- Email: [email protected]
Memantine for the treatment of dementia
Rapid review
Memantine for dementia
Memantine for the treatment of dementia
Gordon K Wilcock
Background The use of cholinesterase inhibitors to correct the cholinergic deficit in patients with mild to moderate Alzheimer’s disease (AD) is well established. However, the treatment is only effective in about half of the patients for whom it is prescribed. Vascular dementia may respond, at least to some extent, to these drugs (T Erkinjuntti and colleagues, Lancet 2002; 359: 1283–90). In 2002, the Committee of Proprietary Medicinal Products recommended that memantine—a drug that acts on the glutamatergic system rather than the cholinergic system—be approved by the European Commission for the treatment of moderately severe to severe AD. Clinical trials have shown some effectiveness of memantine in the treatment of vascular dementia, although it has not been approved for use in this disorder.
Recent developments The results of a study of the effects of memantine on moderate to severe AD have recently been published (B Reisberg and colleagues, N Engl J Med 2003; 348: 1333–41). Reisberg and colleagues treated their patients for 28 weeks, assessed several outcome variables, and found that memantine reduced clinical deterioration without significant adverse effects. This study is important as memantine is the only treatment licensed for patients with more advanced AD.
Where next? Several questions about the use of memantine as a treatment for AD remain to be answered. How beneficial is memantine treatment in routine clinical practice compared with clinical trials? What is the best way to assess treatment effects? How long do the beneficial effects last? Does memantine have neuroprotective, rather than just symptomatic, effects? In addition, we need to know when to switch from cholinesterase inhibitors to memantine or when to co-prescribe memantine with cholinesterase inhibitors. The efficacy of memantine in vascular dementia also requires further investigation.
Lancet Neurology 2003; 2: 503–05
Memantine is an NMDA receptor antagonist that—on the basis of studies in animals—is thought to reduce overstimulation of the NMDA receptor (caused by abnormally high concentrations of glutamate) in its resting state and to restore normal receptor-signalling function. Reduction of excitotoxicity may also have neuroprotective effects by preventing neuronal calcium overload, which has been implicated in the pathogenesis of neurodegenerative diseases. THE LANCET Neurology Vol 2 August 2003
Memantine is well tolerated in clinical trials, and although several adverse effects have been reported (eg, agitation, urinary incontinence, insomnia, diarrhoea, dizziness, headache, falls, and hallucinations), these have typically been of mild to moderate severity and did not differ signifcantly from side-effects reported in the placebo group. In the late 1980s and early 1990s, a few double-blind placebo-controlled trials were done to investigate the effect of memantine for the treatment of dementia syndromes.1–3 More recent studies have clarified the effects of memantine in specific types of dementia. The study by Winblad and Poritis4 was the first to differentiate between the effects of memantine in AD and its effects in vascular dementia. 166 patients with severe dementia (Mini-Mental State Examination [MMSE]5 score <10) were enrolled, 49% classified as having AD and 51% with vascular dementia. Patients were given 10 mg memantine—half the current maximum recommended daily dose—or placebo for 12 weeks and were assessed with several outcome measures, including the Clinical Global Impression of Change scale and a functional scale. The researchers reported positive outcomes with memantine treatment in both types of dementia (table).
