Antidepressant Medication Plus Donepezil for Treating Late-life Depression

Study Overview
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Brief Summary
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This study will determine the effectiveness of combining escitalopram, venlafaxine, or duloxetine with donepezil, a medication used in Alzheimer's disease, in improving memory, concentration, attention, and problem solving abilities, and reducing the risk of depressive relapse in older individuals with depression.

Detailed Description
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The purpose of this research study is to learn if combining an antidepressant medication (escitalopram, venlafaxine, or duloxetine) with a medication used in Alzheimer's Disease (donepezil), in elderly patients age 65 and older with major depression, will help to 1) improve and/or maintain memory, concentration, attention, and problem solving abilities such as ability to balance a checkbook, pay bills, use the telephone, and 2) reduce the risk of depressive symptoms from returning. Study participation will last up to two years. 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 MTLD II study suggest that treating depression does not normalize cognitive functions and may not prevent their progression. We will test a pharmacologic strategy involving the cholinesterase inhibitor donepezil, in combination with maintenance antidepressant pharmacotherapy (escitalopram, venlafaxine, or duloxetine), to improve and to maintain cognitive functioning and functional competence in elderly patients with major depression. We hypothesize that maintenance antidepressant pharmacotherapy combined with donepezil will be superior to maintenance antidepressant pharmacotherapy combined with placebo/clinical management in (1) improving cognitive performance; and (2) slowing progression of cognitive impairment and decline in functional competence. We plan to recruit 200 patients aged 65 and above in current episodes of major depression. Those who respond to antidepressant pharmacotherapy with citalopram, venlafaxine, or duloxetine will then be randomly assigned on a double-blind basis to one of two 24-month treatments: 1)antidepressant pharmacotherapy plus donepezil/clinical management; or 2)antidepressant pharmacotherapy plus placebo/clinical management. For information on related studies, please follow these links: http://clinicaltrials.gov/show/NCT00000377 http://clinicaltrials.gov/show/NCT00178100

Official Title
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Maintenance Therapies in Late-Life Depression: MTLD III

Conditions
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Depression, Dementia

Intervention / Treatment
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* Drug: Escitalopram
* Drug: Donepezil
* Drug: Venlafaxine
* Drug: Placebo
* Drug: Duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current episode of major depression HRS-D 17-item score of 15 or higher Must be able to speak English Willing to discontinue other psychotropics Availability of family member/caregiver Hearing capacity adequate to respond to raised conversational voice Must have no formal diagnosis of dementia Exclusion Criteria: Meets DSM-IV criteria for bipolar disorder, schizophrenia, schizoaffective disorder, or a psychotic disorders Alcohol/drug abuse within 12 months of study entry History of treatment non-adherence in other clinic protocols History of non-response to citalopram in other clinic protocols History of non-tolerance to SSRI therapy

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>escitalopram plus donepezil (DNP)in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation donepezil. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. | Drug: Escitalopram<br>* Escitalopram, 10mg to 20mg daily.<br>* Other names: Lexapro;Drug: Donepezil<br>* Donepezil, 5mg to 10mg daily.<br>* Other names: aricept;Drug: Venlafaxine<br>* Venlafaxine, 150mg to 300mg daily.<br>* Other names: effexor XR;Drug: Duloxetine<br> <br> * Other names: cymbalta;|
| Placebo Comparator: 2<br>escitalopram plus placebo (PBO) in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of venlafaxine or duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. | Drug: Escitalopram<br>* Escitalopram, 10mg to 20mg daily.<br>* Other names: Lexapro;Drug: Venlafaxine<br>* Venlafaxine, 150mg to 300mg daily.<br>* Other names: effexor XR;Drug: Placebo<br> <br> Drug: Duloxetine<br> <br> * Other names: cymbalta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Cognitive Performance | Cognitive performance was assessed with 17 well established and validated individual tests measuring multiple domains. We transformed raw scores for individual tests into Z-scores using the baseline distribution of a non-depressed, cognitively normal, older adult comparison group (N=36)of similar age, education, and medical health recruited concurrently with the depressed participants. These Z-scores were averaged within each neuropsychological area to produce domain scores and then averaged over all 17 tests to calculate a global cognition performance score. | Measured at baseline and Years 1 and 2 in maintenance | 
| Cognitive Instrumental Activities of Daily Living (IADL) | The PASS (a performance-based assessment of instrumental activities of daily living)generates a composite measure of 13 cognitive IADL items capturing performance on activities such as shopping, bill paying, medication management, and home safety. We report the percentage of subjects at each assessment point adjudged to have independent functioning. This was determined by a clinician rater observing subjects perform each task and rating them according to predetermined criteria on a 4 point scale, ranging from 0 (unable) to 3 (independent). | baseline, year 1 and year 2 | 
| Number of Participants With Recurrence of Major Depression | Recurrence of major depressive episodes as determined by SCID/DSM IV: two weeks of low mood and/or anhedonia, together with at least five of the following symptoms: suicidal ideation, low energy, sleep disturbance, appetite disturbance, psychic anxiety or somatic anxiety. In addition, a diagnosis of major depression requires evidence of distress or impairment. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Dementia, Alzheimer's Disease, Cognitive, Donepezil, Memory, Function, Elderly, Late-Life