Memantine for Alzheimer’s Disease: An Updated Systematic Review and Meta-analysis

Abstract

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 in BD compared 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.

Keywords

Alzheimer’s disease behavioral disturbances cognitive function memantine meta-analysis systematic review

INTRODUCTION

Alzheimer’s disease (AD) is a significant public health issue worldwide and one of the outstanding health care challenges of the 21st century [1]. In December 2013, the G8 urged that dementia be made a global priority with the aim of identifying a cure or a disease-modifying therapy by 2025 [1].

Memantine is one of five approved drugs for the treatment of AD worldwide, specifically approved for treating moderate-to-severe AD; the other four cholinesterase inhibitors (ChEIs) include donepezil, galantamine, rivastigmine, and tacrine (tacrine was discontinued in the United States of America in 2013 due to safety concerns) [1]. It is postulated that memantine exerts its therapeutic effect through its action as a low-to-moderate affinity noncompetitive (open-channel), nonselective, voltage-dependent, N-methyl-D-aspartate (NMDA) receptor antagonist, which binds preferentially to NMDA receptor-operated calcium channels [2, 3]. Memantine blocks the effects of sustained, pathologically elevated levels of glutamate that may otherwise lead to neuronal dysfunction [4 –6]. In addition, memantine may also upregulate NMDA receptor expression, causing activation in the presence of a strong stimulus [7]. Nonetheless, the efficacy of memantine administration in patients with AD remains inconclusive.

Our previous meta-analysis showed that there was a trend favoring combination therapy with memantine and ChEIs compared with ChEI monotherapy for treating cognitive impairment [standardized mean difference (SMD) = –0.13, 95% confidence intervals (95% CIs) = –0.26 to 0.01, p = 0.06, N = 6, n = 2,027]; however, considerable heterogeneity was found (I² = 52%) [8]. In performing a sensitivity analysis using data from only studies on patients with moderate-to-severe AD, combination therapy with memantine and ChEIs was superior to ChEI monotherapy in alleviating cognitive impairment (SMD = –0.24, 95% CI = –0.38 to –0.11, p = 0.0003, I² = 16%, N = 3, n = 1,165) [8]. However, this meta-analysis did not provide implications regarding the choice of ChEIs to be combined with memantine. Another meta-analysis showed that memantine monotherapy was superior to a placebo in alleviating cognitive impairment (SMD = –0.27, 95% CI = –0.39 to –0.14, p < 0.0001, I² = 52%, N = 9, n = 2,409) [9]. To date, there has been no robust evidence reported with respect to the efficacy of memantine administration to repair cognitive impairment as a core symptom noted in patients with AD.

The effect size of anti-dementia drugs for cognitive function in patients with AD in randomized trials has been very small [8, 9]. Therefore, even though a meta-analysis can increase the statistical power for group comparisons and can overcome the limitation of sample size in underpowered studies [10], it is difficult for a small meta-analysis to accurately estimate the efficacy of anti-dementia drugs because of low statistical power (i.e., insufficient sample size). However, a number of additional randomized trials of memantine have been published since the date of previous meta-analyses [11 –25], suggesting a potentially greater statistical power. In the present study, we conducted an updated and comprehensive systematic review and meta-analysis to achieve conclusive evidence for the efficacy (cognitive function, behavioral disturbances, activities of daily living, severity of disease, global function, and verbal fluency) and safety (discontinuation rate and individual adverse event) of memantine administration in patients with AD. We also performed several sensitivity analyses and meta-regression analyses to detect a clinical modulator, which is associated with the response to memantine.

METHODS

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [26] (PRISMA Checklist). The review has been registered with PROSPERO (http://www.crd.york.ac.uk/PROSPERO/.CRD42017059245).

Search strategy and inclusion criteria

To identify relevant studies, two of the authors (T.K. and S.M.) independently searched MEDLINE, Cochrane library, Scopus, and PsycINFO without language restrictions from the inception of their databases to April 25 2017 using the following search strategy: (“Alzheimer Disease” [Mesh] OR “Alzheimer disease” OR “Alzheimer’s disease”) AND (“Memantine”[Mesh] OR “memantine”) AND (“randomized” OR “random” OR “randomly”). The authors also searched ClinicalTrials.gov (http://clinicaltrials.gov/), ISRCTN registry (https://www.isrctn.com/), and International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/) to include randomized controlled trials as comprehensively as possible and to minimize the possibility of publication bias. Only randomized placebo- or usual care (i.e., not use placebo)-controlled trials of memantine treatment in patients with AD lasting more than 2 weeks were included. The studies that included more than 50% of patients receiving combination therapy were classified in the combination therapy group in this study (Table 1). When a study did not report whether the study administered combination therapy or memantine monotherapy, those studies were excluded from the meta-analysis. The three authors (T.K., S.M., and K.O.) independently assessed the inclusion/exclusion criteria and selected the studies. The references of the included articles and review articles were also searched for citations of additional relevant published and unpublished studies, including conference abstracts.

