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No cognitive benefit seen for donepezil.

NEW ORLEANS -- Donepezil had no effect on cognitive impairment in a recent study of patients with vascular dementia, but the acetylcholinesterase inhibitor was associated with significant improvement on several measures of executive function, Dr. Martin Dichgans reported at International Stroke Conference 2008.

Cholinergic deficits might contribute to cognitive impairment in vascular dementia, and donepezil has been shown to improve measures of functioning, but because most trials of the drug include patients with Alzheimer's disease, it is difficult to determine whether the effects of the drug result from improvements in cognition or improvement in the Alzheimer's disease.

For the current study, 168 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) were included in the randomized double-blind study, which was a phase II proof of concept study. CADASIL is an early-onset form of subcortical ischemic vascular dementia that is unlikely to overlap with Alzheimer's disease, making it a condition well suited for testing the effects of donepezil on cognitive functioning, said Dr. Dichgans of Ludwig-Maximilians University, Munich.

Patients received 5 mg of donepezil or placebo daily for the first 6 weeks of the 18-week trial, then 10 mg daily thereafter; the primary end point was a change from baseline in Vascular-Alzheimer's Disease Assessment Scale-Cognitive subscale (V-ADAS-cog) score, said Dr. Dichgans, who serves as a consultant for Eisai Co., which makes donepezil and sponsored the study.

There was no statistically significant difference between the treatment and placebo groups in regard to the change from baseline V-ADAS-cog scores, but a significant difference was noted between the groups on Trail Making Test part A (TMT A) time and Trail Making Test part B (TMT B) time, which assess the time required to perform specific tasks, and on the Executive Interview (EXIT25), which assesses executive cognitive function. (See box.)

A trend toward improvement on the clock drawing tests CLOX 1 and CLOX 2 scores--which measure executive cognitive function deficits and posterior cortical impairment, respectively--was also seen in the treatment group, compared with the placebo group, Dr. Dichgans said at the conference, which was sponsored by the American Stroke Association.

For the treatment group, CLOX1 score improved from baseline by 0.76, compared with 0.09 for placebo. For the CLOX2 group, treated patients' score improved by 0.52 from baseline, versus 0.05 for patients on placebo.

Clinical relevance of findings on processing speed is unknown, he noted.

Patients in the study had a mean age of 55 years. Inclusion criteria included a baseline score of 10-27 on the Mini-Mental State Exam or a TMT B score that was 1.5 standard deviations below the mean after adjusting for age and education.


Southeast Bureau
Mean Change in Score From Baseline On Executive Function Tests

 Donepezil (n = 84) Placebo (n = 77)

Executive Interview (EXIT25) -1.33 0.14
Trail Making Test part A (TMT A) -11.15 -3.10
Trail Making Test part B (TMT B) -32.21 -8.87

Note: Based on an 18-week study of patients with cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Source: Dr. Dichgans

Note: Table made from bar graph.
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Title Annotation:Neuropsychiatric Medicine
Author:Worcester, Sharon
Publication:Clinical Psychiatry News
Date:Apr 1, 2008
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