Neurofibrillary tangles

Cholinesterase inhibitors (ChEIs) including donepezil, rivastigmine, and galantamine, and the N-methyl-D-aspartate (NMDA) antagonist, memantine, are the only medications currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease (AD). Other agents, such as vitamins, statins, estrogen, ginkgo biloba, anti-inflammatory agents, antidepressants, antipsychotics, and mood stabilizers, have been commonly used, off-label, as combination therapies. Additional needs--such as dealing with progressive cognitive decline, depression, and agitation--are beyond today's monotherapies. Informal surveys of clinicians indicate that unproven combinations are frequently used in routine practice to treat AD. (1)

Rational polypharmacy

Despite concerns about increased side-effects, higher costs, and possibly lower medication adherence with polypharmacy, healthcare professionals and family members are desperate for additional treatment options for AD patients. (2)

Why combination drug therapy? ChEIs cannot be expected to correct every deficit, because acetylcholine deficiency is not the only problem in AD. Several other pathways have been hypothesized to contribute to the pathogenesis of AD, including excess oxidative stress, decreased cerebral metabolic rate, and alterations in several neurotransmitter systems--in addition to the pathologic accumulation of b-amyloid and neurofibrillary tangles. (3) Combination drug therapies, which offer the prospect of additive or synergistic benefits, can be used to target multiple pathologic processes. Other advantages of combination drug therapy include the potential to lower the dose of the more toxic agent and to target specific, unremitting symptoms not relieved by one agent alone.

In balancing these benefits and risks, it is important to take an evidence-based approach. Combination drug therapies--initial versus step-wise approaches--can be found in the treatment of other disease states. Initial combination therapy is the standard of care in the treatment of malignancies and human immunodeficiency virus (HIV). Multiple agents are used to achieve maximum efficacy by aggressively attacking several targets simultaneously to exploit synergy and to minimize individual toxicity. For the treatment of hypertension, a step-wise augmentation approach is commonly employed. Yet even this approach is evolving, as initial fixed-dose combination therapies with two classes of antihypertensive agents have proven to be more effective than monotherapy alone. (4,5)

Combination therapies in AD

Although successfully applied to a variety of disease states, combination strategies in AD have had mixed results to date. The table summarizes recently published combination drug therapy studies in AD. (6-11) There is a paucity of prospective combination drug therapy trials, and of these, only one published prospective randomized controlled trial (RCT) (6) found an incremental benefit for combination drug therapy over monotherapy for AD. The results of several other completed trials of proprietary compounds (where concomitant cholinergic therapy was allowed) are not yet public and therefore not available for review.

ChEI and memantine: Memantine, as an add-on therapy for patients with moderate-to-severe AD on stable doses of donepezil, showed significant benefits on several primary and secondary outcome measures in a 24-week multicenter trial involving 404 patients with moderate-to-severe AD [Mini-Mental State Examination (MMSE) score of 5 to 14, mean 7.9 [+ or -] 3.64]. (6) The average duration of therapy was 129 weeks in the placebo group and 126 weeks in the combination group. Subjects were randomized to receive memantine, titrated to 10 mg bid, or placebo, in addition to donepezil. The donepezil-memantine group performed better than the donepezil-placebo group on cognition (Severe Impairment Battery, SIB), activities of daily living (AD Cooperative Study-Activities of Daily Living Inventory, ADCS-ADL19), and key secondary endpoints, including Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory (NPI), and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). The combination was well tolerated. Despite objectively measurable benefits, improvements exerpienced by the individual patient remain to be better characterized.

Although this was a well-designed and clearly positive study, it did not address the question of whether adding memantine to donepezil is better than switching from donepezil to memantine monotherapy. This study showed a 3.4-point reduction on the SIB between the donepezil-memantine and donepezil-placebo groups (a 3-point reduction on the SIB is approximately equivalent to a 1-point reduction on the MMSE in severe dementia, the exact significance of this as experienced by the individual patient is often difficult to detemine). However, in a study of memantine alone for moderate-to-severe AD, Reisberg et al showed that the memantine group lost an average of 6.1 fewer points on the SIB than placebo group. (12) The smaller effect in the combination study suggests that donepezil may also be effective in moderate-to-severe AD because donepezil could have contributed to the lower benefit observed in the combination study.

The benefit of donepezil in moderate-to-severe AD was also shown in a recent study. (13) However, as the populations enrolled in the two studies differ, such indirect comparison warrants caution. Further, since the study did not include rivastigmine or galantamine, its application to patients on other ChEIs in moderate-to-severe AD awaits further evidence.

Antioxidant combinations: Another large scale RCT (n = 341), sponsored by the National Institutes of Health (NIH), compared patients with moderate AD on placebo, vitamin E (alpha-tocopherol), 1,000 IU bid; selegiline, 10 mg/d; and a combination of vitamin E and selegiline, over 2 years. (7) The combination of vitamin E and selegiline was effective but less so than either agent alone. After adjustment for baseline MMSE, each of the active treatments significantly delayed the time to primary outcome, defined as time to occurence of death, institutionalization, loss of ability to perform basic ADLs, or severe dementia with Clinical Dementia Rating of 3, by 670 days for vitamin E (p = 0.001), by 655 days for selegiline (p = 0.012), and by 585 days for the combination (p = 0.049) as compared with placebo (440 days).

