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Donepezil Fails to Improve Cognition in Patients with CADASIL

Susman, Ed

doi: 10.1097/01.NT.0000316148.27827.bc
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Donepezil did not have a significant effect on cognition among patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

NEW ORLEANS—Donepezil (Aricept), a cholinesterase inhibitor used to treat Alzheimer disease, failed to improve cognition in patients with subcortical dementia associated with the genetic disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), according to a new study.

The multicenter randomized, double blind, placebo-controlled trial investigated the efficacy and safety of donepezil in vascular dementia. But, according to the investigators, active treatment with the drug produced no significant differences in cognition on most tests. The findings were described here at the American Stroke Association International Stroke Conference in February.

“In the primary endpoint — change from baseline in the Vascular-Alzheimer's Disease Assessment Scale-cognitive subscale — there was no significant difference between patients on placebo and those on donepezil,” said study author Martin Dichgans, MD, professor of neurology at the University of Muenchen in Germany, at a late-breaker press briefing. And at no time during the trial did donepezil treatment differ from placebo on the primary measure.

CADASIL is caused by mutations in the Notch 3 gene on the short arm of chromosome 19. The mutations lead to an abnormal accumulation of Notch 3 protein at the cytoplasmic membrane of vascular smooth-muscle cells in cerebral and extracerebral vessels, seen as granular osmiophilic deposits on electron microscopy.

Patients were entered into the study if they were determined to have CADASIL either through screening for the Notch 3 mutation or through biopsy. Scores on neuropsychological tests such as the Mini-Mental Status Exam determined cognitive impairment.

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Patients in the donepezil group received 5 mg donepezil once a day for the first six weeks of the trial and then 10 mg daily for the rest of the trial. Eighty-two patients were assigned placebo, and 86 took donepezil. In the intent to treat population, 77 patients took the placebo and 84 took donepezil.

“The completion rate was 89 percent in the placebo group and 84.9 percent in the donepezil group — and the demographics were well balanced,” Dr. Dichgans said. No differences were seen in other neuropsychological tests, he said. “However, we found a significant treatment effect on several measures of executive function,” he said. The researchers reported significantly higher scores on tests involving motor speed and attention functions (the Trail Making Test A, Trail Making Test B, and EXIT 25-Executive Interview Functional test).

“The rates for adverse events,” Dr. Dichgans said, “were similar for both the donepezil patients and the placebo patients.” About 7.3 percent of placebo patients discontinued due to adverse events compared with 10.5 percent of patients on donepezil. “Donepezil was generally well tolerated, with typical events related to cholinesterase inhibition,” he said.

“Our results emphasize the need for focusing on specific subgroups in clinical trials of patients with vascular dementia,” Dr. Dichgans said. “We need to use dedicated psychological tests for vascular dementia rather than batteries developed for Alzheimer disease. We believe that CADASIL is a good model to assess new pharmaceutical approaches for future trials.”

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“The finding of improvement or in slowing of progression of decline of executive function could be by chance, but this is not the only time that this has been seen,” said Philip Gorelick, MD, the John S. Garvin Professor and head of the department of neurology and rehabilitation at the University of Illinois at Chicago.

He noted that similar results occurred in other trials involving cholinesterase inhibitors for vascular dementia. “We were all hoping it would work, and it just didn't.”

The trial received support from Eisai Pharmaceuticals. Dr. Dichgans disclosed that he received financial support from Eisai. Donepezil had not received FDA labeling for treatment of CADASIL patients.

©2008 American Academy of Neurology