preceded a diagnosis of definite RLS by an average of 11.6 years. Many had a diagnosis of periodic limb movement disorder (PLMD) or met research criteria for probable or possible RLS prior to meeting criteria for definite RLS. These findings suggest that some aspects of RLS can occur long before full diagnostic criteria are present. Comorbidities were common, with parasomnias, ADHD, ODD, anxiety, and depression each found in more than 20% of these cases. The 2003 National Institutes of Health (NIH) diagnostic criteria for pediatric RLS are supported by this work.","DOI":"10.1016/j.sleep.2007.08.012","note":"PMID: 18024165","journalAbbreviation":"Sleep Med","language":"eng","author":[{"family":"Picchietti","given":"Daniel L."},{"family":"Stevens","given":"Hanna E."}],"issued":{"date-parts":[["2008",10]]}}}],"schema":""} (Picchietti & Stevens, 2008) Because iron deficiency is common in children, measuring the ferritin level is reasonable. Different reports showed a relation between low serum ferritin levels and insomnia associated with sleep hyperkinesia (i.e. RLS or PLMs) in children with ADHD or ASD. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ectsqpdsf","properties":{"formattedCitation":"(Abou-Khadra, Amin, Shaker, & Rabah, 2013)","plainCitation":"(Abou-Khadra, Amin, Shaker, & Rabah, 2013)"},"citationItems":[{"id":776,"uris":[""],"uri":[""],"itemData":{"id":776,"type":"article-journal","title":"Parent-reported sleep problems, symptom ratings, and serum ferritin levels in children with attention-deficit/hyperactivity disorder: a case control study.","container-title":"BMC pediatrics","volume":"13","abstract":"BACKGROUND: Sleep problems are common among children with attention-deficit/hyperactivity disorder (ADHD). Serum ferritin levels have been associated with the severity of symptoms and sleep disturbances among children with ADHD. This study was conducted to investigate parent-reported sleep problems in a sample of Egyptian children with ADHD and to examine the relationship between their sleep, symptom-ratings, and low serum ferritin levels. METHODS: Parents of 41 ADHD children, aged 6 to 12 years, filled out the Children's Sleep Habits Questionnaire (CSHQ) and Conners' Parent Rating Scale-Revised: Long Version (CPRS-R:L) in Arabic. Serum ferritin levels were determined with an enzyme-linked immunosorbent assay. The parents of the 62 controls filled out the CSHQ. RESULTS: The ADHD group showed significantly higher scores in CSHQ subscales and total score. Children with serum ferritin levels <30 ng/mL had more disturbed sleep. There were significant negative correlations between sleep duration subscale, total score of CSHQ, and serum ferritin levels. There were no significant differences in hyperactivity, cognitive problems/inattention, oppositional, or ADHD index subscale scores between children with serum ferritin levels <30 ng/mL and those with serum ferritin levels >/= 30 ng/mL. CONCLUSIONS: Sleep problems are common, and this study suggests an association between low serum ferritin levels and sleep disturbances.","DOI":"10.1186/1471-2431-13-217","note":"PMID: 24377840 \nPMCID: PMC3878403","journalAbbreviation":"BMC Pediatr","language":"eng","author":[{"family":"Abou-Khadra","given":"Maha K."},{"family":"Amin","given":"Omnia R."},{"family":"Shaker","given":"Olfat G."},{"family":"Rabah","given":"Thanaa M."}],"issued":{"date-parts":[["2013"]]}}}],"schema":""} (Abou-Khadra, Amin, Shaker, & Rabah, 2013), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"spqj39rou","properties":{"formattedCitation":"(Cortese, Konofal, Bernardina, Mouren, & Lecendreux, 2009)","plainCitation":"(Cortese, Konofal, Bernardina, Mouren, & Lecendreux, 2009)"},"citationItems":[{"id":6164,"uris":[""],"uri":[""],"itemData":{"id":6164,"type":"article-journal","title":"Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder","container-title":"European Child & Adolescent Psychiatry","page":"393-399","volume":"18","issue":"7","source":"CrossRef","DOI":"10.1007/s00787-009-0746-8","ISSN":"1018-8827, 1435-165X","language":"en","author":[{"family":"Cortese","given":"Samuele"},{"family":"Konofal","given":"Eric"},{"family":"Bernardina","given":"Bernardo Dalla"},{"family":"Mouren","given":"Marie-Christine"},{"family":"Lecendreux","given":"Michel"}],"issued":{"date-parts":[["2009",7]]}}}],"schema":""} (Cortese, Konofal, Bernardina, Mouren, & Lecendreux, 