Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer’s Disease: A Literature Review Evidence (2024)

Abstract

INTRODUCTION

Two types of drugs have been approved for the symptomatic treatment of Alzheimer’s disease (AD): the cholinesterase inhibitors (ChEIs) and memantine. There is a growing interest to know whether the combination of these drugs is safe and if it adds any clinical benefit to patients.

OBJECTIVE

To systematically review published medical literature assessing the efficacy and tolerability of a combination treatment of memantine and donepezil in AD patients.

METHODS

We searched PubMed for English and Spanish-language literature, using the terms “Alzheimer’s disease,” “cholinesterase inhibitors,” “donepezil,” and “memantine.” Our review focused on clinical trials and observational studies.

RESULTS

Eleven publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies.

CONCLUSIONS

Available data revealed that the combination of memantine and donepezil slowed down cognitive decline, prolonged functional independence, and improved behavioral symptoms in patients with moderate to severe AD. The long-term use of the dual therapy decreased the risk of nursing home admission. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients.

Keywords: Alzheimer’s disease, memantine, donepezil, cholinesterase inhibitors, combined therapy

INTRODUCTION

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. This disorder is characterized by cognitive decline, impaired performance of activities of daily living, and behavioral and psychiatric symptoms. The frequency of dementia, especially AD, increases exponentially with age, and it affects 1 in 10 people over 65 years of age and about half the people over 85.^1,2 It is estimated that 25–30 million people worldwide currently suffer from AD and the number of cases will triple by 2040.³ Importantly, AD is the leading cause of disability, institutionalization, and increased mortality in older people in western countries.^4,5 Hence, the magnitude of this devastating disease has a great impact on caregivers and health care systems. Even more, the burden that AD imposes on society is enhanced by the fact that there are no currently curative treatment options for this entity.

There are two types of drugs approved for the symptomatic treatment of patients with AD, the cholinesterase inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) receptor antagonist, memantine. The ChEIs (donepezil, galantamine, and rivastigmine) increase the levels of acetylcholine in the neuronal synaptic cleft by decreasing hydrolysis of acetylcholine through blocking the acetylcholinesterase.⁶ Randomized clinical trials lasting for 6 months have shown efficacy of donepezil,⁷ galantamine,^8,9 and rivastigmine¹⁰ in patients with mild to moderate AD. Donepezil improved cognition from the early to the severe stages of AD.^11–13 Open-label studies suggest that cognitive benefits last for a few years while patients continue taking these drugs.^14–17 Furthermore, ChEI therapy improves behavioral symptoms at all stages of AD.^18,19 The ChEIs are licensed for mild to moderate AD, except donepezil, which is approved for all stages of AD²⁰ in the US and Japan.

METHODS

We searched PubMed (from 2000 to February, 2010) for English and Spanish-language medical literature using the terms “Alzheimer’s disease,” “cholinesterase inhibitors,” “donepezil,” and “memantine” as the key words. Our review focused on clinical trials and observational studies, but review papers were excluded. We also included published articles where all three ChEIs were used in combination with memantine, being that donepezil is the most prescribed.

RESULTS

The search strategy yielded 45 citations, of which 34 were excluded on the basis of abstract. Finally, 11 publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies (Table 1).

Table 1.

Studies Assessing the Efficacy and Tolerability of a Combination Treatment of Donepezil and Memantine in Patients with Alzheimer’s Disease

