Major Depressive DisorderPhase 4CAARENCT02332291
Connectivity Affecting the Antidepressant REsponse Study
A Phase 4 study testing Escitalopram and Bupropion XL in people with Major Depressive Disorder, run by Vanderbilt University Medical Center at 1 site in United States.
Trial summary
It can be difficult to achieve remission in individuals with late-life depression (LLD) and they often require aggressive treatment. This challenge is in part due to age-related vascular changes that are common in LLD. Read more about this study
- Who is it for?
- Ages 60 years and older
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Escitalopram and Bupropion XL
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 95 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2015to Aug 2020
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 60 years or older.
- Current diagnosis of major depressive disorder (DSM-IV-TR), single episode, recurrent or chronic, without psychotic features, as detected by Mini-International Neuropsychiatric Inventory (MINI) and clinical exam.
- Minimum MADRS score ≥ 15.
- Mini-Mental State Exam ≥ 24.
- Fluent in English.
Who cannot join
- Current or past diagnoses of other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) symptoms occurring during a depressive episode
- History of alcohol or drug dependence or abuse in the last three years
- History of developmental disorder or Intelligence Quotient score < 70
- Presence of acute suicidality
- Acute grief (< 1 month)
- Current or past psychosis
Show all 14Show fewer
- Primary neurological disorder, including but not limited to dementia, stroke, brain tumors, epilepsy, Parkinson's disease, or demyelinating diseases
- MRI contraindications
- Any physical or intellectual disability adversely affecting ability to complete assessments
- Electroconvulsive therapy in last 6 months
- Use of antidepressant medications or other psychotropic medications in the last 4 weeks (or the last 6 weeks for fluoxetine). Occasional use of benzodiazepines or non-benzodiazepine sedatives (such as zolpidem, eszopiclone, or zaleplon) during this period is allowable.
- A failed therapeutic trial of escitalopram in the current depressive episode (defined as at least 6 weeks of treatment at a daily dose of 10mg or higher)
- Known allergy or hypersensitivity to escitalopram or bupropion
- Current or planned psychotherapy
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt Psychiatric Hospital
Nashville, Tennessee, 37212
About this study
Official title: Connectivity Affecting the Antidepressant REsponse (The CAARE Study)
It can be difficult to achieve remission in individuals with late-life depression (LLD) and they often require aggressive treatment. This challenge is in part due to age-related vascular changes that are common in LLD. Successful antidepressant treatment involve changes across affective, cognitive, and default mode networks. We hypothesize that in LLD, vascular disease adversely affects response to antidepressants by disrupting connectivity of these networks. The primary goal of this project is to characterize how focal vascular damage affects regional connectivity and response to antidepressants. Based on past work and pilot data, we a priori focus on the cingulum bundle and uncinate fasciculus. These key fiber bundles connect frontal, temporal, and cingulate regions involved in cognition and affective responses. Our central hypothesis is that ischemic damage to the cingulum bundle and uncinate fasciculus contributes to structural and functional connectivity deficits of those tracts. This results in a disconnection effect that alters the function of connected regions. In turn, this increases the risk of a poor response to antidepressants.
Our approach is to enroll up to 130 adults over age 60 years with a diagnosis of Major Depressive Disorder. Subjects will complete clinical evaluation, cognitive testing, and MRI/functional MRI (fMRI) sessions, including an fMRI emotional oddball task that includes attentional and affective components. Participants will be stratified by cerebral lesion severity and randomized in a 2:1 ratio to a double-blinded 8-week trial of escitalopram or matching placebo. Those who do not remit will transition to an 8-week trial of open-label bupropion, an antidepressant with a different mechanism of action. This will allow us to determine if different and distinct circuit deficits affect response to antidepressants with different mechanisms of action while also accounting for the placebo response.
Read the detailed description
Individuals with late-life depression (LLD) experience high levels of disability, mortality, and poor responses to antidepressants. The MRI hallmark of 'vascular depression' in this population is significant ischemic white matter lesion (WML) severity, a finding associated with poor antidepressant outcomes. Despite observations of diffuse white matter disease in LLD, we propose in our "disconnection hypothesis" that focal damage to fiber tracts negatively affects the function of connected regions, resultantly contributing to cognitive deficits and clinical symptoms such as depression severity and negativity bias. Focal WMLs may also reduce the likelihood of an antidepressant response when the specific antidepressant used acts on neurotransmitter systems projecting through the damaged fiber tract. This implies that the effect of tract damage on clinical response may differ between drugs with different mechanism of action.