2009), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"553hjetmg","properties":{"formattedCitation":"(Dosman et al., 2007)","plainCitation":"(Dosman et al., 2007)"},"citationItems":[{"id":6130,"uris":[""],"uri":[""],"itemData":{"id":6130,"type":"article-journal","title":"Children with autism: effect of iron supplementation on sleep and ferritin","container-title":"Pediatric Neurology","page":"152-158","volume":"36","issue":"3","source":"PubMed","abstract":"To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an 8-week open-label treatment trial with oral iron supplementation was conducted as a pilot study. At baseline and posttreatment visits, parents completed a Sleep Disturbance Scale for Children and a Food Record. Blood samples were obtained. Thirty-three children completed the study. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 microg/L to 29 microg/L), as did mean corpuscular volume and hemoglobin, suggesting that low ferritin in this patient group resulted from insufficient iron intake. Similar prevalence of low ferritin at school age as preschool age indicates that children with autism spectrum disorder require ongoing screening for iron deficiency.","DOI":"10.1016/j.pediatrneurol.2006.11.004","ISSN":"0887-8994","note":"PMID: 17352947","shortTitle":"Children with autism","journalAbbreviation":"Pediatr. Neurol.","language":"eng","author":[{"family":"Dosman","given":"Cara F."},{"family":"Brian","given":"Jessica A."},{"family":"Drmic","given":"Irene E."},{"family":"Senthilselvan","given":"Ambikaipakan"},{"family":"Harford","given":"Mary M."},{"family":"Smith","given":"Ryan W."},{"family":"Sharieff","given":"Waseem"},{"family":"Zlotkin","given":"Stanley H."},{"family":"Moldofsky","given":"Harvey"},{"family":"Roberts","given":"S. Wendy"}],"issued":{"date-parts":[["2007",3]]}}}],"schema":""} (Dosman et al., 2007) A recent review showed an increased incidence of periodic limb movements of sleep (42%) compared with controls (8%) in 53 pediatric patients with ASD with low serum ferritin level (below 35 ng/ml); sleep fragmentation and poor sleep efficiency were associated with lower median ferritin level. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2e13rs72h7","properties":{"formattedCitation":"(Youssef, Singh, Huntington, Becker, & Kothare, 2013)","plainCitation":"(Youssef, Singh, Huntington, Becker, & Kothare, 2013)"},"citationItems":[{"id":6132,"uris":[""],"uri":[""],"itemData":{"id":6132,"type":"article-journal","title":"Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders","container-title":"Pediatric Neurology","page":"274-278","volume":"49","issue":"4","source":"PubMed","abstract":"OBJECTIVE: Although children with autism spectrum disorders experience a range of sleep disturbances, exact mechanisms are not well-characterized. We investigated the association of serum-ferritin to sleep fragmentation and periodic limb movements of sleep using polysomnography in children with autism spectrum disorders.\nMETHODS: We conducted a retrospective chart review of children with autism spectrum disorders followed from 1990 to 2010. Inclusion criteria were availability of polysomnography data and ferritin levels within 12 months of each other. The following variables on polysomnography characterized sleep fragmentation: increased arousal index, alpha intrusions, and reduced sleep efficiency. The data were compared with age- and gender-matched controls.\nRESULTS: Of 9791 children with autism spectrum disorders identified, 511 had a ferritin level, 377 had polysomnography data, and 53 had both ferritin and polysomnography data. As compared with the controls (86 ng/mL), the median ferritin level was 27 ng/mL in the study autism spectrum disorders population (53 patients) (P < 0.01), 27 ng/mL in autism spectrum disorder subjects with periodic limb movements of sleep (25 patients) (P?= 0.01), and 24 ng/mL in autism spectrum disorders subjects with sleep fragmentation (21 patients) (P?= 0.02). Within the autism spectrum disorders population, median ferritin levels were significantly lower in patients with poor sleep efficiency (7 ng/mL) versus those with normal sleep efficiency (29 ng/mL) (P?= 0.01). The prevalence of periodic limb movements of sleep was 47% in autism spectrum disorders compared with 8% in controls (P < 0.01).