Aricept Redux

Three months ago I wrote a column arguing that in the U.S. we over-use donepezil (Aricept), a drug widely touted as helpful in early Alzheimer’s disease (“Americans, Alzheimer’s, and Aricept,” February 1, 2006). In Britain, by contrast, careful review of all the available studies led to the recommendation by NICE (the independent National Institute for Health and Clinical Excellence) against routine use of this medication. Now a new study suggests that donepezil may help patients with advanced Alzheimer’s disease, people who need help with basic tasks such as bathing and dressing and who have profound cognitive impairment (see B. Winblad, L. Kilanter, S. Erikkson et al, “Donepezil in Patients with Severe Alzheimer’s Disease: Double-Blind, Parallel Group, Placebo-Controlled Study,” Lancet 2006; 367:1057-65). How can this be? Are we seeing an attempt to find some use, any use, for this drug, which does not appear to be tremendously useful in early Alzheimer’s patients, the group in whom it was initially targeted?

The new study was carried out in Swedish nursing homes. Subjects were randomized to receive either donepezil or placebo and they were treated for 6 months. The treated group showed slight improvement in tests of mental function and a lower rate of deterioration in basic activities of daily living compared to controls. But before families rush to request donepezil for their relatives, we should consider the intriguing possibility raised by the study’s authors: perhaps what the donezpezil did was to counteract the negative effects of the many other medications these individuals were taking. Virtually all the people in the study (99%) were taking other medications, and 80% were on psychoactive medications intended to control their behavior. We know that the brains of individuals with dementia are very sensitive to chemicals that affect the nervous system—they are very prone to developing delirium, or an acute confusional state. Before concluding that all patients with severe dementia should be given donepezil, we need to study its effectiveness in demented persons who are on no other medications. Only then can we figure out whether we should dole out more donepezil (assuming that the “statistically significant” benefits are in fact clinically meaningful)—or give patients a drug holiday, discontinuing the many potentially toxic medicines they are currently taking.