Despite randomization, there was a trend toward higher baseline MMSE scores in the placebo group and lower baseline MMSE scores in the vitamin E group. Only after adjusting for baseline MMSE did the primary endpoints demonstrate difference among the treatment and placebo groups. Secondary outcomes included six additional measures of cognition, behavior, and function (MMSE, AD Assessment Scale, Blessed Dementia Scale, Equivalent Institutional Service, Dependence Scale, and Behavior Rating Scale for Dementia). Two of the measures, the Blessed Dementia Scale and the Dependence Scale, showed significant differences between the treatment groups compared with placebo, but again no difference between monotherapy compared with the combination. The need to adjust for baseline MMSE despite initial randomization potentially introduced bias and weakened the study's conclusions. An accompanying editorial also raised a concern about the validity of the composite outcome measure used. (14) Therefore, it is difficult to draw definitive conclusions from this study.

The efficacy of the selegiline and vitamin E study raises the question of whether vitamin E or selegiline might be added to a ChEI. Despite little evidence for its use, the combination of vitamin E with a ChEI has achieved widespread popularity among clinicians, largely because of the negligible toxicity of vitamin E.

An observational cohort study has reported efficacy of a donepezil and vitamin E combination. (10) The authors reviewed 130 charts from 1997-2001 and included 40 patients (MMSE 10 to 24) who were on stable doses of donepezil (> 5 mg/d) and vitamin E (> 1,000 IU/d) over a 3-year period. This cohort was compared with patients from the Consortium to Establish a Registry for AD (CERAD) database from 1986-1996. It showed that cumulative MMSE score deterioration on the combination therapy was 1.43 [+ or -] 4.19, 4.05 [+ or -] 4.75, and 6.27 [+ or -] 5.68, for years 1, 2, and 3, respectively. Average cumulative change in the CERAD group was 3.36 [+ or -] 4.57, 6.51 [+ or -] 5.36, and 9.12 [+ or -] 6.01 after 1, 2, and 3 years, respectively. The treatment group performed significantly better than the CERAD controlled group (which received no treatment). The use of a non-randomized, retrospective cohort as the control group severely limited the internal validity of this study. Thus, the donepezil and vitamin E combination is not supported by current evidence; additional prospective trials are needed.

ChEI and estrogen: ChEI and estrogen combination therapies have been studied in two RCTs and several retrospective analyses.8-9 In a post-hoc analysis of a tacrine trial (n=343; MMSE 10 to 26), patients on estrogen replacement therapy prior to study entry improved on the AD Assessment Scale-Cognitive Scale (ADAS-Cog) and CIBIC more than women not receiving estrogen who were randomized to either tacrine or placebo. (8) The study's conclusions were limited by its retrospective design and possible selection bias (eg, women who were taking estrogen were younger and better educated).

A rivastigmine and hormone replacement therapy (HRT) combination was studied in a 28-week RCT (n=117) in mild-to-moderate AD (MMSE 10 to 26). Compared with rivastigmine and placebo, the combination was no better in several measures including ADAS-Cog, Instrumental Activities of Daily Living Scale (IADL), NPI, and Clinical Global Change Scale (CGC-plus). (9) Because each arm had less than 60 patients, under-powering is possible.

The estrogen story exemplifies the need for prospective studies since previous retrospective studies favoring estrogen use were not confirmed by RCTs. In fact, data from the Women's Health Initiative has shown that HRT (as conjugated equine estrogen) may contribute to the risk of dementia. (15) Therefore, conclusions drawn from observational or retrospective studies may be premature and need to be cautiously interpreted.

Other emerging studies. Because inflammation and atherosclerosis have been postulated as additional mechanisms contributing to AD, (3) nonsteroidal anti-inflammatory drugs (NSAIDS) and statins have been investigated as additional treatment options. Epidemiologic studies showed that NSAIDS appear promising in AD, although with mixed results. (16) Several RCTs (6 to 12 months) in mild-to-moderate AD patients comparing cyclooxygenase-2 (COX-2) inhibitors versus placebo have been completed but not published.

Statin use was examined in a retrospective analysis of three trials with AD patients (n = 1,325) on galantamine, in which 6.9% of the patients were on statins. Patients who were on statins did not show additional cognitive benefits over those not taking statins, but tended to have more motor side effects. (16) Several prospective studies with statins are underway. One pilot study of 64 mild-to-moderate AD patients taking atorvastatin and concurrent ChEIs reportedly showed promising results by slowing decline on the MMSE and ADAS-Cog. (17)

Ongoing trials of various other strategies, including vitamins, mifepristone (glucocorticoid antagonist), anti-amyloid agents, growth factors, antidepressants, (18) and antipsychotics have permitted concurrent use of ChEIs and hence are de-facto combination drug therapy studies. The results of these trials are anticipated.

