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Cited by 363Dementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatments

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease

Doody, Rachelle S.·2001·Archives of Neurology
DOI 10.1001/archneur.58.3.427
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Abstract

BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

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  • Longer term benefits of cholinesterase inhibitors, from 2 to 4 or more years, have been demonstrated in open-label extension and long-term prospective observational clinical cohort studies.

    “Longer term benefits, from 2 to 4 or more years have been demonstrated in open-label extension 69,[88][89][90] and long-term prospective observational clinical cohort studies.[91][92][93][94][95]”

    From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [69]

  • Discontinuation of cholinesterase inhibitor treatment is, on aggregate, harmful.

    “Discontinuation of ChEI treatment is, on aggregate, harmful.”

    From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [69]

  • Patients taken off, or those inconsistently taking, anti-AD medications progress more rapidly than those who continue treatments, particularly cholinesterase inhibitors.

    “Patients taken off, or those inconsistently taking, anti-AD medications progress more rapidly than those who continue treatments, particularly ChEIs.”

    From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [69]

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Authors
Doody, R. S.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Doody, Rachelle S.
Venue
Archives of Neurology
Publisher
American Medical Association (AMA)
Published
2001-03-01
Volume
58
Issue
3
Pages
427
ISSN
0003-9942 (ISSN-L)
DOI
10.1001/archneur.58.3.427
OpenAlex
W2064649894
Cited by
362
References
14
Citations by year
2026: 3 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 11 · 2017: 5 · 2016: 8 · 2015: 14 · 2014: 7 · 2013: 13 · 2012: 11
FWCI
21.77
Type
journal article
Language
en
Open access
closed
Locations
  • Archives of Neurology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
donepezil, Alzheimer's disease, acetylcholinesterase inhibitors, long-term treatment, cognitive function, Clinical Dementia Rating, adverse events, drug discontinuation, symptomatic treatment
MeSH terms
Donepezil, Aged, Alzheimer Disease, Cholinesterase Inhibitors, Double-Blind Method, Female, Humans, Indans, Male, Middle Aged, Neuropsychological Tests, Piperidines, Treatment Outcome

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