Table 1

Characteristics of included randomized controlled trials

Table 1.1. Monotherapy
Study, country, sponsorship	Total n	Methods	Patients	Age (mean±SD), y	Male (%)	Race (%)	Baseline cognitive function scales (mean±SD)	Intervention, Dose (mg/day)	n	Efficacy outcomes^c
		(1) Study design	(1) Diagnosis
		(2) Duration	(2) Inclusion criteria
		(3) Analyzed population	(3) Study defined disease severity
Bakchine 2007 [45], International, Industry	470	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	73.8	36.8	Caucasian: 100	ADAS-cog: 25.6, MMSE: 18.7	MEM 20 mg (Fi)	318	MEM = PLA: ADAS-cog, ADCS-ADL23, CIBIC-Plus, NPI12
								PLA	152
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 11–23
		(3) ITT	(3) mild to moderate
Fox 2012 ^a [13], UK, Industry	153	(1) DB-RCT	(1) AD, NINCDS-ADRDA	84.7	26.2	Caucasian: 98.0, Other: 2.0	MMSE: 7.3 SIB: 53.4	MEM 20 mg (Fi)	74	MEM >PLA: NPI12, SIB, MMSE MEM = PLA: CGI-C, CMAI
								PLA	79
		(2) 12 weeks	(2) age ≥ 45 y, MMSE 19 ≥, CMAI ≥ 45
		(3) ITT	(3) moderate to severe
Howard 2012 [46], UK, Non-industry	295	(1) DB-RCT	(1) AD, NINCDS-ADRDA	76.9	37.6	Caucasian: 96.6, AA: 2.7, Other: 0.7	MMSE: 9.2	MEM 20 mg (Fi)	76	MEM >PLA: BADLS, MMSE MEM = PLA: DEMQOL-proxy, GHQ-12, NPI12
								PLA	73
		(2) 52 weeks	(2) age ≥ 50 y, MMSE 5–13
		(3) OC	(3) moderate to severe
Kitamura 2011 [43], Japan, Industry	315	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	73.3±9.4	29.3	Japanese: 100	MMSE: 10.1±3.0, SIB: 71.1±17.8	MEM 20 mg (Fi)	100	MEM >PLA: FAST (20 mg), MMSE (20 mg), SIB (20 mg) MEM = PLA: ADCS-ADL19, CIBIC-Plus, FAST (10 mg), MMSE (10 mg), NPI10, SIB (10 mg)
								MEM 10 mg (Fi)	107
								PLA	108
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 5–14, FAST 6a-7a
		(3) FAS	(3) moderate to severe
MA3301^b [20], Japan, Industry	565	(1) DB-RCT	(1) AD, NINCDS-ADRDA	73.7±8.5	32.7	Japanese: 100	ADAS-cog: NR, MMSE: 17.5±3.6	MEM 20 mg (Fi)	188	MEM >PLA: ADAS-cog (10 mg), CGBRS, CIBIC-Plus, MMSE MEM = PLA: ADAS-cog (20 mg), CDR-SB, DAD
								MEM 10 mg (Fi)	191
								PLA	186
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 10–23, CDR 1-2
		(3) FAS	(3) mild to moderate
Nakamura 2011 [47], Japan, Industry	432	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	74.6±8.4	35.7	Japanese: 100	MMSE: 9.9±3.0, SIB: 71.0±17.9	MEM 20 mg (Fi)	221	MEM >PLA: Behave-AD, SIB MEM = PLA: CIBIC-Plus, FAST, MENFIS
								PLA	211
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 5–14, FAST 6a-7a
		(3) FAS	(3) moderate to severe
Peskind 2006 [48], USA, Industry	403	(1) DB-RCT	(1) AD, NINCDS-ADRDA	77.5	41.2	Caucasian: 91.3, Other: 8.7	ADAS-dog: 27.3, MMSE: 17.3	MEM 20 mg (Fi)	201	MEM >PLA: ADAS-cog, CIBIC-Plus, NPI12 MEM = PLA: ADCS-ADL23
								PLA	202
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 10–22
		(3) ITT	(3) mild to moderate
Reisberg 2003 [49], USA, Industry	252	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	76.1±8.1	32.5	Caucasian: 90.1, AA: 4.4, Other: 5.6	MMSE: 7.9±3.6, SIB: 67.1	MEM 20 mg (Fi)	126	MEM >PLA: ADCS-ADL (sev), FAST, SIB MEM = PLA: CIBIC-Plus, GDS, MMSE, NPI12
								PLA	126
		(2) 28 weeks	(2) age ≥ 50 y, MMSE 3–14, GDS 5-6, FAST ≥ 6a
		(3) ITT	(3) moderate to severe
Schmidt 2008 [50], Austria, Industry	37	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	76.2±5.2	36.1	NR	ADAS-cog: 27.5±10.6, MMSE: 19.0±2.9	MEM 20 mg (Fi)	NR	MEM = PLA: ¹⁸F-FDG PET (all brain areas), MRI (total brain and hippocampal volume)
								PLA	NR
		(2) 52 weeks	(2) age ≥ 50 y, MMSE 14–22
		(3) ITT	(3) mild to moderate
van Dyck 2007 [51], USA, Industry	350	(1) DB-RCT	(1) AD, NINCDS-ADRDA	78.2	28.6	Caucasian: 80.9 Other: 19.1	MMSE: 10.1, SIB: 76.4	MEM 20 mg (Fi)	178	MEM = PLA: ADCS-ADL19, BGP, CIBIC-Plus, FAST, NPI12, SIB
								PLA	172
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 5–14
		(3) ITT	(3) moderate to severe
Wang 2013 [52], China, Industry	26	(1) DB-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	65.2	36.4	Chinese: 100	ADAS-cog: 43.2, MMSE: 12.1 SIB: 68.4	MEM, 20 mg (Fi)	13	MEM >PLA: FDG-PET (CMRgl declines bilaterally in precuneus/posterior cingulate, parietotemporal, and frontal cortex), SIB MEM = PLA: ADAS-cog, CSF biomarkers (t-tau, p-tau, Aβ40, Aβ42), MMSE, NPI
								PLA	13
		(2) 24 weeks	(2) age 50–90 y, MMSE 4–20
		(3) OC	(3) moderate to severe

Table 1.2 Combination therapy
Study, country, sponsorship	Total n	Methods	Patients	Age (mean±SD), y	Male (%)	Race (%)	Baseline cognitive function scales (mean±SD)	Intervention, Dose (mg/day)	n	Efficacy outcomes^c
	(1) Study design	(1) Diagnosis
	(2) Duration	(2) Inclusion criteria
	(3) Analyzed population	(3) Study defined disease severity
Araki 2014 [11], Japan, Non-industry	37	(1) O-RCT	(1) AD, DSM-IV and ICD-10	78.8±7.7	48.6	Japanese: 100	MMSE: 16.1	MEM 20 mg (Fi) + DON (100%, NR)	19	MEM + DON >DON: CDT, CGI-I, MMSE, NPI10, ZBI MEM + DON = DON: NIRS (mean of all channels)
								DON (100%, NR)	18
		(2) 24 weeks	(2) HDS-R 3–16
		(3) FAS	(3) moderate to severe
Ashford 2011 [12], USA, Industry	17	(1) DB-RCT	(1) AD, DSM-IV	76.0	61.5	Caucasian: 69.2, Asian: 30.8	ADAS-cog: 45.1, MMSE: 20.8	MEM 20 mg (Fi) + DON (86%, NR)	9	MEM + DON = PLA + DON: ADAS-cog, NAA/Cr ratio in inferior parietal cortex
								PLA + DON (67%, NR)	8
		(2) 52 weeks	(2) age 50–95 y, MMSE 7–28
		(3) OC	(3) mild to moderate
Choi 2011 [53], South Korea, Industry	172	(1) O-RCT	(1) AD, NINCDS-ADRDA	74.9	20.5	Korean: 100	ADAS-cog: 28.5, MMSE: 16.6	MEM (Fl, 19.9 mg) + RIV patch (100%, 17.6 mg)	88	MEM + RIV patch <RIV patch: CMAI MEM + RIV patch = RIV patch: ADAS-cog, ADCS-ADL, CDR-SB, FAB, MMSE, NPI12
								RIV patch (100%, 17.3 mg)	84
		(2) 16 weeks	(2) age 50–90 y, MMSE 10–20
		(3) ITT	(3) mild to moderate
Creţu 2008 [54], Romania, Non-industry	43	(1) O-RCT	(1) AD, DSM-IV-TR	72.5	37.2	NR	ADAS-cog: 33.8 MMSE: 15.0	MEM 20 mg (Fi) + DON (100%, NR)	22	NR
								DON (100%, NR)	21
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 10–17
		(3) NR	(3) moderate to severe
Dysken 2014 [55], USA, Industry	307	(1) DB-RCT	(1) AD, NINCDS-ADRDA	79.1	97.1	Caucasian: 85.7, AA: 13.4, Other: 0.9	ADAS-cog: 19.3 MMSE: 20.8	MEM 20 mg (Fl) + ChEIs [DON (65%, NR), GAL (30%, NR), RIV (5%, NR)]	155	MEM + ChEIs = PLA+ ChEIs: ADAS-cog, ADCS-ADL, CAS, MMSE, NPI12
								PLA + ChEIs [DON (63%, NR), GAL (36%, NR), RIV (1%, NR)]	152
		(2) 26 to 208 weeks (mean 118 weeks)	(2) MMSE 12–26
		(3) ITT	(3) mild to moderate
Grossberg 2013 [56], International, Industry	677	(1) DB-RCT	(1) AD, DSM-IV-TR and NINCDS-ADRDA	76.5	28.0	Caucasian: 94.1, Other: 5.9	MMSE: 10.8, SIB: 76.0	MEM-ER 28 mg (Fi) + ChEIs [DON (69%, 8.0 mg), GAL (21%, 13.5 mg), RIV (9%, 6.8 mg)]	342	MEM (ER) + ChEIs >PLA + ChEIs: CIBIC-Plus, NPI12, SIB, VFT MEM (ER) + ChEIs = PLA + ChEIs: ADCS-ADL19
								PLA + ChEIs [DON (63%, 7.8 mg), GAL (20%, 13.5 mg), RIV (12%, 6.8 mg)]	335
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 3–14
		(3) ITT	(3) moderate to severe
Herrmann 2013 [14], Canada, Industry	369	(1) DB-RCT	(1) AD, NINCDS-ADRDA	74.9	41.7	NR	MMSE: 11.8, SIB: 82.1	MEM 20 mg (Fi) + ChEIs (combination therapy 95%)	182	MEM + ChEIs = PLA + ChEIs: ADCS-ADL19, CIBIC-Plus, CMAI, NPI12, SIB
								PLA + ChEIs (combination therapy 97%)	187
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 5–15, NPI ≥ 13, NPI agitation/aggression score ≥ 1
		(3) FAS	(3) moderate to severe
Howard 2012 [46], UK, Non-industry	295	(1) DB-RCT	(1) AD, NINCDS-ADRDA	77.4	31.5	Caucasian: 93.2 AA: 3.4, Other: 3.4	MMSE: 9.1	MEM 20 mg (Fi) + DON (100%, 10 mg)	73	MEM + DON >PLA + DON: NPI12 MEM + DON = PLA + DON: BADLS, DEMQOL-proxy, GHQ-12, MMSE
								PLA + DON (100%, 10 mg)	73
		(2) 52 weeks	(2) age ≥ 50 y, MMSE 5–13
		(3) OC	(3) moderate to severe
IE2201 ^b [25], Japan, Industry	35	(1) DB-RCT	(1) AD, NINCDS-ADRDA	73.2±6.7	54.3	Japanese: 100	ADAS-cog: 25.7 MMSE: 15.6	MEM 20 mg (Fi) + DON (83%, NR)	12	MEM + DON = PLA + DON: ADAS-cog, MMSE
								MEM 10 mg (Fi) + DON (91%, NR)	11
								PLA + DON (100%, NR)	12
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 10–20
		(3) FAS	(3) moderate
Nakamura 2016 [15], Japan, Industry	546	(1) DB-RCT	(1) AD, DSM-IV-TR and NINCDS-ADRDA	78.5	27.2	Japanese: 100	MMSE: 10.8, SIB: 77.0	MEM 20 mg (Fi) + DON (100%, 6.9 mg)	273	MEM + DON = PLA + DON: Behave-AD, CGBRS, SIB
								PLA + DON (100%, 6.9 mg)	273
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 1–14, SIB 30–85
		(3) FAS	(3) moderate to severe
NCT00768261^b [23], USA, Industry	39	(1) O-RCT	(1) AD, NINCDS-ADRDA	NR	NR	NR	NR	MEM 20 mg (Fi) + DON (100%, NR)	NR	NR
								DON (100%, NR)	NR
		(2) 104 weeks	(2) age 50–80 y, CDR 0.5-1
		(3) NR	(3) mild
Peters 2015 [16], Germany, Industry	226	(1) DB-RCT	(1) AD, GDCN and NINCDS-ADRDA	72.4	36.3	NR	ADAS-cog: 19.5 MMSE: 22.2	MEM 20 mg (Fi) + GAL-CR (100%, 24 mg)	112	MEM + GAL-CR = PLA +GAL-CR: ADAS-cog, ADCS-ADL, CDR-SB, NPI10
								PLA + GAL-CR (100%, 24 mg)	114
		(2) 52 weeks	(2) age ≥ 50 y, MMSE 15–26
		(3) ITT	(3) mild to moderate
Porsteinsson 2008 [57], USA, Industry	433	(1) DB-RCT	(1) AD, NINCDS-ADRDA	75.4	47.8	NR	ADAS-cog: 27.4 MMSE: 16.8	MEM 20 mg (Fi) + ChEIs [DON (71%, 9.5 mg), GAL (14%, 19.7 mg), RIV (15%, 9.2 mg)]	217	MEM + ChEIs = PLA + ChEIs: ADAS-cog, CIBIC-Plus, ADCS-ADL, NPI12, MMSE
								PLA + ChEIs [DON (63%, 8.9 mg), GAL (16%, 19.4 mg), RIV (20%, 10.0 mg)]	216
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 10–22
		(3) ITT	(3) mild to moderate
Saxton 2012 [17], International, Industry	265	(1) DB-RCT	(1) AD, NINCDS-ADRDA	74.9	41.7	Caucasian: 90.9, Other: 9.1	MMSE: 15.8	MEM 20 mg (Fi) + ChEIs [DON (32%, NR), GAL (20%, NR), RIV (1%, NR)]	136	MEM + ChEIs >PLA + ChEIs: ASHA-FACS, CGI-C MEM + ChEIs = PLA + ChEIs: FLCI, OPT
								PLA + ChEIs [DON (30%, NR), GAL (21%, NR), RIV (2%, NR)]	129
		(2) 12 weeks	(2) age ≥ 50 y, MMSE 10–19
		(3) ITT	(3) moderate
Tariot 2004 [58], USA, Industry	404	(1) DB-RCT	(1) AD, NINCDS-ADRDA	75.5	35.0	Caucasian: 91.3 Other: 8.7	MMSE: 10.0, SIB: 79.0	MEM 20 mg (Fi) + DON (100%, 9.3 mg)	203	MEM + DON >PLA + DON: ADCS-ADL, BGP, CIBIC-Plus, NPI12, SIB
									PLA + DON (100%, 9.5 mg)	201
		(2) 24 weeks	(2) age ≥ 50 y, MMSE 5–14
		(3) ITT	(3) moderate to severe
Wilkinson 2012 [18], International, Industry	278	(1) DB-RCT	(1) AD, NINCDS-ADRDA	74.0	43.0	Caucasian: 99.6 Other: 0.04	MMSE: 16.9	MEM 20 mg (Fi) + ChEIs (combination therapy 72%)	134	MEM + ChEIs >PLA + ChEIs: CFT, COWAT MEM + ChEIs = PLA + ChEIs: ADAS-cog (OT), MMSE, MRI (brain atrophy rates based on BBSI measurements, hippocampal atrophy rate), NPI10, Stroop C, Stroop-I
								PLA + ChEIs (combination therapy 71%)	144
		(2) 52 weeks	(2) age ≥ 50 y, MMSE 12–20
		(3) FAS	(3) moderate
Zheng 2011 [19], China, Non-industry	32	(1) O-RCT	(1) AD, DSM-IV and NINCDS-ADRDA	86.0±4.8	100	Chinese: 100	ADAS-cog: 38.0 MMSE: 15.1	MEM 20 mg (Fi) + DON (100%, 10 mg)	16	MEM + DON >DON: NPI12 MEM + DON = DON: ADAS-cog, MMSE, PSMS/IADL
									DON (100%, 10 mg)	16
		(2) 16 weeks	(2) age ≥ 80 y, MMSE 26 ≥
		(3) ITT	(3) NR^d
NCT00097916^b [21], USA, Industry	34	(1) DB-RCT	(1) AD, NINCDS-ADRDA	NR	NR	NR	NR	MEM 20 mg (Fi) + NR	NR	NR
								PLA + NR	NR
		(2) 12 weeks	(2) age ≥ 50 y, MMSE 3–18, NPI agitation/aggression score ≥ 4
		(3) NR	(3) moderate to severe
NCT00476008^b [22], USA, Industry	43	(1) DB-RCT	(1) AD, NR	79.3±6.2	65.1	NR	27.9	MEM 20 mg (Fi) + NR	22	NR
								PLA + NR	21
		(2) 52 weeks	(2) age ≥ 60 y, MMSE ≥ 23
		(3) NR	(3) mild
NCT00933608^b [24], USA, Industry	17	(1) DB-RCT	(1) AD, NR	69.7±7.1	35.3	NR	NR	MEM 20 mg (Fi) + NR	7	NR
								PLA + NR	10
		(2) 16 weeks	(2) age 55–90 y, family history of AD
		(3) ITT	(3) NR

^acombination therapy = 21.5%. ^bunpublished study. ^cprimary outcomes in each study are underlined. ^dBecause mean MMSE score was 15.1, we classified this study as a study which included patients with moderate Alzheimer disease. AA, African-American; AD, Alzheimer disease; ADAS-cog (OT), Alzheimer’s Disease Assessment Scale-cognitive subscale (orientation test); ADCS-ADL (sev), Alzheimer’s Disease Cooperative Study–Activities of Daily Living (modified for more severe dementia); ASHA-FACS, American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults; BADLS, Bristol Activities of Daily Living Scale; BBSI, brain boundary shift integral; Behave-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; BGP, Behavioral Rating Scale for Geriatric Patients; CAS, Caregiver Activity Survey; CDR-SB, Clinical Dementia Rating scale–sum of boxes; CDT, clock drawing test; CFT, Category Fluency Test; CGBRS, Crichton Geriatric Behavioural Rating Scale; CGI-C, Clinical Global Impression Change; CGI-I, Clinical Global Impression Improvement; ChEI, cholinesterase inhibitor; CIBIC-Plus, Clinician’s Interview-Based Impression of Change plus caregiver input; CMAI, Cohen-Mansfield Agitation Inventory; CMRgl, cerebral metabolic rates for glucose; COWAT, Controlled Oral Word Association Test; CSF, cerebrospinal fluid; DAD, Disability Assessment for Dementia; DB-RCT, double-blind randomized controlled trial; DON, donepezil; DSM-IV(-TR), Diagnostic and Statistical Manual of Mental Disorders 4th edition (-text revision); ER, extended-release; FAB, Frontal Assessment Battery; FAS, full analysis set; FAST, Functional Assessment Staging; FDG-PET, fluorodeoxy glucose positron emission tomography; Fi, fixed dose; Fl, flexible dose; FLCI, Functional Linguistic Communication Inventory; GAL (-CR), galantamine (continuous-release); GDCN, German Dementia Competence Network; GDS, Global Deterioration Scale; GHQ-12, General Health Questionnaire 12; HDS-R, Hasegawa’s dementia scale-revision; ICD-10, International Classification of Diseases 10th edition; ITT, intention to treat; MEM, memantine; MENFIS, Mental Function Impairment Scale; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; n, number of patients; NAA/Cr, n-acetyl aspartate and creatine; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; NIRS, near-infrared spectroscopy; NPI, Neuropsychiatric Inventory; NR, not reported; OC, observed case; OPT, Oral Production Test; O-RCT, open label randomized controlled trial; PLA, placebo; p-tau, phospho-tau; PSMS/IADL, Physical Self-Maintenance Scale and Instrumental Activities of Daily Living; RCT, randomized controlled trial; RIV, rivastigmine; SD, standard deviation; SIB, Severe Impairment Battery; t-tau, total tau; UC, usual care; UK, United Kingdom; USA, United States of America; VFT, verbal fluency test; y, years; ZBI, Zarit Burden Interview.

Data synthesis and outcome measures

Three primary outcomes were assessed including two efficacy measures: improvement in cognitive function and reduction in behavioral disturbances, and a safety measure: all-cause discontinuation. Cognitive function scores were derived from the Mini-Mental State Examination (MMSE) [27], Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) [28], and Severe Impairment Battery (SIB) [29] score. The behavioral disturbances score included the Neuropsychiatric Inventory [30] and the Behavioral Pathology in Alzheimer’s Disease Rating Scale [31]. The secondary outcome measures for efficacy included the MMSE score, ADAS-cog score, SIB score, activities of daily living [the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL 19/23) Items [32, 33], physical self-maintenance scale and instrumental activities of daily living [34], the Disability Assessment of Dementia (DAD) [35], and the Bristol Activities of Daily Living Scale [36]], global function related scales score [Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) [37], clinical global impression change (CGI-C), clinical global impression-improvement (CGI-I) [38], and the Clinical Dementia Rating scale (CDR) [39]], Functional Assessment Staging instrument score [40], verbal fluency [verbal fluency test (VFT) [41] and controlled oral word association test (COWAT) [42]], and discontinuation due to inefficacy. The secondary outcome measures for safety included discontinuation due to adverse events and the incidence of individual adverse events. For three-arm (memantine 10 mg/day, memantine 20 mg/day, and placebo) studies [20 , 43], we combined data of the memantine 10 mg/day arm with that of the memantine 20 mg/day arm.

Data extraction

Two authors (T.K. and S.M.) independently extracted data from the included studies. Where possible, we used an intention-to-treat (ITT) or a full analysis set (FAS) population. When such data were unavailable, the results for observed case (OC) analysis were extracted from each study. When the data required for meta-analysis were missing, we contacted the investigators (or the industries) of the relevant study and requested unpublished data.

Meta-analysis methods

The meta-analysis was conducted using Review Manager software [44]. The random effects model was selected for this meta-analysis because of the potential heterogeneity across studies. Dichotomous outcomes were presented as risk ratios (RRs) 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. Continuous outcomes were analyzed using the mean difference (MD) or, when different studies used different scales, the SMD. Lower MMSE, SIB, ADCS-ADL, DAD, VFT, and COWAT scores indicate more impairment or more severe symptoms; hence, we reversed the algebraic sign of the numerical scores for these scales. We assessed the methodological quality of the trials, according to the Cochrane risk-of-bias criteria [10]. Study heterogeneity was tested using the I² statistic, considering I²≥50% to reflect considerable heterogeneity [10]. In addition, we performed several sensitivity analyses, including tests for subgroup differences, to detect confounding factors of primary outcomes for efficacy (cognitive function and behavioral disturbances) as follows: analyzed population (ITT or FAS population versus OC population), severity of disease (mild-to-moderate versus moderate and moderate-to-severe), sponsorship (industry versus non-industry), blinding (double-blind versus open-label), control (placebo-controlled versus usual care-controlled), memantine formulation (extended-release versus immediate-release), memantine dose (memantine 20 mg/day studies versus combined with memantine 10 mg/day + 20 mg/day studies), donepezil (studies with more than 50% of patients receiving donepezil versus other ChEIs studies), galantamine (studies with more than 50% of patients receiving galantamine versus other ChEIs studies), and rivastigmine (studies with more than 50% of patients receiving rivastigmine versus other ChEIs studies). A meta-regression analysis was performed to evaluate the association between the result of meta-analysis on cognitive function and behavioral disturbances and certain modulators [MMSE scores at baseline (for cognitive function only), patient age, sample size, study duration, and percent male] using Comprehensive Meta-Analysis software version 2, (Biostat Inc., Englewood, NJ, USA). Finally, we utilized funnel plots to explore potential publication bias. Egger’s regression test was used to detect publication bias in meta-analyses using the same software.

