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Memantine More Effective Than Placebo for Treatment of Alzheimer Disease in Patients Receiving Donepezil

Memantine therapy, compared with placebo, is more effective in treating Alzheimer disease (AD) in patients with moderate to severe disease who are also undergoing donepezil therapy.

"To our knowledge, this is the first published, prospective, double-blind, placebo-controlled study examining the benefits of an NMDA [N-methyl-D aspartate] receptor antagonist in patients with AD receiving a stable dose of donepezil," writes Pierre N. Tariot, MD, University of Rochester Medical Center, New York, the United States, and colleagues for the Memantine Study Group.

Between June 2001 and June 2002, the researchers randomised 404 patients receiving stable doses of donepezil for probable AD, according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association criteria. Two hundred and three received memantine, starting at 5 mg/d and titrated to 20 mg/d, and 201 received placebo for 24 weeks. Other stable concomitant medications, including antidepressants, antihypertensives, anti-inflammatory medications, atypical antipsychotics, antiparkinsonian drugs, anticoagulants, laxatives, diuretics, and sedatives or hypnotic medications were permitted.

The patients treated with placebo showed fewer improvements than those receiving memantine in analyses using the last observation carried forward approach. Mean changes from baseline scores in Severe Impairment Battery were -2.5 versus 0.9; scores in the 19-item Alzheimer Disease Cooperative Study-Activities of Daily Living Inventory were -3.4 versus -2.0; scores in the Clinician's Interview-Based Impression of Change Plus Caregiver Input were 4.66 versus 4.41; scores in the Neuropsychiatric Inventory were 3.7 versus -0.1; and scores in the Behavioral Rating Scale for Geriatric Patients were 2.3 versus 0.8 in the placebo versus memantine groups, respectively.

The week 24 observed case analyses also favoured memantine therapy over placebo in the patient population.

Overall, 12.4% of the placebo group patients discontinued therapy due to adverse events compared with 7.4% of the memantine group. The memantine group experienced confusion and headache more frequently than the placebo group - 7.9% versus 2.0% and 6.4% versus 2.5%, respectively. Conversely, the placebo group experienced diarrhoea and faecal incontinence more frequently than the memantine group - 8.5% versus 4.5% and 5.0% versus 2.0%, respectively.

"These efficacy findings confirm and extend results from previous placebo-controlled trials of memantine in dementia," the authors note, adding that the long-term effects of memantine and cholinesterase inhibitor treatment are the focus of other ongoing trials.

JAMA 2004;291:317-324.

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