Autism Blog - Clinical trial of Donepezil for improving REM sleep in autistic children

23 Mar 2010

Author: Sullivan
Comments: 11

Clinical trial of Donepezil for improving REM sleep in autistic children

A recent lecture I heard discussed how as many as 25% of autistic children get little or no REM (rapid eye movement) sleep. REM sleep is an important sleep phase and it is thought this could contribute to cognition and behavior problems in these children.

Anecdotally (and probably confirmed by studies is my guess) many autistic children have sleep problems. Children are reported to sleep fewer hours, have problems getting to sleep and wake up in the middle of the night. This new result, to me at least, is the first I’ve heard of reduction or lack in REM sleep.

In response to this finding, a clinical trial is underway to study the use of Donepezil (Aricept) with autistic children.

The clinical trial description is:

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.

My guess is that some are thinking, “why look at this drug when many already use melatonin to help autistic children sleep”. After all, Aricept is an Alzheimer’s drug, with little study in children.

OK, I admit I did. So I did a quick search and found that melatonin has not been found to increase REM sleep.

Aside from my reservations about giving an Alzheimer’s drug to 2 year olds, this is the type of clinical trial I like to see. A clear question is presented that is supported by data. A clear outcome (increased REM sleep) is measurable. Secondary outcomes, improved cognition and behavior, are also measurable and defined.

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Comments

11 Responses to “Clinical trial of Donepezil for improving REM sleep in autistic children”

Corina Becker
March 23rd, 2010
06:01:53

Also putting my reservations about giving an Alzheimer’s drug to kids, I’m now curious about possible studies with the adult autistic population.

I’m also wondering exactly what were the results of my sleep studies when I go in for sleep apnea studies and such. It’ll be interesting, I think.

But yes, I also like the way in which this study is set up.
Laurentius Rex
March 23rd, 2010
09:41:58

It’s big pharma at it again, if it were legal they would market cigarretes and alcohol for kids too.

It may be that Aricept is only one of a number of lifestyle drugs, that has a universal effect which just happens to be useful for Alzheimer’s, and of no more consequence than taking caffeine to stay awake.

For what is worth, I think there is a lot of bull talked about sleep it may well be that some folk are adapted to make do with less of it. I certainly do not think a life time of catastrophic sleeping patterns has de-enhanced my cognitive capacity, unless you would assume that had my sleep been repaired I might instead be composing symphonies while taking my spanner to the faults in the LHC and finding a few Higgs Bosons in my pocket as a reward :)
David N. Brown
March 23rd, 2010
10:41:22

The simplest explanation for trouble sleeping is some kind of sensory issue. I have huge problems with lights. About a year ago, I got rid of an LED alarm clock because it kept me awake at night.
Katie
March 23rd, 2010
11:38:55

I’m an autistic adult and my sleep study showed me to have only 25%of the REM sleep an adult should have. I don’t know if it affects my cognition or not.
Laurentius Rex
March 23rd, 2010
15:11:32

No the simplest explanation is a lack of any regular diurnal rhythm.
Ian MacGregor
March 23rd, 2010
18:44:24

There have already been open-label and double blind crossover studies for this drug.

This one I have not been able to locate

Chez MG, Buchanan TM, Becker M, Kessler J, Aimonovitch MC, Mrazek SR (2003) Donepezil hydrochloride: a double-blind study in autistic children. J Pediatric Neurol 1:83–88.

Perusing through some of the articles I found that it may cause oneiric confusion. I had to look it up. Oneiric means having to do with dreams.

One thing I’ve often wondered is whether my daughter dreams and what she dreams of. She is not able to tell me herself.
Sullivan
March 23rd, 2010
19:13:40

Ian MacGregor,

Thanks for that reference.