Study	Study Type (Duration)	Number of Subjects	Inclusion Criteria	Outcome Measures	Result
MEM-MD-02 study³⁰	Randomized controlled trial (24 weeks)	404	Moderate to severe AD on donepezil	Primary: SIB, ADCS-ADL₁₉ Secondary: CIBIC-Plus, NPI, BGP	Benefits of combined therapy on all outcome measures. No differences in adverse events between both groups
MEM-MD-12 study³⁵	Randomized controlled trial (24 weeks)	433	Mild to moderate AD on any ChEI (67% on donepezil)	Primary: ADAS-cog, CIBIC-Plus Secondary: ADCS-ADL₂₃, NPI, RUD	No benefits of combined therapy over ChEI monotherapy. No differences in adverse events between both groups
DOMINO-AD study³⁶	Randomized controlled trial (52 weeks)	800	Moderate to severe AD on donepezil	Primary: SMMSE, BADLS Secondary: NPI, EQ-5D, DEMQOL-proxy, GHQ-12, CSRI, and institutionalization	Ongoing
Hartmann and Mobius²⁹	Observational study (4-month follow-up)	158	Demented outpatients (77% with AD) treated with memantine and a ChEI (84% on donepezil)	Scale assessing tolerability	The combination treatment was well tolerated by almost all patients
Atri et al.³⁷	Observational study (mean follow-up: 30 months)	382	Probable AD	IMC subscale of BDS, WADLS	Combined therapy slowed cognitive and functional decline in AD patients compared with monotherapy and no treatment
Schneider et al.³⁸	Observational study (2-year follow-up)	188	Mild AD	ADAS-cog, MMSE, CDR, FAQ	AD patients on combined therapy were more functionally impaired and showed greater decline on MMSE and CDR than those on ChEI monotherapy
Lopez et al.³⁹	Observational study (mean follow-up: 62.4 months)	943	Probable AD with at least a 1 year of follow-up	Time to nursing home admission and death	Combined therapy significantly delayed the time to nursing home admission, but had no effect on survival

Open in a new tab

Abbreviations: AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL₁₉: Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory, 19-item version; ADCS-ADL₂₃: Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory, 23-item version; BADLS: Bristol Activities of Daily Living Scale; BDS: Blessed Dementia Scale; BGP: Behavioral Rating Scale for Geriatric Patients; CDR: Clinical Dementia Rate; ChEI: cholinesterase inhibitor; CIBIC-Plus: Clinician’s Interview-Based Impression of Change Plus Caregiver Input; CSRI: Client Service Receipt Inventory; EQ-5D: EuroQol EQ-5D; FAQ: Functional Activities Questionnaire; GHQ-12: General Health Questionnaire 12; IMC: Information-Memory-Concentration; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; RUD: Resource Utilization in Dementia scale; SIB: Severe Impairment Battery; SMMSE: standardized Mini-Mental State Examination; WADLSP: Weintraub Activities of Daily Living Scale.

Randomized controlled trials

Tariot and colleagues conducted a randomized, double-blind, placebo-controlled trial (the MEM-MD-02 study) where 404 patients with moderate to severe AD on donepezil for more than 6 months and at a stable dose (5–10 mg/d) were assigned to receive memantine (target dose of 20 mg/d) or placebo for 24 weeks.³⁰ The primary efficacy parameters in this study was the change from baseline on the Severe Impairment Battery (SIB), a scale composed by nine domains (social interaction, memory, orientation, language, attention, praxis, visuospatial, construction, and orientation to name), and on a modified 19-item Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL₁₉) at week 24. The secondary outcomes included a Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory (NPI), and the Behavioral Rating Scale for Geriatric Patients (BGP). This clinical trial showed benefits of treatment with memantine versus treatment with placebo on all primary and secondary outcome measures, which means benefits on cognitive function, activities of daily living, behavior, and clinical global status. Specially, treatment with memantine for 24 weeks resulted in stabilization of cognitive function with a .9 increase in SIB score from baseline, whereas in the placebo group there was a decline with a 2.5 decrease in the SIB score compared to baseline. Moreover, there were no differences in adverse events between memantine and placebo groups. Confusion was more frequent in patients taking memantine, but it was mild in intensity and duration. Hence, this trial first demonstrated that donepezil and memantine were safe and more effective than donepezil alone in patients with moderate to severe AD.

Several post hoc analyses have been published from this trial to further understand the benefits observed with the combined therapy.^31–34 An exploratory reanalysis of cognitive function showed significant effects of donepezil and memantine specifically on memory, language, and praxis domains of the SIB.³² Similarly, Feldman et al.³³ examined the ADCS-ADL₁₉ data including ADL items and new subscales derived from factor analysis to evaluate the effects of donepezil and memantine on activities of daily living (ADL). The items analysis showed significant benefits of the combined therapy on activities such as grooming, toileting, conversing, watching television, and being left alone, while the subscale evaluation showed improvements on higher-level function and connectedness/autonomy item subgroups. Finally, Cummings et al.³⁴ re-examined the impact of the combined therapy on AD patients’ behavioral symptoms. At the end of the MEM-MD-02 study, the mean total NPI score increased by 1.7 points (worsening behavior) in the placebo group, while the score was similar to baseline in the memantine group (p=.002). Analyses of NPI domains revealed significant differences at week 24 in favor of the memantine-donepezil group for agitation, irritability, and appetite/eating changes. Among patients with no behavioral symptoms at baseline, those treated with memantine-donepezil, never showed greater emergence of such symptoms than the placebo group. In fact, those on the combined therapy exhibited significant fewer emergences of agitation, irritability, and nighttime behavior. This improvement in behavioral symptoms was reflected in caregiver distress. In fact, caregivers of patients on memantine and donepezil had significantly less distress at the end of the study for agitation/aggression, nighttime behavior, and eating change.

