Treating Cognition and Function in Patients With Alzheimer Disease

The optimal duration of treatment with cholinesterase inhibitors is uncertain. Most blinded trials have been conducted for 6 months; however, trials lasting 1 year have shown sustained effi-cacy.^5,6 In addition, longer-term studies with donepezil(Drug information on donepezil) suggest that patients continue to derive modest benefit from treatment for 2 to 3 years.⁷

Cholinesterase inhibitors are standard, modestly effective therapy for mild to moderate AD based on accumulated evidence from several pivotal large-scale trials involving all agents presently available within the class (donepezil [Aricept], rivastigmine(Drug information on rivastigmine) [Exelon], and galantamine(Drug information on galantamine) [Reminyl, Razadyne]).³ Despite the postulated differences in mechanisms of action of the cholinesterase inhibitors, Ritchie and colleagues⁴ demonstrated similar degrees of efficacy for the 3 agents. They conducted a meta-analysis of randomized trials assessing efficacy and safety and conducted regression analyses to compare the effect of dosage on clinical outcomes and completion rates.

Compared with placebo, all 3 drugs showed beneficial effects on cognitive tests. For donepezil and rivastigmine, larger doses were associated with larger symptomatic cognitive effects as assessed by the Alzheimer’s Disease Assessment Scale Cognitive Subscale, a commonly used outcome measure. Clinical global improvement was shown to be superior for each drug over placebo.

The optimal duration of treatment with cholinesterase inhibitors is uncertain. Most blinded trials have been conducted for 6 months; however, trials lasting 1 year have shown sustained efficacy.^5,6 In addition, longer-term studies with donepezil suggest that patients continue to derive modest benefit from treatment for 2 to 3 years.⁷

As a class, cholinesterase inhibitors are generally well tolerated. The most common adverse effects include nausea, vomiting, diarrhea, loss of appetite, weight loss, muscle cramps, and insomnia. Administering these medications with a meal helps reduce the risk of side effects. Cholinesterase inhibitors are contraindicated in patients with cardiac conduction abnormalities, such as left bundle-branch block and sick sinus syndrome, as well as gastric ulcer disease, in which bleeding has occurred.

Memantine (Namenda), an N-methyl D-aspartate receptor noncompetitive antagonist, was approved by the FDA for the treatment of moderate to severe AD. Reisberg and colleagues⁸ reported a beneficial effect of memantine(Drug information on memantine) treatment on cognitive and functional measures. As measured by the Severe Impairment Battery, cognition was stable for the first 12 weeks of therapy in the memantine-treated patients, who, at end point, had significantly less impairment than did the placebo-treated patients. Memantine also delayed decline in functional ability compared with placebo.

In a double-blind combination study, moderately to severely impaired patients with AD were randomized to receive donepezil plus placebo (monotherapy) or donepezil plus memantine.⁹ Compared with donepezil monotherapy, combination therapy with donepezil and memantine resulted in modest cognitive improvement, reduced decline in activities of daily living, and a reduced frequency of neuropsychiatric symptoms.

Winblad and Poritis¹⁰ reported on a 12-week trial of memantine monotherapy in institutionalized patients with severe AD or vascular dementia (Mini- Mental State Examination score, less than 10). Memantine led to improvement in global outcomes as well as in functioning and behavior.