Combination Treatment Study for Memory Impairment and Depression

In the elderly, the most common neuropsychiatric disorders are depression (DEP) and cognitive impairment (CI). Their co-occurrence (DEP-CI) may exceed chance. The lack of research in DEP-CI, the need to determine early prognostic indicators, and to develop optimal treatment strategies, was emphasized by a NIH consensus panel. Since depression in patients with CI increases the risk of conversion to dementia, treatment strategies for DEP-CI have longer-term implications beyond acute antidepressant treatment response. However, in DEP-CI, there is a lack of data on treatment response of mood symptoms to antidepressant treatment and of cognitive deficits to cognitive enhancer treatment, and the long-term prognosis in these patients remains unclear. The investigators have initial pilot data showing that donepezil was superior to placebo in improving memory performance in DEP-CI patients, and pilot data showing that patients with DEP-CI treated with combined escitalopram and memantine have a low conversion rate to dementia, primarily Alzheimer's disease (AD), over one year. This proposal is for the first study to explicitly examine cognitive change, including conversion to dementia, in a randomized, double-blind, placebo-controlled donepezil treatment trial in DEP-CI patients treated openly with antidepressants. The investigators will conduct systematic follow-up to evaluate 18-month outcome. In addition to apolipoprotein E ε4 genotype, the investigators will explore MRI hippocampal and entorhinal cortex atrophy and odor identification deficits as biomarkers that moderate response. This pilot trial will enroll about 80 DEP-CI patients who present to the departments of Psychiatry, Neurology and Internal Medicine at NYSPI/Columbia University and Duke University medical centers, ensuring broad representation for clinical relevance. In the treatment protocol, all 80 DEP-CI patients will receive open antidepressant treatment with citalopram for 8 weeks. At 8 weeks, citalopram responders will continue to be treated on citalopram, while non-responders will switch to venlafaxine treatment for an additional 8 weeks. At 16 weeks, all subjects will be randomized to add-on donepezil or placebo (N.B. Patients with a prior history of nonresponse to both citalopram and venlafaxine will be enrolled in the protocol and treated with bupropion and subsequently with doctor's choice of antidepressant). Patients will be followed for a total period of up to 18 months in the trial, with antidepressant treatment adjusted as needed based on clinical response and side effects, i.e., open antidepressant treatment is continuous for all subjects throughout the trial and is not the experimental intervention. The investigators chose to study antidepressant plus donepezil compared to placebo based on our pilot data and to increase the likelihood of obtaining a signal. Aim 1 (primary aim of the study). To assess change in cognitive status over 18 months in antidepressant-treated DEP-CI patients comparing donepezil to placebo. Hypothesis 1. Antidepressant-treated DEP-CI patients on donepezil will show a lower rate of conversion to dementia, primarily AD, compared to antidepressant-treated DEP-CI patients on placebo by the end of the 18-month trial. Hypothesis 2 (secondary). Compared to the placebo group, the donepezil group will show better cognitive outcome by the end of the 18-month trial (SRT total recall: primary measure; modified ADAS-cog: secondary measure). Hypothesis 3 (secondary). At the end of 24 weeks on add-on donepezil or placebo, the donepezil group will show better cognitive outcome than placebo (SRT total recall: primary measure; modified ADAS-cog: secondary measure). Aim 2: To evaluate moderators of treatment on cognitive change in the 18-month donepezil-placebo trial, based on the view that patients with incipient AD brain pathology will have superior cognitive outcome on donepezil. These Aim 2 hypotheses are considered exploratory. Hypothesis 1. Patients with the apolipoprotein E ε4 allele (homozygote or heterozygote), compared to patients without this allele, will have better cognitive outcome on donepezil compared to placebo. Hypothesis 2. Lower scores on the UPSIT (odor identification test) at baseline will be associated with better cognitive outcome on donepezil compared to placebo. Hypothesis 3. Smaller MRI hippocampal and entorhinal cortex volumes (atrophy) will be associated with better cognitive outcome on donepezil compared to placebo.