Memantine for the treatment of AD To build on the results reported by Winblad and Poritis4 in patients with AD, Reisberg and colleagues6 studied patients with moderate to severe AD who were aged 50 years or more and were living in the community. A diagnosis of probable AD was made on the basis of accepted standard criteria and all participants had an MMSE score between 3 and 14 at baseline. In this 28 week, double-blind, placebocontrolled study, patients were randomly assigned to receive placebo or a daily 20 mg dose of memantine. Efficacy assessments were done at baseline, 4 weeks, 12 weeks, and at 28 weeks (or earlier termination). Primary outcome measures were the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global score,7 and an activities of daily living inventory (designed for use in more severe dementia)8,9 at 28 weeks compared with baseline. The CIBIC-Plus global score gives an indication of overall global change relative to baseline and consists of a
GKW is at the Department of Care of the Elderly, University of Bristol, UK. Correspondence: Professor Gordon Wilcock, Department of Care of the Elderly, University of Bristol, Frenchay Hospital, Bristol, BS16 1LE, UK. Tel +44 (0) 117 975 3948; fax 44 (0) 117 957 3955; email [email protected]
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
503
Rapid review
Memantine for dementia
Summary of the four main double-blind placebo-controlled studies of memantine Study Winblad and Poritis, 19994
Protocol details 12 week study of 166 patients with severe dementia AD 49%; vascular dementia 51% Memantine (10 mg) daily or placebo
Outcome Significant benefit on intention-to-treat analysis of a global impression of change scale (CGI-C) and on a “care dependency” scale
Reisberg et al, 20036
28 week study of 252 patients with moderate to severe AD Memantine (20 mg) daily or placebo
Benefit of memantine treatment on CIBIC-Plus that was significant on observed case analysis (p<0·05). On intention-to-treat analysis, p=0·06 Outcome significant in favour of memantine on ADL scale and one of the secondary endpoints (SIB)
Orgogozo et al, 200215 28 week study of 321 patients with mild to moderate vascular dementia Memantine (20 mg) daily or placebo
Significant improvement on intention-to-treat analysis of cognition (ADAS-Cog) Some effect, but not significant, of memantine on CIBIC-Plus Some significant effect of memantine on secondary endpoints
Wilcock et al, 200216
Significant improvement on intention-to-treat analysis of cognition (ADAS-Cog) No significant difference in a global impression of change scale (CGI-C) No significant difference in secondary endpoints
28 week study of 579 patients with mild to moderate vascular dementia Memantine (20 mg) daily or placebo
CGI-C=clinical global impressions-C; CIBIC-plus=Interview-Based Impression of Change Plus Caregiver Input; SIB=severe impairment battery; ADAS-Cog=Alzheimer’s disease assessment scale-cognitive subscale.
seven-point scale—from 1 (substantially improved) through 4 (no change) to 7 (substantially worse). This type of global assessment is now thought to be an essential accompaniment to cognitive and functional scales and was done by experienced clinicians who did not know the results of any of the other assessments and were not aware of any adverse events reported by the participants. Although memantine had no significant effect in the intention-totreat analysis (p=0·06), a significant beneficial effect of memantine was reported in the analysis of data for all patients who were available for assessment at 28 weeks (p=0·03). Scores on the activities of daily living scale were similar in both groups at baseline, but at 28 weeks, patients in the memantine group had significantly better outcome than patients in the placebo group both in the intention to treat analysis (p=0·02) and in cases observed at 28 weeks (p=0·003). Beneficial effects of memantine were reported for three of the other outcome measures: the Severe Impairment Battery (which measures cognitive impairment in advanced AD10,11); the Functional Assessment Staging scale;12 and the Resource Utilisation in Dementia instrument (which assesses caregiver burden and economic data13). Memantine did not increase the frequency of adverse events. There are, however, some limitations to this study; 28% of the participants (23% in the memantine group compared with 33% in the placebo group) did not complete the trial, which the researchers attribute to the advanced stage of disease in the study participants. Data were not obtained at 28 weeks for most of the participants who discontinued the trial early, which may have affected the interpretation of the results. About 75% of the total healthcare costs of AD are associated with the advanced stages of the disease, particularly when institutional care is required. A study investigating the economic features of memantine treatment suggests that its use in moderate to severe AD results in overall cost savings compared with placebo.14
504
