Dementia, Depression
Conditions
Keywords
Depression, Dementia, Alzheimer's Disease, Cognitive, Donepezil, Memory, Function, Elderly, Late-Life
Brief summary
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
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
Interventions
DRUGEscitalopram
Escitalopram, 10mg to 20mg daily.
DRUGDonepezil
Donepezil, 5mg to 10mg daily.
DRUGVenlafaxine
Venlafaxine, 150mg to 300mg daily.
DRUGPlacebo
DRUGDuloxetine
Sponsors
National Institute of Mental Health (NIMH)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Cognitive Performance | Measured at baseline and Years 1 and 2 in maintenance | 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. |
| Cognitive Instrumental Activities of Daily Living (IADL) | baseline, year 1 and year 2 | 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). |
| Number of Participants With Recurrence of Major Depression | 2 years | 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. |
Countries
United States
Participant flow
Recruitment details
220 signed consent; 158 participants completed pre-randomization testing; 130 participants were randomized. Of these 130, 67 randomized to donepezil augmentation and 63 to placebo.
Pre-assignment details
28 enrolled participants were not randomized due to the following reasons: dementia (19), consent withdrawal (4), con-compliance with research procedures (3), supervening medical problems that precluded participation (2).
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily) | 67 |
| Placebo Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo | 63 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 0 |
| Overall Study | medical complications | 2 | 0 |
| Overall Study | Physician Decision | 12 | 8 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Placebo | Donepezil | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 63 Participants | 67 Participants | 130 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 73.9 years STANDARD_DEVIATION 5.8 | 73.1 years STANDARD_DEVIATION 6.5 | 73.5 years STANDARD_DEVIATION 6.2 |
| Region of Enrollment United States | 63 participants | 67 participants | 130 participants |
| Sex: Female, Male Female | 51 Participants | 49 Participants | 100 Participants |
| Sex: Female, Male Male | 12 Participants | 18 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 67 | 0 / 63 |
| serious Total, serious adverse events | 3 / 67 | 1 / 63 |
Outcome results
Primary
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).
Time frame: baseline, year 1 and year 2
Population: Some participants refused this testing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Donepezil | Cognitive Instrumental Activities of Daily Living (IADL) | Baseline (N=33; N=34) | 54.10 Percentage of participants |
| Donepezil | Cognitive Instrumental Activities of Daily Living (IADL) | Year 1 (N=23; N=25) | 62.16 Percentage of participants |
| Donepezil | Cognitive Instrumental Activities of Daily Living (IADL) | Year 2 (N=11; N=17) | 36.67 Percentage of participants |
| Placebo | Cognitive Instrumental Activities of Daily Living (IADL) | Baseline (N=33; N=34) | 61.82 Percentage of participants |
| Placebo | Cognitive Instrumental Activities of Daily Living (IADL) | Year 1 (N=23; N=25) | 54.35 Percentage of participants |
| Placebo | Cognitive Instrumental Activities of Daily Living (IADL) | Year 2 (N=11; N=17) | 47.22 Percentage of participants |
Primary
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.
Time frame: Measured at baseline and Years 1 and 2 in maintenance
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Global Cognitive Performance | Year 2 N=42; N=49) | -0.31 Z-score | Standard Deviation 0.92 |
| Donepezil | Global Cognitive Performance | Baseline (N=67;N=63) | -0.47 Z-score | Standard Deviation 0.88 |
| Donepezil | Global Cognitive Performance | Year 1 (N=45; N=57) | -0.23 Z-score | Standard Deviation 0.79 |
| Placebo | Global Cognitive Performance | Baseline (N=67;N=63) | -0.47 Z-score | Standard Deviation 0.76 |
| Placebo | Global Cognitive Performance | Year 1 (N=45; N=57) | -0.65 Z-score | Standard Deviation 0.81 |
| Placebo | Global Cognitive Performance | Year 2 N=42; N=49) | -0.56 Z-score | Standard Deviation 0.9 |
Primary
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.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Donepezil | Number of Participants With Recurrence of Major Depression | 19 participants |
| Placebo | Number of Participants With Recurrence of Major Depression | 11 participants |
Comparison: We followed the intention to treat principle. We used Kaplan-Meier curves to quantify the percentage of participants who were free of depression recurrence over time. Cox proportional hazard models quantified hazard ratios comparing the 2 treatment groups.p-value: 0.0595% CI: [1, 4.41]Log Rank
Post Hoc
Percentage of Participants With Mild Cognitive Impairment Converting to Dementia.
Conversion to dementia was ascertained by the University of Pittsburgh Alzheimer Disease Research Center (ADRC), using data on neuropsychological performance and IADL functioning, as well as other relevant clinical data. Diagnoses were made according to National Alzheimer Coordinating Center criteria.
Time frame: 2 year
Population: This is the percent of participants with mild cognitive impairment (MCI) in each arm of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Donepezil | Percentage of Participants With Mild Cognitive Impairment Converting to Dementia. | 10 Percent of Participants |
| Placebo | Percentage of Participants With Mild Cognitive Impairment Converting to Dementia. | 33 Percent of Participants |