The paper you note is here:
https://tspace.library.utoronto.ca/bitstream/1807/1649/1/pn03015.pdf

The side effect profile of DH use in children suggests that in most children it can be tolerated with irritability, hyperactivity, and mild gastrointestinal upset seen in a subset of participants. Decreasing the daily dosage from 2.5 to 1.25 milligrams often ameliorated persistent side effects. The most common adverse event was the concomitant increase in mood swings and lability. Reports of increases in lability, crying, and irritability were often accompanied by reports of increased exploration of environment and increased affection, for example.

I saw another paper on the use of this drug for memory issues in epileptics. Both of these papers were inconclusive.
Sullivan
March 23rd, 2010
19:47:31

Ian MacGregor,

The question about dreaming is very interesting.
passionlessDrone
March 24th, 2010
03:20:04

Hi Sullivan –
Thanks for posting this. I had the exact same thoughts regarding melatonin that you did. Anyways, the availability of REM sleep time as a more empirical measurement than the fuzzy nature of behavioral evaluations is a nice touch, but I tend to think that (maybe?) the overall thought process behind this trial is a bit more wide ranging considering this drugs usage in Alzheimers. (I doubt increased REM is the only thing going on once you start tinkering around with neurotransmitters like this.)

We tried a different acetylcholinesterase inhibitor (galantamine) with Luke, but the side effects were quick in coming and convinced us that whatever benifit it might eventually provide couldn’t be worth it.

I saw a really neat NOVA science now regarding sleep and how much is being learned about how the brain learns during sleep. It was completely fascinating, and it does occur to me (now) that there is a possible link between the sleep problems in many children with autism and difficulties learning.

http://www.pbs.org/wgbh/nova/s.....10/01.html

– pD
passionlessDrone
March 26th, 2010
15:00:43

Hello friends –
This study hit my inbox this morning on one of my alerts and I thought I’d post it:

Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus and nucleus accumbens in old rats after chronic donepezil administration

In Alzheimer’s disease brains morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been observed. These changes are particularly reflected in the decrement of both the dendritic tree and spine number. Donepezil is a potent and selective acetylcholinesterase inhibitor used in the treatment of Alzheimer’s disease. We have studied the effect of oral administration of this drug on the morphology of neuronal cells from the brain of aged rats. We examined dendrites of pyramidal neurons of the PFC, dorsal or ventral hippocampus and medium spiny neurons of the nucleus accumbens (NAcc). Donepezil (1 mg/Kg, vo) was administrated every day for 60 days to rats aged 10 and 18 months. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 12 and 20 months ages, respectively. In all Donepezil treated-rats a significant increment of the dendritic spines number in pyramidal neurons of the PFC, dorsal hippocampus was observed. However, pyramidal neurons of the ventral hippocampus and medium spiny cells of the NAcc only showed an increase in the number of their spines in 12 months old-rats. Our results suggest that Donepezil prevents the alterations of the neuronal dendrite morphology caused by aging

No mention of REM sleep patterns in the rodents. I’m not up to speed as much as I’d like to be on the subtleties of dendritic spine modifications in autism versus say, Alzheimer’s (calling Dr. Treg), but I’d still say we are largely groping in the dark as to the effects of this kind of stuff.

OK!

– pD
dr treg
March 26th, 2010
20:03:24

From relatively recent papers
1. Alzheimer`s disease seems to be associated with reduced numbers of large dendritic spines.
http://cercor.oxfordjournals.o.....t/19/3/586
2. Autism seems to be associated with increased dendritic spine densities.
http://www.ncbi.nlm.nih.gov/pubmed/19896929

Generally speaking it seems as though in mental retardation the short thick spines/leaves are reduced, but long thin spines/leaves are increased in number in the surface of the brain (cortex).
http://www.sciencemag.org/cgi/...../4169/1126

Donepezil may also have anti-inflammatory actions on microglia.
http://www.sciencedirect.com/s.....09bbb2cc8c

Perhaps animal studies of the effects of donepezil on dendritic spines and the immune system say in Fragile X syndrome could have been performed before human studies on 2 year olds.