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Vol. 24, No. 1, 2007
Issue release date: June 2007
Dement Geriatr Cogn Disord 2007;24:20–27
(DOI:10.1159/000102568)

Memantine in Moderate to Severe Alzheimer’s Disease: a Meta-Analysis of Randomised Clinical Trials

Winblad B.a · Jones R.W.b · Wirth Y.c · Stöffler A.c · Möbius H.J.c
aKarolinska Institutet, Stockholm, Sweden; bResearch Institute for the Care of the Elderly, Bath, UK; cMerz Pharmaceuticals GmbH, Frankfurt, Germany
email Corresponding Author

Abstract

The efficacy of memantine in Alzheimer’s disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician’s Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer’s Disease Assessment Scale – Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer’s Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports memantine’s clinically relevant efficacy in patients with moderate to severe AD.


 goto top of outline Key Words

  • Memantine
  • Alzheimer’s disease, moderate to severe
  • Meta-analysis
  • Cognition
  • Function
  • Global status

 goto top of outline Abstract

The efficacy of memantine in Alzheimer’s disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician’s Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer’s Disease Assessment Scale – Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer’s Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports memantine’s clinically relevant efficacy in patients with moderate to severe AD.

Copyright © 2007 S. Karger AG, Basel


 goto top of outline References
  1. Farlow MR: Moderate to severe Alzheimer disease: definition and clinical relevance. Neurology 2005;65:S1–S4.

    External Resources

  2. Perneczky R, Wagenpfeil S, Komossa K, Grimmer T, Fiehl J, Kurz A, et al: Mapping Scores onto Stages: Mini-Mental State Examination and Clinical Dementia Rating. Am J Geriatr Psychiatry 2006;14:139–144.
  3. Danysz W, Parsons CG: The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 2003;18(suppl 1):S23–S32.

    External Resources

  4. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ, for the Memantine Study Group: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  5. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, for the Memantine Study Group: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317–324.
  6. Gauthier S, Wirth Y, Möbius HJ: Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int J Geriatr Psychiatry 2005;20:459–464.
  7. Doody R, Wirth Y, Schmitt F, Möbius HJ: Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer’s disease. Dement Geriatr Cogn Disord 2004;18:227–232.
  8. Cummings JL, Schneider E, Tariot PN, Graham SM for the Memantine MD-02 Study Group: Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57–63.
  9. Bakchine S, Pascual-Gangnant L, Loft H: Results of a randomised, placebo-controlled 6-month study of memantine in the treatment of mild to moderate Alzheimer’s disease in Europe. 9th Congr Eur Fed Neurol Soc (EFNS), Athens, 2005.
  10. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S for the Memantine MEM-MD-10 Study Group: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006;14:704–715.
  11. Forest laboratories. Clinical Trial Registry. www.forestclinicaltrials.com/CTR/CTRController/CTRHome. Accessed August 2006.
  12. Reisberg B, Schneider L, Doody R, Anand R, Feldman H, Haraguchi H, Kumar R, Lucca U, Mangone CA, Mohr E, Morris JC, Rogers S, Sawada T: Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11(suppl 3):S8–S18.

    External Resources

  13. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al: Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S22–S32.

    External Resources

  14. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  15. Schmitt FA, Ashford W, Ernesto C, Saxton J, Schneider LS, Clark CM, Ferris SH, Mackell JA, Schafer K, Thal LJ: The Severe Impairment Battery: concurrent validity and the assessment of longitudinal change and in Alzheimer’s disease. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S51–S56.

    External Resources

  16. Saxton J, McGonigle KL, Swihart AA, Boller F: The Severe Impairment Battery. The University of Pittsburgh of the Commonwealth System of Higher Education. Suffolk, Thames Valley Test Company 1993, pp 1–16.
  17. Galasko DR, Schmitt FA, Jin S, Saxton J, Bennett D, Sano M, Ferris SH: Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging 2000;21(suppl 1):S168.

    External Resources

  18. Galasko D, Schmitt F, Thomas R, Jin S, Bennett D; Alzheimer’s Disease Cooperative Study: Detailed assessment of activities of daily living in moderate to severe Alzheimer’s disease. J Int Neuropsychol Soc 2005;11:446–453.
  19. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314.
  20. Rockwood K, MacKnight C: Assessing the clinical importance of statistically significant improvement in anti-dementia drug trials. Neuroepidemiology 2001;20:51–56.
  21. Rockwood K, Black SE, Robillard A, Lussier I: Potential treatment effects of donepezil not detected in Alzheimer’s disease clinical trials: a physician survey. Int J Geriatr Psychiatry 2004;19:954–960.
  22. Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006;1:CD005593.
  23. Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, et al: Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry 2007;78:36–42.
  24. Cummings JL, McRae T, Zhang R: Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 2006;14:605–612.
  25. Doody R, Tariot P, Pfeiffer E, Olin J, Graham S, Bell J: Meta-analysis of 6-month memantine clinical trials in Alzheimer’s disease. Ann Neurol 2005;58:S49.
  26. McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev 2006;2:CD003154.

