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Published in final edited form as: Eur Neurol J. 2011 July 1; 3(1): 15–19.
Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer’s Disease: A Literature Review Evidence Mario Riverol1,3, Andrea Slachevsky4,5, and Oscar L. López1,2 1Department
of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Department
of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3Department
of Neurology, Clínica Universidad de Navarra, Pamplona, Spain
4Unidad
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de Neurología Cognitiva y Demencia, Servicio de Neurología, Hospital del Salvador. Facultad de Medicina Universidad de Chile, Santiago, Chile 5Servicio
de Neurologia, Clínica Alemana, Santiago, Chile
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.
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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
Correspondence: Mario Riverol, University of Pittsburgh School of Medicine, Oxford Building, Suite 830, 3501 Forbes Avenue, Pittsburgh, PA 15213, USA. [email protected]. Disclosure: M. Riverol and A. Slachevsky declare no competing interests. O.L. López was a consultant for Pfizer and Lundbeck.
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INTRODUCTION NIH-PA Author Manuscript
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.
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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.
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The NMDA receptor antagonist, memantine modulates glutamate activity at the postsynaptic membrane and reduces calcium influx into the cell. The tonic activation of the NMDA receptor in AD is thought to disrupt memory and learning, and hypothetically is implicated in cholinergic neuron death throughout excitotoxic mechanisms.21 There are conflicting results regarding the benefit of memantine in mild to moderate AD,22,23 but in moderate to severe disease stages, it reduces clinical deterioration.24,25 Meta-analysis of randomized clinical trials have confirmed the benefit of memantine on cognitive, functional, global, and behavioral measures in patients with moderate to severe AD.26 While there are few head-tohead comparison trials between different ChEIs and ChEIs and memantine, the similarity in efficacy against placebo suggests that efficacy isn’t substantially different among treatments.27 Because ChEIs and memantine improve AD symptoms through different mechanisms of action and they may overlap in the management of AD, there is a growing interest to know whether the combination of these drugs is safe and adds any clinical benefit for patients. In fact, in the clinical practice, dual therapy is often prescribed to patients with moderate to severe AD and even to patients with mild cognitive impairment (MCI) or early-stage AD.28 Combined therapy is usually administered as memantine added to a cholinesterase inhibitor that was started months or years earlier.28,29 In this article, we review the published
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literature about the efficacy and tolerability of a combination therapy of memantine and donepezil in patients with AD.
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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).
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Randomized controlled trials
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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-
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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.
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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.
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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 shortterm efficacy of the combined therapy versus monotherapy or placebo in moderate to severe impaired patients.
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Observational studies
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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.
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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.
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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.
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CONCLUSION NIH-PA Author Manuscript
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).
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References
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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. [PubMed: 17132970] 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. [PubMed: 17132971] 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. [PubMed: 16832078] 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, doubleblind, placebo-controlled trial. Curr Alzheimer Res. 2008; 5(1):83–89. [PubMed: 18288936] 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. [PubMed: 19630974] 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. [PubMed: 18580597] 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. [PubMed: 21220675] 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. [PubMed: 19204022] 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. [PubMed: 17519086]
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NIH-PA Author Manuscript Randomized controlled trial (24 weeks)
Randomized controlled trial (52 weeks)
Observational study (4-month follow-up)
Observational study (mean follow-up: 30 months)
Observational study (2-year follow-up)
Observational study (mean follow-up: 62.4 months)
MEM-MD-12 study35
DOMINO-AD study36
Hartmann and Mobius29
Atri et al.37
Schneider et al.38
Lopez et al.39
Eur Neurol J. Author manuscript; available in PMC 2014 October 07. 943
188
382
158
800
433
404
Number of Subjects
Probable AD with at least a 1 year of follow-up
Mild AD
Probable AD
Demented outpatients (77% with AD) treated with memantine and a ChEI (84% on donepezil)
Moderate to severe AD on donepezil
Mild to moderate AD on any ChEI (67% on donepezil)
Moderate to severe AD on donepezil
Inclusion Criteria
Time to nursing home admission and death
ADAS-cog, MMSE, CDR, FAQ
IMC subscale of BDS, WADLS
Scale assessing tolerability
Primary: SMMSE, BADLS Secondary: NPI, EQ-5D, DEMQOL-proxy, GHQ-12, CSRI, and institutionalization
Primary: ADAS-cog, CIBIC-Plus Secondary: ADCS-ADL23, NPI, RUD
Primary: SIB, ADCS-ADL19 Secondary: CIBIC-Plus, NPI, BGP
Outcome Measures
Combined therapy significantly delayed the time to nursing home admission, but had no effect on survival
AD patients on combined therapy were more functionally impaired and showed greater decline on MMSE and CDR than those on ChEI monotherapy
Combined therapy slowed cognitive and functional decline in AD patients compared with monotherapy and no treatment
The combination treatment was well tolerated by almost all patients
Ongoing
No benefits of combined therapy over ChEI monotherapy. No differences in adverse events between both groups
Benefits of combined therapy on all outcome measures. No differences in adverse events between both groups
Result
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-MemoryConcentration; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; RUD: Resource Utilization in Dementia scale; SIB: Severe Impairment Battery; SMMSE: standardized MiniMental State Examination; WADLSP: Weintraub Activities of Daily Living Scale.
