Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology.

Marwan Sabbagh,Jeffrey Cummings

doi:10.1186/1471-2377-11-21

Abstract

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

Highlights

Alzheimer’s disease (AD) is a progressive disorder that advances from a period of mild cognitive impairment through moderate and severe stages
The meta-analysis reported an increase in cholinergic adverse events (AEs) when the dose was increased from 5 mg/d to 10 mg/d
This increase was generally attributed to the outdated practice of increasing the donepezil dose after just 1 week of treatment, and the authors concluded that both doses were well tolerated in this study population

Summary

Background

Alzheimer’s disease (AD) is a progressive disorder that advances from a period of mild cognitive impairment through moderate and severe stages. As seen in the mild to moderate AD population, an increased incidence of treatment-emergent AEs (TEAEs) was observed in the donepezil 10 mg/d group (83.3%) versus the donepezil 5 mg/d group (78.2%) in this study This difference was not statistically significant and the higher dose was seen to be safe and well tolerated in patients with advanced AD [18]. In a post hoc analysis of patients with more severe cognitive impairment (baseline MMSE, 0-16), significant differences favoring donepezil 23 mg/d were demonstrated on both the SIB (Figure 1B) and the CIBIC-plus In this subpopulation, representing 70% of patients in the study, the LS mean between-treatment difference in change in SIB score was 3.1 points (p < 0.0001) at Week 24. 18.6% of patients treated with donepezil 23 mg discontinued due to TEAEs, A

Improvement

Conclusions

Alzheimer’s Association