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To investigate the cognitive effects of the N-methyl-D-aspartate receptor antagonist, memantine, with a post-hoc exploratory reanalysis of a 24-week randomized, double-blind, placebo-controlled, parallel group clinical trial comparing memantine (20 mg per day) to placebo in patients with moderate to severe Alzheimer disease (AD) receiving treatment with the cholinesterase inhibitor, donepezil.The effects of memantine on individual items of the Severe Impairment Battery (SIB), subscale performance, and 3 post-hoc–derived aggregate subscales were investigated. Analyses were based on the intention-to-treat population using last observation carried forward and observed cases approaches. The SIB components were assessed at baseline, weeks 4, 8, 12, 18, and 24.The mean change from baseline by visit and at study end point on the SIB showed statistically significant differences between the memantine and placebo groups at all visits beginning at week 8 (last observation carried forward and observed cases). The SIB subscale analysis showed statistically significantly greater effects of memantine than placebo on memory, language, and praxis. When the SIB domains were aggregated using a face valid approach to create 3 higher-order subscales, memantine treatment resulted in statistically significant differences on memory, language, and praxis compared with placebo.These post-hoc analyses support the beneficial effects of memantine on cognition observed in a previously reported clinical trial. The results presented here suggest an effect of memantine on memory, language, and praxis in patients with moderate to severe AD and support the efficacy of memantine for the treatment of cognitive deficits in AD.