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
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
MEM-MD-02
Randomized controlled trial (24 weeks)
Study Type (Duration)
study30
Study
Studies Assessing the Efficacy and Tolerability of a Combination Treatment of Donepezil and Memantine in Patients with Alzheimer’s Disease
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Table 1 Riverol et al. Page 9
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Published in final edited form as: Eur Neurol J. 2011 July 1; 3(1): 15–19.
Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer’s Disease: A Literature Review Evidence Mario Riverol1,3, Andrea Slachevsky4,5, and Oscar L. López1,2 1Department
of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Department
of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3Department
of Neurology, Clínica Universidad de Navarra, Pamplona, Spain
4Unidad
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de Neurología Cognitiva y Demencia, Servicio de Neurología, Hospital del Salvador. Facultad de Medicina Universidad de Chile, Santiago, Chile 5Servicio
de Neurologia, Clínica Alemana, Santiago, Chile
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.
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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
Correspondence: Mario Riverol, University of Pittsburgh School of Medicine, Oxford Building, Suite 830, 3501 Forbes Avenue, Pittsburgh, PA 15213, USA. [email protected]. Disclosure: M. Riverol and A. Slachevsky declare no competing interests. O.L. López was a consultant for Pfizer and Lundbeck.
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INTRODUCTION NIH-PA Author Manuscript
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.
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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.
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The NMDA receptor antagonist, memantine modulates glutamate activity at the postsynaptic membrane and reduces calcium influx into the cell. The tonic activation of the NMDA receptor in AD is thought to disrupt memory and learning, and hypothetically is implicated in cholinergic neuron death throughout excitotoxic mechanisms.21 There are conflicting results regarding the benefit of memantine in mild to moderate AD,22,23 but in moderate to severe disease stages, it reduces clinical deterioration.24,25 Meta-analysis of randomized clinical trials have confirmed the benefit of memantine on cognitive, functional, global, and behavioral measures in patients with moderate to severe AD.26 While there are few head-tohead comparison trials between different ChEIs and ChEIs and memantine, the similarity in efficacy against placebo suggests that efficacy isn’t substantially different among treatments.27 Because ChEIs and memantine improve AD symptoms through different mechanisms of action and they may overlap in the management of AD, there is a growing interest to know whether the combination of these drugs is safe and adds any clinical benefit for patients. In fact, in the clinical practice, dual therapy is often prescribed to patients with moderate to severe AD and even to patients with mild cognitive impairment (MCI) or early-stage AD.28 Combined therapy is usually administered as memantine added to a cholinesterase inhibitor that was started months or years earlier.28,29 In this article, we review the published
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literature about the efficacy and tolerability of a combination therapy of memantine and donepezil in patients with AD.
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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).
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Randomized controlled trials
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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-
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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.
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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.
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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 shortterm efficacy of the combined therapy versus monotherapy or placebo in moderate to severe impaired patients.
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Observational studies
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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.
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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.
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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.
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CONCLUSION NIH-PA Author Manuscript
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).
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NIH-PA Author Manuscript Randomized controlled trial (24 weeks)
Randomized controlled trial (52 weeks)
Observational study (4-month follow-up)
Observational study (mean follow-up: 30 months)
Observational study (2-year follow-up)
Observational study (mean follow-up: 62.4 months)
MEM-MD-12 study35
DOMINO-AD study36
Hartmann and Mobius29
Atri et al.37
Schneider et al.38
Lopez et al.39
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188
382
158
800
433
404
Number of Subjects
Probable AD with at least a 1 year of follow-up
Mild AD
Probable AD
Demented outpatients (77% with AD) treated with memantine and a ChEI (84% on donepezil)
Moderate to severe AD on donepezil
Mild to moderate AD on any ChEI (67% on donepezil)
Moderate to severe AD on donepezil
Inclusion Criteria
Time to nursing home admission and death
ADAS-cog, MMSE, CDR, FAQ
IMC subscale of BDS, WADLS
Scale assessing tolerability
Primary: SMMSE, BADLS Secondary: NPI, EQ-5D, DEMQOL-proxy, GHQ-12, CSRI, and institutionalization
Primary: ADAS-cog, CIBIC-Plus Secondary: ADCS-ADL23, NPI, RUD
Primary: SIB, ADCS-ADL19 Secondary: CIBIC-Plus, NPI, BGP
Outcome Measures
Combined therapy significantly delayed the time to nursing home admission, but had no effect on survival
AD patients on combined therapy were more functionally impaired and showed greater decline on MMSE and CDR than those on ChEI monotherapy
Combined therapy slowed cognitive and functional decline in AD patients compared with monotherapy and no treatment
The combination treatment was well tolerated by almost all patients
Ongoing
No benefits of combined therapy over ChEI monotherapy. No differences in adverse events between both groups
Benefits of combined therapy on all outcome measures. No differences in adverse events between both groups
Result
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-MemoryConcentration; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; RUD: Resource Utilization in Dementia scale; SIB: Severe Impairment Battery; SMMSE: standardized MiniMental State Examination; WADLSP: Weintraub Activities of Daily Living Scale.
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
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
MEM-MD-02
Randomized controlled trial (24 weeks)
Study Type (Duration)
study30
Study
Studies Assessing the Efficacy and Tolerability of a Combination Treatment of Donepezil and Memantine in Patients with Alzheimer’s Disease
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Table 1 Riverol et al. Page 9