Memantine for the treatment of vascular dementia The effect of memantine on vascular dementia of mild to moderate severity has been assessed in two large randomised, double-blind, placebo-controlled studies (table),15,16 in which a total of 900 participants fulfilling standardised diagnostic criteria were enrolled. Both studies lasted for 28 weeks, compared memantine (20 mg) with placebo, and used the AD Assessment Scale–cognitive subscale (ADAS-cog)17 to assess cognitive change, with a global assessment scale (the CIBIC-Plus,7 or the Clinical Global Impression of Change18) as primary outcome measures. Orgogozo and co-workers15 reported a significant improvement (2 points) in the memantine group on the intention-to-treat analysis of the ADAS-cog scale. The memantine group marginally improved compared with baseline, whereas the placebo group deteriorated over the course of the study. This difference between groups was more pronounced when only the scores of patients who completed the 28 weeks trial and had measurements for all efficacy variables were analysed; patients given memantine improved by 1 point compared with a deterioration of 1·4 points in the placebo group. In addition memantine was most effective in the more severely demented patients. Similar results—in terms of the intention-to-treat analysis of cognition and greater benefit in more severely affected patients—were reported by Wilcock and colleagues.16 In both studies, the differences in the global primary outcome measures were not statistically significant and secondary outcome measures showed inconsistent benefits. The type of vascular damage may influence the efficacy of memantine;19 the treatment effect is greatest in patients with small-vessel disease, in whom the severity of dementia increases more rapidly than those with large-vessel disease. Overall, the results from these three studies4,15,16 suggest that memantine is beneficial for the treatment of vascular dementia and it was safe and well tolerated in patients. There is evidence of improvement in cognition in patients treated with memantine, especially in those with more advanced
THE LANCET Neurology Vol 2 August 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Rapid review
Memantine for dementia
disease, which indicates that further study in a population similar to that of the recent AD trial6 would be worthwhile. Such a study may also confirm that the benefit shown on non-cognitive outcome measures is greatest in more severely demented people. The design of trials in patients with vascular dementia has been based on those done in AD, rather than on the underlying processes specific to vascular dementia, which may account for the minor effects of memantine on some outcome measures. The design of trials in patients with vascular dementia should reflect the pattern of decline and types of vascular damage in these patients, and should incorporate more specific neuropsychological assessment that includes more effective measures of executive function.
Memantine combined with a cholinesterase inhibitor The only available data on combined treatment with memantine and a cholinesterase inhibitor is from a conference abstract.20 In this 24-week double-blind placebocontrolled trial, 403 patients with moderate to severe AD (MMSE score of 5–14), who had already been taking donepezil for 6 months, received either donepezil with memantine or donepezil with placebo. At 24 weeks, cognitive function (Severe Impairment battery10,11), rate of decline (AD Cooperative Study Inventory–Activities of Daily living9), and the CIBIC-Plus,7 were significantly improved in the combined treatment group compared with the donepezil and placebo group. However, this report is preliminary until the full trial report is published. Additional studies investigating combination of memantine with different cholinesterase inhibitors are underway. Combination-treatment regimens seem to be on the horizon. References 1
2
3
4
5
6
7
8
Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine: results of a phase II double-blind study. Pharmacopsychiatry 1988; 21: 144–46. Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome: a double-blind, placebo controlled trial. Arzneimittelforschung 1991; 41: 773–80. Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome: a double-blind placebo-controlled study. Arzneimittelforschung. 1992; 42: 904–13. Winblad B, Poritis N. Memantine in severe dementia: results of the M-Best study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriat Psychiatry 1999; 14: 135–46. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975; 12: 189–98. 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: 1333–41. Reisberg B, Schneider L, Doody R, et al. Clinical global measures of dementia: position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997; 11 (suppl 3): 8–18.
THE LANCET Neurology Vol 2 August 2003
9
10
11
12
13
14
Search strategy Data for this review were identified by searches of PubMed and requests for relevant papers and other articles from the pharmaceutical companies involved. All double-blind, placebo-controlled studies in demented individuals were included.