Future needs

Whereas a definitive cure for Alzheimer's disease is unlikely in the near future, it can be predicted that multiple interventions will be needed. Currently, only combinations of symptom-targeted therapies are feasible in practice because these are the only agents clinically indicated in patients with AD. ChEIs, memantine, or both will likely become foundation therapies to which other agents are added. Premature adaptation of results from retrospective studies into clinical practice should be cautioned. Conclusions from retrospective investigations have not necessarily endured the more rigorous RCT design. Nevertheless, due to limited resources, it is not feasible to test every possible combination. Thus, rational combinations will need to be selected based on monotherapy trials, available experimental data, and the drugs' relative safety.

This review did not find any evidence to support definitively the use of initial combination drug therapy in early AD. The study on the use of memantine in moderate-to-severe AD as an add-on combination to ChEIs is not only a positive study but also is likely the most judiciously designed study published thus far. Lessons can be learned from this study and from failed combination drug therapy studies with respect to well-defined a priori clinical outcome measures, statistical power calculation, internal validity, and avoidance of premature conclusions from post-hoc analyses.

Additionally, use of clinical, neuropsychologic, and imaging outcomes in the future may increase the sensitivity of detecting combination regimens that are effective in modifying the course of AD.

Given the widespread use of off-label therapies in AD, our review highlights the paucity of published prospective combination drug therapy trials in AD and the lack of efficacy for most combinations evaluated to date. As our population ages and the prevalence of AD rises, there is an urgent need for collaborative efforts between government, industry, academia, and patient groups to address this gap.

References

(1.) Doraiswamy PM, Steffens, DC. Combination therapy for early Alzheimer's disease: What are we waiting for? J Am Geriatr Soc 1998; 46(10):1322-4.

(2.) Doraiswamy PM. Interventions for mild cognitive impairment and Alzheimer disease: New strategies, new hope. Am J Geriatr Psychiatry 2003; 11(2):120-2.

(3.) Cummings JL. Alzheimer's disease. N Engl J Med 2004; 351(1):56-67.

(4.) Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomized trials. BMJ 2003; 326(7404):1427.

(5.) Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003; 289(19):2560-72.

(6.) Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to several Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004; 291(3):317-24.

(7.) Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997; 336(17):1216-22.

(8.) Schneider LS, Farlow M. Combined tacrine and estrogen replacement therapy in patients with Alzheimer's disease. Ann N Y Acad Sci 1997; 826:317-22.

(9.) Rigaud AS, Andre G, Vellas B, Touchon J, Pere JJ; French Study Group. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology 2003; 60(1):148-9.

(10.) Klatte ET, Scharre DW, Nagaraja HN, Davis RA, Beversdorf DQ. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis Assoc Disord 2003; 17(2):113-6.

(11.) Gutterman EM, Markowitz JS, Joan Amatniek J, et al. Effects of statins on cognitive maintenance of patients with Alzheimer disease in pooled, randomized, placebo-controlled clinical trials of galantamine. Poster presented at 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy. April 3-6, 2002. Geneva, Switzerland.

(12.) Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003; 348(14):1333-41.

(13.) Feldman H, Gauthier S, Hecker J, et al. Efficacy of donepezil on maintenance of activities of daily living in patients with moderate to severe Alzheimer's disease and the effect on caregiver burden. J Am Geratr Soc 2003; 51(6):737-44.

(14.) Drachman DA, Leber P. Treatment of Alzheimer's Disease--searching for a breakthrough, settling for less. N Engl J Med 1997; 336(17):1245-7.

(15.) Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291(24):2959-68.

(16.) Andersen K, Launer LJ, Ott A,Hoes AW, Breteler MM, Hofman A. Do nonsteroidal anti-inflammtory drugs decrease the risk for Alzheimer's disease? The Rotterdam Study. Neurology 1995; 45(8):1441-5.

(17.) Sparks DL, Sabbagh M, Connor DJ, et al. Benefits of atorvastatin in subjects with Alzheimer's disease: Abstract. Circ, In press.

(18.) Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil. Int J Geriatr Psychiatry 2004; 19(1):9-18.

Glen Xiong, MD * P. Murali Doraiswamy, MD

Dr. Xiong is chief resident in internal medicine and psychiatry at Duke Univeristy Medical Center, Durham, NC.

Dr. Doraiswamy is director, psychiatry clinical trials, Duke University Medical Center, Durham, NC.

Disclosure: Dr. Xiong has no real or apparent conflict of interest with the subject under discussion. Dr. Doraiswamy has received research grants and honoraria from Forest, Pfizer, Eisai, Novartis, and Janssen, pharmaceutical companies that market or develop dementia drugs.

This review is based on a talk given by Dr. Doraiswamy at the 2003 annual meeting of the American Psychiatric Association.

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