Background: In older persons, cognitive impairment and depression are often intertwined. Older persons with a major depressive episode have a 25 to 30 percent chance of developing cognitive impairment within one year, and cognitive impairment can also be a feature of late-life depression. Cholinesterase inhibitors such as donepezil (Aricept) may temporarily prevent progression of mild cognitive impairment but could also worsen symptoms of depression because of the potential role of the cholinergic pathway in mediating mood. Reynolds and colleagues compared donepezil and antidepressant therapy with placebo and antidepressant therapy to determine which was more effective at improving cognitive performance.

The Study: The authors recruited 130 community-living adults 65 years or older who had a major depressive episode with a score of at least 15 on the Hamilton Rating Scale for Depression (HAM-D), and who were cognitively normal (73 patients) or had mild cognitive impairment (57 patients). Participants were excluded if they had dementia or a substance abuse disorder.

All patients received 12 to 16 weeks of open antidepressant therapy to achieve remission of depression symptoms (defined as a HAM-D score of 10 or less for three consecutive weeks). Patients continued their antidepressant therapy and were randomized to receive either placebo or donepezil in a dosage of 10 mg per day (5 mg per day was used with 30 patients who could not tolerate the higher dosage). Patients were followed for two years. Cognitive instrumental activities of daily living were assessed at baseline and periodically during the study. Primary outcomes measured included global neuropsychological functioning, cognitive instrumental activities of daily living status, and recurrence of major depression.

Results: The donepezil group had better cognitive status at 12 months compared with the placebo group, but this was not sustained at two years. The donepezil group had a higher overall recurrence rate of major depression than the placebo group at two years (35 versus 19 percent, respectively; P = .05; hazard ratio = 2.09). Twelve (21 percent) of the 57 patients who had mild cognitive impairment initially developed dementia during the study, including nine patients in the placebo group and three patients in the donepezil group. Post-hoc analysis showed that patients taking donepezil who had mild cognitive impairment were significantly less likely to develop dementia than patients with similar cognitive impairment in the placebo group (10 versus 33 percent, respectively; P = .05), but the risk of recurrent depression in these patients remained higher (44 versus 12 percent, respectively; P = .03). The analysis did not show the same reduction in progression to mild cognitive impairment or dementia in the cognitively intact group, nor did it show any reduction of depression relapse.

Conclusion: In cognitively intact but depressed older patients, donepezil has no clear benefit for preventing depression recurrence or the development of mild cognitive impairment or dementia. Among older depressed patients with mild cognitive impairment, donepezil may help prevent progression to dementia over two years, but at a greater risk of recurrent depression.