\nCONCLUSION: Children with autism spectrum disorders had significantly lower ferritin levels compared with controls. In addition, they experience a higher prevalence of sleep fragmentation, obstructive sleep apnea, and periodic limb movements of sleep than children with ASD and no sleep complaints. Our preliminary observations, which have not been described before, need to be validated in multicenter prospective studies.","DOI":"10.1016/j.pediatrneurol.2013.06.012","ISSN":"1873-5150","note":"PMID: 24053984","journalAbbreviation":"Pediatr. Neurol.","language":"eng","author":[{"family":"Youssef","given":"Julie"},{"family":"Singh","given":"Kanwaljit"},{"family":"Huntington","given":"Noelle"},{"family":"Becker","given":"Ronald"},{"family":"Kothare","given":"Sanjeev V."}],"issued":{"date-parts":[["2013",10]]}}}],"schema":""} (Youssef, Singh, Huntington, Becker, & Kothare, 2013) In 102 children (68 with ASD, 18 typically developing, and 16 with developmental delay) there was an increase of PLMs, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"itqem9l7u","properties":{"formattedCitation":"(Lane et al., 2015)","plainCitation":"(Lane et al., 2015)"},"citationItems":[{"id":6134,"uris":[""],"uri":[""],"itemData":{"id":6134,"type":"article-journal","title":"Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children With Autism","container-title":"Pediatric Neurology","page":"343-349","volume":"53","issue":"4","source":"PubMed","abstract":"OBJECTIVE: Recent data suggest that both disordered sleep and low serum iron occur more frequently in children with autism compared with children with typical development. Iron deficiency has been linked to specific sleep disorders. The goal of the current study was to evaluate periodic limb movements in sleep and iron status in a group of children with autism compared with typically developing children and children with nonautism developmental delay to determine if iron status correlated with polysomnographic measures of latency and continuity and periodic limb movements in sleep.\nMETHODS: A total of 102 children (68 with autism, 18 typically developing, 16 with developmental delay) aged 2 to 7 years underwent a one-night modified polysomnography study and phlebotomy at the National Institutes of Health to measure serum markers of iron status (ferritin, iron, transferrin, percent transferrin saturation).\nRESULTS: No serum iron marker was associated with periodic limb movements of sleep or any other sleep parameter; this did not differ among the diagnostic groups. No significant differences among groups were observed on serum iron markers or most polysomnogram parameters: periodic limb movements in sleep, periodic limb movements index, wake after sleep onset, or sleep efficiency. Children in the autism group had significantly less total sleep time. Serum ferritin was uniformly low across groups.\nCONCLUSIONS: This study found no evidence that serum ferritin is associated with polysomnogram measures of latency or sleep continuity or that young children with autism are at increased risk for higher periodic limb movements index compared with typically developing and developmental delay peers.","DOI":"10.1016/j.pediatrneurol.2015.06.014","ISSN":"1873-5150","note":"PMID: 26231264\nPMCID: PMC4610130","journalAbbreviation":"Pediatr. Neurol.","language":"eng","author":[{"family":"Lane","given":"Rebecca"},{"family":"Kessler","given":"Riley"},{"family":"Buckley","given":"Ashura Williams"},{"family":"Rodriguez","given":"Alcibiades"},{"family":"Farmer","given":"Cristan"},{"family":"Thurm","given":"Audrey"},{"family":"Swedo","given":"Susan"},{"family":"Felt","given":"Barbara"}],"issued":{"date-parts":[["2015",10]]}}}],"schema":""} (Lane et al., 2015) but serum ferritin level was not significantly correlated to any sleep parameter.Iron supplementation (6 mg/kg/day of elemental iron) in 33 children with ASD showed an improvement of restless sleep score but no relation was found with serum ferritin concentrations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"26slv5icrv","properties":{"formattedCitation":"(Dosman et al., 2007)","plainCitation":"(Dosman et al., 2007)"},"citationItems":[{"id":6130,"uris":[""],"uri":[""],"itemData":{"id":6130,"type":"article-journal","title":"Children with autism: effect of iron supplementation on sleep and ferritin","container-title":"Pediatric Neurology","page":"152-158","volume":"36","issue":"3","source":"PubMed","abstract":"To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an 8-week open-label treatment trial with oral iron supplementation was conducted as a pilot study. At baseline and posttreatment visits, parents completed a Sleep Disturbance Scale for Children and a Food Record. Blood samples were obtained. Thirty-three children completed the study. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 microg/L to 29 microg/L), as did mean corpuscular volume and hemoglobin, suggesting that low ferritin in this patient group resulted from insufficient iron intake. Similar prevalence of low ferritin at school age as preschool age indicates that children with autism spectrum disorder require ongoing screening for iron deficiency.","DOI":"10.1016/j.pediatrneurol.2006.11.004","ISSN":"0887-8994","note":"PMID: 17352947","shortTitle":"Children with autism","journalAbbreviation":"Pediatr. Neurol.","language":"eng","author":[{"family":"Dosman","given":"Cara F."},{"family":"Brian","given":"Jessica A."},{"family":"Drmic","given":"Irene E."},{"family":"Senthilselvan","given":"Ambikaipakan"},{"family":"Harford","given":"Mary M."},{"family":"Smith","given":"Ryan W."},{"family":"Sharieff","given":"Waseem"},{"family":"Zlotkin","given":"Stanley H."},{"family":"Moldofsky","given":"Harvey"},{"family":"Roberts","given":"S. Wendy"}],"issued":{"date-parts":[["2007",3]]}}}],"schema":""} (Dosman et al., 2007) When poor sleep is reported in children with ADHD or NDDs, serum ferritin levels should be monitored and questions on restless sleep should be asked. If ferritin levels are less than 50 mcg per L, 1–2 mg/kg/day of elemental iron (up to 6 mg/ kg/day of elemental iron) should be administered. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1he60k9opo","properties":{"formattedCitation":"(Abou-Khadra et al., 2013)","plainCitation":"(Abou-Khadra et al., 2013)"},"citationItems":[{"id":776,"uris":[""],"uri":[""],"itemData":{"id":776,"type":"article-journal","title":"Parent-reported sleep problems, symptom ratings, and serum ferritin levels in children with attention-deficit/hyperactivity disorder: a case control study.","container-title":"BMC pediatrics","volume":"13","abstract":"BACKGROUND: Sleep problems are common among children with attention-deficit/hyperactivity disorder (ADHD). Serum ferritin levels have been associated with the severity of symptoms and sleep disturbances among children with ADHD. This study was conducted to investigate parent-reported sleep problems in a sample of Egyptian children with ADHD and to examine the relationship between their sleep, symptom-ratings, and low serum ferritin levels. METHODS: Parents of 41 ADHD children, aged 6 to 12 years, filled out the Children's Sleep Habits Questionnaire (CSHQ) and Conners' Parent Rating Scale-Revised: Long Version (CPRS-R:L) in Arabic. Serum ferritin levels were determined with an enzyme-linked immunosorbent assay. The parents of the 62 controls filled out the CSHQ. RESULTS: The ADHD group showed significantly higher scores in CSHQ subscales and total score. Children with serum ferritin levels <30 ng/mL had more disturbed sleep. There were significant negative correlations between sleep duration subscale, total score of CSHQ, and serum ferritin levels. There were no significant differences in hyperactivity, cognitive problems/inattention, oppositional, or ADHD index subscale scores between children with serum ferritin levels <30 ng/mL and those with serum ferritin levels >/= 30 ng/mL. CONCLUSIONS: Sleep problems are common, and this study suggests an association between low serum ferritin levels and sleep disturbances.","DOI":"10.1186/1471-2431-13-217","note":"PMID: 24377840 \nPMCID: PMC3878403","journalAbbreviation":"BMC Pediatr","language":"eng","author":[{"family":"Abou-Khadra","given":"Maha K."},{"family":"Amin","given":"Omnia R."},{"family":"Shaker","given":"Olfat G."},{"family":"Rabah","given":"Thanaa M."