RESULTS

Study characteristics

Of the 2,239 results obtained from our literature search, we excluded the following: 1,498 because they were duplicates, 693 after a review of the abstract or title, and 28 articles after a review of the full text [22 review articles, four single-arm studies, and two same studies]. Ten studies were retrieved by searching through the review articles and clinical trial registries (Supplementary Material 1). A total of 30 studies (n = 7,567; memantine monotherapy versus placebo: N = 11, n = 3,298; combination therapy with memantine and cholinesterase inhibitors versus ChEIs monotherapy: N = 17 comparisons, n = 4,175) were identified [11–25 , 45–58]. Seven of the 30 studies were not published in English [15 , 54] (Table 1). NCT00097916, NCT00476008, and NCT00933608 did not report whether these studies administered memantine monotherapy or combination therapy; hence, the studies were excluded from the meta-analysis [21 , 24].

For the 11 monotherapy studies, the mean duration was 28.4 weeks, the mean patient age was 75.5 years, and the percent male was 33.9. All studies were double-blind, randomized, placebo-controlled trials. The memantine dose was 20 mg/day in all studies other than the Kitamura 2011 study and the MA3301 study (both included three-arms: a memantine 10 mg/day arm, a memantine 20 mg/day arm, and a placebo arm) [20, 43]. Although two studies used OC populations in their analyses, we included these data in our meta-analysis to increase the sample size as much as possible [46, 52]. One of the 11 studies was not sponsored by a pharmaceutical company [46].

For the 17 combination studies, the mean duration was 29.4 weeks, the mean patient age was 76.5 years, and percent male was 47.0. Although five of the 17 studies were open-label studies, i.e., not placebo-controlled study [11 , 53, 54], the other 12 studies were double-blind, randomized, placebo-controlled trials. One of the 17 studies was a memantine-extended-release study [56]. The memantine dose was 20 mg/day in all studies except the IE2201 study (three-arms: a memantine 10 mg/day arm, a memantine 20 mg/day arm, and a placebo arm) [25]. Two studies used OC populations in their analyses [12, 46] and four were not sponsored by a pharmaceutical company [11 , 54]. The Creţu study and NCT00768261 did not report any available data for performing our meta-analysis [23, 54], and hence, were excluded from the meta-analysis.

Evaluations regarding the methodological quality of the included studies were performed according to the Cochrane risk-of-bias criteria, as shown in Supplementary Material 2.

Results of the memantine monotherapy meta-analysis

Efficacy outcomes

Memantine administration compared to placebo administration showed a significant improvement in all efficacy outcomes (cognitive function scores: SMD = –0.24, 95% CIs = –0.34 to –0.15, p < 0.00001, I² = 35% ; N = 10, n = 3,004; Fig. 1, Table 2.1 and the behavioral disturbances score: SMD = –0.16, 95% CIs = –0.29 to –0.04, p = 0.01, I² = 52% ; N = 9, n = 2,389; Fig. 2, Table 2.1, and Supplementary Material 3). The data for cognitive function scores and the behavioral disturbances score in each treatment group were simulated with no publication bias (Funnel plot: Supplementary Material 4, Egger’s test p-value: cognitive function scores = 0.359, behavioral disturbances score = 0.370).

Fig.1

Cognitive function. 95% CI, 95% confidence interval; IV, inverse variance; COMB, combination therapy; MONO, monotherapy; Std. Mean Difference, standardized mean difference.

Fig.2

Behavioral disturbances. 95% CI, 95% confidence interval; IV, inverse variance; COMB, combination therapy; MONO, monotherapy; Std. Mean Difference, standardized mean difference.

Table 2

Efficacy outcomes

Table 2.1. Monotherapy
Outcomes	N	n	I²	SMD/MD^a [95%CIs]	p
Cognitive function	10	3004	35%	–0.24 [–0.34, –0.15]	< 0.00001
MMSE	6	1393	0%	–0.85 [–1.18, –0.52]^a	< 0.00001
ADAS-cog	4	1430	0%	–1.02 [–1.66, –0.39]^a	0.002
SIB	6	1491	51%	–3.56 [–5.44, –1.69]^a	0.0002
Behavioral disturbances	9	2389	52%	–0.16 [–0.29, –0.04]	0.01
ADL	7	2403	6%	–0.09 [–0.18, –0.01]	0.03
Clinical global impression	8	2868	0%	–0.20 [–0.27, –0.12]	< 0.00001
FAST	4	1269	0%	–0.28 [–0.42, –0.14]^a	< 0.0001
	N	n	I²	RR [95%CIs]	p
Discontinuation due to inefficacy	5	1525	0%	0.36 [0.17, 0.74]	0.006 ^b

Table 2.2. Combination therapy
Outcomes	N	n	I²	SMD/MD^a [95%CIs]	p
Cognitive function	14	3402	56%	–0.11 [–0.22, 0.01]	0.06
MMSE	8	1269	50%	–0.38 [–1.06, 0.29]^a	0.27
ADAS-cog	7	1129	3%	0.11 [–0.30, 0.52]^a	0.60
SIB	4	1914	68%	–1.55 [–3.09, –0.00]^a	0.05
Behavioral disturbances	10	2909	77%	–0.20 [–0.36, –0.03]	0.02
ADL	9	2531	64%	–0.00 [–0.15, 0.14]	0.95
Clinical global impression	8	2387	72%	–0.18 [–0.34, –0.01]	0.04
Verbal fluency	2	876	0%	–0.23 [–0.36, –0.09]	0.0008
	N	n	I²	RR [95%CIs]	p
Discontinuation due to inefficacy	10	3277	0%	0.51 [0.26, 0.99]	0.05 ^c

ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL, activities of daily living; FAST, Functional Assessment Staging; MMSE, Mini-Mental State Examination; SIB, Severe Impairment Battery. Bold face were significant. 95% CIs, 95% confidence intervals; MD, mean difference; N, number of studies; n, number of patients; RR, risk ratio; SMD, standardized mean difference.^amean difference. ^bnumber needed to harm (NNH): not significant ^cNNH: not significant.

Sensitivity analysis

We did not detect considerable heterogeneity with respect to cognitive function scores (I² = 35%), and any evident confounding factors in the sensitivity analyses (Fig. 3, Table 3.1, and Supplementary Material 5). However, we detected considerable heterogeneity with respect to the behavioral disturbances score (I² = 52%). In the sensitivity analysis of the moderate-severe AD subgroup, considerable heterogeneity was not found (I² = 36% ; Fig. 3). Memantine administration showed a significant reduction in the behavioral disturbances score compared to the placebo group (SMD = –0.20, 95% CIs = –0.34 to –0.07, p = 0.003; N = 7, n = 1,558; Fig. 3, Table 3.2, and Supplementary Material 5).