Conclusions Memantine is available for the treatment of moderate to severe AD in Europe, but must be assessed by the National Institute of Clinical Excellence before it can become widely available in the UK, where some doctors are already prescribing it subject to funding limitations. At present, it may be best to limit memantine treatment to patients with AD and an MMSE score of 14 or below, and to develop shared care protocols with primary care, similar to those in use for cholinesterase inhibitors. Memantine is a promising potential treatment for vascular dementia. However, further assessment with appropriate methodology would help to clarify the extent and areas of benefit, and whether it really is more effective at different stages of dementia severity. Conflict of interest
GKW has received travel support from Merz and received consultancy fees from Lundbeck, but not in relation to memantine. GKW was also an investigator in the MMM500 study.
Role of the funding source
No funding sources were involved in the writing of this review or in the decision to submit it for publication.
Galasko DR, Schmitt FA, Jin S, et al. Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging 2000; 21 (Suppl 1): S168. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S33–39. Panisset M, Roudier M, Saxton J, Boller F. Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994; 51: 41–45. Schmitt FA, Ashford W, Ernesto C, et al. The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S51–56. Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer’s disease: reliability, validity, and ordinality. Int Psychogeriatr 1992; 4 (suppl 1): 55–69. Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of the healthcare resource utilisation and caregiver time in anti-dementia drug trials. In: Wimo A, Jonsson B, Karlsson G, Winblad B, eds. Health economics of dementia. Chichester: John Wiley, 1998: 465–99. Wimo A, Winblad B, Stoffler A, Wirth Y, Mobius H. Resource utilisation and cost analysis of memantine
15
16
17 18
19
20
in patients with moderate to severe Alzheimer’s disease. Pharmacoeconomics 2003; 21: 327–40. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002; 33: 1834–39. Wilcock G, Mobius HJ, Stoeffler A, on behalf of the MMM 500 group. A double-blind placebocontrolled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002; 17: 297–305. Mohs RC, Cohen L. Alzheimer’s Disease Assessment Scale (ADAS). Psychopharmacol Bull 1988; 24: 627–50. Guy W. CGI: clinical global impressions. In: Guy W, ed. ECDEU Assessment manual for psychopharmacology, revised edn. Rockville: National Institutes of Health, 1976: 217–20. Wilcock G, Stoeffler A, Sahin K, Mobius HJ. Neuroradiological findings and the magnitude of cognitive benefit by memantine treatment: a subgroup analysis of two placebo-controlled clinical trials in vascular dementia. Eur Neuropsychopharmacol 2000; 10 (suppl 3): S360. Farlow MR, Tariot PN, Grossberg GT, Gergel I, Graham S, Jin J. Memantine/donepezil dual therapy is superior to placebo/donpezil therapy for treatment of moderate to severe Alzheimer’s disease. Neurology 2003; 60 (suppl 1): S48.003.
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
505
Memantine for dementia
Memantine for the treatment of dementia
Gordon K Wilcock
Background The use of cholinesterase inhibitors to correct the cholinergic deficit in patients with mild to moderate Alzheimer’s disease (AD) is well established. However, the treatment is only effective in about half of the patients for whom it is prescribed. Vascular dementia may respond, at least to some extent, to these drugs (T Erkinjuntti and colleagues, Lancet 2002; 359: 1283–90). In 2002, the Committee of Proprietary Medicinal Products recommended that memantine—a drug that acts on the glutamatergic system rather than the cholinergic system—be approved by the European Commission for the treatment of moderately severe to severe AD. Clinical trials have shown some effectiveness of memantine in the treatment of vascular dementia, although it has not been approved for use in this disorder.
Recent developments The results of a study of the effects of memantine on moderate to severe AD have recently been published (B Reisberg and colleagues, N Engl J Med 2003; 348: 1333–41). Reisberg and colleagues treated their patients for 28 weeks, assessed several outcome variables, and found that memantine reduced clinical deterioration without significant adverse effects. This study is important as memantine is the only treatment licensed for patients with more advanced AD.
