PLACEBO-CONTROLLED TRIAL OF DONEPEZIL FOLLOWING ANTIDEPRESSANT TREATMENT IN PATIENTS WITH COMORBID DEPRESSION AND COGNITIVE IMPAIRMENT

Abstract

In patients with comorbid depression and cognitive impairment, antidepressants are commonly used but the utility of cholinesterase inhibitors (CheI) as cognitive enhancers is not established. Eighty elderly (55–95 years old) depressed, cognitively impaired (DEP-CI) patients participated in the DOTCODE study at two sites: Columbia and Duke University Medical Centers. 40 of 79 patients who received antidepressant medication in the initial phase met criteria for amnestic mild cognitive impairment (MCI). After 16 weeks of open-label antidepressant treatment with antidepressants, primarily citalopram or venlafaxine, 61 patients were randomized to receive 62 weeks of the CheI donepezil 5–10 mg daily or placebo in a randomized, double-blind trial. Linear mixed effects models with random subject-specific intercepts were used to model ADAS-Cog13 and Selective Reminding Test (SRT) Total Immediate Recall over the course of the study. All models include baseline value of the outcome, age, study site, treatment, visit week, and the interaction between treatment and visit week (and interaction terms to test for moderators). In the first 16 weeks, depression improved in most patients and 39 of 61 randomized patients (64%) met responder criteria. In the 61 randomized patients, donepezil did not differ from placebo in change in the co-primary measures of ADAS-Cog13 (F=0.18, p=0.83) and SRT total recall (F=0.06, p=0.9). Four patients were diagnosed with probable Alzheimer's disease by end-trial. Apolipoprotein E e4 allele and MRI hippocampal volume were unrelated to differences in outcomes between donepezil and placebo. Periventricular hyperintensities (PVH) did not distinguish changes in cognition on donepezil from placebo on ADAS-Cog13 (F1,39 = 0.14, p = 0.71) but did on SRT total recall (F1,39 = 4.23, p = 0.04); less PVH was associated with greater improvement with donepezil on SRT total recall. In patients with comorbid depression and cognitive impairment, the addition of donepezil following antidepressant medication treatment did not improve cognition compared to placebo, though donepezil treatment was associated with better cognition in patients with less cerebrovascular disease. The findings add to those from studies in mild cognitive impairment without depression that have not demonstrated superiority for CheI over placebo in improving cognition.