Fig.3

Monotherapy: sensitivity analysis/subgroup analysis about primary outcomes for efficacy. 95% CI, 95% confidence interval; IV, inverse variance; MONO, monotherapy; Std. Mean Difference, standardized mean difference.

Table 3

Sensitivity analysis/subgroup analysis

Table 3.1. Memantine monotherapy for cognitive function
Subgroup	N	n	I²	SMD [95%CIs]	p	Test for subgroup differences
ITT/FAS population studies	8	2877	45%	–0.23 [–0.34, –0.13]	< 0.00001	p = 0.41, I² = 0%
OC population study	2	127	0%	–0.39 [–0.74, –0.04]	0.03
Mild-moderate Alzheimer’s disease studies	3	1408	0%	–0.17 [–0.28, –0.06]	0.002	p = 0.17, I² = 47.2%
Moderate-severe Alzheimer’s disease studies	7	1596	41%	–0.30 [–0.43, –0.16]	< 0.0001
Non-industry sponsored study	1	105	na	–0.35 [–0.73, 0.04]	0.08	p = 0.59, I² = 0%
Industry sponsored studies	9	2899	40%	–0.24 [–0.34, –0.14]	< 0.00001
Memantine 20 mg/day studies	8	2137	47%	–0.26 [–0.38, –0.13]	0.0001	p = 0.62, I² = 0%
Combined with memantine 10 mg/day + 20 mg/day studies	2	867	0%	–0.21 [–0.35, –0.07]	0.004

Table 3.2. Memantine monotherapy for behavioral disturbances
Subgroup	N	n	I²	SMD [95%CIs]	p	Test for subgroup differences
ITT/FAS population studies	7	2262	61%	–0.15 [–0.29, –0.01]	0.04	p = 0.40, I² = 0%
OC population study	2	127	0%	–0.31 [–0.66, 0.04]	0.08
Mild-moderate Alzheimer’s disease studies	2	831	79%	–0.05 [–0.36, 0.26]	0.74	p = 0.38, I² = 0%
Moderate-severe Alzheimer’s disease studies	7	1558	36%	–0.20 [–0.34, –0.07]	0.003
Non-industry sponsored study	1	105	na	–0.36 [–0.74, 0.03]	0.07	p = 0.31, I² = 3.9%
Industry sponsored studies	8	2284	55%	–0.15 [–0.28, –0.01]	0.03
Memantine 20 mg/day studies	8	2075	57%	–0.18 [–0.32, –0.04]	0.01	p = 0.41, I² = 0%
Combined with memantine 10 mg/day + 20 mg/day studies	1	314	na	–0.06 [–0.30, 0.17]	0.60

Table 3.3. Combination therapy for cognitive function
Subgroup	N	n	I²	SMD [95%CIs]	p	Test for subgroup differences
ITT/FAS population studies	12	3280	62%	–0.11 [–0.23, 0.01]	0.08	p = 0.91, I² = 0%
OC population study	2	122	0%	–0.09 [–0.44, 0.27]	0.63
Mild-moderate Alzheimer’s disease studies	5	1062	42%	0.00 [–0.17, 0.18]	0.98	p = 0.13, I² = 56.1%
Moderate-severe Alzheimer’s disease studies	9	2340	54%	–0.17 [–0.31, –0.03]	0.02
Non-industry sponsored studies	3	169	74%	–0.41 [–1.13, 0.31]	0.26	p = 0.39, I² = 0%
Industry sponsored studies	11	3233	53%	–0.09 [–0.20, 0.02]	0.10
Double-blind studies	11	3187	53%	–0.09 [–0.20, 0.02]	0.11	p = 0.36, I² = 0%
Open-label studies	3	215	73%	–0.42 [–1.10, 0.27]	0.24
Placebo-controlled studies	11	3187	53%	–0.09 [–0.20, 0.02]	0.11	p = 0.36, I² = 0%
Non placebo-controlled studies	3	215	73%	–0.42 [–1.10, 0.27]	0.24
Memantine-extended-release study	1	659	na	–0.21 [–0.36, –0.06]	0.007	p = 0.26, I² = 21.9%
Memantine-immediate-release study	13	2743	56%	–0.10 [–0.22, 0.03]	0.14
Memantine 20 mg/day studies	13	3367	58%	–0.10 [–0.22, 0.02]	0.09	p = 0.29, I² = 9.6%
Combined with memantine 10 mg/day + 20 mg/day studies	1	35	na	–0.48 [–1.19, 0.22]	0.18
Donepezil studies	10	2508	49%	–0.18 [–0.31, –0.05]	0.006	p = 0.02, I² = 80.3%
ChEIs other than donepezil studies	4	894	26%	0.05 [–0.11, 0.20]	0.53
Galantamine study	1	190	na	0.29 [0.00, 0.57]	0.05	p = 0.006, I² = 86.6%
ChEIs other than galantamine studies	13	3212	44%	–0.14 [–0.24, –0.03]	0.01
Rivastigmine study	1	158	na	–0.10 [–0.41, 0.22]	0.55	p = 0.93, I ²= 0%
ChEIs other than rivastigmine studies	13	3244	59%	–0.11 [–0.23, 0.01]	0.08

Table 3.4. Combination therapy for behavioral disturbances
Subgroup	N	n	I²	SMD [95%CIs]	p	Test for subgroup differences
ITT/FAS population studies	9	2797	79%	–0.19 [–0.37, –0.01]	0.04	p = 0.60, I² = 0%
OC population study	1	112	na	–0.30 [–0.67, 0.07]	0.11
Mild-moderate Alzheimer’s disease studies	3	861	0%	0.00 [–0.13, 0.14]	0.98	p = 0.02, I² = 82.5%
Moderate-severe Alzheimer’s disease studies	7	2048	82%	–0.33 [–0.57, –0.09]	0.007
Non-industry sponsored studies	3	169	88%	–1.27 [–2.45, –0.08]	0.04	p = 0.05, I² = 73.7%
Industry sponsored studies	7	2740	36%	–0.09 [–0.18, 0.01]	0.08
Double-blind studies	7	2694	40%	–0.11 [–0.21, –0.01]	0.04	p = 0.15, I² = 52.1%
Open-label studies	3	215	92%	–1.17 [–2.61, 0.27]	0.11
Placebo-controlled studies	7	2694	40%	–0.11 [–0.21, –0.01]	0.04	p = 0.15, I² = 52.1%
Non placebo-controlled studies	3	215	92%	–1.17 [–2.61, 0.27]	0.11
Memantine-extended-release study	1	639	na	–0.20 [–0.35, –0.04]	0.01	p = 0.90, I² = 0%
Memantine-immediate-release study	9	2270	79%	–0.21 [–0.41, –0.01]	0.04
Donepezil studies	8	2427	79%	–0.27 [–0.47, –0.07]	0.007	p = 0.02, I² = 83.0%
ChEIs other than donepezil studies	2	482	0%	0.06 [–0.12, 0.24]	0.53
Rivastigmine study	1	158	na	0.01 [–0.30, 0.33]	0.93	p = 0.20, I² = 40.0%
ChEIs other than rivastigmine studies	9	2751	79%	–0.22 [–0.41, –0.04]	0.02

Bold face were significant. ChEIs. cholinesterase inhibitors; FAS, full analysis set; ITT, intention-to-treat; N, number of studies; n, number of patients; na, not applicable; OC, observed case; SMD, standardized mean difference.

