Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial

Am J Geriatr Psychiatry. 2018 Oct;26(10):1050-1060. doi: 10.1016/j.jagp.2018.05.008. Epub 2018 Jun 28.


Objective: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment.

Methods: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire).

Results: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo.

Conclusion: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

Keywords: Mild cognitive impairment; antidepressants; cholinesterase inhibitor; clinical trial; depression.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antidepressive Agents, Second-Generation / administration & dosage
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Cholinesterase Inhibitors / administration & dosage
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / pharmacology*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / epidemiology
  • Comorbidity
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / epidemiology
  • Donepezil / administration & dosage
  • Donepezil / adverse effects
  • Donepezil / pharmacology*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Middle Aged
  • Off-Label Use
  • Outcome Assessment, Health Care*


  • Antidepressive Agents, Second-Generation
  • Cholinesterase Inhibitors
  • Donepezil

Associated data