title: Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy.
abstract: BACKGROUND
  Cognitive impairment in late-life depression is a core feature of the illness.
  
  
  OBJECTIVE
  To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment.
  
  
  METHODS
  Randomized, double-blind, placebo-controlled maintenance trial.
  
  
  METHODS
  University clinic.
  
  
  METHODS
  One hundred thirty older adults aged 65 years and older with recently remitted major depression.
  
  
  METHODS
  Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo.
  
  
  METHODS
  Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression.
  
  
  RESULTS
  Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression.
  
  
  CONCLUSIONS
  Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00177671.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, PA 15213, USA. reynoldscf@upmc.edu.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Reynolds
authors.forename: Meryl A
authors.initials: MA
authors.lastname: Butters
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.forename: Mary Amanda
authors.initials: MA
authors.lastname: Dew
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lenze
authors.forename: Margo
authors.initials: M
authors.lastname: Holm
authors.forename: Joan C
authors.initials: JC
authors.lastname: Rogers
authors.forename: Sati
authors.initials: S
authors.lastname: Mazumdar
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Houck
authors.forename: Amy
authors.initials: A
authors.lastname: Begley
authors.forename: Stewart
authors.initials: S
authors.lastname: Anderson
authors.forename: Jordan F
authors.initials: JF
authors.lastname: Karp
authors.forename: Mark D
authors.initials: MD
authors.lastname: Miller
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Whyte
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stack
authors.forename: Ariel
authors.initials: A
authors.lastname: Gildengers
authors.forename: Katalin
authors.initials: K
authors.lastname: Szanto
authors.forename: Salem
authors.initials: S
authors.lastname: Bensasi
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Kaufer
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
mesh_terms: D000203:Activities of Daily Living / Q000523:psychology; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000187:drug effects* / Q000523:psychology; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control / Q000523:psychology; D000077265:Donepezil; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D055502:Secondary Prevention; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil