Predictors of discontinuation, efficacy, and safety of memantine treatment for Alzheimer’s disease: meta-analysis and meta-regression of 18 randomized clinical trials involving 5004 patients

Abstract

BackgroundThe risk-benefit relationship of memantine treatment for Alzheimer’s disease (AD) remains unclear. In addition, variability between the results of clinical trials has been observed. The aim of this study was to investigate the risk-benefit relationship of memantine treatment in patients with AD and to determine the predictor effect of patient, intervention, and study design related covariates.MethodsA systematic review and meta-analysis of double-blind, placebo controlled clinical trials was performed. Primary outcomes were all-cause discontinuation, discontinuation due to adverse events (AE) and efficacy on cognitive function. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence intervals were calculated. Meta-regression was conducted to identify related covariates. Cochrane Collaboration tool was used to evaluate the risk of bias of included trials.ResultsEighteen studies involving 5004 patients were included. No differences between memantine and placebo were found for all-cause treatment discontinuation (OR=0.97 [0.82, 1.14]) and discontinuation due to AE (OR=1.18 [0.91, 1.53]). Memantine showed small improvement on cognitive function (SMD=0.15 [0.08, 0.22]). Baseline functional ability was positively associated with all-cause treatment discontinuation and discontinuation due to AE.ConclusionsOur study suggests that memantine has a very small efficacy on AD symptomatology and its safety profile is similar to that of placebo. No evidence of treatment discontinuation improvement with memantine is found, indicating a dubious risk-benefit relationship. No intervention characteristic or subgroup of patients clearly shows a significantly better risk-benefit relationship.PROSPERO registrationCRD42014015696.Electronic supplementary materialThe online version of this article (10.1186/s12877-018-0857-5) contains supplementary material, which is available to authorized users.

Roles of glutamate receptors in a novel in vitro model of early, comorbid cerebrovascular, and Alzheimer’s diseases

“…Patients diagnosed with Alzheimer's disease are frequently treated with memantine, either alone or in combination with inhibitors of acetylcholinesterase (Arvanitakis, Shah, & Bennett, 2019;Glinz et al, 2019). However, clinical benefits of memantine are highly variable and have been questioned in several meta-analytic reviews, particularly for cases classified as mild AD (Blanco-Silvente et al, 2018;Folch et al, 2018;McShane et al, 2019). A similar case is verified for patients diagnosed with vascular cognitive impairment (Farooq, Min, Goshgarian, & Gorelick, 2017;Jin & Liu, 2019).…”

“…Franzmeier et al, 2019), on the assumption that such subclinical conditions may be associated with minor vascular impairement and/or low levels of AβOs. Using this experimental model, we further investigated the roles of glutamate receptors, which have been implicated in numerous basic, translational, and clinical approaches to both CVD and AD (Baskys & Cheng, 2012;Blanco-Silvente, Capella, Garre-Olmo, Vilalta-Franch, & Castells, 2018;Brody & Strittmatter, 2018;Cherry, Lenze, & Lang, 2014;Domin et al, 2016;Goniotaki et al, 2017;Lopez-Valdes et al, 2014;McShane et al, 2019;Okuizumi et al, 2018). Our results revealed a hitherto unappreciated synergy between subtoxic OGD and AβO, and unveiled complex roles of glutamate receptors on neurodegeneration in the hippocampus under conditions that mimic early, comorbid CVD/AD.…”

Stratifying risk for dementia onset using large‐scale electronic health record data: A retrospective cohort study

“…Although currently marketed treatments for dementia exhibit modest efficacy overall, they are considered to be most effective when used early in the disease course. [1][2][3] As such, early detection of those who will develop dementia is a public health priority. 4 To date, the only validated in vivo markers of early or preclinical disease rely on positron emission tomography imaging, although such imaging is not definitive in diagnosis, 5,6 and widespread clinical deployment of positron emission tomography is not feasible at present.…”

“…Although currently marketed treatments for dementia exhibit modest efficacy overall, they are considered to be most effective when used early in the disease course . As such, early detection of those who will develop dementia is a public health priority …”

Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

“…Moreover, a meta-analysis by Blanco et al . of memantine shows that its effect is indistinguishable from the placebo effect, which calls for an immediate search to find an alternate candidate with high efficacy for treating AD [ 11 ].…”