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

Charles F. Reynolds, Meryl A. Butters, Oscar Lopez, Bruce G. Pollock, Mary Amanda Dew, Benoit H. Mulsant, Eric J. Lenze, Margo Holm, Joan C. Rogers, Sati Mazumdar, Patricia R. Houck, Amy Begley, Stewart Anderson, Jordan F. Karp, Mark D. Miller, Ellen M. Whyte, Jacqueline Stack, Ariel Gildengers, Katalin Szanto, Salem BensasiDaniel I. Kaufer, M. Ilyas Kamboh, Steven T. DeKosky

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


Context: Cognitive impairment in late-life depression is a core feature of the illness. Objective: To test whether donepezil hydrochloride and antidepressanttherapyis superior toplaceboandantidepressanttherapyinimprovingcognitiveperformanceandinstrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment. Design: Randomized, double-blind, placebocontrolled maintenance trial. Setting: University clinic. Participants: One hundred thirty older adults aged 65 years and older with recently remitted major depression. Interventions: Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo. Main Outcome Measures: Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression. Results: Donepezil and antidepressant therapy temporarily improved global cognition (treatment×time interaction, F2,126=3.78; P=.03), but effect sizes were small (Cohen d=0.27, group difference at 1 year).Amarginal 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.

Original languageEnglish (US)
Pages (from-to)51-60
Number of pages10
JournalArchives of General Psychiatry
Issue number1
StatePublished - Jan 2011
Externally publishedYes

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health


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