Donepezil effects on cerebral blood flow in older adults with mild cognitive deficits. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial.
Cerebral blood flow (CBF) was assessed during a verbal recall task using [(15)O]water positron emission tomography (PET) in older adults with mild cognitive deficits participating in a placebo-controlled donepezil trial. The placebo group demonstrated reduced CBF in the left frontal and temporal regions over the 6-month period, while those receiving donepezil did not. The placebo group's performance did not change on a list-learning task, while the donepezil group's performance improved, despite having had lower performance at intake. These findings suggest that donepezil treatment may be associated with a relative maintenance of CBF and improved list-learning. To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI).
                A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations.
                Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.
                Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.
There are two included studies which reported results for cognitive function. One study demonstrated a modest treatment effect in cognitive function as assessed by ADAS-Cog13 but not for other outcomes assessing different domains of cognitive function. Donepezil was associated with significantly more adverse effects compared with placebo, mostly gastrointestinal. From the second study, there is no evidence that donepezil delays the onset of AD. There is no evidence to support the use of donepezil for patients with MCI. The putative benefits are minor, short lived and associated with significant side effects.