Depression Clinical Trial
Official title:
Pilot Combination Treatment Trial of Mild Cognitive Impairment With Depression
Patients presenting with depression (DEP) and cognitive impairment (CI), represent a unique,
understudied population that is difficult to diagnose, treat and estimate prognosis. Our
pilot data, supported by the literature, suggest that many DEP-CI patients show cognitive
decline and often convert to dementia, primarily Alzheimer's disease (AD). In DEP-CI, there
is a lack of data on treatment response of mood symptoms to antidepressant treatment and
particularly of cognitive deficits to cognitive enhancer treatment. Our initial pilot data in
a double-blind study showed that donepezil was superior to placebo in improving memory in
antidepressant-treated DEP-CI patients. In a second pilot study, open label es-citalopram
plus memantine treatment led to a low rate of conversion to dementia.
In this proposed pilot clinical trial, the investigators will evaluate, treat and follow a
broad sample of 80 DEP-CI patients at NYSPI/Columbia University Medical Center (N = 40) and
Duke University Medical Center (N = 40). Recruitment will be from clinics and/or
advertisements. In the treatment protocol, all 80 DEP-CI patients will receive baseline mood
and memory assessments and open antidepressant treatment with citalopram for 8 weeks. At 8
weeks, repeat assessment will occur and patients whose depression has responded to citalopram
will be randomized to add-on donepezil or placebo. Non-responders to citalopram will receive
open treatment with venlafaxine and will be randomized 8 weeks later (16 weeks of open
antidepressant treatment) to add-on donepezil or placebo. Patients will be followed for a
total period of 18 months with continuous open antidepressant treatment during the trial.
Donepezil is being studied in order to increase the likelihood of obtaining a signal. If the
results are positive, the investigators can begin clarifying the mechanism(s) in subsequent
trials. Baseline apolipoprotein E e4 genotype, odor identification deficits, and MRI
hippocampal and entorhinal cortex atrophy will be explored as predictors of donepezil
response in the 18-month trial. Improving cognition and delaying conversion to a clinical
diagnosis of dementia in this high risk group will enhance quality of life, reduce family
burden, and markedly diminish overall health care costs.
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.
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