EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease

Eur J Neurol. 2015 Jun;22(6):889-98. doi: 10.1111/ene.12707. Epub 2015 Mar 25.


Background and purpose: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL).

Methods: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Results: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak.

Conclusions: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.

Keywords: Alzheimer's disease; EFNS/ENS Guidelines; Grading of Recommendations Assessment, Development and Evaluation; cholinesterase inhibitors; dementia; memantine; meta-analysis; treatment.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Cholinesterase Inhibitors / therapeutic use*
  • Drug Therapy, Combination*
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Humans
  • Memantine / therapeutic use*
  • Practice Guidelines as Topic*


  • Cholinesterase Inhibitors
  • Excitatory Amino Acid Antagonists
  • Memantine