}],"issued":{"date-parts":[["2013"]]}}}],"schema":""} (Abou-Khadra et al., 2013), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"j933ro5vb","properties":{"formattedCitation":"(Cortese, Konofal, et al., 2009)","plainCitation":"(Cortese, Konofal, et al., 2009)"},"citationItems":[{"id":6164,"uris":[""],"uri":[""],"itemData":{"id":6164,"type":"article-journal","title":"Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder","container-title":"European Child & Adolescent Psychiatry","page":"393-399","volume":"18","issue":"7","source":"CrossRef","DOI":"10.1007/s00787-009-0746-8","ISSN":"1018-8827, 1435-165X","language":"en","author":[{"family":"Cortese","given":"Samuele"},{"family":"Konofal","given":"Eric"},{"family":"Bernardina","given":"Bernardo Dalla"},{"family":"Mouren","given":"Marie-Christine"},{"family":"Lecendreux","given":"Michel"}],"issued":{"date-parts":[["2009",7]]}}}],"schema":""} (Cortese, Konofal, et al., 2009). Parents should be asked for a personal and family history of hemochromatosis. Vitamin DClinical research on the relation between vitamin D and sleep is ongoing, and a few studies have been published on the role of vitamin D metabolism and sleep disorders. Preliminary data suggest the possibility that altered vitamin D metabolism could play an important role in the presentation and severity of sleep disorders. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1utqn02en","properties":{"formattedCitation":"(McCarty, Chesson, Jain, & Marino, 2014)","plainCitation":"(McCarty, Chesson, Jain, & Marino, 2014)"},"citationItems":[{"id":1075,"uris":[""],"uri":[""],"itemData":{"id":1075,"type":"article-journal","title":"The link between vitamin D metabolism and sleep medicine.","container-title":"Sleep medicine reviews","page":"311-319","volume":"18","issue":"4","abstract":"Vitamin D is a hormone that interacts with intranuclear receptors to effect transcriptional changes in many cell types including those in gut, bone, breast, prostate, brain, skeletal muscle, and the immune system. Inadequacy of vitamin D is widely prevalent, and leads to the classic diseases of bone demineralization as well as to more recently recognized problems such as nonspecific pain and noninflammatory skeletal myopathy, which may disrupt sleep and directly cause daytime impairment. Emerging lines of evidence suggest that low vitamin D levels increase the risk for autoimmune disease, chronic rhinitis, tonsillar hypertrophy, cardiovascular disease, and diabetes. These conditions are mediated by altered immunomodulation, increased propensity to infection, and increased levels of inflammatory substances, including those that regulate sleep, such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, and prostaglandin D2 (PD2). Together, the recent reports suggest a role for inadequate vitamin D in the development of symptoms of wake impairment commonly associated with sleep disorders. Persistent inadequacy of vitamin D may also increase the risk for obstructive sleep apnea via promotion of adenotonsillar hypertrophy, airway muscle myopathy, and/or chronic rhinitis. Much remains to be learned concerning the complex relationship between chronically low levels of vitamin D, normal sleep, sleep disruption, and daytime neurocognitive impairment.","DOI":"10.1016/j.smrv.2013.07.001","note":"PMID: 24075129","journalAbbreviation":"Sleep Med Rev","language":"eng","author":[{"family":"McCarty","given":"David E."},{"family":"Chesson","given":"Andrew L. Jr"},{"family":"Jain","given":"Sushil K."},{"family":"Marino","given":"Andrew A."}],"issued":{"date-parts":[["2014",8]]}}}],"schema":""} (McCarty, Chesson, Jain, & Marino, 2014) Low vitamin D concentrations may impact sleep quality via increased pain, myopathy, immune dysregulation, and cardiovascular disease.The few published studies suggest vitamin D supplementation may improve sleep quality; especially in patients with neurologic complaints who also have evidence of abnormal sleep. Most patients have improvement in neurologic symptoms and sleep but only by maintaining a narrow range of 25(OH) vitamin D3 blood levels of 60–80 ng/ml. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1eebrsg6hj","properties":{"formattedCitation":"(Gominak & Stumpf, 2012)","plainCitation":"(Gominak & Stumpf, 2012)"},"citationItems":[{"id":6138,"uris":[""],"uri":[""],"itemData":{"id":6138,"type":"article-journal","title":"The world epidemic of sleep disorders is linked to vitamin D deficiency","container-title":"Medical Hypotheses","page":"132-135","volume":"79","issue":"2","source":"PubMed","abstract":"An observation of sleep improvement with vitamin D supplementation led to a 2 year uncontrolled trial of vitamin D supplementation in 1500 patients with neurologic complaints who also had evidence of abnormal sleep. Most patients had improvement in neurologic symptoms and sleep but only through maintaining a narrow range of 25(OH) vitamin D3 blood levels of 60-80 ng/ml. Comparisons of brain regions associated with sleep-wake regulation and vitamin D target neurons in the diencephalon and several brainstem nuclei suggest direct central effects of vitamin D on sleep. We propose the hypothesis that sleep disorders have become epidemic because of widespread vitamin D deficiency. The therapeutic effects together with the anatomic-functional correspondence warrant further investigation and consideration of vitamin D in the etiology and therapy of sleep disorders.","DOI":"10.1016/j.mehy.2012.03.031","ISSN":"1532-2777","note":"PMID: 22583560","journalAbbreviation":"Med. Hypotheses","language":"eng","author":[{"family":"Gominak","given":"S. C."