Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

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.

Eligibility Criteria:
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