Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

Emory University57 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Depression

Interventions

Levodopa+carbidopaDRUG

Sinemet is a combination of 250 mg levodopa and 50 mg carbidopa. Sinemet will be administered orally at Visit 1 or Visit 2.

PlaceboDRUG

A placebo is a sugar pill that has no therapeutic effect and will be administered orally at Visit 1 or Visit 2.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (1)

Emory University Hospital

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

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).

Time frame: 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).

Time frame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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