We propose that the cingulum bundle (CB) and uncinate fasciculus (UF) are key tracts in LLD as they are components of cognitive, affective and default mode networks and contain monoamine neurotransmitter projections. Supporting our model, past work implicates CB and UF deficits in LLD and our new pilot data associates tract damage with poor antidepressant response.
In a cohort of up to 130 depressed elders we will test our central hypotheses: a) focal CB and UF WMLs disrupt connectivity and function of connected regions and contribute to cognitive deficits and affective symptoms; and b) antidepressants acting on neurotransmitter systems projecting through these tracts will be less effective.
Overall Study Design: After obtaining informed consent, we will assess for eligibility. Individuals who meet eligibility criteria will complete neuropsychological testing and a one-hour magnetic resonance imaging (MRI). Subjects will then be randomized in a 2:1 ratio to receive either blinded escitalopram or identical placebo. After 8 weeks of study drug, they will be assessed for remission. Those whose depression has remitted will end their study participation. Those who remain symptomatic will be transitioned to open-label bupropion for 8 weeks, after which their participation will end. We will work with participants on plans for clinical care after the study and will offer two additional visits to facilitate that transition.
Specific Aim 1: To characterize the effect of cingulum bundle (CB) and uncinate fasciculus (UF) WMLs on tract connectivity, function of connected regions, and the cognitive and affective presentation of LLD.
Hypothesis 1: Greater CB WML volume is associated with a) reduced resting-state connectivity of frontal, temporal, and cingulate regions and b) deficits in attention, memory and processing speed.
Hypothesis 2: Greater UF WML volume is associated with a) reduced resting state functional connectivity between frontocingulate and medial temporal regions, and b) greater depression severity and negativity bias.
Exploratory Hypothesis: Greater CB WML volume is associated with failure of anterior and posterior default mode network nodes to deactivate during attentional components of the fMRI task. Greater UF WML volume is associated with greater medial temporal reactivity during the functional MRI task.
Specific Aim 2: To determine whether deficits in tract structural / functional connectivity predict nonremission to antidepressant treatments and if these relationships vary based on antidepressant mechanism of action.
Hypothesis 3: Nonremission to escitalopram will be predicted by: a) greater WML volume in the CB and UF, and b) reduced resting functional connectivity between structures connected by the CB and UF. Greater WML severity and reduced functional connectivity in these tracts will not significantly predict response to placebo.
Hypothesis 4: Nonremission to bupropion will be predicted by a) greater WML volume in the UF but not CB, and b) reduced resting functional connectivity deficits between structures connected by the UF but not CB.
Exploratory Aims: Expl. Aim 1) To determine if specific cognitive measures may serve as markers of focal tract WML damage. Expl. Aim 2) To use whole-brain multimodal imaging approaches to examine how connectivity differences in other brain regions may also predict nonremission to antidepressants.
- Conditions
- Major Depressive Disorder
- Being tested
- Escitalopram, Bupropion XL
- Keywords
- Depression, Geriatrics, Elderly, MRI, Antidepressants
- Medical subject headings
- Depressive Disorder, Major, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EscitalopramDrug
Also called Lexapro
Escitalopram 10-20mg daily
Bupropion XLDrug
Also called Wellbutrin XL
Bupropion XL 150-450mg daily
| Study group | Role | What they receive |
|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Active comparator | 8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters Receives: Drug: Escitalopram; Drug: Bupropion XL |
| Blinded Placebo / Open-Label Bupropion | Placebo comparator | 8 weeks of blinded placebo, followed by 8 weeks of open-label bupropion xl for nonremitters. Receives: Drug: Bupropion XL |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients With Remission of Depression
Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated measure of depression severity. Higher scores indicate greater depression severity, ranging 0-60. This will be used to define remission as a final score of 7 or less
Measured: From Baseline up to Week 16
Secondary outcomes (4)
Change in Depression Severity, Clinician Rated
Depression severity was measured by a study clinician using the MADRS. Higher scores indicate greater depression severity, ranging 0-60. Change calculated as Final MADRS - Baseline MADRS, so a negative score means greater improvement.
Measured: Baseline to week 8
Change in Depression Severity, Self Rated
Self-rated depression severity was measured by the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report of depression severity ranging from 0-27, with higher scores indicating greater depression severity.
Measured: Baseline to week 8
Change in Depression Severity, Clinician Rated
Change in depression severity will be measured by the MADRS. Higher scores indicate greater depression severity, ranging 0-60. Change calculated as Final MADRS - Baseline MADRS, so a negative score means greater improvement.
Measured: Week 8 to week 16
Change in Depression Severity, Self Rated
Change in self-reported depression severity was measured by the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). This scale ranges from 0-27, with higher scores indicating greater depression severity. Change is calculated as final score less baseline score, so a negative value indicates a decrease in depression severity.
