Lack of Evidence for the Efficacy of Memantine in Mild Alzheimer Disease

Objective: We directly assessed the clinical trials' evidence for memantine's efficacy in mild Alzheimer disease (AD). Memantine is indicated in the United States and Europe for moderate to severe AD, which is diagnosed if a patient has a Mini-Mental State Examination (MMSE) score of less than 15 or less than 20, respectively. Yet memantine is very frequently prescribed for mild AD and mild cognitive impairment, and a manufacturer-sponsored meta-analysis claimed its efficacy in mild AD. Data Sources, Study Selection, and Data Extraction: Manufacturer-sponsored meta-analyses, registries, presentations, and publications were systematically searched for randomized placebo-controlled, parallel-group clinical trials of memantine in patients with mild to moderate AD. The trials' characteristics and outcomes were extracted by one reviewer and checked by another. Meta-analyses were performed as inverse variance-weighted averages of mean differences using fixed-effects models. Summary results for patients with mild AD were obtained by contrasting the summary results for patients with mild or moderate AD with the summary results for the subset of patients with moderate AD. Data Synthesis: Three trials were identified that included 431 patients with mild AD (ie, with MMSE scores of 20-23) and 697 patients with moderate AD (ie, with MMSE scores of 10-19). There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined: mean differences (95% confidence intervals [CIs]) on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus), the Alzheimer Disease Cooperative Study-activities of daily living (ADCS-ADL) scale, and the Neuropsychiatric Inventory (NPI) were -0.17 (95% CI, -1.60 to 1.26), -0.09 (95% CI, -0.30 to 0.12), 0.62 (95% CI, -1.64 to 2.71), and 0.09 (95% CI, -2.11 to 2.29), respectively. For patients with moderate AD, there were small differences on the ADAS-cog and the CIBIC-plus, -1.33 (95% CI, -2.28 to -0.38) and -0.16 (95% CI, -0.32 to 0.00), respectively, but no differences on the ADCS-ADL scale (-0.57 [95% CI, -1.75 to 0.60]) or the NPI (0.25 [95% CI, -1.48 to 1.99]). Conclusions: Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.