Effects of Bupropion Versus Escitalopram on Reward Circuitry and Motivational Deficits in Patients With Major Depression and Increased Inflammation and Anhedonia
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC)
研究概览
简要总结
This study is designed to determine whether bupropion (vs escitalopram) increases functional connectivity (FC) within reward-related neurocircuits and decreases motivational deficits in depressed patients with increased inflammation and anhedonia. Participants will be randomized to take bupropion extended release (XL) or escitalopram for 8 weeks.
详细描述
The goal of the proposed research is to determine the mechanism of action of an antidepressant of known efficacy (bupropion) and to tie this mechanism of action to a biomarker of inflammation in support of precision medicine for the treatment of major depression (MD). MD is a devastating disease affecting approximately 10% of US adults and being the leading cause of disability worldwide. Despite availability of several classes of antidepressant medications, initial treatment response is low (around 30%), and approximately 1/3 of depressed patients are non-responsive to conventional antidepressant therapies. Although extensive reviews of the literature suggest that available antidepressant medications are equally effective, recent studies suggest that there may be differential responsiveness to conventional antidepressants among subgroups of depressed patients. One subgroup of depressed patients who may exhibit differential antidepressant responsiveness are those with increased markers of inflammation. Data from previous studies support the notion that differential responsiveness to conventional antidepressants exists and may be revealed by pretreatment levels of inflammation as indexed by the inflammatory biomarker C-reactive protein (CRP).
This study proposes to use a mechanistic clinical trial design with drugs of known efficacy to take the first step toward establishing whether antidepressants that target dopamine (e.g. bupropion) might be a better choice for depressed patients with increased inflammation and anhedonia than an selective serotonin reuptake inhibitor (SSRI). Accordingly, 50 depressed patients with a CRP>2mg/L and increased anhedonia will be randomized to 8 weeks of bupropion or escitalopram in order to analyze data from 40 patients (accounting for drop outs). All depressed patients will undergo functional magnetic resonance imaging (fMRI) to examine functional connectivity in reward-related circuits at baseline and 4 and 8 weeks along with objective and clinical assessments of Research Domain Criteria (RDoC) positive (motivational) valence constructs at baseline and 2, 4, 6 and 8 weeks.
The researchers hypothesize that patients who receive bupropion versus escitalopram will exhibit increased functional connectivity between ventral striatum and ventromedial prefrontal cortex in association with decreased motivational deficits and anhedonia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 25 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •willing and able to give written informed consent
- •a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) MD, current as diagnosed by the Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V)
- •score of ≥16 on the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR)
- •off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine); concomitant administration of up to 2 mg of clonazepam or its equivalent per day will be allowed, but not within 12 hours of study assessments
- •CRP>2mg/L
- •Inventory of Depressive Symptomatology (IDS-SR) anhedonia subscale score ≥5
排除标准
- •history of any autoimmune disorder
- •history of hepatitis B or C infection or human immunodeficiency virus infection
- •history of any type of cancer requiring treatment with more than minor surgery
- •unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination and laboratory testing)
- •history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry (as determined by SCID)
- •an active eating disorder or antisocial personality disorder
- •a history of a cognitive disorder or ≤28 on the Mini-Mental State Exam unless otherwise approved by the PI
- •pregnancy or lactation
- •chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications
- •use of NSAIDS or oral glucocorticoids at any time during the study
- •any contraindication for MRI scanning
- •failure of more than 2 antidepressant trials in the current episode
- •Intolerance of bupropion or escitalopram
- •BMI >40 (to exclude severe obesity)
- •due to the high co-morbidity between anxiety disorders and depression, the study team plans to include patients with anxiety-related disorders excluding obsessive-compulsive disorder (OCD) if depression is the primary diagnosis. Patients with stable medical conditions and on medications for those conditions will not be excluded. Concomitant administration of up to 2 mg of clonazepam or its equivalent per day will be allowed, but not within 12 hours of study assessments.
- •sexually active participants are required to use medically approved birth control methods as defined in the Birth Control Method Form for the duration of the study
研究组 & 干预措施
Bupropion
Participants randomized to take bupropion for 8 weeks.
干预措施: Bupropion XL (Drug)
Escitalopram
Participants randomized to take escitalopram for 8 weeks.
干预措施: Escitalopram (Drug)
结局指标
主要结局
Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC)
时间窗: Baseline, Week 4, Week 8
Targeted FC is calculated as the degree of correlation in activity between a 3mm3 radius sphere in VS and the vmPFC cluster identified as being reward-sensitive in neuroimaging meta-analyses and as used to define vmPFC in previous work. Subject-level correlations for degree of vmPFC-VS FC is Fisher's Z transformed {Z(R)=0.5ln\[(1+R)/(1-R)\]}, a standard method for calculating fMRI functional connectivity, whereby greater Z-scores reflected stronger correlated functional magnetic resonance imaging (fMRI) activity (i.e., higher VS-vmPFC connectivity). For each study timepoint, Z-scores will be extracted and the change in mean FC values compared to baseline will be calculated. The central value is 0, and the standard deviation depends on the sample variance. Increasing values indicate increasing connectivity between the indicated brain regions (VS and vmPFC). There are no relevant thresholds, and there is no direct interpretation of results in terms of clinical improvement.
次要结局
- Inventory of Depressive Symptomatology - Self-Report (IDS-SR)(Baseline, Week 2, Week 4, Week 6, Week 8)
- Snaith-Hamilton Pleasure Scale (SHAPS-C) Score(Baseline, Week 2, Week 4, Week 6, Week 8)
- Motivation and Pleasure Scale-Self-Report (MAP-SR) Score(Baseline, Week 2, Week 4, Week 6, Week 8)
- Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT)(Baseline, Week 2, Week 4, Week 8)