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Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review
  1. Lucy E Farrimond1,
  2. Emmert Roberts2,
  3. Rupert McShane3
  1. 1University of Oxford Medical School, Oxford, UK
  2. 2Bristol Royal Infirmary, University Hospitals of Bristol Trust, National Health Service, Severn Deanery, Bristol, UK
  3. 3Cochrane Dementia and Cognitive Improvement Group (CDCIG), Nuffield Department of Medicine, University of Oxford, Oxford, UK
  1. Correspondence to Dr Rupert McShane; rupert.mcshane{at}


Background Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer.

Objectives To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results.

Design Systematic review and meta-analysis of randomised controlled trials.

Data sources The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011.

Data synthesis Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine.

Results Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=−0.29, 95% CI −0.45 to −0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=−0.20, 95% CI −0.31 to −0.09), cognition (SMD=−0.25, 95% CI −0.36 to −0.14) and behaviour and mood (SMD=−0.17, 95% CI −0.32 to −0.03) but not on function (SMD=−0.04, 95% CI −0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found ‘no significant benefit’ on any clinical measures at 1 year.

Conclusions These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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  • To cite: Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review. BMJ Open 2012;2:e000917. doi:10.1136/bmjopen-2012-000917

  • Contributors LEF and RM contributed to drafting, analysis and design. ER extracted data and contributed to drafting and conclusions. RM is the guarantor.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement As this is a systematic review, there are no original data.

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