A double-blind, placebo-controlled trial was conducted to assess the efficacy and tolerability of memantine in patients with mild to moderate AD who were already taking a ChEI.³⁵ The primary efficacy analyses were change from baseline on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and on the CIBIC-Plus. Secondary outcomes included the modified 23-item Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL₂₃), the NPI, and the Resource Utilization in Dementia scale (RUD). There were 433 subjects that were randomized to treatment; 216 were assigned to receive placebo (only ChEI) and 217 to memantine. All three ChEIs were permitted, but donepezil was the most frequently used (67% of patients). The type and frequency of adverse events were similar between both groups. But, this study did not show any advantage of this drug regimen on primary or secondary efficacy measures over ChEI monotherapy after 6 months of treatment.

Finally, there is an on-going randomized, double-blind, placebo-controlled trial (the DOMINO-AD study) that was started in the United Kingdom in 2008.³⁶ This study included patients with moderate to severe AD on donepezil, in which the treating physician has doubts about the treatment benefits. Patients were randomized to receive donepezil, memantine, donepezil and memantine, or placebo. Primary outcomes include measures of cognition (Standardized Mini-Mental State Examination [SMMSE]) and ADL (Bristol ADL Scale). Secondary outcomes include measures of behavioral symptoms (NPI), quality of life (EuroQol EQ-5D and DEMQOL-proxy), caregiver burden (General Health Questionnaire 12), cost-effectiveness (Client Service Receipt Inventory), and institutionalization. The duration of the study is 52 weeks. So, in a few years we will have more data about the short-term efficacy of the combined therapy versus monotherapy or placebo in moderate to severe impaired patients.

Observational studies

An observational study to assess the safety and tolerability of memantine in combination with ChEIs in demented patients was performed in Germany.²⁹ In this study, questionnaires were distributed to physicians to collect data of demented patients on combined therapy for a 4-month observational period. Most of the 158 surveyed patients were diagnosed with AD (77%), but other dementias were included. Memantine was mainly combined with donepezil (84%). The tolerability of the combination treatment was rated as very good or good for nearly all patients (98%) and no serious adverse events were reported.

Long-term effects of this dual therapy, mainly the combination of donepezil and memantine, have been assessed in three observational studies. Atri et al.³⁷ followed 382 subjects with a clinical diagnosis of probable AD for a mean time of 30 months. There were 144 patients that were not on any antidementia drug, 122 received a cholinesterase inhibitor alone, and 116 were taking memantine and a cholinesterase inhibitor. Cognition and functional activity were evaluated in all subjects using the Information-Memory-Concentration subscale of the Blessed Dementia Scale and the Weintraub ADL scale at 6-month intervals. This study showed that those patients on the combined therapy presented the slowest rate of cognitive progression and functional decline of the three groups. On the other hand, Schneider et al. ³⁸ have recently published a paper reporting the differences on cognition and functional measures of 402 MCI patients and 188 subjects with mild AD who were taking different treatment regimens (no treatment, ChEI only, or combination treatment) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The most frequently used ChEI was donepezil. Of those MCI patients, 84.7% who were taking a ChEI were on donepezil, and 77.4% of those in the mild AD group who were on this class of drugs were receiving donepezil. The main clinical outcomes were the ADAS-Cog, Clinical Dementia Rating (CDR) scale, MMSE, and Functional Activities Questionnaire. Baseline and 2-year outcomes were compared in mild AD patients taking only ChEIs with those on combined treatment; and the later group showed greater clinical decline on the MMSE and CDR scales. However, given that none of the randomized clinical trials found that ChIEs and memantine worsened the course of AD, a toxic effect of the combined therapy is unlikely. Probably Schneider and colleagues’ results could be explained by the decision to add memantine to those subjects who were progressing faster.