Measured: Week 8 to week 16
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2015 (estimated)
- Study startApr 2015
- Primary completionAug 2020
- Study completionAug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 95 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Warren Taylor, Vanderbilt University Medical Center
- Investigators
- Warren D Taylor, MD, MHSc, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02332291
- Sponsor's protocol ID
- 141137
- Acronym
- CAARE
- Status last verified
- Aug 2021
- First submitted
- 30 Dec 2014
- Last updated
- 21 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Ahmed R, Boyd BD, Elson D, Albert K, Begnoche P, Kang H, Landman BA, Szymkowicz SM, Andrews P, Vega J, Taylor WD. Influences of resting-state intrinsic functional brain connectivity on the antidepressant treatment response in late-life depression. Psychol Med. 2023 Oct;53(13):6261-6270. doi: 10.1017/S0033291722003579. Epub 2022 Dec 9.
PubMed 36482694
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Connectivity Affecting the Antidepressant REsponse (The CAARE Study)
- ClinicalTrials.gov ID
- NCT02332291
- Acronym / sponsor ID
- CAARE / 141137
- Conditions
- Major Depressive Disorder
- Keywords
- Depression, Geriatrics, Elderly, MRI, Antidepressants
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 95 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Study start
- Apr 2015 (actual)
- Primary completion
- Aug 2020 (actual)
- Study completion
- Aug 2020 (actual)
- First posted
- 6 Jan 2015 (estimated)
- Results
- Posted 21 Sep 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
It can be difficult to achieve remission in individuals with late-life depression (LLD) and they often require aggressive treatment. This challenge is in part due to age-related vascular changes that are common in LLD. Successful antidepressant treatment involve changes across affective, cognitive, and default mode networks. We hypothesize that in LLD, vascular disease adversely affects response to antidepressants by disrupting connectivity of these networks. The primary goal of this project is to characterize how focal vascular damage affects regional connectivity and response to antidepressants. Based on past work and pilot data, we a priori focus on the cingulum bundle and uncinate fasciculus. These key fiber bundles connect frontal, temporal, and cingulate regions involved in cognition and affective responses. Our central hypothesis is that ischemic damage to the cingulum bundle and uncinate fasciculus contributes to structural and functional connectivity deficits of those tracts. This results in a disconnection effect that alters the function of connected regions. In turn, this increases the risk of a poor response to antidepressants.
Our approach is to enroll up to 130 adults over age 60 years with a diagnosis of Major Depressive Disorder. Subjects will complete clinical evaluation, cognitive testing, and MRI/functional MRI (fMRI) sessions, including an fMRI emotional oddball task that includes attentional and affective components. Participants will be stratified by cerebral lesion severity and randomized in a 2:1 ratio to a double-blinded 8-week trial of escitalopram or matching placebo. Those who do not remit will transition to an 8-week trial of open-label bupropion, an antidepressant with a different mechanism of action. This will allow us to determine if different and distinct circuit deficits affect response to antidepressants with different mechanisms of action while also accounting for the placebo response.
Detailed description
Individuals with late-life depression (LLD) experience high levels of disability, mortality, and poor responses to antidepressants. The MRI hallmark of 'vascular depression' in this population is significant ischemic white matter lesion (WML) severity, a finding associated with poor antidepressant outcomes. Despite observations of diffuse white matter disease in LLD, we propose in our "disconnection hypothesis" that focal damage to fiber tracts negatively affects the function of connected regions, resultantly contributing to cognitive deficits and clinical symptoms such as depression severity and negativity bias. Focal WMLs may also reduce the likelihood of an antidepressant response when the specific antidepressant used acts on neurotransmitter systems projecting through the damaged fiber tract. This implies that the effect of tract damage on clinical response may differ between drugs with different mechanism of action.
We propose that the cingulum bundle (CB) and uncinate fasciculus (UF) are key tracts in LLD as they are components of cognitive, affective and default mode networks and contain monoamine neurotransmitter projections. Supporting our model, past work implicates CB and UF deficits in LLD and our new pilot data associates tract damage with poor antidepressant response.
In a cohort of up to 130 depressed elders we will test our central hypotheses: a) focal CB and UF WMLs disrupt connectivity and function of connected regions and contribute to cognitive deficits and affective symptoms; and b) antidepressants acting on neurotransmitter systems projecting through these tracts will be less effective.