    External Resources


 goto top of outline Author Contacts

Yvonne Wirth
Merz Pharmaceuticals GmbH
Eckenheimer Landstr. 100
DE–60318 Frankfurt/Main (Germany)
Tel. +49 69 1503 507, Fax +49 69 1503 803, E-Mail yvonne.wirth@merz.de


 goto top of outline Article Information

Accepted: March 6, 2007
Published online: May 10, 2007
Number of Print Pages : 8
Number of Figures : 6, Number of Tables : 2, Number of References : 26


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 24, No. 1, Year 2007 (Cover Date: June 2007)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The efficacy of memantine in Alzheimer’s disease (AD) has been investigated in multiple randomised, placebo-controlled phase III trials. Recently, the indication label for memantine in Europe was extended to cover patients with moderate to severe AD, i.e. Mini-Mental State Exam total scores below 20. The efficacy data for memantine in this patient subgroup has been summarised by a meta-analysis of 1,826 patients in six trials. Efficacy was assessed using measures of global status (Clinician’s Interview-Based Impression of Change Plus Caregiver Input), cognition (Alzheimer’s Disease Assessment Scale – Cognitive Subscale, or Severe Impairment Battery), function (Alzheimer’s Disease Cooperative Study Activities of Daily Living 19- or 23-item scale), and behaviour (Neuropsychiatric Inventory). Results (without replacement of missing values) showed statistically significant effects for memantine (vs. placebo) in each domain. Memantine was well tolerated, and the overall incidence rates of adverse events were comparable to placebo. This meta-analysis supports memantine’s clinically relevant efficacy in patients with moderate to severe AD.



 goto top of outline Author Contacts

Yvonne Wirth
Merz Pharmaceuticals GmbH
Eckenheimer Landstr. 100
DE–60318 Frankfurt/Main (Germany)
Tel. +49 69 1503 507, Fax +49 69 1503 803, E-Mail yvonne.wirth@merz.de


 goto top of outline Article Information

Accepted: March 6, 2007
Published online: May 10, 2007
Number of Print Pages : 8
Number of Figures : 6, Number of Tables : 2, Number of References : 26


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 24, No. 1, Year 2007 (Cover Date: June 2007)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Farlow MR: Moderate to severe Alzheimer disease: definition and clinical relevance. Neurology 2005;65:S1–S4.

    External Resources

  2. Perneczky R, Wagenpfeil S, Komossa K, Grimmer T, Fiehl J, Kurz A, et al: Mapping Scores onto Stages: Mini-Mental State Examination and Clinical Dementia Rating. Am J Geriatr Psychiatry 2006;14:139–144.
  3. Danysz W, Parsons CG: The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 2003;18(suppl 1):S23–S32.

    External Resources

  4. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ, for the Memantine Study Group: Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.
  5. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, for the Memantine Study Group: Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317–324.
  6. Gauthier S, Wirth Y, Möbius HJ: Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int J Geriatr Psychiatry 2005;20:459–464.
  7. Doody R, Wirth Y, Schmitt F, Möbius HJ: Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer’s disease. Dement Geriatr Cogn Disord 2004;18:227–232.
  8. Cummings JL, Schneider E, Tariot PN, Graham SM for the Memantine MD-02 Study Group: Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57–63.
  9. Bakchine S, Pascual-Gangnant L, Loft H: Results of a randomised, placebo-controlled 6-month study of memantine in the treatment of mild to moderate Alzheimer’s disease in Europe. 9th Congr Eur Fed Neurol Soc (EFNS), Athens, 2005.
  10. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S for the Memantine MEM-MD-10 Study Group: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006;14:704–715.
  11. Forest laboratories. Clinical Trial Registry. www.forestclinicaltrials.com/CTR/CTRController/CTRHome. Accessed August 2006.
  12. Reisberg B, Schneider L, Doody R, Anand R, Feldman H, Haraguchi H, Kumar R, Lucca U, Mangone CA, Mohr E, Morris JC, Rogers S, Sawada T: Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11(suppl 3):S8–S18.

    External Resources

  13. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al: Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S22–S32.

    External Resources

  14. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  15. Schmitt FA, Ashford W, Ernesto C, Saxton J, Schneider LS, Clark CM, Ferris SH, Mackell JA, Schafer K, Thal LJ: The Severe Impairment Battery: concurrent validity and the assessment of longitudinal change and in Alzheimer’s disease. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S51–S56.

    External Resources

  16. Saxton J, McGonigle KL, Swihart AA, Boller F: The Severe Impairment Battery. The University of Pittsburgh of the Commonwealth System of Higher Education. Suffolk, Thames Valley Test Company 1993, pp 1–16.
  17. Galasko DR, Schmitt FA, Jin S, Saxton J, Bennett D, Sano M, Ferris SH: Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging 2000;21(suppl 1):S168.

    External Resources

  18. Galasko D, Schmitt F, Thomas R, Jin S, Bennett D; Alzheimer’s Disease Cooperative Study: Detailed assessment of activities of daily living in moderate to severe Alzheimer’s disease. J Int Neuropsychol Soc 2005;11:446–453.
  19. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314.
  20. Rockwood K, MacKnight C: Assessing the clinical importance of statistically significant improvement in anti-dementia drug trials. Neuroepidemiology 2001;20:51–56.
  21. Rockwood K, Black SE, Robillard A, Lussier I: Potential treatment effects of donepezil not detected in Alzheimer’s disease clinical trials: a physician survey. Int J Geriatr Psychiatry 2004;19:954–960.
  22. Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006;1:CD005593.
  23. Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, et al: Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry 2007;78:36–42.
  24. Cummings JL, McRae T, Zhang R: Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 2006;14:605–612.
  25. Doody R, Tariot P, Pfeiffer E, Olin J, Graham S, Bell J: Meta-analysis of 6-month memantine clinical trials in Alzheimer’s disease. Ann Neurol 2005;58:S49.
  26. McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev 2006;2:CD003154.

    External Resources