Lopez et al.³⁹ conducted an observational study to assess the risk of institutionalization and death of AD patients on different medication regimens (ChEI alone, combined therapy, or no treatment, and where 75% of treated patients used donepezil). Two historical cohorts with a clinical diagnosis of probable AD were evaluated. In cohort 1 (N = 943 patients), 140 subjects used memantine and a ChEI, 387 used only a ChEI, and 416 used neither, while in cohort 2 (N = 429), 289 subjects were on ChEI monotherapy and 140 on the combined therapy. The mean follow-up time was 62.3 months. The main finding from this study was that the dual therapy further delays nursing home admission from that time afforded by ChIEs alone. Therefore, dual therapy induces an improvement on cognition, function, and behavior in AD patients that results in a longer time at home prior to residential care.

CONCLUSION

This review of the limited literature about therapy with memantine and donepezil in AD shows that this combination is safe compared to donepezil alone. Available data also revealed that combined therapy seems to slow down cognitive decline, prolongs functional independence, and improves behavioral symptoms in patients with moderate to severe AD. In addition, pharmacoeconomic studies showed that such treatment reduced lifetime total cost of care in AD patients.⁴⁰ However, these clinical benefits have not been demonstrated in subjects with mild AD. In the long-term, dual therapy seems to slow the rate of cognitive progression and functional decline of patients, delays the nursing home admission, but has no effect on survival. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients.

Acknowledgments

M. Riverol is supported by a grant from Fundación Caja Madrid (Spain). O.L. López is supported in part by grants AG200098 and AG05133-27 from the National Institute on Aging. A. Slachevsky is supported in part by grant Fondecyt 1100975 from Conicyt (Chile).

Footnotes

Disclosure: M. Riverol and A. Slachevsky declare no competing interests. O.L. López was a consultant for Pfizer and Lundbeck.

