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Effectiveness of Donepezil Therapy in Advanced Alzheimer’s Disease
Dementia [DAD], both instrumental and basic activities of daily Figure 3: Japanese Study
living (ADL) measures) and behaviour (NPI) compared with patients
A
receiving placebo.
8
*
*
6
*
*
*
*
In addition to the specific treatment effects for the patients, the
4
*
*
Clinical
MSAD study further looked at the effect of treatment on carer
improvement
2
burden.
18
Carers completed a diary throughout the study recording
time spent caring and were assessed using a Caregiver Stress Scale.
0
At baseline, carer stress and time spent caring were similar between -2
Clinical
the treatment groups. The level of decline in patients in both
-4
decline
instrumental and basic ADLs was significantly slower with donepezil
Mean SIB change from baseline
-6
treatment compared with placebo in this study. After 24 weeks of
treatment, the overall carer ratings were significantly better for
-8
Week 8 Week 16 Week 24 -FAS-LOCF
carers of donepezil-treated patients than for those caring
Placebo Donepezil 5mg/d Donepezil 10mg/d
for placebo patients. Carers of placebo patients spent almost one
hour more each day providing care than the carers of those
receiving donepezil. Therefore, treatment may also provide benefits B
to those caring for patients with severe AD.
Improved
In all four of these studies treatment with donepezil had a
consistently significant and positive effect on cognition. Where
global function was measured with the CIBIC-plus, again results
No change
were positive in favour of donepezil. With the ADCS-ADL-sev, the
results were mixed, with a positive result from the Swedish study
and no significant difference from the multinational and Japanese
Worsened
studies. MSAD measured function with DAD and, again, the result
was positive in favour of donepezil. Positive effects on measures of 0 10 20 30 40 50
behaviour were seen in MSAD trial, and there were trends for
Patients (%)
possible effects in both the Swedish and multinational studies.
Placebo Donepezil 5mg/d Donepezil 10mg/d
These studies also showed that donepezil is safe and well tolerated
Effect of donepezil treatment on (A) Severe Impairment Battery (SIB) scores (data represent
in the severe AD population.
13–16
The safety and tolerability data
change from baseline at each time point using observed cases at weeks eight, 16 and 24,
from patients receiving donepezil in the cited studies were similar
and the full analysis set–last observation carried forward [FAS–LOCF] population at
end-point; error bars represent standard error of the mean; *p<0.001 versus placebo) and (B)
to those in patients receiving placebo and did not differ
Clinician’s Interview-Based Impression of Change-plus care-giver interview (CIBIC-plus)
substantially from data obtained in patients with mild to moderate
scores (three-category collapsed analysis) at end-point (FAS-LOCF); overall p=0.001 for
donepezil 10mg/day versus placebo.
AD. Side effects were typical of ChEI therapy (diarrhoea and
hallucinations), and were primarily transient and mild to moderate has found the combination therapy to be a cost-effective
in severity. therapy option.
22
Donepezil and Memantine in Combination Conclusions
The N-methyl-D-aspartate (NMDA) receptor antagonist memantine Studies of patients with severe AD have shown that, far from being a
is currently licensed for the treatment of MSAD. A number of stage at which all hope is lost, there are tangible benefits of treatment
published studies have shown that combination therapy to patients and carers. The initiation of treatment at the severe stage
(memantine plus donepezil) can be useful, particularly in the of the disease is worthwhile, and treatment that has shown benefits
advanced stages of the disease, with few additional tolerability seen throughout the course of the disease should be continued.
issues.
19–21
Guidelines advocate the treatment of patients with Donepezil has strong efficacy data in AD from the mild to the severe
severe AD (MMSE score <10) with memantine in combination stage
6–9,13–17,23–26
and has been shown to be effective for treating all
with a ChEI as required,
12
and a pharmacoeconomic evaluation domains of AD.
13–17,23–27
■
1. Aguero-Torres H, Fratiglioni L, Winblad B, Int J Geriatr 7. Doody RS, et al., Arch Neurol, 2001;58(3):427–33. 17. Feldman H, et al., Neurology, 2001;57(4):613–20.
Psychiatry, 1998;13:755–66. 8. Mohs RC, Doody RS, Morris JC, et al., Neurology, 18. Feldman H, et al., J Am Geriatr Soc, 2003;51(6):737–44.
2. Feldman HH, Woodward M, Neurology, 2005;65:S10–17. 2001;57(3):481–8. 19. Tariot PN, et al., JAMA, 2004;291(3):317–24.
3. National Institute of Health and Clinical Excellence. 9. Holmes C, Wilkinson D, Dean C, et al., Neurology, 20. Feldman HH, et al., Alzheimer Dis Assoc Disord, 2006;20(4):
Appraisal Consultation Document: Quick Reference 2004;63(2):214–19. 263–8.
Guide – Donepezil, galantamine, rivastigmine (review) and 10. Geldmacher DS, et al., J Am Geriatr Soc, 2003;51(7):937–44. 21. Schmitt FA, et al., Alzheimer Dis Assoc Disord, 2006;20(4):
memantine for the treatment of Alzheimer’s disease 11. Caltagirone C, et al., Drugs Aging, 2005;22(Suppl. 1):1–26. 255–62.
(amended), 2007. Available at: www.nice.org.uk/ 12. Waldemar G, Dubois B, Emre M, et al., Eur J Neurol, 22. Weycker D, et al., Curr Med Res Opin, 2007;23(5):1187–97.
nicemedia/pdf/TA111QRGSept07.pdf 2007;14:e1–26. 23. Rogers SL, et al., Neurology, 1998;50(1):136–45.
4. Wilkinson D, Sganga A, Stave C, et al., Int J Clin Pract Suppl, 13. Winblad B, Kilander L, Eriksson S, et al., Lancet, 24. Burns A, et al., Dement Geriatr Cogn Disord, 1999;10(3):
2005;(146):27–31. 2006;367(9516):1057–65. 237–44.
5. Eisai Inc, Aricept US Prescribing Information, Woodcliff 14. Black SE, Doody RS, Li H, et al., Neurology, 2007;69:459–69. 25. Rogers SL, et al., Arch Intern Med, 1998;158(9):1021–31.
Lake, NJ: Eisai Inc., 2006. 15. Homma A, Imai Y, Tago H, et al., Dement Geriatr Cog Disorder, 26. Gauthier S, et al., Int Psychogeriatr, 2002;14(4):389–404.
6. Winblad B, et al., Dement Geriatr Cogn Disord, 2006;21 2008; in press. 27. Johannsen P, et al., CNS Drugs, 2006;20(4):311–25.
(5–6):353–63. 16. Feldman H, et al., Int J Geriatr Psychiatry, 2005;20(6):559–69.
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