Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

Study Overview
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Brief Summary
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The purpose of this study is to learn more about the changes that happen in the brain and the body when a person is depressed. This study will determine if the level of inflammation in the body is related to symptoms of depression, how well the person thinks, and how certain brain regions communicate.

Detailed Description
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Cytokines released by an activated immune system have been associated with decreased brain dopamine and the development of depression. Biomarkers of inflammation, such as inflammatory cytokines and acute-phase proteins like C-reactive protein (CRP), are elevated in a significant proportion of patients with mood and psychiatric disorders. The investigators will study if administration of Levodopa (L- 3,4-dihydroxyphenylalanine [DOPA]-carbidopa, 250/25mg) to depressed patients with high inflammation will 1) increase corticostriatal functional connectivity, and 2) improve objective measures of motivation compared to placebo.

Official Title
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Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa; Inflammation Effects on Corticostriatal Connectivity and Reward: Role of Dopamine

Conditions
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Depression

Intervention / Treatment
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* Drug: Levodopa+carbidopa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects have signed a current version of the Informed Consent and HIPAA documents prior to initiation of study procedures Able to comprehend English Diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM)-V major depression and currently off antidepressant medication, unless otherwise approved by the PI or PI's designee Depression as the primary axis I disorder Negative pregnancy test for women of childbearing potential Not breast feeding At least two CRP tests conducted to establish reliability Exclusion Criteria: Evidence of untreated or poorly controlled endocrine, cardiovascular, pulmonary, hematological, renal, or neurological disease History of central nervous system (CNS) trauma or active seizure disorder requiring medication unless otherwise approved by principal investigator, or PI's designee Current or history of migraines, glaucoma, melanoma, or bleeding disorder of any kind Autoimmune or inflammatory disorder of any kind Embedded metallic objects, prosthetics made of paramagnetic metals, aneurysmal clips and/or a history of claustrophobia Chronic infection (e.g. hepatitis B or C or Human Immunodeficiency Virus infection) Chronic use of agents known to affect the immune system including glucocorticoid therapy within the past 6 months, methotrexate within the past 1 year, chemotherapy of any kind (past or present), immunotherapy of any kind (past or present), aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; within the past 2 weeks), statins (within the past 1 month), vaccinations (within the past 2 weeks), topical steroids (within the past 2 weeks), and antibiotics (within the past two weeks) unless otherwise approved by principal investigator or PI's designee. Suicide attempt within six months of screening, or active suicidal intent or plan, or score >2 on Hamilton Depression Rating Scale (HDRS), or Quick Inventory of Depressive Symptomatology Self-Report (QIDS) or Patient Health Questionnaire (PHQ-9) Suicide Item, unless otherwise approved by the PI or PI's designee A positive pregnancy test Organ transplants Current or history of cancer within the past five years besides basal cell carcinoma, unless otherwise approved by the PI or PI's designee A score of <28 on the Mini Mental Status Exam (MMSE), unless otherwise approved by the PI or PI's designee Wide Range Achievement Test (WRAT-3) score indicating less than 8th grade reading level, unless otherwise approved by the PI or PI's designee Either QIDS <14 or PHQ-9 <15, or HDRS <18, unless otherwise approved by the principal investigator or PI's designee History of the following: schizophrenia, schizoaffective disorder, other (non mood disorder) psychosis, depression secondary to a medical condition, mental retardation, dementia, or delirium Substance dependence [or abuse within the past year (except nicotine)], unless otherwise approved by the PI or PI's designee Body Mass Index >40 to limit the impact of morbid obesity on the results, unless otherwise approved by the principal investigator or PI's designee Antisocial personality disorder diagnosis as assessed during clinical interview, as well as a history of hospitalization and/or recurrent suicidal behavior judged to be directly due to the personality disorder Current eating disorder (except binge eating related to depression) unless approved by PI or PI's designee Current obsessive-compulsive disorder (OCD), exclusionary only if impacting daily functioning, as assessed by clinical interview Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with participating in or completing the protocol Smoking more than 1/2 pack a day or e-cigarette equivalent, unless approved by the PI or PI's designee Initiation of any of the following medications, unless otherwise approved by the PI or PI's designee: Aspirin or Aspirin-like compounds, Ibuprofen or Naproxen Sodium, Cholesterol medications, Antibiotics, Herbal Medications, Psychiatric or Psychotropic Medications, Omega-3 supplements, Topical Steroids, Vaccinations Currently on antidepressant medication, unless otherwise approved by the PI or PI's designee

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sinemet/Placebo<br>Subjects with major depression will be given Sinemet (a combination of 250 mg of levodopa and 50 mg of carbidopa) at one study visit and placebo at the other study visit. Sinemet will be given first followed by placebo at the subsequent visit. | Drug: Levodopa+carbidopa<br>* Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.<br>* Other names: Sinemet;Drug: Placebo<br>* A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.<br>|
| Active Comparator: Placebo/Sinemet<br>Subjects with major depression will be given placebo at one study visit and Sinemet (a combination of 250 mg of levodopa and 50 mg of carbidopa) at the other study visit. Placebo will be given first followed by Sinemet at the subsequent visit. | Drug: Levodopa+carbidopa<br>* Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.<br>* Other names: Sinemet;Drug: Placebo<br>* A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Functional Corticostriatal Connectivity | Corticostriatal connectivity was assessed by functional magnetic resonance imaging (fMRI). Resting-state and task-based (monetary incentive delay [MID]) fMRI scans were conducted on a 3 Tesla Siemens Trio MRI scanner. Subject-level correlations for degree of cortical and striatal functional connectivity were Fisher's Z transformed {Z(R)=0.5ln[(1+R)/(1-R)]}, a standard method for calculating fMRI functional connectivity. Greater Fisher's Z-scores reflected stronger correlated fMRI activity (i.e., higher corticostriatal connectivity). | Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Correlation Coefficient Between Change in Corticostriatal Connectivity and Levels of Plasma C-reactive Protein and Other Immune Markers | Peripheral blood samples were analyzed for levels of immune markers like plasma C-reactive protein (CRP), interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), tumor necrosis factor (TNF) -alpha, soluble cytokine receptor2 (TNFR 2), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1). | Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effort-Expenditure for Rewards Task (EEfRT) Neurocognitive Test | The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial task used to objectively assess motivation. Possible results range between 0 to1 with 1 being a better outcome. Results show mean probability of hard (high effort) choice. | At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| The Trail Making Test (TMT) Neurocognitive Assessment | The Trail Making Test (TMT) is used to measure basic attention and psychomotor processing speed. Time taken to complete each task is recorded in seconds, whereby the greater the number of seconds, the slower the psychomotor speed. | At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Digit Symbol Task Neurocognitive Test | The Digit Symbol Task was used to assess graphomotor speed, visual scanning and memory processing speed involving numbers and a corresponding blank box where subjects are asked to fill in matching symbol as fast as they can. Results show the average number of correct symbols completed in up to 100 boxes in 90 seconds. | At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Finger Tapping Task (FTT) Neurocognitive Test | The Finger Tapping Task (FTT) assesses motor speed and can detect subtle motor impairment. The test measures the average number of taps per 10 second trial. A greater number of taps reflects faster motor speed. | At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Reaction Time Task (CANTAB) Neurocognitive Test | The reaction time test includes simple and choice reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses. The task provided distinction between reaction (or decision) time and movement latencies (milliseconds) based on touch responses made to a single (simple) or chosen from multiple (choice) stimuli flashed on a computer screen. Results show mean response latency in milliseconds. | At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Multidimensional Fatigue Inventory (MFI) Self-report Questionnaire | The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure severity of fatigue based on five dimensions of fatigue, general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The total MFI scores range from 20 to 100 where high scores indicate greater fatigue. | At baseline and Visit 1, Visit 2 (spaced by approximately 1 week) | 
| Snaith-Hamilton Pleasure Scale (SHAPS) Self-report Questionnaire | The Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale with high psychometric validity for assessing the presence of anhedonia, was used to assess hedonic capacity. Participants rated how much they agreed or disagreed with the 14 items phrased as I would enjoy __ based on their ability to experience pleasure. Of the four possible response categories (Definitely Agree, Agree, Disagree, and Strongly Disagree), either of the Disagree responses received a score of 1 and either of the Agree responses received a score of 0. The SHAPS score calculated as the sum of these 14 items ranged from 0 to 14, and higher SHAPS scores indicated greater anhedonia. | Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo | 
| Inventory of Depressive Symptoms-Self Report (IDS-SR) Questionnaire | The Inventory of Depressive Symptoms-Self Report (IDS-SR) is a 30-item self-report instrument with excellent psychometric properties for measuring symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that is widely used to measure depression severity in clinical trials. Response scores are summed and range from 0 to 84, with higher scores reflecting greater depression severity. | At baseline and Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week) | 
| Beck Depression Inventory (BDI-II), Anhedonia Subscale Score | The Beck Depression Inventory-II (BDI-II) is a widely used self-report for measuring depression severity over the past two weeks and the anhedonia subscale is one of several validated subscales in the BDI-II. Responses are given on a 4-point scale where 0 = the symptom of depression has not been experienced and 3 = the symptom of depression is severe. The anhedonia subscale score is created by summing responses to four items of the BDI-II that assess loss of pleasure, loss of interest, loss of energy, loss of sex drive. The total score of the anhedonia subscale ranges from 0 to 12 where higher scores reflect greater severity of anhedonia symptoms. | Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week) | 
| Profile of Mood States (POMS) Scale | The Profile of Mood States (POMS) scale is a 30-item psychological rating scale used to assess transient, distinct mood states. Participants rate the extent to which they feel unhappy, blue, lonely, gloomy, and worthless on a scale from 0 (not at all) to 4 (extremely). Scores range from 0 to 120 with higher scores reflecting a more negative mood state. | Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo | 
| State-Trait Anxiety Inventory (STAI) State Scale | The 20-item self-report State-Trait Anxiety Inventory (STAI) State scale was used to measure severity of anxiety symptoms. Total scores range from 20 to 80 with higher scores reflecting greater anxiety. Scores in the high 40s are considered clinically significant. | Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo | 
| Change in Motivation and Pleasure (MAP) Scale Score | The motivation and pleasure (MAP) questionnaire is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. This scale was used to assess self-reported changes in symptoms of anhedonia before and after inflammation blockade. Respondents respond to statements about daily activities on a scale from 0 (no pleasure/not at all) to 4 (extreme pleasure/very often). Total scores range from 0 to 72 where higher scores indicate greater motivation and effort given to everyday situations. | Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammation, Anhedonia, Psychomotor retardation