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, (and epileptiform discharges), 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 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 outcome measure of the 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 might 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, data analysis is underway and the pilot study is no longer enrolling subjects. It has long been known that as many as 1/3 of individuals with ASD have seizures. Abnormal electroencephalograms (EEGs) (without seizure activity) are even more prevalent (Spence &Schneider, 2009). In an ongoing study at the NIMH, approximately one-half of children with ASD without epilepsy had epileptiform discharges present on overnight EEG. The relationship between this abnormal activity and autism symptoms has not yet been studied;however, data from other epilepsy syndromes suggest that these epileptiform discharges contribute to behavioral and cognitive deficits. We have designed a trial to test whether the administration of divalproex sodium, a commonly used anti-epileptic medication, will be effective in reducing the epileptiform discharges in children with autism. As a secondary outcome we will investigate whether or not reduction of the epileptiform discharges will result in improved behavior and more rapid intellectual and social development in children with ASD. This pilot trial is a double blind randomized placebo controlled trial for children with ASD who are 3-10 years of age and who have frequent epileptiform discharges. The trial will last 6 months with a 3 month open label extension phase. Overnight EEGs will be used to detect changes in epileptiform activity at baseline, 3 and 6 months. A variety of cognitive and behavioral measures will be employed to investigate the effect changes in EEG have on the autism phenotype. The protocol was recently approved by the CNS IRB and is now open for enrollment. Interested parties can find additional information about this trial at: www.clinicaltrials.gov/ct2/show/NCT01170325?term=autism+and+bethesda&rank=9
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| 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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