In this second competing continuation of R37 MH43832-16 (""""""""Maintenance Therapies in Late Life Depression"""""""": MTLD-III), we aim to investigate pharmacologic strategies for improving and stabilizing cognitive functioning in late-life depression and minimizing progression of cognitive and associated functional impairment. Cognitive impairment in late-life depression has not been adequately addressed in previous intervention research, is a core feature of the illness, contributes markedly to disability and impaired quality of life, and is an overlooked but potentially critical target of intervention. Data from the current MTLD-II study suggest that Mild Cognitive Impairment is highly prevalent in late-life depression; and that treating depression does not normalize cognitive functions and does not prevent their progression, e.g., patients continue to demonstrate loss of memory and of executive functions despite continued recovery from depression on SSRI pharmacotherapy with paroxetine. Therefore, in MTLD-III, we will test a pharmacologic strategy involving the cholinesterase inhibitor (ChEI) donepezil, in combination with maintenance citalopram therapy (CIT + DON), to improve and to maintain cognitive functioning and functional competence in elderly patients with major depression. This work will be pursued collaboratively with our Alzheimer Disease Research Center. We hypothesize that citalopram (CIT) combined with donepezil (DON) will be superior to CIT combined with placebo/clinical management in: (1) improving cognitive performance; and (2) slowing progression of cognitive impairment and decline in functional competence. Two hundred patients aged 70 and above in current episodes of major depression will be recruited. Those who respond to antidepressant pharmacotherapy with citalopram (or to venlafaxine, in the case of citalopram non-response) will then be randomly assigned on a double-blind basis to one of two 24-month treatments (n=70-80/cell): 1) citalopram + donepezil/clinical management; or 2) CIT+placebo/clinical management. Randomization will be stratified by the presence/absence of Mild Cognitive Impairment. Depressed subjects will undergo repeated assessment of cognitive and functional status after response to antidepressant treatment (T1) and after three (T2), twelve (T3), and 24 months (T4) of maintenance treatment with either (CIT + DON) or (CIT + PBO). Subjects will exit the study if they demonstrate: (a) failure to respond to initial antidepressant pharmacotherapy; (b) recurrence of a major depressive episode during maintenance; or (c) dementia. Non-depressed control subjects (n=50) will participate in an identical schedule of assessments to provide a bench mark for interpreting both cognitive and functional trajectories seen in depressed subjects. The MTLD-III study will be the first controlled, long-term evaluation of strategies for improving and maintaining cognitive and functional competence in late-life depression. Testing ways of """"""""staying well, staying sharp"""""""" is the objective of the MTLD-III protocol. The application has been amended (A1).
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