Meta-regression analysis

Meta-regression analysis showed that the effect size of memantine administration with respect to cognitive function scores was associated with MMSE scores at baseline (coefficient = 0.039, 95% CIs = 0.008 to 0.0699, p = 0.0136) and percent male (coefficient = –0.0276, 95% CIs = –0.0509 to –0.0044, p = 0.0199; Table 4.1 and Supplementary Material 6). The effect size of memantine administration with respect to the behavioral disturbances score was associated with sample size (coefficient = 0.0013, 95% CIs = 0.00 to 0.0026, p = 0.0439; Table 4.2 and Supplementary Material 6).

Table 4

Meta-regression analysis

Table 4.1. Memantine monotherapy for cognitive function
Covariate	Coefficient	Standard error	95% lower	95% upper	p
MMSE score at baseline	0.039	0.0158	0.008	0.0699	0.0136
Duration of study	0.0005	0.0069	–0.013	0.014	0.9436
Age	0.0039	0.0038	–0.0036	0.0115	0.3089
Percent male	–0.0276	0.0119	–0.0509	–0.0044	0.0199
Sample size	–0.0003	0.0005	–0.0012	0.0006	0.4809

Table 4.2. Memantine monotherapy for behavioral disturbances
Covariate	Coefficient	Standard error	95% lower	95% upper	p
Duration of study	0.0082	0.009	–0.0094	0.0259	0.3606
Age	–0.0047	0.0048	–0.0141	0.0047	0.329
Percent male	–0.0127	0.0158	–0.0436	0.0182	0.419
Sample size	0.0013	0.0007	0	0.0026	0.0439

Table 4.3. Combination therapy for cognitive function
Covariate	Coefficient	Standard error	95% lower	95% upper	p
MMSE score at baseline	0.0255	0.0186	–0.011	0.0621	0.1709
Duration of study	0.0005	0.0034	–0.0061	0.0072	0.8727
Age	–0.006	0.0045	–0.0147	0.0028	0.1795
Percent male	–0.0029	0.0044	–0.0115	0.0057	0.5117
Sample size	0.0002	0.0004	–0.0005	0.001	0.5648

Table 4.4. Combination therapy for behavioral disturbances
Covariate	Coefficient	Standard error	95% lower	95% upper	p
Duration of study	0.0107	0.0048	0.0013	0.0202	0.0264
Age	–0.0062	0.0047	–0.0153	0.0029	0.1818
Percent male	–0.0119	0.0065	–0.0246	0.0008	0.0665
Sample size	0.0011	0.0006	–0.0001	0.0023	0.0731

Bold face were significant; MMSE, Mini-Mental State Examination.

Safety outcomes

No significant difference was found in all-cause discontinuation between memantine and placebo treatment groups (RR = 0.94, 95% CIs = 0.80–1.11, p = 0.47, I² = 14% ; N = 11, n = 3,151; Fig. 4). The data for all-cause discontinuation in each treatment group were simulated with no publication bias (Funnel plot: Supplementary Material 4, Egger’s test p-value = 0.658). However, memantine administration was associated with a higher incidence of dizziness (RR = 1.53, 95% CIs = 1.02–2.28, p = 0.04, NNH = 50) and somnolence (RR = 2.36, 95% CIs = 1.02–5.50, p = 0.05, NNH = not significant) compared with placebo administration (Supplementary Material 7). On the other hand, memantine administration was associated with a lower incidence of agitation (RR = 0.70, 95% CIs = 0.50–0.97, p = 0.03, NNH = not significant), increased blood potassium (RR = 0.20, 95% CIs = 0.04–0.97, p = 0.05, NNH = not significant), and psychotic symptoms (RR = 0.50, 95% CIs = 0.28–0.92, p = 0.03, NNH = not significant) compared with placebo administration (Supplementary Material 7). There were no significant differences in other adverse events between the treatment groups (Supplementary Material 7).

Fig.4

All-cause discontinuation. 95% CI, 95% confidence interval; COMB, combination therapy; M-H, Mantel-Haenszel; MONO, monotherapy.

Results of the combination therapy meta-analysis

Efficacy outcomes

Combination therapy showed a trend toward superiority to ChEI monotherapy in improving cognitive function scores (SMD = –0.11, 95% CIs = –0.22 to 0.01, p = 0.06, I² = 56% ; N = 14, n = 3,402; Fig. 1 and Table 2.2). Combination therapy compared to ChEI monotherapy showed a significant reduction in the behavioral disturbances score (SMD = –0.20, 95% CIs = –0.36 to –0.03, p = 0.02, I² = 77% ; N = 10, n = 2,909; Fig. 2 and Table 2.2). The Egger’s test for cognitive function scores identified no publication bias (p = 0.453), while publication bias was identified for the behavior disturbances score (p = 0.0264) (Funnel plot: Supplementary Material 4). In addition, combination therapy was superior to ChEI monotherapy for the SIB score, Clinical global impression score, verbal fluency scores, and discontinuation due to inefficacy (Table 2.2 and Supplementary Material 3).

Sensitivity analysis

We detected considerable heterogeneity with respect to the cognitive function scores (I² = 56%). In the sensitivity analyses of the OC population subgroup, mild-moderate AD subgroup, memantine-extended-release subgroup, combined with memantine 10 mg/day + 20 mg/day subgroup, donepezil subgroup, ChEIs other than donepezil subgroup, galantamine subgroup, ChEIs other than galantamine subgroup, and rivastigmine subgroup, the considerable heterogeneity disappeared (Fig. 5, Table 3.3, and Supplementary Material 5). Moreover, among these subgroups, the subgroups in which combination therapy was superior to ChEI monotherapy regarding cognitive function included the memantine-extended-release subgroup (SMD = –0.21, 95% CIs = –0.36 to –0.06, p = 0.007, I² = not applicable; N = 1, n = 659), donepezil subgroup (SMD = –0.18, 95% CIs = –0.31 to –0.05, p = 0.006, I² = 49% ; N = 10, n = 2,508), and ChEIs other than galantamine subgroup (SMD = –0.14, 95% CIs = –0.24 to –0.03, p = 0.01, I² = 44% ; N = 13, n = 3,212; Table 3.3 and Supplementary Material 5). On the other hand, combination therapy with memantine and galantamine was inferior to ChEI monotherapy (SMD = 0.29, 95% CIs = 0.00 to 0.57, p = 0.05, I² = not applicable; N = 1, n = 190; Table 3.3 and Supplementary Material 5).

Fig.5

Combination therapy: sensitivity analysis/subgroup analysis about primary outcomes for efficacy. 95% CI, 95% confidence interval; IV, inverse variance; COMB, combination therapy; Std. Mean Difference, standardized mean difference.

