The Effect of Donepezil (Aricept(Registered Trademark)) on REM Sleep in Children With Autism
Condition: Autism; Cognition Disorder
MeSH terms: Autistic Disorder; Cognition Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will test whether donepezil (Aricept(Registered Trademark)), a drug that is
      approved by the Food and Drug Administration to treat Alzheimer's disease, can increase rapid
      eye movement (REM) sleep in children with autism and autism spectrum disorder (ASD). Some
      children with autism and ASD spend very little time in REM sleep. In some studies, decreased
      REM sleep has been associated with learning and behavior problems. Donepezil can increase REM
      sleep in some adults with different disorders. If it can increase REM sleep in children in
      this study, it might be able to be used in future studies to see if it can help learning and
      behavior problems in children with autism and ASD.

      Children between 2 and 10 years of age with autism or an ASD whose percentage of REM sleep
      time is well below the average for children of the same age may be eligible for this study.
      Candidates are screened with a medical history, physical and neurological examinations, blood
      tests, electroencephalogram (EEG) and a sleep study. The sleep study requires an overnight
      stay at the NIH Clinical Center in which the child is monitored with electrodes for EEG and
      heartbeat recording, a tube taped below the nose to measure airflow, a probe on a finger to
      record oxygen levels and a small watch-like machine on the wrist to record movements.

      Participating children may be required to have up to six overnight stays for sleep studies at
      the Clinical Center. The children start by taking 1.25 mg of donepezil for 2 to 4 weeks. Then
      they are admitted to the NIH Clinical Center for a sleep study, blood tests and EKG. Those
      whose REM sleep increases to normal levels stay on 1.25 mg of donepezil for 8 more weeks,
      after which they are admitted to the Clinical Center for a final physical examination, blood
      draw and sleep study. That ends their participation in the study.

      Children whose REM sleep does not increase to normal on 1.25 mg of donepezil are given a
      higher dose (2.5 mg) for 2 to 4 weeks, and the above procedure is repeated. Those whose REM
      sleep does not increase to normal on 2.5 mg of donepezil take 5 mg of the drug for 2 to 4
      weeks, and the above procedure is repeated once more. Children whose REM sleep does not
      increase to normal on 5 mg of donepezil stop the medication and end their participation in
      the study.

      At each study visit, study researchers talk to the parents and examine the children to
      determine if donepezil is affecting the child's behavior and if the child is hav...
    

Detailed description: 
      Autism spectrum disorders are defined by aberrant development of communication and
      socialization in 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 over the past decade and according to some, the current numbers
      indicate a prevalence of 1 per 150 (CDC, MMWR 2007, Feb 9th release). Despite the pressing
      need to identify causal factors, etiology remains elusive. Furthermore, the heterogeneity of
      presentation complicates attempts to locate autism's home in the brain.

      Polysomnography is a reliable non-invasive tool that can be used to study the basic
      pathophysiological mechanisms of autism and other developmental and neuropsychiatric
      disabilities. Our preliminary data in young children with autism supports a growing body of
      literature demonstrating that sleep architecture is abnormal in this disorder. Previous
      studies in children with autism have identified various abnormalities in REM sleep including
      the following: immature organization, decreased quantity, abnormal twitches, undifferentiated
      sleep and REM sleep behavior disorder characterized by the absence of the muscle atonia that
      is normal in REM sleep and resulting in an acting out of dreams phenomenon (Tanguay et al
      ,.1976, Elia et al., 2000, Diomedi et al. 1999, and Thirumalai et al., 2002).

      Our cohort spent an abnormally short time in the REM sleep 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. The function of REM sleep and its
      relationship to cognition and overall neurological health is unknown and a subject of ongoing
      research. We know from animal studies that REM sleep increases after intensive learning
      sessions. These laboratory findings formed the basis for the hypothesis that this sleep stage
      is important for cognitive processes and that REM sleep may be useful as an indicator of
      brain plasticity. Current studies continue to add support for this idea. REM sleep has most
      recently been implicated in the process of human memory consolidation and several studies
      suggest that it is crucial to normal cognitive function and in the processing of emotion in
      memory systems. 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 Alzheimer's disease.

      This proposal is for a 6 to 20 week, single arm, open-label study to evaluate the ability of
      donepezil hydrochloride to enhance REM sleep in children with autism spectrum disorder found
      to have a low SPT REM% (defined as below 2 standard deviations of observed normative data for
      age). All patients will come through the screening protocol 06-M-0065. Those who meet a
      research diagnosis of autism spectrum disorder and are ages 2 to 11 (through the tenth year)
      will be evaluated for inclusion/exclusion criteria for the study.

      The primary outcome measure of this protocol is to increase the SPT REM% in children with
      autism such that their REM/non-REM ratios begin to approach normative values. Donepezil
      enhanced REM sleep has been achieved in young healthy adults, in elderly, healthy adults and
      in elderly, demented adults with Alzeheimer's disease. Furthermore, the studies in Alzheimer
      disease by Mizuno et al showed a positive correlation between improved cognition and
      increased SPT REM %. If REM sleep is necessary for normal cognition, and its deficiency or
      absence can be remedied by pharmacologic intervention, then it may follow that improvement of
      REM sleep correlates with improved short and long term cognition in children with autism.
      Donepezil enhanced REM sleep has not been documented in children. Polysomnography provides a
      non-invasive tool to assess the effects of enhancing cholinergic tone on the abnormal sleep
      architecture we have documented in our pediatric, autistic population.
    

Intervention name(s): Donepezil hydrochloride; Increase REM sleep percentage
Intervention type(s): Drug; Behavioral
Intervention MeSH terms: Donepezil
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: Autism; Cognitive Disorder; Sleep; Autism Spectrum Disorder; ASD