Connectivity Affecting the Antidepressant REsponse (The CAARE Study)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 95
- 试验地点
- 1
- 主要终点
- Number of Patients With Remission of Depression
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≥
- •Mini-Mental State Exam ≥
- •Fluent in English.
排除标准
- •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
- •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
研究组 & 干预措施
Blinded Escitalopram / Open-Label Bupropion
8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters
干预措施: Escitalopram (Drug)
Blinded Escitalopram / Open-Label Bupropion
8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters
干预措施: Bupropion XL (Drug)
Blinded Placebo / Open-Label Bupropion
8 weeks of blinded placebo, followed by 8 weeks of open-label bupropion xl for nonremitters.
干预措施: Bupropion XL (Drug)
结局指标
主要结局
Number of Patients With Remission of Depression
时间窗: 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
次要结局
- Change in Depression Severity, Clinician Rated(Week 8 to week 16)
- Change in Depression Severity, Self Rated(Week 8 to week 16)
研究者
Warren Taylor
Professor of Psychiatry
Vanderbilt University Medical Center