We also detected considerable heterogeneity with respect to the behavioral disturbances score (I² = 77%). In the sensitivity analyses of the OC population subgroup, mild-moderate AD subgroup, industry sponsored subgroup, double-blind subgroup, placebo-controlled subgroup, memantine-extended-release subgroup, ChEIs other than donepezil subgroup, and rivastigmine subgroup, the considerable heterogeneity disappeared (Fig. 5, Table 3.4, and Supplementary Material 5). Combination therapy was superior to ChEI monotherapy in reducing behavioral disturbances in the double-blind, placebo-controlled subgroup (SMD = –0.11, 95% CIs = –0.21 to –0.01, p = 0.04, I² = 40% ; N = 7, n = 2,694) and in the memantine-extended-release subgroup (SMD = –0.20, 95% CIs = –0.35 to –0.04, p = 0.01, I² = not applicable; N = 1, n = 639; Table 3.4 and Supplementary Material 5).

Meta-regression analysis

Although no modulators showed an association with the effect size of combination therapy regarding cognitive function (Table 4.3), the effect size of combination therapy with respect to the behavioral disturbances score was associated with the study duration (coefficient = 0.0107, 95% CIs = 0.0013 to 0.0202, p = 0.0264; Table 4.4 and Supplementary Material 6).

Safety outcomes

There was no significant difference in all-cause discontinuation between all treatment groups (RR = 1.00, 95% CIs = 0.87–1.14, p = 0.98, I² = 9% ; N = 14, n = 3,908; Fig. 4). The data for all-cause discontinuation in each treatment group were simulated with no publication bias (Funnel plot: Supplementary Material 4, Egger’s test p-value = 0.855). However, combination therapy was associated a higher incidence of at least one adverse event (RR = 1.05, 95% CIs = 1.00–1.09, p = 0.05, NNH = 33), somnolence (RR = 2.29, 95% CIs = 1.24–4.21, p = 0.008, NNH = not significant), and weight increase (RR = 2.31, 95% CIs = 1.27–4.23, p = 0.006, NNH = 33) compared with ChEI monotherapy (Supplementary Material 7). There were no significant differences in other adverse events between the treatment groups (Supplementary Material 7).

DISCUSSION

In this updated and comprehensive systematic review and meta-analysis of memantine administration in patients with AD, the memantine monotherapy group showed significant efficacy compared with the placebo group in improving cognitive function in patients with all levels of AD severity and reducing behavioral disturbances in moderate-severe AD, without exhibiting differences in the safety outcome of all-cause discontinuation. Combination therapy was also well-tolerated and showed a significant reduction in behavioral disturbances in the studies included in the higher quality design subgroup, such as double blind, placebo-controlled studies. In improving cognitive function, combination therapy with memantine and any ChEIs only showed a positive trend compared with ChEI monotherapy. However, when only studies of combination therapy with memantine and donepezil were included, combination therapy was superior to ChEI monotherapy.

Overall, our meta-analysis favors the use of memantine as a first line drug in treating AD. However, our data suggest that clinicians should pay close attention to the patient’s physical condition. There was a risk of dizziness/vertigo and somnolence with memantine monotherapy and a risk of somnolence and weight increase with combination therapy even though these risks appeared to be small.

In the combination therapy meta-analysis, there were considerable heterogeneities regarding both primary outcomes (cognitive function and behavioral disturbances). In the sensitivity analysis based on donepezil or other ChEIs studies, combination therapy with memantine and donepezil was superior to ChEI monotherapy in improving cognitive function without considerable heterogeneity. Therefore, these findings suggest that memantine is more compatible with donepezil than with other ChEIs. Furthermore, when performing sensitivity analysis based on high quality design (i.e., double-blind, placebo-controlled studies) or other studies, combination therapy ameliorated behavioral disturbances in patients with AD compared to ChEI monotherapy in the high-quality design subgroup without considerable heterogeneity. Therefore, it appears that the major confounding factor contributing to the heterogeneity was data from studies with low quality design.

Among ChEIs, the donepezil subgroup showed the greatest improvement in cognitive function, suggesting that donepezil is the best ChEI to be combined with memantine. Furthermore, combination therapy with memantine and galantamine was found to be inferior to galantamine monotherapy in improving cognitive function scores. However, as there was only one such study on combination therapy with memantine and galantamine, this finding does not provide robust evidence for this therapeutic combination. It is possible that the pharmacologic effects of memantine are antagonistic to those of galantamine. Galantamine inhibits acetylcholinesterase and is a potent allosteric potentiating ligand of nicotinic acetylcholine receptors α4β2, α3β4, and α6β4, and α7/serotonin 3 receptors in certain areas of the brain [59]. Therefore, galantamine increases the release of a number of neurotransmitters, including acetylcholine, dopamine, norepinephrine, serotonin, γ-aminobutyric acid, and glutamate [60]. Memantine is an antagonist for various receptors (NMDA receptors, serotonin-3 receptors, and nicotinic acetylcholine receptors, including alpha-7 receptor) and is a dopamine D₂ receptor agonist [61].

It should be noted that we detected significant publication bias with respect to behavioral disturbances in the meta-analysis of combination therapy. The effect size of two open-label studies were outliers [11, 19] (Supplementary Material 4). We also detected some associations between clinical modulators and cognitive function and behavioral disturbances; however, each effect size was very small. Moreover, because we did not address multiple comparisons, these significant effects may be a false-positive error arising from the number of meta-regression analyses performed [10].

There were several limitations in this study that need to be addressed. First, patient characteristics differed between the studies examined, including symptom severity, inclusion criteria, race, ethnicity, and study duration. These differences could generate heterogeneity when combining data for systematic review and meta-analysis. In fact, there was considerable heterogeneity regarding primary outcomes. Second, the number of studies and patients in the meta-analyses of some outcomes, such as SIB and verbal fluency, were small. Third, most studies included in this study were industry sponsored studies. Therefore, there is a possibility of sponsorship bias in our results. Fourth, our study focused on memantine treatment for AD. The study using the Veterans Affairs prescription database reported that memantine treatment was associated with an increased life-expectancy compared with donepezil treatment [62]. We considered that a network meta-analysis of anti-dementia drugs for the AD regarding efficacy and safety is required because a network meta-analysis combines direct and indirect evidence to address the absence of randomized trials that directly compare all the interventions of interest. A network meta-analysis should provide evidence for the best pharmacological intervention for AD.

Conclusions

Our results favor memantine administration as a first line anti-dementia drug for the treatment of AD. The current results suggest that the addition of memantine to ChEIs, especially donepezil, can provide further benefit in treating AD and its symptoms of dementia and behavioral disturbances.

Footnotes

ACKNOWLEDGMENTS

We thank Mr. Shohei Yasuda (Daiichi Sankyo Company, Limited), Mr. Masato Kobayashi (Daiichi Sankyo Company, Limited), Mr. Kazuto Sato (Daiichi Sankyo Company, Limited), Dr. Jun Horiguchi (Department of Psychiatry, Faculty of Medicine, Shimane University), Dr. Rei Wake (Department of Psychiatry, Faculty of Medicine, Shimane University), Dr. John Wesson Ashford Jr (Department of Psychiatry and Behavioral Sciences Stanford School of Medicine), Dr. Robert Howard (Department of Old Age Psychiatry and Psychopathology, King’s College London), and Dr. Patrick Phillips (MRC Clinical Trials Unit at UCL Inst of Clinical Trials &Methodology) for providing information for this study. A part of data which we could not get enough information from published articles nor unpublished studies was provided by Daiichi Sankyo Co., Ltd.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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