BTG - Pharmacotherapy of Alzheimer's Disease - Current and Future Perspectives
BTG - Pharmacotherapy of Alzheimer's Disease - Current and Future Perspectives
There have been significant advances in the pharmacotherapy of Alzheimer’s Disease (AD) over the past 25 years. This article summarizes some of the evidence for the safety and efficacy of cholinesterase inhibitors (CI) and memantine in the symptomatic treatment of AD. It also looks at the design of on-going studies attempting to modify disease progression and the challenges facing the pharmacotherapy of AD.
Natural History of Alzheimer’s Disease
The natural history of AD can be broadly considered as comprising a pre-symptomatic stage during which a number of pathological events take place (an early symptomatic or prodromal stage currently described as amnestic mild cognitive impairment (aMCI)), which entails cognitive manifestations but no significant functional impairment, and symptomatic mild, moderate, and severe stages. Each of these stages could be targeted for specific drug treatments requiring different trial designs and outcomes. For example, a healthy elderly population can be tested with a safe antioxidant versus placebo over a period of five years, using incident dementia as the primary outcome. However, an aMCI population can be tested with a CI versus placebo over a three-year period, using conversion to dementia as primary outcome. On the other hand, patients with AD must be offered a CI as standard of care, to which a novel drug or placebo is added over one year or longer, with slower than expected decline in cognitive, global, or functional autonomy as primary end-points.
The milestones of AD have been defined (see Table 1). Some of these could be targeted for treatment with a good chance of alleviating symptoms and a positive potential impact on the cost of care.1 Results of just one study by the Alzheimer Disease Cooperative Study (ADCS) group, showing delayed loss of autonomy and even death in moderate to severe stages of AD by using alpha-tocopherol, influenced clinical practice to use vitamin E in all stages of AD, at least in the US.2 This practice changed because a meta-analysis of clinical studies using high doses of tocopherol suggested a higher mortality.
Symptomatic domains in dementia include cognition, activities of daily living (ADL) and behavior. In many patients, early changes in mood and anxiety precede the formal diagnosis of AD. Cognitive and functional ADL decline are relatively linear over time, whereas neuropsychiatric symptoms peak midway into the disease and improve spontaneously through the severe stage as motor skills become impaired; at this stage, patients may exhibit Parkinson-like physical signs.3 These natural fluctuations in the intensity of symptomatic domains through the stages of AD have an impact on trial design and outcomes.
2. Sano M, Ernesto C,Thomas R G et al., “A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease”, N Engl J Med (1997);336: pp. 1,216–1,222.
3. Gauthier S,Thal L J, Rossor M N,“The future diagnosis and management of Alzheimer’s disease”, in Gauthier S (ed.), Clinical Diagnosis and Management of Alzheimer’s Disease, London: Martin Dunitz (2001); pp. 369–378.
4. Rosen W G, Mohs R C, Davis K, “A new rating scale for Alzheimer’s disease”, Am J Psychiatry (1984);141: pp. 1,356–1,364.
5. Galasko D, Bennett D, Sano M et al.,“An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease”, Alzheimer Dis Assoc Disord (1997);11 (suppl. 2): pp. S33–S39.
6. Reisberg B, Borenstein J, Salob S P et al.,“Behavioural symptoms in Alzheimer’s disease: phenomenology and treatment”, J Clin Psychiatry (1987);48 (suppl.): pp. 9–15.
7. Gélinas 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: pp. 471–481.
8. Cummings J L, Mega M, Gray K et al., “The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia”, Neurology (1994);44: pp. 2,308–2,314.
9. Panisset M, Saxton J et al.,“Severe Impairment Battery : a neuropsychological test for severely demented patients”, Arch Neurol (1994);51: pp. 41–45.
10. Fahn S, Elton R, “United Parkinson’s Disease Rating Scale”, S Fahn, C Marsden, M Golstein et al. (eds.), Recent Developments in Parkinson’s Disease (1987), Florham Park: Macmillan Healthcare. pp. 153–163.
11. Leber P,“Guidelines for clinical evaluation of antidementia drugs”,Washington, DC: US Food and Drug Administration (1990).
12. Folstein M F, Folstein S E, McHugh, P R,“Mini Mental State: a practical method for grading the cognitive state of patients for the clinician”, J Psychiatric Res (1975);12: pp. 189–198.
13. Winblad B, Engedal K, Soininen H et al., “Donepezil Nordic Study Group: a 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD”, Neurology (2001);57: pp. 489–495.
14. Roman G C,Wilkinson D G, Doody R et al., “Donepezil in vascular dementia: combined analysis of two large-scale clinical trials.” Dement Geriatr Cogn Disord (2005);20: pp. 338–344.
15. Cohen-Mansfield J, Marx M S, Rosenthal A S,“A description of agitation in a nursing home”, J Gerontology (1989);44: pp. M77–M84.
16. Gauthier S,Wirth Y, Möbius H J,“Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomized, controlled studies”, Int J Geriatr Psychiatry (2005);20: pp. 459–464.
17. Doody R S, Winblad B, Jelic V, “Memantine: a glutamate antagonist for treatment of Alzheimer’s disease”, in Gauthier S, Scheltens P, Cummings J L (eds.), Alzheimer’s Disease and Related Disorders Annual, London: Martin Dunitz (2004): pp. 137–144.
18. Hughes C P, Berg L, Danziger W L, Coben L A, Martin R L, “A new clinical scale for the staging of dementia”, Brit J Psychiatry (1982);140: pp. 566–572.
19. Gervais F, “Gag mimetics: potential to modify underlying disease process in AD”, Neurobiol Aging (2004);25 (suppl.1); pp. S11–12.
