Psychiatric Times.
No. 4
Benefits of Early Pharmacological Treatment in Alzheimer Disease
By M. Saleem Ismail, MD, Connie Brand, RN, and Kimberly Martin, RN |
April 1, 2007
Dr Ismail is assistant professor of psychiatry at the University of Rochester and director of psychiatric consultation service at Monroe Community Hospital in Rochester, NY. Connie Brand is a clinical research coordinator and Kimberly Martin is a research nurse with the Alzheimer Disease Care Research and Education (AD-CARE) program at the University of Rochester. Dr Ismail reports that he has received research support from the National Institute on Aging, Pfizer/Eisai, and he is on the speakers' bureau for Eisai/Pfizer, and Forest. Connie Brand and Kimberly Martin have no conflicts of interest concerning this article.
Early treatment influences long-term outcomes
The antidementia treatments produce modest yet consistent benefit in maintaining patients' cognitive abilities, daily function, and behavioral control. How does early treatment differ from delayed treatment and how does continuous treatment alter the natural course of AD? Does initiating treatment very early produce more substantial benefits? Should treatment be initiated for patients with MCI? These questions have been addressed in some of the recent analyses.
Data from 1-year "delayed start" studies and longer-term observational studies suggest that patients who started receiving active treatment after a delay of 6 months did not achieve as optimal an outcome at the end of the study period. In a 6-month placebo-controlled study of galantamine(Drug information on galantamine) with a 6-month open extension, patients who received placebo in the double-blind phase were crossed over to open treatment.7 These patients showed expected initial decline in cognitive performance followed by the expected improvement when galantamine was begun. The cognitive performance in these patients improved but did not "catch up" to the level in those patients who had been receiving continuous therapy. Similar results were also seen in studies of donepezil(Drug information on donepezil). Patients for whom active treatment was delayed did experience cognitive benefit, but at the end of the 3-year study, cognitive outcome scores favored early and continuous treatment.10 These data suggest that delaying therapy might deprive some patients of an optimal response.
In yet another study to support early intervention, 153 patients with AD who had an average MMSE score of 24 (very mild AD) were randomized to receive placebo or donepezil. While the placebo group failed to improve on primary cognitive measures, treatment with donepezil resulted in significant improvements in cognitive function over 24 weeks.19 This finding is thought-provoking. It is possible that the rate of cognitive decline and potential benefit of intervention in early AD is different from what is typically seen in studies of patients with greater cognitive severity.
The rate of progression in patients with AD is heterogeneous. Lopez and colleagues36 have expanded on their previous report that treatment with AChEIs alters the natural course of AD.14 Their recent analysis shows that patients taking an AChEI were twice as likely to progress slowly as patients with AD who were not treated with an AChEI. This is clinically meaningful, since the rate of decline can impact the caregiver's ability to provide care, which influences a patient's ability to live in the community.
A critical "tipping point" for caregivers is emergence of unmanageable psychopathology in patients with AD. In another study, open-label donepezil was dispensed for 12 weeks, followed by randomization to placebo or donepezil for another 12 weeks. Patients treated with donepezil showed improvement in behavioral symptoms that was maintained during the randomization phase. Patients who were switched to placebo after 12 weeks experienced behavioral deterioration.37
Mild cognitive impairment: a window of opportunity
In a progressive illness such as AD, it is obvious that individuals move through a transitional phase during which symptoms are not severe enough to warrant a dementia diagnosis. MCI represents that transition between normal aging and dementia. Persons with MCI have a subjective sense of memory decline that is recognized by family or clinical providers. These individuals do not have appreciable functional impairment.38 The concept of amnestic MCI, however imperfect, comes closest to identifying AD before the onset of dementia. This construct has been used in several clinical trials and some have suggested that MCI is very early AD.39 Further validation comes from a recent study in which 99% of participants with amnestic MCI who progressed to dementia were classified as having AD after 3 years of follow-up.40
The benefits of treatment are likely to be more substantial if treatment is initiated before the threshold for dementia diagnosis is crossed. Therefore, the concept of MCI has inspired clinicians and researchers to action. Two recent studies have explored the potential for treating patients for MCI. In a 24-week, double-blind, placebo-controlled trial there was a significant difference favoring donepezil on a secondary outcome measure, although the primary measures failed to show benefit for donepezil.26
Encouraging results were also seen from the Alzheimer's Disease Cooperative Study MCI clinical trial.40 The results indicate that patients taking donepezil were at reduced risk for progressing to AD during the first 18 months; however, this advantage disappeared at the end of 3 years. The study compared the effects of donepezil 10 mg daily, vitamin E(Drug information on vitamin e) 2100 IU daily, and placebo in delaying the progression from MCI to AD in 769 patients. In a subset of patients who had the apoE4 allele, donepezil appeared to decrease the probability of progression to AD for the full 36 months of the study. Thus, a diagnosis of amnestic MCI may provide a window of opportunity for intervention and for limiting the suffering of patients and their caregivers.
Conclusion
Relentless decline is observed in patients with AD who do not receive treatment. In the absence of a cure, stabilization and slowing the progression are valuable objectives. Early diagnosis and treatment can help us achieve these goals. Recent data point to a broader range of effects of antidementia drug treatment, including favorable effects on behavior, daily functions, and caregiver burden. Data from year-long placebo-controlled studies and observational data converge on the conclusion that long-term benefits are likely with treatment. Patients who received active treatment on average were better off than patients who did not receive treatment. Furthermore, the provocative "delayed start" data suggest that delaying the onset of treatment may result in less favorable outcomes. These findings are strengthened by some, but not all, additional data from studies of very mild AD and MCI.
