Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials
Open accessAbstract
OBJECTIVES: Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents. DATA SOURCES: The terms "donepezil", "rivastigmine", and "galantamine", limited by "randomized-controlled-trials" were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language. STUDY SELECTION: All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality. RESULTS: 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale--cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws--for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation. CONCLUSION: Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.
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Cholinesterase inhibitors are associated with diarrhea, nausea, and vomiting, and less commonly with symptomatic bradycardia and syncope.
“Cholinesterase inhibitors are associated with diarrhea, nausea, and vomiting, and less commonly with symptomatic bradycardia and syncope.153 155”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [155]
The ‘Adverse events of cholinesterase inhibitors’ section (page unavailable in our copy) identifies nausea, vomiting, and diarrhoea among the most common adverse events. It does not identify symptomatic bradycardia or syncope as less common adverse events; searches for those terms found no supporting passage. (LLM, conf=0.88)
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Cites
Kok, J. S., Berg, I. J., & Scherder, E. J. A. (2013) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000353441 · Cited by 20,589 · see citing works
The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia
Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A., & Gornbein, J. (1994) · Neurology · doi:10.1212/wnl.44.12.2308 · Cited by 7,568 · see citing works
A new rating scale for Alzheimer's disease
(1984) · American Journal of Psychiatry · doi:10.1176/ajp.141.11.1356 · Cited by 4,175 · see citing works
Moher, D., Schulz, K. F., & Altman, D. G. (2001) · BMC Medical Research Methodology · doi:10.1186/1471-2288-1-2 · Cited by 2,755 · see citing works
Moher, D., Schulz, K. F., Altman, D. G., & for the CONSORT Group* (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-134-8-200104170-00011 · Cited by 1,426 · see citing works
Rivastigmine for Alzheimer’s disease.
Birks, J. S., Chong, L.-Y., & Grimley Evans, J. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001191.pub4 · Cited by 534 · see citing works
Flagged first, then by citations
Research works printed but not linked: 30
- Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Qual- ity Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-66.
- Fritze J. Prescription of psychotropic drugs: results and commentaries to the drug pre- scription report 2004 [in German]. Psychoneurology 2005;31:46-52.
- Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia 1996;7:293-303.
- Rogers SL, Doody RS, Mohs RC, Friedhoff LT, and the Donepezil Study Group. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Arch Intern Med 1998;158:1021-31. (Rogers 1998a in table 3.)
- Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT, and the Donepezil Study Group. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998;50:136-45. (Rogers 1998b in table 3.)
- Burns A, Friedhoff LT, Gauthier S, Hecker J, Moller HJ, Petit H, et al. The effects of donepezil in Alzheimer's disease-results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237-44.
- Greenberg SM, Tennis MK, Brown LB, Gomez-Isla T, Hayden DL, Schoenfeld DA, et al. Donepezil therapy in clinical practice: a randomised crossover study. Arch Neurol 2000;57:94-9.
- Homma A, Takeda M, Imai Y, Udaka F, Hasegawa K, Kameyama M, et al. Clinical effi- cacy and safety of donepezil on cognitive and global function in patients with Alzheim- er's disease: a 24-week, multicenter, double-blind, placebo-controlled study in Japan. Dement Geriatr Cogn Disord 2000;11:299-313.
- Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E, and the Donepezil MSAD Study Investigators Group. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57:613-20.
- Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481-8.
- Tariot PN, Cummings JL, Katz IR, Mintzer, J, Perdomo CA, Schwam EM, Whalen E, and the Donepezil Nursing Home Study Investigators Group. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzhe- imer's disease in the nursing home setting. J Am Geriatr Soc 2001;49:1590-9.
- Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-95.
- AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105- 15.
- Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, et al. The effi- cacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004;63:214-9.
- Agid Y, Dubois B, on behalf of the International Rivastigmine Investigators, Anand R, Gharabawi G. Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type. Curr Ther Res Clin Exp 1998;59:837-45.
- Corey-Bloom J, Anand R, Veach J, for the ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and the safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998;1:55-65.
- Forette F, Anand R, Gharabawi G. A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon). Eur J Neurol 1999;6:423-9.
- Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;318:633-40.
- Potkin SG, Anand R, Fleming, K, et al. Brain metabolic and clinical effects of rivastig- mine in Alzheimer's disease. Int J Neuropsychopharmacol 2001;4:223-30.
- Raskind MA, Peskind ER, Wessel T, Yuan W, and the Galantamine USA-1 Study Group. A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8.
- Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer's disease: a randomized, controlled trial. J Neurol Neuro- surg Psychiatry 2001;71:589-95.
- Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269- 76.
- Wilcock GK, Lilienfeld S, Gaens E on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheim- er's disease: multicentre randomised controlled trial. BMJ 2000;321:1-7.
- Wilkinson D, Murray J, in collaboration with the Galantamine Research Group. Galan- tamine: a randomized, double-blind, dose comparison in patients with Alzheimer's dis- ease. Int J Geriatr Psychiatry 2001;16:852-7.
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical Diag- nosis of Alzheimer's Disease: report of the NINCDS/ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-44.
- Wood S, Cummings JL, Hsu MA, Barclay TB, Wheatley MV, Yarema KT, et al. The use of the neuropsychiatric inventory in nursing home residents: characterization and measurement. Am J Geriatr Psychiatry 1999;8:75-83.
- Brane G, Gottfries CG, Winblad B. The Gottfries-Brane-Steen scale: validity, reliability and application in anti-dementia drug trials. Dement Geriatr Cogn Disord 2001;12:1-14.
- DeJong R, Osterlund OW, Roy GW. Measurement of quality-of-life changes in patients with Alzheimer's disease. Clin Ther 1989;11:545-54.
- Whitehead A, Perdomo C, Pratt RD, Birks J, et al. Donepezil for the symptomatic treat- ment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials. Int J Geriatr Psychiatry 2004;19:624-33.
- Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 2004;12:358-69.
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- Authors
- Kaduszkiewicz, H., Zimmermann, T., Beck-Bornholdt, H.-P., & van den Bussche, H.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Kaduszkiewicz, Hanna
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2005-08-04
- Volume
- 331
- Issue
- 7512
- Pages
- 321-327
- ISSN
- 0007-1447 (ISSN-L)
- 0959-8138
- 1468-5833
- PMC
- PMC1183129
- OpenAlex
- W2024214628
- Cited by
- 522
- References
- 6
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 21 · 2020: 13 · 2019: 15 · 2018: 23 · 2017: 27 · 2016: 18 · 2015: 21 · 2014: 24 · 2013: 27 · 2012: 33
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- BMJ (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, cholinesterase inhibitors, donepezil, rivastigmine, galantamine, pharmacotherapy, cognitive outcomes, Alzheimer's Disease Assessment Scale, methodological quality of trials, treatment efficacy
- MeSH terms
- Rivastigmine, Donepezil, Alzheimer Disease, Cholinesterase Inhibitors, Galantamine, Humans, Indans, Piperidines, Randomized Controlled Trials as Topic, Treatment Outcome, Phenylcarbamates
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