title: 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).
abstract: 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 -1.68-11.70; 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK. Electronic address: clive.ballard@kcl.ac.uk.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: Institute for Ageing, University of Newcastle, Newcastle Upon Tyne, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gerry
authors.affiliation: Department of Primary Care Health Services, University of Oxford, Oxford, UK.
authors.forename: Ly-Mee
authors.initials: LM
authors.lastname: Yu
authors.affiliation: Institutionen för Neurobiologi, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
authors.affiliation: Oxford Health NHS Foundation Trust, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Merritt
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Corbett
authors.affiliation: Institute for Ageing, University of Newcastle, Newcastle Upon Tyne, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Davison
authors.affiliation: Institute for Ageing, University of Newcastle, Newcastle Upon Tyne, UK.
authors.forename: Narenda
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Zunera
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Byron
authors.initials: B
authors.lastname: Creese
authors.affiliation: Oxford Health NHS Foundation Trust, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Loughlin
authors.affiliation: Oxford Health NHS Foundation Trust, Oxford, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Bannister
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Burns
authors.affiliation: North Essex Partnership Foundation NHS Trust, Chelmsford, UK.
authors.forename: Soe Nyunt
authors.initials: SN
authors.lastname: Win
authors.affiliation: Faculty of Brain Sciences, University College London, London, UK.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Walker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy*; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008134:Long-Term Care; D008297:Male; D008559:Memantine / Q000009:adverse effects* / Q000627:therapeutic use; D061214:Patient Safety; D011446:Prospective Studies; D011595:Psychomotor Agitation / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D018570:Risk Assessment; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome / Q000453:epidemiology / Q000503:physiopathology; D028761:Withholding Treatment
chemical_list: D014150:Antipsychotic Agents; D008559:Memantine
keywords: Alzheimer; antipsychotic; dementia; memantine; neuropsychiatric; withdrawal