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DURHAM, N.C. – A drug already approved for treating patients with Alzheimer's disease might also boost the expressive language skills of children with Down syndrome, according to the results of a preliminary clinical trial conducted at Duke University Medical Center.

If confirmed in a larger trial, language improvements stemming from the drug known as donepezil hydrochloride (Aricept®) could potentially help maximize learning in children with the condition. Down syndrome affects one in every 800 live births and is the most common genetic cause of mental retardation worldwide, the researchers said.

The 22-week trial included seven children with Down syndrome between the ages of eight and 13 and their primary caregivers. After taking the drug for 16 weeks, the children showed improvements in their ability to communicate thoughts and feelings, the Duke team reported in the Oct. 15, 2004, issue of the American Journal of Medical Genetics Part A. While the promising results warrant further study, the researchers emphasized caution given limitations of the open, preliminary trial, in which researchers, patients and their families knew they were receiving the drug. The researchers do not recommend prescribing the drug to children with Down syndrome until more rigorous studies are done.

The findings in children mirror those of an earlier small trial led by the team, which tested donepezil's effects in adults with Down syndrome, said study investigator Priya Kishnani, M.D., medical geneticist and co-director of the Down syndrome clinic at Duke.

"In the very first trial of donepezil in adults with Down syndrome an improvement in communication, attention span and mood was noted," said Kishnani. This prompted a second trial exploring potential language benefits in adults with Down syndrome. While results of both studies showed promise, she added, treatment could have its most meaningful effects in childhood, the time of rapid learning and development.

"A therapy that could change the lives of people with Down syndrome early in childhood, making them more active learners, could really maximize their benefit and quality of life," she said.

Down syndrome, which results from an extra copy of chromosome 21, affects more than 350,000 families in the U.S. alone. Approximately 10,000 babies with the chromosomal abnormality are born each year in the United States, Kishnani said. The risk of having a child with Down syndrome increases with increasing maternal age.

Individuals with Down syndrome possess varying degrees of mental retardation, ranging from very mild to severe. They also often suffer from other medical conditions, including heart disease, thyroid disease, celiac disease and early brain changes associated with Alzheimer's disease. Medical advances have nonetheless extended the expected life span of people with Down syndrome -- with many now living to age 55 and beyond, according to the National Down Syndrome Society.

"As people with Down syndrome continue to live longer, therapies that might increase their quality of life are of paramount importance," Kishnani said. "Yet there remains no available pharmacological treatment that can help patients with Down syndrome improve aspects of cognition, communicate better and live more independently. It's an unmet need."

Similarities in brain pathology and neurochemistry between Down syndrome and Alzheimer's disease first led the research team to consider that donepezil might offer relief to people with Down syndrome, Kishnani said. Both conditions are characterized by a failure to produce enough of a chemical nerve messenger, or neurotransmitter, known as acetylcholine in the brain. Without a sufficient supply of the neurotransmitter, people experience problems with learning and memory, among other deficits. However, it remains unclear in individuals with Down syndrome how early that decline occurs, she added.

Donepezil blocks the enzyme that normally breaks down acetylcholine in the brain, thus increasing the availability of the nerve messenger.

The researchers enrolled seven children with Down syndrome and their caregivers in the trial. All trial participants were verbal and able to hear speech at a conversational level. The children took donepezil daily for 16 weeks, followed by a 6-week "washout" period that allowed the drug to leave their system. The team used standardized language tests to measure the skills of each participant at 8-week intervals.

"There has been no standard for assessing changes in language for individuals with Down syndrome in a clinical trial," explained Duke language pathologist James Heller, first author of the study. "We started at ground zero to put together a workable battery of tests."

The battery examined a variety of language skills through tests that required the children to interpret pictures, repeat sentences of increasing complexity and make associations among related words, among other tasks, Heller said. The researchers recorded testing sessions for independent review and scoring by a second language pathologist.

After taking donepezil for 16 weeks, the children exhibited significant improvements over their baseline performance on a language test known as the clinical evaluation of language fundamentals, third edition, (CELF-3) with particular improvement in their expressive language performance, they reported. At baseline, the children's average CELF-3 age score was equivalent to a child 4 years and 3 months old. That score increased to an average age score of 4 years and 7 months over the course of the study, with some children exhibiting no change and others demonstrating an 8 month gain in age score. Children achieved the largest gains on tests of word and sentence structure, they found.

"You expect that children with Down syndrome will show improvements in language skills over time, but certainly not at the rate we observed in most participants over the course of the study," Heller said.

The standardized test results complemented anecdotal evidence provided by the participating caregivers, Kishnani noted. While taking donepezil, parents reported that their children with Down syndrome were more expressive than usual about likes and dislikes, better able to make everyday connections, and more easily engaged in conversation, she recalled.

Children taking donepezil showed no significant improvement on a second language test of problem solving (TOPS), which assesses children's language-based thinking abilities and strategies using logic and experience.

Another research group outside of Duke also has found that donepezil and a related drug improve the language performance of children with autism, suggesting that such therapies might alleviate language impairments associated with a variety of developmental disabilities, the researchers said.

The results should be interpreted with caution, however, said the researchers. "Because the patients and their families knew they were receiving the drug, we do have concerns about a possible placebo effect or effects from greater attention from the caregivers," Kishnani said.

Therefore, a larger, randomized trial must confirm the initial findings before the drug should be prescribed to Down syndrome patients. The team also hopes to test whether language improvements can be sustained with continued use of the drug.

Other collaborators include Gail Spiridigliozzi, Ph.D.; P. Murali Doraiswamy, M.D. and genetic counselors; Jennifer Sullivan and Bythe Crissman, all of Duke. The authors have received research grants and honoraria from companies including Pfizer, Novartis, Eisai, Jannsen, Merck, Forest, Lilly, GlaxoSmithKline and Wyeth. They have no financial ties to any of these companies. The research team has a patent pending on the use of similar drugs for another disorder.