Cognitive function is impaired in late-life depression, which contributes to disability and impaired quality of life. In addition, depression is considered a possible risk for dementing illness. A randomized, double-blind, placebo-controlled maintenance trial was undertaken to compare the effect of donepezil, a cholinesterase inhibitor, and antidepressant treatment with placebo and antidepressant treatment on cognitive performance and instrumental activities of daily living, as well as on recurrence of depression over a 2-year period.
The study involved 130 adults aged 65 years and older with recently remitted major depression. In terms of neuropsychological performance, subjects in the donepezil group showed a temporary positive point at 1 year that was not maintained at the 2-year follow-up. However, even at 1 year, the effect sizes were not statistically significant. In the donepezil group, a marginal benefit was found on global neuropsychological performance (C-IADL).
Perhaps more interestingly and disturbingly, however, in the overall cohort, subjects in the donepezil group were more likely than those in the placebo group to experience a recurrence of major depression (35% vs. 19%, respectively, p = 0.05; hazard ratio = 2.09). Post hoc subgroup analyses revealed 57 subjects with mild cognitive impairment (MCI), 30 in the donepezil group and 27 in the placebo group. Of these, 12 subjects, 3 receiving donepezil and 9 receiving placebo, progressed to dementia at the 2-year follow-up. The MCI subgroup had recurrence rates of major depression of 44% with donepezil versus 12% with placebo (p = 0.03).
Furthermore, in cognitively intact patients after remission of depression (n = 73), donepezil did not appear to decrease progression to MCI or dementia or prevent recurrence of depression. In conclusion, the benefits of donepezil (modest cognitive and functional improvement and slowing of the rate of conversion to dementia) and the risk of recurrence of major depression need to be evaluated before it is used as an augmentation in the maintenance treatment of depression in old age.