Donepezil therapy in clinical practice - A randomized crossover study

Objective: To determine the efficacy of donepezil hydrochloride for the tre atment of Alzheimer disease in patients drawn from clinical practice. Design: Two-center, randomized, placebo-controlled, double-masked crossover study. Setting: Memory disorders units at Massachusetts General and Brigham and Wo men's hospitals, Boston. Patients: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0 +/- 9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. Interventions: Placebo wash-in, followed in randomized sequence by (1) done pezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washo ut for 6 weeks and (2) placebo treatment for 6 weeks. Primary Outcome Measure: Change in Alzheimer's Disease Assessment Scale cog nitive subscale scores from the beginning to the end of the two 6-week trea tment periods. Results: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17 +/- 0. 98 points (95% confidence interval, 0.20-4.10 points) during donepezil ther apy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver -rated global impression (donepezil vs placebo: proportion improved, 0.24 v s 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the p resence of the apolipoprotein E epsilon 4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients) . Serious events possibly related to drug use were seizure, pancreatitis, a nd syncope (1 patient each). Conclusion: This independent confirmation of data from phase 3 trials sugge sts that donepezil therapy modestly improves cognition in patients with Alz heimer disease who are encountered in clinical practice.