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Efficacy of memantine for agitation in Alzheimer’s dementia: a randomised double-blind placebo controlled trial


Fox, Chris, Crugel, Monica, Maidment, Ian, Auestad, Bjorn Henrik, Coulton, Simon, Treloar, Adrian, Ballard, Clive, Boustani, Malaz, Katona, Cornelius, Livingston, Gill


Plos One, Volume: 7, No.: 5, Pages.: e35185-e35185

Year of Publication



Background: Agitation in Alzheimer’s disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD.; Methods and Findings: We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p = 0.012) and 12 (-9.6; -15.0 to -4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD.; Conclusions: Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms.; Trial Registration: NCT00371059.; Trial Registration: International Standard Randomised Controlled Trial 24953404.;

Bibtex Citation

@article{Fox_2012, doi = {10.1371/journal.pone.0035185}, url = {}, year = 2012, month = {may}, publisher = {Public Library of Science ({PLoS})}, volume = {7}, number = {5}, pages = {e35185}, author = {Chris Fox and Monica Crugel and Ian Maidment and Bjorn Henrik Auestad and Simon Coulton and Adrian Treloar and Clive Ballard and Malaz Boustani and Cornelius Katona and Gill Livingston}, editor = {John C. S. Breitner}, title = {Efficacy of Memantine for Agitation in Alzheimer's Dementia: A Randomised Double-Blind Placebo Controlled Trial}, journal = {{PLoS} {ONE}} }


aged, aged, 80 and over, alzheimer disease, dementia, drug therapy, female, humans, male, memantine, psychomotor agitation, therapeutic use

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes

Behaviour, Cognition


Hospital Inpatient Care, Long Term Residential Care without medically trained staff

Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions

Anti-Alzheimer medications, e.g.: donezepil, galantamine, rivastigmine, memantime