Where next? Several questions about the use of memantine as a treatment for AD remain to be answered. How beneficial is memantine treatment in routine clinical practice compared with clinical trials? What is the best way to assess treatment effects? How long do the beneficial effects last? Does memantine have neuroprotective, rather than just symptomatic, effects? In addition, we need to know when to switch from cholinesterase inhibitors to memantine or when to co-prescribe memantine with cholinesterase inhibitors. The efficacy of memantine in vascular dementia also requires further investigation.
Lancet Neurology 2003; 2: 503–05
Memantine is an NMDA receptor antagonist that—on the basis of studies in animals—is thought to reduce overstimulation of the NMDA receptor (caused by abnormally high concentrations of glutamate) in its resting state and to restore normal receptor-signalling function. Reduction of excitotoxicity may also have neuroprotective effects by preventing neuronal calcium overload, which has been implicated in the pathogenesis of neurodegenerative diseases. THE LANCET Neurology Vol 2 August 2003
Memantine is well tolerated in clinical trials, and although several adverse effects have been reported (eg, agitation, urinary incontinence, insomnia, diarrhoea, dizziness, headache, falls, and hallucinations), these have typically been of mild to moderate severity and did not differ signifcantly from side-effects reported in the placebo group. In the late 1980s and early 1990s, a few double-blind placebo-controlled trials were done to investigate the effect of memantine for the treatment of dementia syndromes.1–3 More recent studies have clarified the effects of memantine in specific types of dementia. The study by Winblad and Poritis4 was the first to differentiate between the effects of memantine in AD and its effects in vascular dementia. 166 patients with severe dementia (Mini-Mental State Examination [MMSE]5 score <10) were enrolled, 49% classified as having AD and 51% with vascular dementia. Patients were given 10 mg memantine—half the current maximum recommended daily dose—or placebo for 12 weeks and were assessed with several outcome measures, including the Clinical Global Impression of Change scale and a functional scale. The researchers reported positive outcomes with memantine treatment in both types of dementia (table).
Memantine for the treatment of AD To build on the results reported by Winblad and Poritis4 in patients with AD, Reisberg and colleagues6 studied patients with moderate to severe AD who were aged 50 years or more and were living in the community. A diagnosis of probable AD was made on the basis of accepted standard criteria and all participants had an MMSE score between 3 and 14 at baseline. In this 28 week, double-blind, placebocontrolled study, patients were randomly assigned to receive placebo or a daily 20 mg dose of memantine. Efficacy assessments were done at baseline, 4 weeks, 12 weeks, and at 28 weeks (or earlier termination). Primary outcome measures were the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global score,7 and an activities of daily living inventory (designed for use in more severe dementia)8,9 at 28 weeks compared with baseline. The CIBIC-Plus global score gives an indication of overall global change relative to baseline and consists of a
GKW is at the Department of Care of the Elderly, University of Bristol, UK. Correspondence: Professor Gordon Wilcock, Department of Care of the Elderly, University of Bristol, Frenchay Hospital, Bristol, BS16 1LE, UK. Tel +44 (0) 117 975 3948; fax 44 (0) 117 957 3955; email [email protected]
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
503
Rapid review
Memantine for dementia
Summary of the four main double-blind placebo-controlled studies of memantine Study Winblad and Poritis, 19994
Protocol details 12 week study of 166 patients with severe dementia AD 49%; vascular dementia 51% Memantine (10 mg) daily or placebo
Outcome Significant benefit on intention-to-treat analysis of a global impression of change scale (CGI-C) and on a “care dependency” scale
Reisberg et al, 20036
28 week study of 252 patients with moderate to severe AD Memantine (20 mg) daily or placebo
Benefit of memantine treatment on CIBIC-Plus that was significant on observed case analysis (p<0·05). On intention-to-treat analysis, p=0·06 Outcome significant in favour of memantine on ADL scale and one of the secondary endpoints (SIB)
Orgogozo et al, 200215 28 week study of 321 patients with mild to moderate vascular dementia Memantine (20 mg) daily or placebo
Significant improvement on intention-to-treat analysis of cognition (ADAS-Cog) Some effect, but not significant, of memantine on CIBIC-Plus Some significant effect of memantine on secondary endpoints
Wilcock et al, 200216
Significant improvement on intention-to-treat analysis of cognition (ADAS-Cog) No significant difference in a global impression of change scale (CGI-C) No significant difference in secondary endpoints
28 week study of 579 patients with mild to moderate vascular dementia Memantine (20 mg) daily or placebo
CGI-C=clinical global impressions-C; CIBIC-plus=Interview-Based Impression of Change Plus Caregiver Input; SIB=severe impairment battery; ADAS-Cog=Alzheimer’s disease assessment scale-cognitive subscale.
