Other Agents
Various other pharmacologic approaches to treat AD have been studied. A
large RCT with Gingko biloba suggested that it had modest effects at improving
cognition (80). A recent review by the Canadian Coordinating Office for
Health Technology Assessment concluded that results of available trials
on the use of Gingko biloba for dementia suggest smaller effects than those
of the ChEIs (81). Gingko biloba is a plant extract that contains numerous
pharmacologically active components, some of which have been theorized
to act as antioxidants, antiinflammatories, or neurotransmitter modulators.
Because it is unknown which of the active components contribute to its
cognitive enhancing effects and the standardized preparations are not available,
many clinicians are unlikely to recommend its use. Cerebrolysin is a peptide
compound made from porcine brain proteins and theorized to have neuroprotective
effects (82,83). The need to administer this compound by intravenous (IV)
infusion may limit its practical use. Memantine is a glutamate-gated N-methyl-D-aspartate
(NMDA) receptor channel blocker that has shown promise in treating patients
with severe dementia (84). The search for immunotherapy to block beta-amyloid
deposition has also appeared promising, even though research on one vaccine
was recently halted due to adverse effects (85). Finally, several pharmaceuticals
that also attempt to block amyloid deposition by acting as secretase inhibitors
are in the early stages of development.
Clinical Practice Guidelines
Clinical Practice Guidelines (CPG) are systematically and formally defined
recommendations for health care providers that help with decision making
on interventions for specific clinical problems (86). Three CPGs of dementia
management are most pertinent to Canadian psychiatrists. First, in May
1997, the American Psychiatric Association (APA) published Practice Guideline
for the Treatment of Patients with Alzheimer’s Disease and Other Dementias
of Late Life (87). At that time, available drug interventions were limited,
but recommendations that patients with mild to moderate AD “may be offered”
treatment with tacrine or donepezil was supported by “substantial clinical
confidence.” Treatment with vitamin E (“substantial clinical confidence”)
or selegiline (“moderate clinical confidence”) could also be considered.
Second, later that year, in October 1997, the American Association of Geriatric
Psychiatry, the Alzheimer Association, and the American Geriatric Society
published a consensus statement on the Diagnosis and Treatment of Alzheimer’s
Disease and Related Disorders (88). Once again, the availability of data
limited recommendations, but they also suggested that physicians “may consider”
a trial of tacrine or donepezil for patients with mild to moderate AD.
In contrast to the APA Guidelines, they noted that the evidence for the
clinical use of Gingko biloba, vitamin E, and selegiline was “inconclusive.”
Third, in June 1999, the Canadian Consensus Conference on Dementia published
the guidelines that were more far-reaching, comprehensive, and comprised
several pharmacologic recommendations (89). When present, physicians should
treat vascular risk factors, including arterial hypertension, hypercholesterolemia,
diabetes mellitus, smoking, use of anticoagulation for atrial fibrillation,
and secondary prevention of transient ischemic attacks (TIAs) and stroke.
The use of NSAID and HRT was not recommended on the basis of available
evidence. The guidelines recommended that donepezil “can be prescribed
to informed and willing patients with mild to moderate dementia due to
probable AD,” though they also noted that no evidence supported the use
of the drug in preventing AD or the treatment of more severe stages. With
respect to the use of vitamin E and Gingko biloba, there was insufficient
evidence to recommend their use; conversely, a dissenting opinion was published
which argued that vitamin E had been shown to slow progression of AD and
that there was potential for additional health benefits with its use.
The limitations of CPGs have been well documented, not the least of which
is poor physician adherence (90). The CPGs reviewed above are clearly outdated:
numerous pivotal trials and important studies have been published since
1999. In fact, in the year 2001 alone, over 30 major studies on AD pharmacotherapy
were published, most of which have direct implications for CPGs (91). Without
electronic posting of such guidelines and frequent regular "live updates,"
all dementia CPGs will likely be outdated by their date of publication—a
true testament to the expansion of research in this area of therapeutics.
Recommendations and Conclusions
Based on the previous review, evidence-based recommendations for the pharmacotherapy
of AD and other dementias can be made. Regardless of etiology, physicians
should pay particular attention to vascular risk factors—and especially
ensure adequate treatment and monitoring of hypertension, diabetes, and
cholesterol levels. Clinicians should provide anticoagulation or antiplatelet
therapy for patients with a history of TIAs or stroke. Although RCT evidence
is lacking, recommending a multivitamin with folate and B-complex vitamins
may decrease homocysteine levels and, most likely, will be well tolerated
(and well accepted by most patients). Clinicians should offer patients
with AD, VaD, and DLB at least 1 trial of a ChEI, while considering a second
ChEI if the first is not tolerated or is ineffective. ChEI use in AD should
be considered not only in patients with mild-to-moderate illness but also
in cases of moderate-to-severe illness. In dementia patients, HRT and
antiinflammatory treatment should not be prescribed as the primary therapeutic
indication at this time. The use of Gingko biloba cannot be recommended,
owing to insufficient data and practical administration issues. However,
physicians could consider the use of vitamin E, although more data are
necessary to recommend its use with any confidence, and recent studies
have dampened the enthusiasm for benefits beyond dementia.