},{"family":"Stumpf","given":"W. E."}],"issued":{"date-parts":[["2012",8]]}}}],"schema":""} (Gominak & Stumpf, 2012) Vitamin D is related to dopamine metabolism; it could be useful to investigate vitamin levels in association with iron parameters in children with NDDs and insomnia associated with motor hyperactivity during sleep.Orexin antagonistsRecently, orexin neuropeptides have been identified as regulators of the sleep/wakefulness transition and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"212qtu9rle","properties":{"formattedCitation":"(Chow & Cao, 2016)","plainCitation":"(Chow & Cao, 2016)"},"citationItems":[{"id":5783,"uris":[""],"uri":[""],"itemData":{"id":5783,"type":"article-journal","title":"The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress","container-title":"Nature and Science of Sleep","page":"81-86","volume":"8","source":"PubMed","abstract":"Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep-wake regulation came from narcolepsy-cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep-wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep-wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.","DOI":"10.2147/NSS.S76711","ISSN":"1179-1608","note":"PMID: 27051324\nPMCID: PMC4803263","shortTitle":"The hypocretin/orexin system in sleep disorders","journalAbbreviation":"Nat Sci Sleep","language":"eng","author":[{"family":"Chow","given":"Matthew"},{"family":"Cao","given":"Michelle"}],"issued":{"date-parts":[["2016"]]}}}],"schema":""} (Chow & Cao, 2016) Orexin hold an important role in the wakefulness promoting ascending arousal system by having an excitatory effect on almost every wake promoting neuronal group of reticular ascending system (RAS) and represent the critical modulators of the sleep wake cycle homeostasis. The orexin receptor antagonists can be classified on the basis of receptor binding affinities, either as Selective Orexin Receptor Antagonists (SORAs; i.e. selective for OX1 or OX2 receptors) or Dual Orexin Receptor Antagonists (DORAs; i.e. compound with spread binding capacity to OX1 and OX2). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jb365ooo5","properties":{"formattedCitation":"(Kumar, Chanana, & Choudhary, 2016)","plainCitation":"(Kumar, Chanana, & Choudhary, 2016)"},"citationItems":[{"id":5723,"uris":[""],"uri":[""],"itemData":{"id":5723,"type":"article-journal","title":"Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs","container-title":"Pharmacological reports: PR","page":"231-242","volume":"68","issue":"2","source":"PubMed","abstract":"The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine.","DOI":"10.1016/j.pharep.2015.09.002","ISSN":"1734-1140","note":"PMID: 26922522","shortTitle":"Emerging role of orexin antagonists in insomnia therapeutics","journalAbbreviation":"Pharmacol Rep","language":"eng","author":[{"family":"Kumar","given":"Anil"},{"family":"Chanana","given":"Priyanka"},{"family":"Choudhary","given":"Supriti"}],"issued":{"date-parts":[["2016",4]]}}}],"schema":""} (Kumar, Chanana, & Choudhary, 2016) It was hypothesized that antagonizing both orexin receptors would elicit the most powerful sleep-promoting effects. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2bs888jg7m","properties":{"formattedCitation":"(Morairty et al., 2012)","plainCitation":"(Morairty et al., 2012)"},"citationItems":[{"id":5729,"uris":[""],"uri":[""],"itemData":{"id":5729,"type":"article-journal","title":"Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone","container-title":"PloS One","page":"e39131","volume":"7","issue":"7","source":"PubMed","abstract":"The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking \"drive\".","DOI":"10.1371/journal.pone.0039131","ISSN":"1932-6203","note":"PMID: 22768296\nPMCID: PMC3388080","journalAbbreviation":"PLoS ONE","language":"eng","author":[{"family":"Morairty","given":"Stephen R."},{"family":"Revel","given":"Florent G."