seven-point scale—from 1 (substantially improved) through 4 (no change) to 7 (substantially worse). This type of global assessment is now thought to be an essential accompaniment to cognitive and functional scales and was done by experienced clinicians who did not know the results of any of the other assessments and were not aware of any adverse events reported by the participants. Although memantine had no significant effect in the intention-totreat analysis (p=0·06), a significant beneficial effect of memantine was reported in the analysis of data for all patients who were available for assessment at 28 weeks (p=0·03). Scores on the activities of daily living scale were similar in both groups at baseline, but at 28 weeks, patients in the memantine group had significantly better outcome than patients in the placebo group both in the intention to treat analysis (p=0·02) and in cases observed at 28 weeks (p=0·003). Beneficial effects of memantine were reported for three of the other outcome measures: the Severe Impairment Battery (which measures cognitive impairment in advanced AD10,11); the Functional Assessment Staging scale;12 and the Resource Utilisation in Dementia instrument (which assesses caregiver burden and economic data13). Memantine did not increase the frequency of adverse events. There are, however, some limitations to this study; 28% of the participants (23% in the memantine group compared with 33% in the placebo group) did not complete the trial, which the researchers attribute to the advanced stage of disease in the study participants. Data were not obtained at 28 weeks for most of the participants who discontinued the trial early, which may have affected the interpretation of the results. About 75% of the total healthcare costs of AD are associated with the advanced stages of the disease, particularly when institutional care is required. A study investigating the economic features of memantine treatment suggests that its use in moderate to severe AD results in overall cost savings compared with placebo.14
504
Memantine for the treatment of vascular dementia The effect of memantine on vascular dementia of mild to moderate severity has been assessed in two large randomised, double-blind, placebo-controlled studies (table),15,16 in which a total of 900 participants fulfilling standardised diagnostic criteria were enrolled. Both studies lasted for 28 weeks, compared memantine (20 mg) with placebo, and used the AD Assessment Scale–cognitive subscale (ADAS-cog)17 to assess cognitive change, with a global assessment scale (the CIBIC-Plus,7 or the Clinical Global Impression of Change18) as primary outcome measures. Orgogozo and co-workers15 reported a significant improvement (2 points) in the memantine group on the intention-to-treat analysis of the ADAS-cog scale. The memantine group marginally improved compared with baseline, whereas the placebo group deteriorated over the course of the study. This difference between groups was more pronounced when only the scores of patients who completed the 28 weeks trial and had measurements for all efficacy variables were analysed; patients given memantine improved by 1 point compared with a deterioration of 1·4 points in the placebo group. In addition memantine was most effective in the more severely demented patients. Similar results—in terms of the intention-to-treat analysis of cognition and greater benefit in more severely affected patients—were reported by Wilcock and colleagues.16 In both studies, the differences in the global primary outcome measures were not statistically significant and secondary outcome measures showed inconsistent benefits. The type of vascular damage may influence the efficacy of memantine;19 the treatment effect is greatest in patients with small-vessel disease, in whom the severity of dementia increases more rapidly than those with large-vessel disease. Overall, the results from these three studies4,15,16 suggest that memantine is beneficial for the treatment of vascular dementia and it was safe and well tolerated in patients. There is evidence of improvement in cognition in patients treated with memantine, especially in those with more advanced
THE LANCET Neurology Vol 2 August 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Rapid review
Memantine for dementia
disease, which indicates that further study in a population similar to that of the recent AD trial6 would be worthwhile. Such a study may also confirm that the benefit shown on non-cognitive outcome measures is greatest in more severely demented people. The design of trials in patients with vascular dementia has been based on those done in AD, rather than on the underlying processes specific to vascular dementia, which may account for the minor effects of memantine on some outcome measures. The design of trials in patients with vascular dementia should reflect the pattern of decline and types of vascular damage in these patients, and should incorporate more specific neuropsychological assessment that includes more effective measures of executive function.
