Autism spectrum disorders are defined by deficits of communication and socialization and the presence of restrictive and/or repetitive behaviors. Recent epidemiologic studies have documented an increase in the number of children identified with autism spectrum disorder (ASD) over the past decade and according to some, the current numbers indicate that as many as 1% of children have an ASD. The life-long impairments in communication and social function are often complicated by the presence of medical comorbidities, including epilepsy, (and epileptiform discharges), gastrointestinal disturbances and sleep disorders. Little is known about the pathophysiology of these comorbid conditions and even less about treatment of these disorders in autistic individuals. A variety of traditional medical and alternative biomedical approaches have been tried and anecdotally reported to be useful for one or a few individuals, but none has proven efficacious when subjected to a randomized, placebo-controlled investigation. Thus, identifying the etiology, pathophysiology and treatment of the medical comorbidities of autism is an important goal for research. When multiplied by the millions of children reported to be affected by ASD, the potential public health impact is tremendous. Sleep disorders in ASD are of particular interest to our research group and can be reliably investigated using polysomnography (PSG), a non-invasive recording of a variety of sleep parameters. Preliminary observations from another of our projects, "Clinical and Behavioral Phenotyping of Autism and Related Disorders", (MH002868-03) revealed that children with autism spent an abnormally short time in the Rapid Eye Movement (REM) stage of sleep compared to total sleep time and had a prolonged latency to REM sleep. Rapid Eye Movement sleep is thought to play a key role in learning and memory, with some hypothesizing that memory consolidation occurs primarily during REM sleep. REM sleep is also crucial to a variety of other cognitive processes, including the processing of emotion in the memory system. Although its relationship to human neurodevelopment is unknown, animal studies have shown that REM sleep increases after intensive learning sessions. These laboratory findings formed the basis for the hypothesis that REM sleep is important for learning and that REM sleep also may be a useful indicator of brain plasticity. Donepezil hydrochloride has been shown to normalize REM sleep among young healthy adults;among elderly healthy adults;and among elderly demented adults with Alzheimers disease. Furthermore, research by Mizuno et al showed a positive correlation between improved cognition and increased SPT REM % among elderly adults with Alzheimers disease. Thus, it is possible that donepezil treatment could produce benefits not only in the quality of the children's sleep, but also in their ability to learn and remember and consequently, in their overall behavioral health and neurodevelopment. A small open-label pilot study of donepezil hydrochloride was undertaken to evaluate its ability to enhance REM sleep in 2 to 11 year-old children with autism who exhibit a low SPT REM% (defined as below 2 standard deviations of observed normative data for age). The primary purpose of the study was to determine the minimum dosage of donepezil required to normalize the amount of REM sleep. The side-effects profile of donepezil was also of interest in this pilot study, as there has been little previous experience with pediatric administration of the drug. Results of this study were recently published, showing 2.5 mg per day of donepezil was sufficient to significantly increase REM sleep as a percentage of total sleep in children with autism. The drug was also shown to decrease REM latency. The pilot data provide support for a larger, placebo-controlled study to investigate the use of donepezil in the treatment of sleep problems in children with ASD. An additional goal of the trial will be to evaluate impact of donepezil administration and REM sleep normalization on the core symptoms of autism, and also on the children's overall behavior, development and cognition. Subject enrollment will commence as soon as approvals are received from the NIH Combined Neurosciences (CNS) Institutional Review Board (IRB) and information about the trial will then be posted at ClinicalTrials.gov

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$339,591
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Zip Code
Buckley, Ashura W; Holmes, Gregory L (2016) Epilepsy and Autism. Cold Spring Harb Perspect Med 6:a022749
Smith, Elizabeth; Thurm, Audrey; Greenstein, Deanna et al. (2016) Cortical thickness change in autism during early childhood. Hum Brain Mapp 37:2616-29
Gaughan, Thomas; Buckley, Ashura; Hommer, Rebecca et al. (2016) Rapid Eye Movement Sleep Abnormalities in Children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). J Clin Sleep Med 12:1027-32
Thurm, Audrey; Tierney, Elaine; Farmer, Cristan et al. (2016) Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update. J Neurodev Disord 8:12
Buckley, Ashura W; Scott, Rod; Tyler, Anna et al. (2015) State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder. EBioMedicine 2:1905-15
Lane, Rebecca; Kessler, Riley; Buckley, Ashura Williams et al. (2015) Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children With Autism. Pediatr Neurol 53:343-9
Hommer, Rebecca E; Swedo, Susan E (2015) Schizophrenia and autism-related disorders. Schizophr Bull 41:313-4
Coury, Daniel L; Swedo, Susan E; Thurm, Audrey E et al. (2014) Treating the whole person with autism: the proceedings of the Autism Speaks National Autism Conference. Curr Probl Pediatr Adolesc Health Care 44:26-47
Buckley, Ashura; Wingert, Katherine; Swedo, Susan et al. (2013) First night effect analysis in a cohort of young children with autism spectrum disorder. J Clin Sleep Med 9:67-70
Buckley, Ashura Williams; Sassower, Kenneth; Rodriguez, Alcibiades J et al. (2011) An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders. J Child Adolesc Psychopharmacol 21:353-7

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