Overall Study Design: After obtaining informed consent, we will assess for eligibility. Individuals who meet eligibility criteria will complete neuropsychological testing and a one-hour magnetic resonance imaging (MRI). Subjects will then be randomized in a 2:1 ratio to receive either blinded escitalopram or identical placebo. After 8 weeks of study drug, they will be assessed for remission. Those whose depression has remitted will end their study participation. Those who remain symptomatic will be transitioned to open-label bupropion for 8 weeks, after which their participation will end. We will work with participants on plans for clinical care after the study and will offer two additional visits to facilitate that transition.
Specific Aim 1: To characterize the effect of cingulum bundle (CB) and uncinate fasciculus (UF) WMLs on tract connectivity, function of connected regions, and the cognitive and affective presentation of LLD.
Hypothesis 1: Greater CB WML volume is associated with a) reduced resting-state connectivity of frontal, temporal, and cingulate regions and b) deficits in attention, memory and processing speed.
Hypothesis 2: Greater UF WML volume is associated with a) reduced resting state functional connectivity between frontocingulate and medial temporal regions, and b) greater depression severity and negativity bias.
Exploratory Hypothesis: Greater CB WML volume is associated with failure of anterior and posterior default mode network nodes to deactivate during attentional components of the fMRI task. Greater UF WML volume is associated with greater medial temporal reactivity during the functional MRI task.
Specific Aim 2: To determine whether deficits in tract structural / functional connectivity predict nonremission to antidepressant treatments and if these relationships vary based on antidepressant mechanism of action.
Hypothesis 3: Nonremission to escitalopram will be predicted by: a) greater WML volume in the CB and UF, and b) reduced resting functional connectivity between structures connected by the CB and UF. Greater WML severity and reduced functional connectivity in these tracts will not significantly predict response to placebo.
Hypothesis 4: Nonremission to bupropion will be predicted by a) greater WML volume in the UF but not CB, and b) reduced resting functional connectivity deficits between structures connected by the UF but not CB.
Exploratory Aims: Expl. Aim 1) To determine if specific cognitive measures may serve as markers of focal tract WML damage. Expl. Aim 2) To use whole-brain multimodal imaging approaches to examine how connectivity differences in other brain regions may also predict nonremission to antidepressants.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Active comparator | Drug: Escitalopram, Drug: Bupropion XL8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters |
| Blinded Placebo / Open-Label Bupropion | Placebo comparator | Drug: Bupropion XL8 weeks of blinded placebo, followed by 8 weeks of open-label bupropion xl for nonremitters. |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age 60 years or older.
- Current diagnosis of major depressive disorder (DSM-IV-TR), single episode, recurrent or chronic, without psychotic features, as detected by Mini-International Neuropsychiatric Inventory (MINI) and clinical exam.
- Minimum MADRS score ≥ 15.
- Mini-Mental State Exam ≥ 24.
- Fluent in English.
Key exclusion criteria (14 listed)
- Current or past diagnoses of other Axis I psychiatric disorders, except for generalized anxiety disorder (GAD) symptoms occurring during a depressive episode
- History of alcohol or drug dependence or abuse in the last three years
- History of developmental disorder or Intelligence Quotient score < 70
- Presence of acute suicidality
- Acute grief (< 1 month)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EscitalopramAlso: LexaproEscitalopram 10-20mg daily | Drug | Blinded Escitalopram / Open-Label Bupropion |
| Bupropion XLAlso: Wellbutrin XLBupropion XL 150-450mg daily | Drug | Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion |
Primary outcome
Number of Patients With Remission of Depression
Time frame: From Baseline up to Week 16
Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated measure of depression severity. Higher scores indicate greater depression severity, ranging 0-60. This will be used to define remission as a final score of 7 or less
4 secondary outcomes
Change in Depression Severity, Clinician Rated
Time frame: Baseline to week 8
Change in Depression Severity, Self Rated
Time frame: Baseline to week 8
Change in Depression Severity, Clinician Rated
Time frame: Week 8 to week 16
Change in Depression Severity, Self Rated
Time frame: Week 8 to week 16
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36482694Ahmed R, Boyd BD, Elson D, Albert K, Begnoche P, Kang H, Landman BA, Szymkowicz SM, Andrews P, Vega J, Taylor WD. Influences of resting-state intrinsic functional brain connectivity on the antidepressant treatment response in late-life depression. Psychol Med. 2023 Oct;53(13):6261-6270. doi: 10.1017/S0033291722003579. Epub 2022 Dec 9.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Warren D Taylor, MD, MHSc principal investigator
Vanderbilt University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Escitalopram and Bupropion XL in people with Major Depressive Disorder, run by Vanderbilt University Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With Remission of Depression (time frame: From Baseline up to Week 16). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02332291, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2021.