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Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

BMJ 2005; 331 doi: (Published 04 August 2005) Cite this as: BMJ 2005;331:321
  1. Hanna Kaduszkiewicz, research fellow (kaduszki{at},
  2. Thomas Zimmermann1, research fellow,
  3. Hans-Peter Beck-Bornholdt1, professor,
  4. Hendrik van den Bussche1, director
  1. 1 Department of Primary Medical Care, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Martinistraβe 52, D-20246 Hamburg, Germany
  1. Corresponding author: H Kaduszkiewicz
  • Accepted 29 April 2005


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.


  • Contributors HK, TZ and HPBB developed the design of this review, performed the literature search, analysed and interpreted the trials. The article was written by HK and revised repeatedly by TZ, HPBB, and HvdB. The final version was approved by HvdB. HK is the guarantor.

  • Funding None.

  • Competing interests None declared.

  • Ethics approval Not required.

  • Accepted 29 April 2005
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