},{"family":"Malherbe","given":"Pari"},{"family":"Moreau","given":"Jean-Luc"},{"family":"Valladao","given":"Daniel"},{"family":"Wettstein","given":"Joseph G."},{"family":"Kilduff","given":"Thomas S."},{"family":"Borroni","given":"Edilio"}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} (Morairty et al., 2012) Currently, the most widely debated DORA molecules (almorexant and suvorexant) administered to healthy volunteers and patients with insomnia, effectively reduced the number of awakenings and sleep latency while increasing total sleep time. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2fir0h30sn","properties":{"formattedCitation":"(Kumar et al., 2016)","plainCitation":"(Kumar et al., 2016)"},"citationItems":[{"id":5723,"uris":[""],"uri":[""],"itemData":{"id":5723,"type":"article-journal","title":"Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs","container-title":"Pharmacological reports: PR","page":"231-242","volume":"68","issue":"2","source":"PubMed","abstract":"The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine.","DOI":"10.1016/j.pharep.2015.09.002","ISSN":"1734-1140","note":"PMID: 26922522","shortTitle":"Emerging role of orexin antagonists in insomnia therapeutics","journalAbbreviation":"Pharmacol Rep","language":"eng","author":[{"family":"Kumar","given":"Anil"},{"family":"Chanana","given":"Priyanka"},{"family":"Choudhary","given":"Supriti"}],"issued":{"date-parts":[["2016",4]]}}}],"schema":""} (Kumar et al., 2016)The most frequent dose dependent adverse effects are mild somnolence, headaches, dizziness and abnormal dreams. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ammbp1aca","properties":{"formattedCitation":"(Bennett, Bray, & Neville, 2014)","plainCitation":"(Bennett, Bray, & Neville, 2014)"},"citationItems":[{"id":5727,"uris":[""],"uri":[""],"itemData":{"id":5727,"type":"article-journal","title":"Suvorexant, a dual orexin receptor antagonist for the management of insomnia","container-title":"P & T: A Peer-Reviewed Journal for Formulary Management","page":"264-266","volume":"39","issue":"4","source":"PubMed","abstract":"Suvorexant, a dual orexin receptor antagonist for the management of insomnia.","ISSN":"1052-1372","note":"PMID: 24757363\nPMCID: PMC3989084","journalAbbreviation":"P T","language":"eng","author":[{"family":"Bennett","given":"Tiffany"},{"family":"Bray","given":"David"},{"family":"Neville","given":"Michael W."}],"issued":{"date-parts":[["2014",4]]}}}],"schema":""} (Bennett, Bray, & Neville, 2014) The major route of metabolism for almorexant and suvorexant is CYP3A. Suvorexant is the most widely studied and concomitant use with CYP3A Inhibitors is not recommended since the effects could be increased about 2-3 folds (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, ciprofloxacin, diltiazem, erythromycin fluconazole, grapefruit juice, verapamil). On the other hand strong CYP3A Inducers can substantially decrease almorexant and suvorexant exposure (e.g., rifampin, carbamazepine, phenytoin). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1njp4al7d5","properties":{"formattedCitation":"(Kishi, Matsunaga, & Iwata, 2015)","plainCitation":"(Kishi, Matsunaga, & Iwata, 2015)"},"citationItems":[{"id":6156,"uris":[""],"uri":[""],"itemData":{"id":6156,"type":"article-journal","title":"Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials","container-title":"PloS One","page":"e0136910","volume":"10","issue":"8","source":"PubMed","abstract":"OBJECTIVE: We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia.\nMETHODS: Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated.\nRESULTS: The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = -20.16, 95% CI = -25.01 to -15.30, 1889 patients, 3 trials, sTSO: WMD = -7.62, 95% CI = -11.03 to -4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia.\nCONCLUSIONS: Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.","DOI":"10.1371/journal.pone.0136910","ISSN":"1932-6203","note":"PMID: 26317363\nPMCID: PMC4552781","shortTitle":"Suvorexant for Primary Insomnia","journalAbbreviation":"PLoS ONE","language":"eng","author":[{"family":"Kishi","given":"Taro"},{"family":"Matsunaga","given":"Shinji"},{"family":"Iwata","given":"Nakao"}],"issued":{"date-parts":[["2015"]]}}}],"schema":""} (Kishi, Matsunaga, & Iwata, 2015) This category of compounds might be promising for children with NDDs since they act on a different neurotransmitter system with less interactions with other drugs commonly used in these children. Randomized controlled trials are needed to assess both the short- and long-term effects of these medications, as well as their efficacy in comorbid diseases that affect sleep architecture.RECOMMENDATIONS FOR FUTURE RESEARCHThe treatment of insomnia in special populations is a field that still needs to be explored. It is extremely important to improve sleep quality and quantity in children with NDDs since this would lead to improve insomnia related daytime impairments involving not only the child but the entire family. A better quality of sleep could ameliorate daytime behavior and even cognitive development and for sure will lead to an improvement of sleep related psychological distress in the family.The medical approach should consider medical and psychiatric contributing factors, primary sleep disorders and maladaptive behaviors related to sleep. The correct treatment should follow a specific scheme: behavioral treatment strategies through the parents, circadian rhythm regulation and pharmacological treatment.Use of medications for pediatric insomnia should be diagnostically driven, and should be implemented in conjunction with empirically-based behavioral treatment strategies and adequate sleep hygiene Future studies should address a number of shortcomings identified in our review. First, It is imperative to perform new studies to identify objective and specific outcome indicators that could give measures of wake time after sleep onset (WASO), sleep onset latency (SOL), number of awakenings, sleep time or sleep efficiency. Use of actigraphy should be an integrative part of any studies in this field and also integrate information from multiple informants (e.g. parents, teachers, therapists, etc.) Second, we need to understand whether treatments are more effective in certain subgroups, in relation to specific comorbidities (i.e. RLS in children with ADHD or respiratory disturbances in Rett’s syndrome). Third, randomized controlled trials on larger sample of children with NDDs comparing the different drugs with double blind studies should be carried out possibly extended in longitudinal studies to evaluate how symptoms of insomnia changed with the development.Fourth, studies should be devoted to identify specific doses of all agents that may be required in younger children, and the potential for side-effects and drug-drug interactions.Fifth, an important step of future studies would be to analyze in details how sleep improvement through specific drugs could improve the cognitive outcomes in specific populations in the interplay with the cognitive- behavioral therapy.Finally, there is a need to investigate the long-term effectiveness of the different drugs analyzing the possible effects of tolerance and the eventual lack of efficacy over time of specific drugs (i.e. benzodiazepines).CONCLUSIONSInsomnia in children with NDDs, associated with the other neurobehavioral comorbidities, affects the quality of life of both children and families, is associated with poorer developmental outcome, and contributes to worsen behavioral disturbances.Despite the widespread use of pharmacological treatment, the lack of well designed, controlled studies concerning the efficacy, tolerability, dosage, and safety profile of hypnotic medications in children raise the need of further research in this field of sleep medicine. The lack of research in this area is detrimental for children and their families and well conducted trials should be performed based on the physiopathology of the disorders evaluating also the presence of other comorbid sleep disorders and choose the correct drugs not based only on their sedative or anxiolytic effects.Future researches will hopefully lead to a development of a drug with proved efficacy and suitable safety profile that will allow a better health and quality of life of children and adolescents with NDDs and their families.REFERENCES ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY Abou-Khadra, M. K., Amin, O. R., Shaker, O. G., & Rabah, T. M. (2013). Parent-reported sleep problems, symptom ratings, and serum ferritin levels in children with attention-deficit/hyperactivity disorder: a case control study. BMC Pediatrics, 13. , K. W., Molloy, C., Weiss, S. K., Reynolds, A., Goldman, S. E., Burnette, C., … Malow, B. A. (2012). 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