Memantine combined with a cholinesterase inhibitor The only available data on combined treatment with memantine and a cholinesterase inhibitor is from a conference abstract.20 In this 24-week double-blind placebocontrolled trial, 403 patients with moderate to severe AD (MMSE score of 5–14), who had already been taking donepezil for 6 months, received either donepezil with memantine or donepezil with placebo. At 24 weeks, cognitive function (Severe Impairment battery10,11), rate of decline (AD Cooperative Study Inventory–Activities of Daily living9), and the CIBIC-Plus,7 were significantly improved in the combined treatment group compared with the donepezil and placebo group. However, this report is preliminary until the full trial report is published. Additional studies investigating combination of memantine with different cholinesterase inhibitors are underway. Combination-treatment regimens seem to be on the horizon. References 1
2
3
4
5
6
7
8
Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine: results of a phase II double-blind study. Pharmacopsychiatry 1988; 21: 144–46. Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome: a double-blind, placebo controlled trial. Arzneimittelforschung 1991; 41: 773–80. Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome: a double-blind placebo-controlled study. Arzneimittelforschung. 1992; 42: 904–13. Winblad B, Poritis N. Memantine in severe dementia: results of the M-Best study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriat Psychiatry 1999; 14: 135–46. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975; 12: 189–98. 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: 1333–41. Reisberg B, Schneider L, Doody R, et al. Clinical global measures of dementia: position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997; 11 (suppl 3): 8–18.
THE LANCET Neurology Vol 2 August 2003
9
10
11
12
13
14
Search strategy Data for this review were identified by searches of PubMed and requests for relevant papers and other articles from the pharmaceutical companies involved. All double-blind, placebo-controlled studies in demented individuals were included.
Conclusions Memantine is available for the treatment of moderate to severe AD in Europe, but must be assessed by the National Institute of Clinical Excellence before it can become widely available in the UK, where some doctors are already prescribing it subject to funding limitations. At present, it may be best to limit memantine treatment to patients with AD and an MMSE score of 14 or below, and to develop shared care protocols with primary care, similar to those in use for cholinesterase inhibitors. Memantine is a promising potential treatment for vascular dementia. However, further assessment with appropriate methodology would help to clarify the extent and areas of benefit, and whether it really is more effective at different stages of dementia severity. Conflict of interest
GKW has received travel support from Merz and received consultancy fees from Lundbeck, but not in relation to memantine. GKW was also an investigator in the MMM500 study.
Role of the funding source
No funding sources were involved in the writing of this review or in the decision to submit it for publication.
Galasko DR, Schmitt FA, Jin S, et al. Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging 2000; 21 (Suppl 1): S168. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S33–39. Panisset M, Roudier M, Saxton J, Boller F. Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994; 51: 41–45. Schmitt FA, Ashford W, Ernesto C, et al. The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S51–56. Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer’s disease: reliability, validity, and ordinality. Int Psychogeriatr 1992; 4 (suppl 1): 55–69. Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of the healthcare resource utilisation and caregiver time in anti-dementia drug trials. In: Wimo A, Jonsson B, Karlsson G, Winblad B, eds. Health economics of dementia. Chichester: John Wiley, 1998: 465–99. Wimo A, Winblad B, Stoffler A, Wirth Y, Mobius H. Resource utilisation and cost analysis of memantine
15
16
17 18
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