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Pharmacotherapy
Effectiveness of Donepezil Therapy in Advanced Alzheimer’s Disease
Bengt Winblad
Karolinska University Hospital, Stockholm
Abstract
Alzheimer’s disease (AD) is a progressive, degenerative disease. In the advanced stages, cognitive and functional abilities become
compromised to the extent that most patients require total, full-time care, usually in specialised nursing homes. Loss of cognition affects
functional autonomy, which is gradually lost, and psychiatric and behavioural symptoms often become problematic for both patients and
their carers/families. The cholinesterase inhibitor donepezil is licensed for the treatment of mild to moderate AD in many regions
worldwide, with the indication expanded to encompass severe AD in eight countries: the US, Canada, Japan, Australia, India, New Zealand,
Thailand and the Philippines. Approval for use in severe AD was granted by the US Food and Drug Administration (FDA) in 2006 on the
basis of strong evidence from the Swedish Nursing Home Severe AD study. In total, three prospective randomised clinical trials of
donepezil in severe AD have now been conducted and a subanalysis of a fourth study has provided additional information. Overall, these
studies show that donepezil treatment is associated with functional and cognitive benefits in patients with severe AD, although
behavioural benefits were not consistently observed. Donepezil was well tolerated; side effects were transient, mild to moderately severe
and generally cholinergic in nature.
Keywords
Alzheimer’s disease (AD), severe, donepezil
Disclosure: Bengt Winblad has received honoraria to participate in symposia and advisory board meetings from Pfizer, Eisai, Ortho-McNeill Neurologics, Merz, Lundbeck,
Janssen-Cilag and Forest Laboratories. He has received no research grants from nor does he own stocks in these companies. Editorial support was funded by Eisai Inc.
and Pfizer Inc.
Acknowledgements: Additional editorial support was provided by R Daniel of PAREXEL.
Received: 4 April 2008 Accepted: 9 June 2008
Correspondence: Bengt Winblad, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden. E: bengt.winblad@ki.se
About 20% of patients with Alzheimer’s disease (AD) have severe mild to moderate phase of AD, persistent treatment provides
dementia,
1
which presents particular challenges. During the more cognitive benefits,
6,7
slows functional decline,
8
helps behavioural
severe stages, cognitive function continues to decline, functional symptoms
9
and allows patients to stay at home longer.
10
This article
autonomy is lost, psychiatric and behavioural symptoms become will review the clinical evidence for the use of donepezil in patients
increasingly troublesome and patients become less able to with more advanced AD.
communicate and less mobile, eventually leading to a need for
complete care.
2
Guidelines for Treatment of Severe Disease
Treatment guidelines for AD developed in Italy suggest that ChEI
The population with severe AD is often considered to be beyond the therapy should be considered in patients with moderate to severe AD
point at which pharmacological intervention will be beneficial and, (MSAD) and continued in patients who have derived benefit, even in
indeed, some specialists and treatment guidelines recommend those with a Mini-Mental State Examination (MMSE) score <10.
11
The
discontinuing treatment in these patients.
3
However, a large proportion latest guidelines from the European Federation of Neurological
of patients first presenting to physicians with symptoms of AD are Societies
12
advocate the treatment of patients with severe AD (MMSE
already in the moderate to severe stages of the disease.
4
Existing data score <10) with memantine in combination with a ChEI as required. In
suggest that patients and their carers benefit if treatment is initiated or contrast, UK guidelines from the National Institute of Health and
is continued in patients with more advanced AD. Clinical Excellence (NICE) recommend the use of treatment only in
those with moderate disease, continuing treatment while the patient’s
Donepezil, a cholinesterase inhibitor (ChEI) widely used for the MMSE score remains ≥10.
3
treatment of AD, was approved by the US Food and Drug
Administration (FDA) in 2006 for the treatment of severe AD;
5
this Donepezil Treatment for Patients with
represented an extension of the existing licence for the treatment of Severe Alzheimer’s Disease
mild to moderate AD. Licensing in Europe is currently for mild to There have been three large, prospective, randomised clinical trials
13–15
moderate AD. For patients initiating donepezil treatment during the and a post hoc analysis
16
all looking independently at the efficacy of
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