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Treatment of Moderate to Severe Alzheimer's Disease: Rationale and Trial Design

  • Nathan Herrmann (a1)


Moderate to severe Alzheimer's disease (AD) is characterized by increasing cognitive, functional, and behavioural dysfunction that results in increased caregiver burden and, eventually, complete dependence. Despite its significance as a societal health problem, there are few treatment trials of cognitive enhancers or disease modifying agents for this stage of illness. Studies suggest the cholinesterase inhibitors, especially donepezil, may provide benefit. Several studies provide support for the use of the NMDA receptor antagonist memantine as monotherapy or added to a cholinesterase inhibitor for moderate to severe AD. While there are no published guidelines for the treatment of moderate to severe AD, these studies do provide guidance for recommendations for study design and outcome measures. Such studies are urgently needed.


La maladie d'Alzheimer de modérée à sévère est caractérisée par une dysfonction cognitive, fonctionnelle et comportementale progressive qui engendre un fardeau croissant pour les soignants et une dépendance complète éventuelle. En dépit de son importance comme problème de santé au niveau sociétal, il existe peu d'essais thérapeutiques portant sur des stimulateurs cognitifs ou des agents modificateurs de la maladie à ce stade de la maladie. Les études suggèrent que les inhibiteurs de la cholinestérase, spécialement le donépézil sont bénéfiques. Selon plusieurs études, l'utilisation de la mémantine, un antagoniste du récepteur NMDA, en monothérapie ou en association à un inhibiteur de la cholinestérase serait bénéfique dans la MA de modérée à sévère. Bien qu'il n'y ait pas de lignes directrices publiées concernant le traitement de la MA de modérée à sévère, ces études peuvent servir de guide pour formuler des recommandations sur le plan d'étude et les critères d'évaluation. Il est urgent de procéder à de telles études.

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Corresponding author

Department of Psychiatry, Division of Geriatric Psychiatry, Faculty of Medicine, University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada.


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1. Canadian Study of Health and Aging Working Group. Patterns of caring for people with dementia in Canada. Can J Aging. 1994;13:47087.
2. Tariot, PN. Medical management of advanced dementia. J Am Geriatr Soc. 2003;51: S30513.
3. Hux, MJ, O’Brien, BJ, Iskedjian, M, Goeree, R, Gagnon, M, Gauthier, S. Relation between severity of Alzheimer’s disease and costs of caring. CMAJ. 1998;159:45765.
4. Wimo, A, Karlsson, G, Nordberg, A, Winblad, B. Treatment of Alzheimer’s disease with tacrine: a cost-analysis model. Alzheimer Dis Assoc Disord. 1997;11:191200.
5. Di Patre, PL, Read, SL, Cummings, JL, Tomiyasu, U, Vartavarian, LM, Secor, DL, et al. Progression of clinical deterioration and pathological changes in patients with Alzheimer’s disease evaluated at biopsy and autopsy. Neurology. 1999;56:125461.
6. Lanctôt, KL, Herrmann, N, Mazzotta, P. Role of serotonin in the behavioural and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2001;13:521.
7. Herrmann, N, Lanctôt, KL, Khan, LR. The role of norepinephrine in the behavioural and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2004; 16:26176.
8. Lanctôt, KL, Herrmann, N, Mazzotta, P, Khan, LR, Ingber, N. GABA-ergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry. 2004;49:43953.
9. Cacabelos, R, Takeda, M, Winbald, B. The glutamatergic system and neurodegeneration in dementia: preventative strategies in Alzheimer’s disease. Int J Geriatr Psychiatry. 1999; 14:347.
10. Davis, KL, Mohs, RC, Marin, D. Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. JAMA. 1999;281:14016.
11. Feldman, H, Gauthier, S, Hecker, J, Vellas, B, Subbiah, P, Whalen, E. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57:61320.
12. Folstein, MF, Folstein, SE, McHugh, PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:18998.
13. Herrmann, N. Recommendation for the management of behavioural and psychological symptoms of dementia. Can J Neurol Sci. 2001;28(Suppl 1):S96107.
14. Lanctôt, KL, Herrmann, N, Yau, KK, Khan, LR, LouLou, MM, Einarson, TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ. 2003;169:55764.
15. Blesa, R, Davidson, M, Kurza, A, Reichman, W, van Baelen, B, Schwalen, S. Galantamine provides sustained benefits in patients with advanced moderate Alzheimer’s disease for at least 12 months. Dement Geriatr Cogn Disord. 2003;15:7987.
16. Doraiswany, PM, Krishnan, KR, Anand, R, Sohn, H, Danyluk, J, Hartman, RD, et al. Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:70512.
17. Sclan, SG, Reisberg, B. Functional assessment staging (FAST) in Alzheimer’s disease: reliability, validity, and ordinality. Int Psychogeriatr. 1992;4(Suppl 1):S5569.
18. 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):S2232.
19. Saxton, J, McGonigle-Gibson, G, Swihart, A, Miller, VJ, Boller, F. Assessment of the severely impaired patient: description and validation of a new neuropsychological test battery. Psychol Assessment: J Consulting Clin Psychology. 1990;2:298303.
20. Gelinas, I, Gauthier, L, McIntyre, M, Gauthier, S. Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther. 1999;53:47181.
21. Lawton, MP, Brody, EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:17986.
22. Cummings, JL. The neuropsychiatric interview: assessing psychopathology in dementia patients. Neurology. 1994;44: 230814.
23. Feldman, H, Schulzer, M, Wang, S, Tuokko, H, Beattie, BL. The functional rating scale in Alzheimer’s disease assessment: a longitudinal study. In: Iqbal, K, Mortimer, JA, Winbald, B, Wisniewski, HM, editors. Research advances in Alzheimer’s disease and related disorders. Chichester, UK: Wiley; 1995. p. 23541.
24. Pearlin, LI, Mullan, JT, Semple, SJ, Skaff, MM. Caregiving and the stress process: an overview of concepts and their measures. Gerontologist. 1990;30:58394.
25. McHorney, CA, Ware, JE. Construction and validation of an alternate form general mental health scale for the medical outcomes study short-form 36-item health survey. Med Care. 1995;33:1528.
26. Østbye, T, Crosse, E. Net economic costs of dementia in Canada. CMAJ. 1994;151:145764.
27. Tariot, PN, Cummings, JL, Katz, IR, Mintzer, J, Perdomo, CA, Schwam, EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001;49:15909.
28. Morris, JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology. 1993;43:241214.
29. Winblad, B, Poritis, N. Memantine in severe dementia: results of the M-Best study (benefits and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14:13546.
30. Reisberg, B, Ferris, SH, de Leon, MJ, Crook, T. The global deterioration scale (GDS): an instrument for the assessment of primary degenerative dementia (PDD). Am J Psychiatry 1982;139:11369.
31. National Institute of Mental Health. Clinical Global Impressions. In: Guy, W, editor. ECDEU Assessment Manual for Psychopharmacology. National Institute of Mental Health, Rockville, MD. 1986: p. 21722.
32. Van der Kam, P, Mol, F, Wimmers, M. Beoordelingschool voon oudere patienten (BOP). Deventer, the Netherlands: Van Loghum Slaterus; 1971.
33. Ferm, L. Behavioural activities in demented geriatric patients. Geront Clin. 1974;16:18594.
34. Reisberg, B, Doody, R, Stoffler, A, Schmitt, F, Ferris, S, Mobius, HJ. Memantine in moderate-severe Alzheimer’s disease. N Engl J Med. 2003;348:133341.
35. Galasko, DR, Schmitt, FA, Jin, S. Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging. 2000; 21 (suppl 1):S168.
36. Wimo, A, Wetterholm, AL, Mastey, V, Winblad, B. Evaluation of the healthcare resource utilization and caregiver time in antidementia drug trials - a quantitative battery. In: Wimo, A, Johnsson, D, Karlson G. Winblad, B, editors. Health economics of dementia. Chichester, England: John Wiley; 1998. p. 46599.
37. Livingston, G, Katona, C. The place of memantine in the treatment of Alzheimer’s disease: a number needed to treat analysis. Int J Geriatr Psychiatry. 2004;19:91925.
38. Tartiot, PN, Farlow, MR, Grossberg, GT, Graham, SM, McDonald, S, Gergel, I. Memantine treatment in patients with moderate to severe Alzheimer’s disease already receiving donepezil. JAMA. 2004; 291:31724.
39. Sano, M, Ernesto, C, Thomas, RG, Klauber, MR, Schafer, K, Grundman, M, et al. A controlled trial of selegiline, alpha-tocopherol on both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336:121622.
40. Blessed, G, Tomlinson, BE, Roth, M. The association between quantative measures of dementia and of senile changes in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114:797811.
41. Rosen, WG, Mohs, RC, Davis, KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141:135664.
42. Stern, Y, Albert, SM, Sano, M. Assessing patient dependence in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 1994;49: M21622.
43. Tariot, PN, Mack, JL, Patterson, MB. The behaviour rating scale for dementia of the consortium to establish a registry for Alzheimer’s disease: the behavioural pathology committee of the consortium to establish a registry for Alzheimer’s disease. Am J Psychiatry. 1995;152:134957.
44. Drachman, DA, Leber, P. Treatment of Alzheimer’s disease—searching for a breakthrough, settling for less. N Engl J Med. 1997;336:12457.
45. Ferris, SH, Yan, B. Differential diagnosis and clinical assessment of patients with severe Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2003;17(Suppl 3):S925.
46. Doody, RS, Stevens, JC, Beck, C, Dubinsky, RM, Kaye, JA, Gwyther, L, et al. Practice parameter: management of dementia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2001;56:115466.
47. Streiner, DL. Unicorns do exists: a tutorial on “proving” the null hypothesis. Can J Psychiatry. 2003;48:75661.
48. Boller, F, Verny, M, Hugonot-Diener, L, Saxton, J. Clinical features and assessment of severe dementia: a review. Eur J Neurol. 2002;9:12536.


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