Abstract Background We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer’s disease (AD). Methods The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes. Results Nine studies including 2433 patients that met the study’s inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=−0.27, 95% confidence interval (CI)=−0.39 to −0.14, p=0.0001], behavioral disturbances (SMD=−0.12, 95% CI=−0.22 to −0.01, p=0.03), activities of daily living (SMD=−0.09, 95% CI=−0.19 to −0.00, p=0.05), global function assessment (SMD=−0.18, 95% CI=−0.27 to −0.09, p=0.0001), and stage of dementia (SMD=−0.23, 95% CI=−0.33 to −0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Conclusions Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.

Citation: Matsunaga S, Kishi T, Iwata N (2015) Memantine Monotherapy for Alzheimer’s Disease: A Systematic Review and Meta-Analysis. PLoS ONE 10(4): e0123289. https://doi.org/10.1371/journal.pone.0123289 Academic Editor: Terence J. Quinn, University of Glasgow, UNITED KINGDOM Received: September 26, 2014; Accepted: February 17, 2015; Published: April 10, 2015 Copyright: © 2015 Matsunaga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: The authors have no support or funding to report. Competing interests: Dr. Matsunaga has received speaker’s honoraria from Eisai, Janssen, Novartis, Daiichi Sankyo, Ono, Eli Lilly, Takeda, and Otsuka. Dr. Kishi has received speaker’s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Yoshitomi, Otsuka, Meiji, Shionogi, Janssen, Novartis, Tanabe-Mitsubishi, and Pfizer. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer. All authors declare that they have no direct conflicts of interest relevant to this study. No grants or other funding sources were used for this study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Introduction Dementia is not only a significant individual health problem but also a societal burden. Alzheimer’s Disease International reported that over 35 million individuals worldwide currently live with dementia (http://wwwalzcouk/research/world-report). Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive function and other neurobehavioral symptoms. The pathology of AD includes the accumulation of extracellular senile plaques composed primarily of β-amyloid and intracellular neurofibrillary tangles comprising abnormally hyperphosphorylated tau, a microtubule-associated protein [1]. Currently, memantine is available in Japan for the treatment of AD and was approved for the treatment of moderate-to-severe AD by the United States Food and Drug Administration (FDA). Memantine is believed to exert its therapeutic effect by acting as a low-to-moderate affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that binds preferentially to open NMDA receptor-operated calcium channels [2, 3]. This activity-dependent binding blocks NMDA-mediated ion flux and ameliorates the deleterious effects of sustained, pathologically elevated levels of glutamate (excitotoxicity) that may lead to neuronal dysfunction [4]. The efficacy of memantine in the management of patients with AD, vascular dementia, and mixed dementia was assessed in a Cochrane meta-analysis including 12 randomized controlled trials (RCTs) [5]. The meta-analysis showed that memantine was superior to placebo in benefiting cognitive function for mild-to-moderate AD and moderate-to-severe AD [mild-to-moderate AD, using Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) [6], weighted mean difference (WMD) = −0.99, 95% confidence interval (CI) = −0.21 to −1.78, p = 0.013, I2 = 0%, 3 studies, n = 1279; moderate-to-severe AD, using Severe Impairment Battery (SIB) [7], WMD = −2.97, 95% CI = −1.68 to −4.26, p = 0.00001, I2 = 74%, 3 studies, n = 976]. However, the meta-analysis included both memantine monotherapy studies and memantine—cholinesterase inhibitor (ChEI) combination therapy studies. To clarify the clinical pharmacological characteristic of memantine, a meta-analysis should be conducted using data only from memantine monotherapy studies in patients with AD. A recent meta-analysis of 2 studies including 572 patients [8] suggested that memantine monotherapy did not significantly benefit moderate-to-severe AD as assessed by the Neuropsychiatric Inventory (NPI) [9] (WMD = −1.65, 95% CI = −4.78 to 1.49, p = 0.247, I2 = 25.3%, 2 studies, n = not reported). However, apart from the small number of studies and patients, this meta-analysis did not evaluate other outcome measures such as cognitive function, activities of daily living, and global function assessment scores. To clarify whether memantine monotherapy is more efficacious than placebo for patients with AD, we have performed a meta-analysis of memantine monotherapy for AD including 9 studies with a total of 2433 patients.

