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 a prevalence of 1 per 150 (CDC, MMWR 2007, Feb 9th release) The life-long impairments in communication and social function are often complicated by the presence of medical comorbidities, including epilepsy, gastrointestinal disturbances and sleep disorders. Little is known about the pathophysiology of these comorbid conditions and even less about treatment of the symptoms among individuals with autism. 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. Previous studies in children with autism have identified various abnormalities in sleep including immature organization, decreased quantity of sleep, abnormal movements and altered patterns of the stages of sleep. 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 (hereafter referred to as SPT REM% for REM sleep as a percent of sleep period 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. Acetylcholine (Ach) is one of the major neurotransmitters necessary for normal sleep transitions and abnormalities in Ach have been implicated in REM deficient sleep in other populations, most notably Alzheimers disease. Donepezil hydrochloride has been shown to normalize REM sleep in young healthy adults, in elderly, healthy adults and in 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. An open-label clinical trial of donepezil hydrochloride is currently underway 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). Children whose baseline PSG shows that they have low SPT REM% will qualify for donepezil administration at 1.25 mg daily. After one month of donepezil administration, the polysomnography study will be repeated. If SPT REM% has normalized, the trial will be complete and the parents may choose to end their child's study participation or to continue the donepezil at 1.25 mg daily for three additional months. If SPT REM% has not normalized, the dose can be increased to 2.5 mg and the PSG repeated again. If 2.5 mg is also insufficient, the dose can be increased to a maximum of 5.0mg/day. The primary outcome measure of this pilot investigation is to find the dose of donepezil which reliably increases the SPT REM% into the normal range. The side-effects profile of donepezil is also of interest in this pilot study, as there is little previous experience with pediatric administration of the drug. If 1.25, 2.5 or 5.0mg per day of donepezil is consistently effective in normalizing REM sleep, and the drug's side-effects profile is favorable, then a placebo-controlled trial will be initiated to assess the effects of long-term donepezil administration on REM sleep and on autistic symptoms, learning, memory and overall behavior. At the time of this writing, recruitment and screening are still underway for the open-label portion of the trial, but enrollment is expected to be completed early in the next reporting period. The decision whether or not to conduct the larger, placebo-controlled trial should follow closely thereafter. Interested parties can find additional information about the study at: http://clinicaltrials.gov/ct2/show/NCT00695136
| Buckley, Ashura W; Holmes, Gregory L (2016) Epilepsy and Autism. Cold Spring Harb Perspect Med 6:a022749 |
| 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 |
| 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 |
| Smith, Elizabeth; Thurm, Audrey; Greenstein, Deanna et al. (2016) Cortical thickness change in autism during early childhood. Hum Brain Mapp 37:2616-29 |
| 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 |
| Hommer, Rebecca E; Swedo, Susan E (2015) Schizophrenia and autism-related disorders. Schizophr Bull 41:313-4 |
| 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 |
| 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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