Background: The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. Objective: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. Methods: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. Results: Thirty studies (n = 7,567; memantine versus placebo: N= 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N= 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95%CIs) = -0.34, -0.15, p < 0.00001, I2 = 35%] and BD (SMD = -0.16, 95%CIs = -0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95%CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95%CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95%CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction inBDcompared with ChEIs without considerable heterogeneity(SMD = -0.11, 95%CIs = -0.21, -0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95%CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. Conclusions: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.
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