The purpose of this 8-week, double-blind, placebo-controlled, study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Seventy male and female participants with depression, between 25-55 years of age, with higher levels of inflammation and anhedonia will be randomized to receive L-DOPA or matched placebo over 8 weeks. Participants will complete lab tests, medical and psychiatric assessments, motivation and motor tasks, and MRI scans as part of the study. The total length of participation is approximately 10 to 12 weeks.

Depression is a widespread disorder (lifetime prevalence >20%). Current antidepressant medications are effective for many patients; however, more than 30% fail to respond. Of the patients that do respond to treatment, some continue to suffer with primary symptoms of depression like an inability to experience pleasure, called anhedonia. In this regard, one biological pathway that may contribute to symptoms of depression and particularly anhedonia is inflammation.

The purpose of this 8-week, double-blind, placebo-controlled, study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Despite evidence of low dopamine function in patients with depression, the ability of existing dopaminergic therapies, like L-DOPA, to affect brain circuits in depression has yet to be explored. This study will help determine whether an FDA-approved medication, Sinemet (L-DOPA), might be used in the future to treat sub-groups of depressed individuals.

Seventy male and female participants with depression, between 25-55 years of age, with higher levels of inflammation and anhedonia will be randomized to receive L-DOPA or matched placebo over 8 weeks. Participants will complete lab tests, medical and psychiatric assessments, motivation and motor tasks, and MRI scans as part of the study. The total length of participation is approximately 10 to 12 weeks.

Inclusion Criteria:

• a. willing and able to give written informed consent
• b. men or women, 25-55 years of age
• c. a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), current, as diagnosed by the Structured Clinical Interview for DSM-5
• d. score of >10 on the Patient Health Questionnaire-9 (PHQ-9) or HAM-D score ≥18
• e. off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine)
• f. c-reactive protein (CRP) ≥2 mg/L
• g. PHQ-9 anhedonia score ≥2

Exclusion Criteria:

• a. history or evidence (clinical or laboratory) of an autoimmune disorder
• b. history or evidence (clinical or laboratory) of hepatitis B or C infection or human immunodeficiency virus infection
• c. history of any type of cancer requiring treatment with more than minor surgery
• d. unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination, EKG and laboratory testing)
• e. history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; history or current bipolar disorder; history or current gambling disorder; substance abuse/dependence within 6 months of study entry (as determined by standardized clinician interview)
• f. active suicidal plan as determined by a score >3 on item #3 on the HAM-D
• g. an active eating disorder (except for patients with binge eating disorder in whom binging is clearly associated with worsening of mood symptoms)
• h. a history of a cognitive disorder or traumatic head injury involving loss of consciousness
• i. pregnancy or lactation
• j. use of gender affirming hormone therapy
• k. chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications or statins
• l. use of NSAIDS, glucocorticoids, or statins at any time during the study
• m. urine toxicology screen is positive for drugs of abuse, n. any contraindication for MRI scanning
• o. intolerance, sensitivity or contraindication to carbidopa-levodopa (including history of narrow-angle glaucoma, melanoma, gastric and/or duodenal ulcers, bleeding disorders, or frequent migraines)

Only the data - raw and analyzed, or both, depending on the items. Statistical plans an additional information may be shared within the data base but it is not required as the data will be linked to the publications.

After publication, within one year of the end of the project.

Must be NIH investigators and they have to submit an application, including analysis plan, in order to be granted access.