Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease.
OBJECTIVE
To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms.


METHODS
Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency × severity) ≥ 3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status.


RESULTS
Of all NPI items, apathy had the highest proportion of subjects scoring ≥ 3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit.


CONCLUSIONS
Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted.
Waldemar
Gunhild
G
Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. gunhild.waldemar@rh.regionh.dk
Gauthier
Serge
S
Jones
Roy
R
Wilkinson
David
D
Cummings
Jeffrey
J
Lopez
Oscar
O
Zhang
Richard
R
Xu
Yikang
Y
Sun
Yijun
Y
Knox
Sean
S
Richardson
Sharon
S
Mackell
Joan
J
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D057565:Apathy / Q000187:drug effects*; D010054:Brief Psychiatric Rating Scale; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D012720:Severity of Illness Index
D002800:Cholinesterase Inhibitors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil