A Neurobiological Model of Anhedonia

Study Overview
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Brief Summary
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The purpose of this research study is to better understand anhedonia in Major Depressive Disorder by investigating the reward-related neural and inflammatory correlates.

Detailed Description
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Background: Despite extensive research on the treatment of Major Depressive Disorder (MDD) relapse rates are as high as 80%. Of those, 30-40% fall into the severe spectrum called treatment resistant depression (TRD) as they fail to respond to at least two lines of antidepressant treatment interventions. TRD has been linked with anhedonia, the inability to experience pleasure or interest in usually enjoyable activities. The neurobiology of anhedonia is poorly understood with recent literature examining an inflammatory association and linking it to deficits in reward-related brain circuitry. The present study examines neurobiological correlates of anhedonia in MDD and TRD, specifically C-Reactive Protein (CRP), IL-6 and ventral striatal (VS) activity. The study also explores whether VS activity mediates the association between inflammation and anhedonia.

Official Title
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Inflammatory, Behavioral and Neural Markers of Anhedonia in Major Depressive Disorder

Conditions
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Anhedonia, Depression

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current diagnosis of MDD based on the MINI International Neuropsychiatric Interview (MINI) For treatment resistant depression participants: unsuccessful treatment with at least 2 types or doses of antidepressant medication treatment Right-handed Capacity for informed consent Score a 9 or higher on the MADRS Exclusion Criteria: Comorbid Bipolar Disorder Substance use disorder in the last 12 months Schizophrenia, and other psychotic disorders Comorbid illness such as endocrinological illness (e.g. Cushing's disease) rheumatologic illness (e.g., systemic Lupus erythematosus, current treatment with glucocorticoids), and autoimmune diseases (e.g. psoriasis) Pregnancy Daily NSAID or aspirin use and any metallic implant Visual/Hearing Impairments that would keep participant from being able to complete tasks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants with Major Depressive Disorder including TRD<br>Treatment resistant depression (TRD) participants are defined as participants with Major Depressive Disorder (MDD) who fail to respond to at least two lines of antidepressant medication treatment interventions. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Basal inflammatory marker assessment | Quantify the profile of basal inflammatory markers (IL-6 and C-reactive protein) in blood. Blood will be collected within an hour after consent and will be processed by 3 hours. | 1 hour | 
| Behavior during reward-based task - Monetary Incentive Delay Task | Participants will complete the Monetary Incentive Delay (MID) task, a reward-based task, while undergoing functional magnetic resonance imaging (fMRI). Results will include button press reaction time for the MID task. | 30 minutes | 
| Behavior during reward-based task - Reward Probabilistic Reversal Learning Task | Participants will complete a Reward Probabilistic Reversal Learning Task, a reward-based task, while undergoing functional magnetic resonance imaging (fMRI). Results will include choice behavior, either choice A or choice B, (button press) for this task. | 30 minutes | 
| Blood oxygen level dependent (BOLD) activation during reward-based tasks | Participants will undergo functional magnetic resonance imaging (fMRI) while completing the tasks in Outcome 2. Ventral striatum activation during the tasks will be measured by % BOLD signal change. The expected signal change is between .1-.8%. | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mediation model between inflammation and anhedonia | Hierarchical linear mediation analysis will be used to determine if BOLD signal in the ventral striatum during reward based tasks significantly mediates the link between inflammation and anhedonia. | 3 hours | 
| Exploratory inflammatory marker assessment | Exploratory analysis of pro (IL-8, TNF-alpha) and anti- inflammatory marker (IL-10) from blood samples will be conducted. All cytokines will be transformed log(x+1) to correct a positive skew and to maintain a meaningful zero. Outlier cytokine values (>3 standard deviations above the mean) and winsorize will be identified by replacing any value with a z-score of greater than 3 SD with the value of 3 SD from the mean. This will be done for each individual cytokine. Z-scores for each individual's cytokine concentration will be calculated based on the means and standard deviations for each cytokine after winsorizing. The composite cytokine score will then be determined by calculating the mean of the basal cytokine Z-scores for each individual. A composite measure of inflammation may be statistically examined, which would involve combining these cytokines into 1-2 factors. | 3 hours | 
| Exploratory analysis of reward related regions | Exploratory analysis of reward related brain regions (ventromedial prefrontal cortex and orbitofrontal cortex) will be conducted using % BOLD signal change. The expected signal change is between .1-.8%. | 3 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Anhedonia, Reward Related Neural Circuitry, Inflammation