The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer’s disease.
Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, et al.;
Commented by , 23 Aug 2004
Aim of the study
To assess whether donepezil will control neuropsychiatric symptoms in patients with mild to moderate Alzheimer’s disease (AD).
Method
Patients with probable AD in mild to moderate stage defined as MMSE 10 to 27, with a total Neuropsychiatric Inventory (NPI) score greater than 11 points arising from at least three domains of behavior. No prior exposure to a cholinesterase inhibitor was allowed. Open label phase I with donepezil 5mg/day then 10mg/day over 6 weeks, followed by a randomized placebo-controlled double-blind phase II for a further 6 weeks.
Patients were excluded from completing phase II if they deteriorated after randomization more that 2 points on the MMSE relative to their baseline. The primary efficacy outcomes was the NPI, secondary outcomes included the NPI Distress scale (NPI-D) and the MMSE. Efficacy analysis were performed on the ITT population comparing baseline to end of phase I and time of randomization to end of phase II.
Results
134 patients entered phase I, mean age 81; 28% did not complete this phase, primarily because of adverse events. 96 patients entered phase II, mean age 78; 33% did not complete this phase. The overall study completion was 60%.
At baseline the NPI, NPI-D and MMSE scores were 25.9, 13.5 and 19.6 respectively. After 6 weeks on donepezil the scores were 15.2, 7.9 and 20.7, all highly statistically significant. A sub-analysis of the NPI 12 items in patients who were symptomatic at baseline showed a statistically significant difference for all items except elation.
At the end of the 6 weeks on donepezil vs placebo, there was a 6.2 points difference in NPI score (ITT-LOCF unpaired t-test p = 0.02), a 3 points difference in NPI-D score (ITT-LOCF Mann-Whitney U test p = 0.01), and a 1.7 points difference in MMSE score (ITT-LOCF unpaired t-test p = 0.02).
Discussion
As discussed in the accompanying editorial by Herrman & Knopman (ref. 1), this study takes advantage of is a powerful design since all patients are getting active medication first, then are randomized to continue on active drug or withdrawn to placebo, with provision for rescue drug if losing more than a predetermined amount of cognitive abilities. The draw back is the relatively high level of drop outs (40% overall).
These results are consistent with findings from the Moderate to Severe Alzheimer Disease Study where MMSE range was 5 to 17 (ref. 2) and firmly establishes cholinesterase inhibitors as having psychotropic actions that largely compensate for their relatively weak cognitive enhancement effects, such as those found in the AD2000 study.
References
1. Herrman and Knopman, Donepezil therapy for neuropsychiatric symptoms in AD: Methods make the message. Neurology 2004; 63: 200-201
2. Feldman et al, A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease . Neurology 2001; 57: 613-620