Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis

JAMA. 2003 Jan 8;289(2):210-6. doi: 10.1001/jama.289.2.210.


Context: Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of cholinesterase inhibitors are conflicting.

Objective: To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD.

Data sources: We performed a literature search of trials using MEDLINE (January 1966-December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane Controlled Trials Register. We retrieved English- and non-English-language articles for review and collected references from bibliographies of reviews, original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies.

Study selection: We included 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor. Sixteen trials included neuropsychiatric and 18 included functional measures.

Data extraction: Two investigators (N.H.T. and J.H.) independently extracted study methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales and analyzed with the standardized mean difference method.

Data synthesis: For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors.

Conclusions: These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Activities of Daily Living
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / physiopathology
  • Cholinesterase Inhibitors / therapeutic use*
  • Humans
  • Neuropsychological Tests
  • Treatment Outcome


  • Cholinesterase Inhibitors