References

1.Evans DA, Funkenstein HH, Albert MS. Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA. 1989;262(18):2551–2556. [PubMed] [Google Scholar]
2.Fitzpatrick AL, Kuller LH, Ives D, et al. Incidence and prevalence of dementia in the cardiovascular health study. J Am Geriatr Soc. 2004;52 (2):195–204. doi: 10.1111/j.1532-5415.2004.52058.x. [DOI] [PubMed] [Google Scholar]
3.Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366:2112–2117. doi: 10.1016/S0140-6736(05)67889-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Aguero-Torres H, Fratiglioni L, Guo Z, Viitanen M, von Strauss E, Winblad B. Dementia is the major cause of functional dependence in the elderly: 3-year follow-up data from a population-based study. Am J Public Health. 1998;88(10):1452–1456. doi: 10.2105/ajph.88.10.1452. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep. 2009;57(14):1–134. [PubMed] [Google Scholar]
6.Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry. 2000;157:4–15. doi: 10.1176/ajp.157.1.4. [DOI] [PubMed] [Google Scholar]
7.Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50(1):136–145. doi: 10.1212/wnl.50.1.136. [DOI] [PubMed] [Google Scholar]
8.Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD. A six-month, randomized, placebo-controlled trial with a six-month extension. Neurology. 2000;54:2261–2268. doi: 10.1212/wnl.54.12.2261. [DOI] [PubMed] [Google Scholar]
9.Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ. 2000;321(7274):1445–1449. doi: 10.1136/bmj.321.7274.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318(7184):633–638. doi: 10.1136/bmj.318.7184.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease. Arch Neurol. 2004;61:1852–1856. doi: 10.1001/archneur.61.12.1852. [DOI] [PubMed] [Google Scholar]
12.Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double blind, parallel-group, placebo-controlled study. Lancet. 2006;367:1057–1065. doi: 10.1016/S0140-6736(06)68350-5. [DOI] [PubMed] [Google Scholar]
13.Black SE, Doody RS, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology. 2007;69:459–469. doi: 10.1212/01.wnl.0000266627.96040.5a. [DOI] [PubMed] [Google Scholar]
14.Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2001;58:427–433. doi: 10.1001/archneur.58.3.427. [DOI] [PubMed] [Google Scholar]
15.Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-lab study. Enru Neuropsychopharmacol. 2000;10(3):195–203. doi: 10.1016/s0924-977x(00)00067-5. [DOI] [PubMed] [Google Scholar]
16.Farlow MR, Lilly ML. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years. BMC Geriatr. 2005;5:3. doi: 10.1186/1471-2318-5-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol. 2004;61(2):252–256. doi: 10.1001/archneur.61.2.252. [DOI] [PubMed] [Google Scholar]
18.Holmes C, Wilkinson D, Dean C, et al. The efficacy of denepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004;63:214–219. doi: 10.1212/01.wnl.0000129990.32253.7b. [DOI] [PubMed] [Google Scholar]
19.Cummings JL, Koumaras B, Chen M, Mirski D. Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimers’ disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother. 2005;3(3):137–148. doi: 10.1016/s1543-5946(05)80020-0. [DOI] [PubMed] [Google Scholar]
20.O’Brien JT, Burns A. Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology [published online ahead of print November 18, 2010] J Psychopharmacol. 2010 doi: 10.1177/0269881110387547. [DOI] [PubMed] [Google Scholar]
21.Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003;9(3):275–308. doi: 10.1111/j.1527-3458.2003.tb00254.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Peskind ER, Potkin SG, Pomara N, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry. 2006;14(8):704–715. doi: 10.1097/01.JGP.0000224350.82719.83. [DOI] [PubMed] [Google Scholar]
23.Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis. 2008;13(1):97–107. doi: 10.3233/jad-2008-13110. [DOI] [PubMed] [Google Scholar]
24.Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003;348(14):1333–1341. doi: 10.1056/NEJMoa013128. [DOI] [PubMed] [Google Scholar]
25.van Dyck CH, Tariot P, Meyers BS, Maica-Resnick E. A 24-week randomized controlled trial of memantine in patients with moderate-to-severe Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2007;21(2):136–143. doi: 10.1097/WAD.0b013e318065c495. [DOI] [PubMed] [Google Scholar]
26.Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord. 2007;24(1):20–27. doi: 10.1159/000102568. [DOI] [PubMed] [Google Scholar]
27.Lanctot KL, Rajaram RD, Herrmann N. Therapy for Alzheimer’s disease: how effective are current treatments? Ther Adv Neurol Disord. 2009;2(3):163–180. doi: 10.1177/1756285609102724. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Epstein NU, Saykin AJ, Risacher SL, Gao S, Farlow MR. Differences in medication use in the Alzheimer’s disease neuroimaging initiative: analysis of baseline characteristics. Drugs Aging. 2010;27(8):677–686. doi: 10.2165/11538260-000000000-00000. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Hartmann S, Mobius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol. 2003;18(2):81–85. doi: 10.1097/01.yic.0000054279.38655.74. [DOI] [PubMed] [Google Scholar]
30.Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer’s disease already receiving donepezil. JAMA. 2004;291(3):317–324. doi: 10.1001/jama.291.3.317. [DOI] [PubMed] [Google Scholar]
31.van Dyck CH, Schmitt FA, Olin JT. A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry. 2006;14(5):428–437. doi: 10.1097/01.JGP.0000203151.17311.38. [DOI] [PubMed] [Google Scholar]
32.Schmitt FA, van Dyck CH, Wichems CH, Olin JT. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006;20(4):255–262. doi: 10.1097/01.wad.0000213860.35355.d4. [DOI] [PubMed] [Google Scholar]
33.Feldman HH, Schmitt FA, Olin JT. Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord. 2006;20(4):263–268. doi: 10.1097/01.wad.0000213859.35355.59. [DOI] [PubMed] [Google Scholar]
34.Cummings JL, Schneider E, Tariot PN, Graham SM. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67:57–63. doi: 10.1212/01.wnl.0000223333.42368.f1. [DOI] [PubMed] [Google Scholar]
35.Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008;5(1):83–89. doi: 10.2174/156720508783884576. [DOI] [PubMed] [Google Scholar]
36.Jones R, Sheehan B, Phillips P, et al. DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer’s disease—a multi-centre RCT. Trials. 2009;10:57. doi: 10.1186/1745-6215-10-57. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):209–221. doi: 10.1097/WAD.0b013e31816653bc. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Schneider LS, Insel PS, Weiner MW. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer’s Disease Neuroimaging Initiative. Arch Neurol. 2011;68(1):58–66. doi: 10.1001/archneurol.2010.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80(6):600–607. doi: 10.1136/jnnp.2008.158964. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Weycker D, Taneja C, Edelsberg J, et al. Cost-effectiveness of memantine in moderate-to-severe Alzheimer’s disease patients receiving donepezil. Curr Med Res Opin. 2007;23(5):1187–1197. doi: 10.1185/030079907x188071. [DOI] [PubMed] [Google Scholar]