title: Donepezil and memantine for moderate-to-severe Alzheimer's disease.
abstract: BACKGROUND
  Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease.
  
  
  METHODS
  We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
  
  
  RESULTS
  Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
  
  
  CONCLUSIONS
  In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).
authors.affiliation: Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom. robert.j.howard@kcl.ac.uk
authors.forename: Robert
authors.initials: R
authors.lastname: Howard
authors.forename: Rupert
authors.initials: R
authors.lastname: McShane
authors.forename: James
authors.initials: J
authors.lastname: Lindesay
authors.forename: Craig
authors.initials: C
authors.lastname: Ritchie
authors.forename: Ashley
authors.initials: A
authors.lastname: Baldwin
authors.forename: Robert
authors.initials: R
authors.lastname: Barber
authors.forename: Alistair
authors.initials: A
authors.lastname: Burns
authors.forename: Tom
authors.initials: T
authors.lastname: Dening
authors.forename: David
authors.initials: D
authors.lastname: Findlay
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: Alan
authors.initials: A
authors.lastname: Hughes
authors.forename: Robin
authors.initials: R
authors.lastname: Jacoby
authors.forename: Rob
authors.initials: R
authors.lastname: Jones
authors.forename: Roy
authors.initials: R
authors.lastname: Jones
authors.forename: Ian
authors.initials: I
authors.lastname: McKeith
authors.forename: Ajay
authors.initials: A
authors.lastname: Macharouthu
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.forename: Peter
authors.initials: P
authors.lastname: Passmore
authors.forename: Bart
authors.initials: B
authors.lastname: Sheehan
authors.forename: Edmund
authors.initials: E
authors.lastname: Juszczak
authors.forename: Cornelius
authors.initials: C
authors.lastname: Katona
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.forename: Martin
authors.initials: M
authors.lastname: Knapp
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Sube
authors.initials: S
authors.lastname: Banerjee
authors.forename: Caroline
authors.initials: C
authors.lastname: Onions
authors.forename: Mary
authors.initials: M
authors.lastname: Griffin
authors.forename: Jessica
authors.initials: J
authors.lastname: Adams
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.forename: Tony
authors.initials: T
authors.lastname: Johnson
authors.forename: Peter
authors.initials: P
authors.lastname: Bentham
authors.forename: Patrick
authors.initials: P
authors.lastname: Phillips
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000077265:Donepezil; D004311:Double-Blind Method; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use*; D010352:Patient Dropouts; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011581:Psychological Tests; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D000077265:Donepezil; D008559:Memantine