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A Double-Blind Randomized Placebo-Controlled Withdrawal Trial Comparing Memantine and Antipsychotics for the Long-Term Treatment of Function and Neuropsychiatric Symptoms in People With Alzheimer's Disease (MAIN-AD)

Lookup NU author(s): Dr Clive Ballard, Professor Alan ThomasORCiD, Dr Dag Aarsland, Dr Christopher Davison


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Background: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms.Methods: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality.Results: There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P =.82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.6-11.70; P =.05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks.Discussion: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. (C) 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Publication metadata

Author(s): Ballard C, Thomas A, Gerry S, Yu LM, Aarsland D, Merritt C, Corbett A, Davison C, Sharma N, Khan Z, Creese B, Loughlin P, Bannister C, Burns A, Win SN, Walker Z, MAIN-AD Investigators

Publication type: Article

Publication status: Published

Journal: Journal of the American Medical Directors Association

Year: 2015

Volume: 16

Issue: 4

Pages: 316-322

Print publication date: 01/04/2015

Online publication date: 15/12/2014

ISSN (print): 1525-8610

ISSN (electronic): 1538-9375

Publisher: Elsevier


DOI: 10.1016/j.jamda.2014.11.002


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Funder referenceFunder name
Bristol-Myer Squibb
King's College London
Maudsley NHS Foundation Trust
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre
Bayer Healthcare
Dementia Unit at South London
GE Healthcare
Lundbeck pharmaceutical company
NIHR Newcastle Biomedical Research Unit