McShane R, Westby MJ, Roberts E, et al. Memantine for dementia. Cochrane Database Syst Rev. 2019 Mar 20;3:CD003154. doi: 10.1002/14651858.CD003154.pub6. (Systematic review)

BACKGROUND: Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD.

OBJECTIVES: To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs).

SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information.

SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia.

DATA COLLECTION AND ANALYSIS: We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales.

MAIN RESULTS: Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls.

AUTHORS' CONCLUSIONS: We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.

Discipline Area Score
Psychiatry 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Geriatrics 6 / 7
Neurology 5 / 7
Internal Medicine 6 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

This Cochrane review suggests memantine might help a bit in moderate to severe dementia, but not in mild dementia. I was unclear before. As the drug is not covered in my region, and perception was it did not work well, it is hardly used at all. This might alter that thinking a bit.

Geriatrics rater

This is a meta-analysis confirming what is already known about the modest efficacy of memantine in dementia.

Geriatrics rater

This is a useful update to Cochrane review with new trials. The main changes to current guidelines should be: 1. Memantine can be added to ChE inhibitors in people with moderate-severe Alzheimers. 2. It is almost certainly ineffective in early Alzheimers. More research is needed to establish long term effects and possible use in other types of dementia.

Geriatrics rater

Excellent summary of the data regarding memantine use, which reinforces the recommended use of the medication for advanced dementia and not for earlier stages (which the original data also suggested). As always, it is good to be reminded on proper indications for medications and avoid their use when they likely will not help and may cause harm.

Neurology rater

This is a well written and updated Cochrane review on memantine for dementia. It suggests benefits mainly seen in moderate-severe Alzheimer's disease, with possible benefits also in vascular dementia or other dementias. However, it's no better than placebo in persons with mild dementia. The review authors emphasize the potential value of adding memantine to cholinesterase inhibitors in persons with moderate-severe AD, and also suggest a long-duration trial in milder AD would help to determine whether starting memantine earlier would be safe and effective (as many patients at least in the US use memantine from the earliest stages of AD).
Comments from EvidenceAlerts subscribers

Dr. Lawrence Millhofer (4/16/2019 11:06 AM)

I am a retired internist. My partner was diagnosed with Lewy body disease in 2012 at age 73 and started on Exelon patches for cognitive issues and some hallucinations. Symptoms worsened significantly. After stopping, symptoms returned to baseline and then memantine was started. Hallucinations resolved and his cognitive issues dramatically improved. Gradually Parkinson's motor symptoms developed and he was given levadopa/carbidopa with good results, until in 2017 memory again worsened with intermittent hallucinations. At that time, donepezil was added and again he showed significant improvement despite slow progression of motor symptoms. I realize this is anecdotal but I think every patient deserves a trial of these drugs. My partner is now 80 and living at home and ambulatory independent with a walker!