Donepezil therapy for neuropsychiatric symptoms in AD

The behavioral and psychological symptoms of dementia (BPSD) are common serious problems that affect the quality of life for the patient and their caregiver. BPSD are costly and can result in premature institutionalization. Despite the gravity of BPSD, there are surprisingly few data on the efficacy of any drugs for BPSD beyond antipsychotic agents. Anecdotal and uncontrolled observations on the cholinesterase inhibitors (ChEIs) suggested they might be effective for the management of BPSD. However, many of the early pivotal trials of the ChEIs did not include behavioral measures as outcomes. The majority of the double-blind, placebo-controlled, randomized-controlled trials (RCT) published to date included patients with only minimal BPSD at baseline. In a recently published meta-analysis of these studies, Trinh et al.1 were able to combine data from only six studies that used the current gold standard assessment instrument for behavior, the Neuropsychiatric Inventory (NPI).2 Compared with placebo, ChEIs improved NPI scores by only 1.72 points. Unfortunately, these studies included three trials with the ChEI metrifonate, which was not approved for use in patients with Alzheimer disease (AD) because of concerns about its toxicity. Therefore, despite excellent evidence linking cholinergic deficits to various BPSD, convincing evidence that the available ChEIs have clinically significant effects on behavior in patients with AD has been lacking.3 In this issue of Neurology, Holmes et al.4 report on an RCT of donepezil therapy for neuropsychiatric symptoms in mild to moderate AD. These authors concluded that donepezil had …