Laboratory evidence suggests neuroprotective or possible disease-modifying effects of AChEI and memantine(Drug information on memantine) therapy. These agents may influence disease progression not only by modifying neurotransmitter abnormalities but by influencing abnormal amyloid and tau processing and neurotoxicity. If these findings are substantiated, our goal of pharmacological intervention will shift from symptom management to disease modification—in which case, early therapy (possibly in patients with MCI) will become more important.
References
1. Ernst RL, Hay JW. The US economic and social costs of Alzheimer's disease revisited. Am J Public Health. 1994;84:1261-1264.
2. O'Donnell B, Drachman D, Barnes H, et al. Incontinence and troublesome behaviors predict institutionalization in dementia. J Geriatr Psychiatry Neurol. 1992;5:45-52.
3. Bond J, Stave C, Sganga A, et al. Inequalities in dementia care across Europe: key findings of the Facing Dementia Survey. Int J Clin Prac. 2005;59:8-14.
4. Small GW, Ercoli LM, Silverman DH, et al. Cerebral, metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000; 97:6037-6042.
5. Knopman D, Donohue JA, Gutterman EM. Patterns of care in the early stages of Alzheimer's disease: impediments to timely diagnosis. J Am Geriatr Soc. 2000;48: 300-304.
6. Luchsinger JA, Reitz C, Honig LS. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65:545-551.
7. Feldman H, Gauthier S, Hecker J, et al. A 24- week randomized, double blind study of donepezil in moderate to severe Alzheimer's disease. Neurology. 2001;57: 613-620.
8. Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel group, placebo-controlled study. Lancet. 2006;367:1057-65.
9. Raskind MA, Peskind ER, Wessel T, et al, and the Galantamine USA-1 Study Group. Galantamine in AD: a 6-month randomized placebo-controlled trial with a 6-month extension. Neurology. 2000;54:2261-2268.
10. Winblad B, Wimo A, Engedal K, et al. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy. Dement Geritr Cogn Disord. 2006;21:353-363.
11. Cummings JL, Koumaras B, Chen M, et al. Effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer's disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother. 2005;3:137-148.
12. Cummings JL, Schneider E, Tariot PN, et al. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67: 57-63.
13. Wimo A, Winblad B, Stoffler A, et al. Resource utilization and cost analysis of memantine in patients with moderate to severe Alzheimer's disease. Pharmacoeconomics. 2003;21:327-340.
14. Lopez OL, Becker JT, Wisniewski S, et al. Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease. J. Neurol Neurosurg Psychiatry. 2002;72:310-314.
15. Winblad B, Engedal K, Soininen H, et al, and the Donepezil Nordic Study Group. A 1-year randomized, placebo controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:481-488.
16. Mohs RC, Doody RS, Morris JC, et al. A 1-year placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology. 2001;57:481-488.
17. Farlow M, Anand R, Messura J Jr, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol. 2000;44:236-241.
18. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized placebo-controlled trial of galantamine in Alzheimer's disease. Neurology. 2000;54:2269-2276.
19. Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852-1856.
20. Ernst RL, Hay JW, Fenn C, et al. Cognitive function and cost of Alzheimer disease. Arch Neurol. 1997;54: 687-693.
21. Knopman D, Schneider L, Davis K, et al, for the Tacrine Study Group. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality. Neurology. 1996;47:166-177.
22. Geldmacher DS, Provenzano G, McRae T, et al. Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc. 2003;51:937-944.
23. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA. 2003;289: 210-216.
24. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD001190.
25. Jelic V, Kivipelto M, Winblad B. Clinical trials in mild cognitive impairment: lessons for the future. J Neurol Neurosurg Psychiatry. 2006;77:429-438.
26. Salloway S, Ferris S, Kluger A, et al, for the Donepezil 401 Study Group. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004;63:651-657.
27. Loewenstein DA, Acevedo A, Czaja SJ, Duara R. Cognitive rehabilitation of mildly impaired AD patients on cholinesterase inhibition. Am J of Geriatr Psychiatry. 2004;12:395-402.
28. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA. 1994;271:992-998.
29. Burns A, Rossor M, Hecker J, et al, and the International Donepezil Study Group. The effects of donepezil in Alzheimer's disease—results from a multinational trial. Dement Geriatr Cogn Disord. 1999;10:237-244.
30. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial. Lancet. 2004;363:2105-2115.
31. Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor in patients with mild to moderately severe Alzheimer's disease for the ENA 713 B352 study group. Int J Geriatric Psychopharmacol. 1998;1:55-65.
32. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999;318:633-638.
33. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333-1341.
34. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer's disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-324.
35. Peskind E, Potkin SG, Pomara N, et al. Memantine monotherapy is effective and safe for the treatment of mild to moderate Alzheimer's disease: a randomized controlled trial. Presented at: 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris.
36. Lopez OL, Becker JT, Saxton J, et al. Alteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibition. J Am Geriatr Society. 2005;53:83-87.
37. Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer's disease. Neurology. 2004;63:214-219.
38. Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol. 2005; 62:1160-1163.
39. Morris JC, Strodant M, Miller P, et al. Mild cognitive impairment represents early-stage Alzheimer's disease. Arch Neurol. 2001;58:397-405.
40. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-2388.