Materials and Methods This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10] (S1 PRISMA Checklist). We performed a systematic literature review using the PICO strategy (Patients: AD, Intervention: memantine monotherapy, Comparator: placebo or usual care, and Outcome: cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects). Inclusion Criteria, Search Strategy, Data Extraction, and Outcome Measures We included RCTs of memantine monotherapy for patients with AD, omitting those in which patients were also administered a ChEI, and included studies that were not double blinded and/or placebo controlled (i.e., conventional treatment regimen) in order to obtain a larger patient population exposed to the drug. To identify relevant studies, we searched PubMed, the Cochrane Library databases, Google Scholar, EMBASE, CINAHL, and PsycINFO citations. There were no language restrictions, and we considered all studies published up to October 31, 2014. We used the following key words: “memantine” AND “Alzheimer’s disease” OR “Alzheimer disease.” Additional eligible studies were sought by searching the reference lists from primary articles and relevant reviews. Two authors (S.M. and T.K.) of this meta-analysis scrutinized the patient inclusion and exclusion criteria for the identified studies. When data required for the meta-analysis were missing, the first and/or corresponding authors were contacted for additional information, including endpoint scores. All 3 authors of the current study independently extracted, checked, and entered the data into Review Manager (Version 5.2 for Windows, Cochrane Collaboration, http://ims.cochrane.org/revman). Discrepancies in different coding forms were resolved by discussions between authors (S.M. and T.K.) Data Synthesis and Statistical Analysis Each outcome measure reported here was used in at least 3 out of the 9 included studies. The primary outcome measures for efficacy were cognitive function and behavioral disturbances associated with AD. Cognitive function was measured using the SIB, ADAS-cog, Standardized Mini-Mental State Examination (SMMSE) [11], or MMSE [12]. Two studies [13, 14] used 2 cognitive function scales (SIB and MMSE) and 1 study [15] used the SIB, ADAS-cog, and MMSE scales. Because SIB was the most common instrument used in the studies included in the current meta-analysis for evaluating cognitive function, we used data of SIB when multiple scales were used for this outcome (S1 Appendix). Behavioral disturbances were measured using the NPI and Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) scores [16]. Secondary outcome measures included activities of daily living [Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (modified for more severe dementia) (ADCS-ADLsev) [17], Alzheimer’s Disease Cooperative Study-Activities of Daily Living 19 Items (ADCS-ADL19) scale scores [17, 18], Alzheimer’s Disease Cooperative Study-Activities of Daily Living 23 Items (ADCS-ADL23) scale scores [18], and Bristol Activities of Daily Living Scale (BADLS) scores [19]], global function assessment [Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) [20]], stage of dementia assessment[Functional Assessment Staging instrument (FAST) [21]], rate of drug discontinuation from any cause, discontinuation because of adverse events, and discontinuation because of inefficacy. In addition, we pooled the drug side effects data. We based our analyses on intent-to-treat (ITT) or modified ITT data (i.e., at least 1 dose or at least 1 follow-up assessment). However, we analyzed the complete set of data to ensure that as much information as possible was provided ([22]: SMMSE, NPI, and BADLS scores; [15]: SIB, ADAS-cog, MMSE, and NPI). The meta-analysis was performed using Review Manager. To combine studies, we used the random-effects model by DerSimonian and Laird [23]. The random-effects model is more conservative than the fixed-effects model and produces a wider CI. For continuous data, we calculated Hedges’ g standardized mean difference (SMD) effect sizes and used the cut-off values for small, medium, and large effect sizes (0.2, 0.5, and 0.8, respectively) set out by Cohen [24]. If only 95% CI was reported, we converted the 95% CI to standard deviation [25]. For dichotomous data, the risk ratio (RR) was estimated along with 95% CIs. When the random-effects model showed significant differences between groups, the number needed to harm (NNH) was calculated. The NNH values were then derived from the risk difference (RD) using the formula NNH = 1/RD. We explored study heterogeneity using the I2 statistic, with values of 50% or higher considered to reflect considerable heterogeneity [26]. In cases with I2 values ≥50% for primary outcome measures, we conducted sensitivity analyses to determine the reasons for heterogeneity. Funnel plots were inspected visually to assess the possibility of publication bias. We also assessed the methodological qualities of the articles included in the meta-analysis on the basis of the Cochrane risk of bias criteria (Cochrane Collaboration; http://www.cochrane.org/).

Discussion This study provides an updated, comprehensive meta-analysis of RCTs testing the efficacy of memantine monotherapy for AD. The main results indicate that memantine improves cognitive function, AD-associated behavioral disturbances, activities of daily living, global function assessment, and stage of dementia compared with placebo. However, as these effect sizes were small (SMD = −0.09 to −0.27), they suggest a limited clinical benefit. We also performed sensitivity analyses for several factors; however, we could not detect the causes of heterogeneity. The pooled memantine treatment group exhibited a lower rate of discontinuation because of inefficacy and a lower incidence of agitation compared with the pooled placebo group. Moreover, there were no significant differences in the rates of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Therefore, memantine monotherapy does not appear to worsen the symptoms of AD and is well tolerated, exhibiting a potential beneficial role in the symptom treatment of AD. However, these conclusions must be considered in light of several limitations. The first limitation is that we did not exclude the publication bias. The Cochrane Handbook states that tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis, because when there are fewer studies, the power of the tests is too low to distinguish chance from real asymmetry [25]. Although the funnel plot for primary and secondary outcomes did not suggest the presence of publication bias, the number of studies included in the meta-analysis was slightly small to allow for a definitive interpretation. A second limitation is that our meta-analysis includes gray literature studies such as supported by pharmaceutical companies; we included these articles because they were published in peer-reviewed journals and represented the majority of the articles retrieved. The only non-industry-sponsored study [22] showed that memantine was marginally superior to placebo in cognitive function. Moreover, there was no significant subgroup difference between industry-sponsored and non-industry-sponsored studies (I2 = 0%, p = 0.68). A third limitation is that patients with dementia are known to have poor drug compliance [33], reducing the measured effectiveness. Finally, several studies included in this meta-analysis did not report any available data on symptom scales (disease severity) and safety outcomes; therefore, the outcome results for efficacy and safety did not include data from all 9 studies.

Conclusions Our results suggest that memantine monotherapy is beneficial for the treatment of AD as assessed by multiple scales evaluating cognition, behavioral disturbances, activities of daily living, global function, and stage of dementia. Furthermore, memantine monotherapy appears to be well tolerated. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.

Acknowledgments We thank Dr. Robert Howard (Department of Old Age Psychiatry and Psychopathology, King’s College London) and Dr. Patrick Phillips (MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology) for providing information for the study.

Author Contributions Conceived and designed the experiments: SM TK NI. Performed the experiments: SM TK NI. Analyzed the data: SM TK NI. Contributed reagents/materials/analysis tools: SM TK NI. Wrote the paper: SM TK NI.