Memantine, Donepezil, or Combination Therapy—What is the best therapy for Alzheimer’s Disease? A Network Meta‐Analysis

INTRODUCTION: Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta‐analysis assessed the efficacy of these regimens and placebo in the management of AD. METHODS: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo‐controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens. RESULTS: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)‐5.01, 95% credible interval (95% Crl) −10.73 to 0.86 in the Alzheimer's Disease Assessment Scale‐Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD −2.88, 95% Crl −6.04 to 0.40), daily activities (MD 13.06, 95% Crl −34.04 to 58.92), and neuropsychiatric symptoms (MD −6.84, 95% Crl −10.62 to –2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22). CONCLUSIONS: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost‐effective, because memantine slows the progression of AD.