Most patients who follow these recommendations will have only modest cognitive
or disease-modifying benefits, but even modest benefits may have significant
effects on quality of life, caregiver burden, and societal economic costs.
Nevertheless, these interventions clearly represent only the first small
steps on a long voyage that will eventually see treatments that can prevent
onset, delay progression, and reverse the cognitive, functional, and behavioural
disorders that plague our patients.
Funding and Support
Janssen-Ortho Inc, Pfizer, and Novartis provided honoraria, consultant
fees, and research support for this study.
References
1. Canadian Study of Health and Aging Working Group. Canadian study of
health and aging: study methods and prevalence of dementia. CMAJ 1994;150:899–913.
2. Canadian Study of Health and Aging Working Group. The incidence of dementia
in Canada. Neurology 2000;55:66–73.
3. Hux MJ, O’Brien BJ, Iskedjian M, Goeree R, Gagnon M, Gauthier S. Relation
between disease severity and costs of caring. CMAJ 1998;159:457–65.
4. Ostbye T, Crosse E. Net economic costs of dementia in Canada. CMAJ 1994;151:1457–64.
5. American Psychiatric Association. Diagnostic and statistical manual
of mental disorders (DSM IV). 4th ed. Washington (DC): The American Psychiatric
Association; 1994.
6. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group
under the auspices of department of health and human services task force
on Alzheimer’s disease. Neurology 1984;34:939–44.
7. Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study
of physical activity and cognitive decline in elderly women: women who
walk. Arch Intern Med 2001;161:1703–8.
8. Wilson RS, Mendes deLeon CF, Barnes LL, Schneider SA, Bienias JL, Evans
DA, and others. Participation in cognitively stimulating activities and
risk of incident Alzheimer disease. JAMA 2002;287:742–8.
9. Herrmann N. Recommendations for the management of behavioral and psychological
symptoms of dementia. Can J Neurol Sci 2001;28(Suppl 1):S96–S107.
10. Dunkin JJ, Anderson-Hanley C. Dementia caregiver burden: a review of
the literature and guidelines for assessment and intervention. Neurology
1998;51(Suppl 1):S53–S60.
11. Felician O, Sandson TA. The neurobiology and pharmacotherapy of Alzheimer’s
disease. J Neuropsychiatry Clin Neurosci 1999;11:19–31.
12. Koopmans Summers W, Majoviski LV, Marsh GM, Tachiki K, Kling A. Oral
tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer
type. NEJM 1986;315:1241–5.
13. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients
with Alzheimer’s disease: results of a US multicentre, randomized, double-blind,
placebo-controlled trial. The Donepezil Study Group. Dementia 1996;7:293–303.
14. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind,
placebo-controlled trial of donepezil in patients with Alzheimer’s disease.
Donepezil Study Group. Neurology 1998;50:136–45.
15. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition
and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled
study. Donepezil Study Group. Arch Intern Med 1998;158:1021–31.
16. Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Moller HJ, and others.
The effects of donepezil in Alzheimer’s disease results from a multinational
trial. Dement Geriatr Cogn Disord 1999;10: 237–44.
17. Winblad B, Engedal K, Soininen H, Verhey F, Waldermar G, Wimo A, and
others. A 1-year, randomized, placebo-controlled study of donepezil in
patients with mild to moderate AD. Neurology 2001;57:489–95.
18. Homma A, Takeda M, Imai Y, Udaka F, Hasegawa K, Kameyama J, and others.
Clinical efficacy and safety of donepezil on cognitive and global function
in patients with Alzheimer’s disease. A 24-week, multicenter, double-blind,
placebo-controlled study in Japan. E2020 Study Group. Dement Geriatr Cogn
Disord 2000;11:299–313.
19. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, and others.
A 1-year, placebo-controlled preservation of function survival study of
donepezil in AD patients. Neurology 2001;57:481–8.
20. 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;57:613–20.
21. Agid Y, Dubois B. Efficacy and tolerability of rivastigmine in patients
with dementia of the Alzheimer type. Curr Ther Res 1998;59:837–45.
22. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P,
and others. Efficacy and safety of rivastigmine in patients with Alzheimer’s
disease: international randomised controlled trial. BMJ 1999;318(7184):633–8.
23. Corey-Bloom J, Anand R, Veach J. ENA 713 B352 Study Group. 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. Int J Ger Psychopharmacol 1998;1:55–65.
1 | 2 | 3 | 4 | 5
|
