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)

Published:December 15, 2014DOI:



      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.


      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.


      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 –1.68–11.70; 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.


      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.


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      1. Alzheimer's Disease International. World Alzheimer Report. 2009. Available at: Accessed December 2, 2012.

        • Steinberg M.
        • Shao H.
        • Zandi P.
        • et al.
        Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: The Cache County Study.
        Int J Geriatr Psychiatry. 2008; 23: 170-177
      2. National Institute for Health and Clinical Excellence (NICE). Dementia: Supporting people with dementia and their carers in health and social care. Available at: 2006. Accessed June 16, 2014.

        • Lyketsos C.G.
        • Colenda C.C.
        • Beck C.
        • et al.
        Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease.
        Am J Geriatr Psychiatry. 2006; 14: 561-572
      3. Alzheimer's Society Optimising treatment and care for behavioural and psychological symptoms of dementia: A best practice guide. Available at: 2012. Accessed April 23, 2014.

        • Ballard C.
        • Howard R.
        Neuroleptic drugs in dementia: Benefits and harm.
        Nature Rev Neurosci. 2006; 7: 492-500
        • Schneider L.S.
        • Dagerman K.
        • Insel P.S.
        Efficacy and adverse effects of atypical antipsychotics for dementia: Meta-analysis of randomized, placebo-controlled trials.
        Am J Geriatr Psychiatry. 2006; 14: 191-210
        • Ballard C.G.
        • Gauthier S.
        • Cummings J.L.
        • et al.
        Management of agitation and aggression associated with Alzheimer disease.
        Nat Rev Neurol. 2009; 5: 245-255
        • Ballard C.
        • Creese B.
        • Corbett A.
        • Aarsland D.
        Atypical antipsychotics for the treatment of behavioral and psychological symptoms in dementia, with a particular focus on longer term outcomes and mortality.
        Expert opinion on drug safety. 2011; 10: 35-43
        • Barnes T.R.
        • Banerjee S.
        • Collins N.
        • et al.
        Antipsychotics in dementia: Prevalence and quality of antipsychotic drug prescribing in UK mental health services.
        Br J Psychiatry. 2012; 201: 221-226
        • Ballard C.
        • Margallo–Lana M.
        • Juszczak E.
        • et al.
        Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: Randomised double blind placebo controlled trial.
        BMJ. 2005; 330: 874
        • Schneider L.S.
        • Tariot P.N.
        • Dagerman K.S.
        • et al.
        Nature reviews Neuroscience.
        N Engl J Med. 2006; 355: 1525-1538
        • Bridges-Parlet S.
        • Knopman D.
        • Steffes S.
        Withdrawal of neuroleptic medications from institutionalized dementia patients: Results of a double-blind, baseline-treatment-controlled pilot study.
        J Geriatr Psychiatry Neurol. 1997; 10: 119-126
        • Ballard C.G.
        • Thomas A.
        • Fossey J.
        • et al.
        A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: The neuropsychiatric inventory median cutoff is a predictor of clinical outcome.
        J Clin Psychiatry. 2004; 65: 114-119
        • Ballard C.
        • Lana M.M.
        • Theodoulou M.
        • et al.
        A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial).
        PLoS Med. 2008; 5: e76
        • Ballard C.
        • Hanney M.L.
        • Theodoulou M.
        • et al.
        The dementia antipsychotic withdrawal trial (DART–AD): Long-term follow-up of a randomised placebo-controlled trial.
        Lancet Neurol. 2009; 8: 151-157
        • Devanand D.P.
        • Pelton G.H.
        • Cunqueiro K.
        • et al.
        A 6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer's disease.
        Int J Geriatr Psychiatry. 2011; 26: 937-943
        • Devanand D.P.
        • Mintzer J.
        • Schultz S.K.
        • et al.
        Relapse risk after discontinuation of risperidone in Alzheimer's disease.
        N Engl J Med. 2012; 367: 1497-1507
        • Fossey J.
        • Ballard C.
        • Juszczak E.
        • et al.
        Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: Cluster randomised trial.
        BMJ. 2006; 332: 756-761
        • Cohen-Mansfield J.
        • Lipson S.
        • Werner P.
        • et al.
        Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: A controlled, double-blind study.
        Arch Intern Med. 1999; 159: 1733-1740
        • Ballard C.
        • Margallo-Lana M.
        • O'Brien J.T.
        • et al.
        Top cited papers in International Psychogeriatrics: 6a. Quality of life for people with dementia living in residential and nursing home care: The impact of performance on activities of daily living, behavioral and psychological symptoms, language skills, and psychotropic drugs.
        Int Psychogeriatr/IPA. 2009; 21: 1026-1030
        • Fox C.
        • Crugel M.
        • Maidment I.
        • et al.
        Efficacy of memantine for agitation in Alzheimer's dementia: A randomised double–blind placebo controlled trial.
        PLoS One. 2012; 7: e35185
        • McShane R.
        • Areosa Sastre A.
        • Minakaran N.
        Memantine for dementia.
        Cochrane Database Syst Rev. 2006; : CD003154
        • Wilcock G.K.
        • Ballard C.G.
        • Cooper J.A.
        • Loft H.
        Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer's disease: A pooled analysis of 3 studies.
        J Clin Psychiatry. 2008; 69: 341-348
        • Howard R.
        • McShane R.
        • Lindesay J.
        • et al.
        Donepezil and memantine for moderate-to-severe Alzheimer's disease.
        N Engl J Med. 2012; 366: 893-903
        • McKhann G.
        • Drachman D.
        • Folstein M.
        • et al.
        Clinical diagnosis of Alzheimer's disease: Report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
        Neurology. 1984; 34: 939-944
        • Cohen-Mansfield J.
        • Marx M.S.
        • Rosenthal A.S.
        A description of agitation in a nursing home.
        J Gerontol. 1989; 44: M77-M84
        • Byrne L.M.
        • Wilson P.M.
        • Bucks R.S.
        • et al.
        The sensitivity to change over time of the Bristol Activities of Daily Living Scale in Alzheimer's disease.
        Int J Geriatr Psychiatry. 2000; 15: 656-661
        • Cummings J.L.
        • Mega M.
        • Gray K.
        • et al.
        The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia.
        Neurology. 1994; 44: 2308-2314
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini–mental state.” A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Ballard C.
        • McKeith I.
        • Burn D.
        • et al.
        The UPDRS scale as a means of identifying extrapyramidal signs in patients suffering from dementia with Lewy bodies.
        Acta Neurol Scand. 1997; 96: 366-371
        • Schneider L.S.
        • Olin J.T.
        • Doody R.S.
        • et al.
        Validity and reliability of the Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study.
        Alzheimer Dis Assoc Disord. 1997; 11: S22-S32
        • Auer S.
        • Reisberg B.
        The GDS/FAST staging system.
        Int Psychogeriatr/IPA. 1997; 9: 167-171
      4. Health & Social Care Information Centre. National Dementia and Antipsychotic Prescribing Audit. Available at: 2012. Accessed September 8, 2014.