This study will test the hypothesis that Janus kinase (JAK) signaling is involved in major depression (MD) with high inflammation by determining whether its inhibition with baricitinib can improve functional connectivity in reward and motor circuits in association with improved motivation and motor function in MD patients enriched for high C-reactive protein (CRP) and anhedonia.

Many people with depression also have high inflammation, which may be a cause of some of their depression symptoms. This study is being done to learn how inflammation affects the brain to cause symptoms of depression like anhedonia, low motivation and motor slowing. This will be tested using a medication called baricitinib that blocks one aspect of inflammation involving Janus kinase (JAK) signaling. The population to be included in this study are patients with depression and symptoms of anhedonia who have high inflammation as determined by a blood test. Patients must also be free of uncontrolled medical illnesses. Patients enrolled in the study will be randomly treated with either baricitinib or a placebo (matching sugar pill) for 8 weeks and assessed for markers of inflammation in the blood and symptoms of depression using self-reported and clinician-guided assessments. In addition, brain scans and computerized testing will be done to measure brain function and levels of motivation and motor speed. Participation in the study will include at least 8 visits over 2-3 months, including screening. Subjects will be recruited from local clinics and from the Atlanta community using social media ads. Approximately 100 subjects will be enrolled for this study to obtain 60 subjects who will be randomized to baricitinib or placebo. Blood and information from the brain scans, computerized testing and assessments of depression will be saved for future use. Consent to participate in the study will be obtained either remotely or in person by a trained staff member.

Inclusion Criteria:

1. willing and able to give written informed consent;
2. men or women, 25-55 years of age;
3. a primary diagnosis of DSM-V major depression, current, or Bipolar, depressed type as diagnosed by the SCID-V;
4. score of >14 on the PHQ-9 from screening and HAM-D score ≥18 for study entry;
5. off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine),
6. CRP ≥3 mg/L,
7. PHQ-9 anhedonia score ≥2.

Exclusion Criteria:

1. history or evidence (clinical and laboratory) of an autoimmune disorder
2. history or evidence (clinical or laboratory) of hepatitis B or C infection or human immunodeficiency virus infection;
3. history of any type of cancer requiring treatment with more than minor surgery;
4. unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination, EKG and laboratory testing);
5. significant hematological abnormalities at screening (ANC < 1500, Hgb<10, platelet< 100,000)
6. history of progressive multifocal leukoencephalopathy,
7. history of deep venous thrombosis,
8. history of cardiovascular disease (coronary artery disease, congestive heart failure, stroke - controlled hypertension is OK),
9. major surgery within 8 weeks prior to screening or will require major surgery during the study,
10. current or recent (<4 weeks prior to randomization) viral (including COVID-19), bacterial, fungal, or parasitic infection or any other active or recent infection,
11. symptomatic herpes zoster infection at or within 12 weeks of randomization,
12. history of disseminated/complicated herpes zoster (for example, ophthalmic zoster or CNS involvement),
13. cirrhosis of the liver from any cause,
14. any of the following specific abnormalities on screening laboratory tests: ALT or AST >2 x upper limits of normal (ULN), alkaline phosphatase (ALP) ≥2 x ULN, total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must have total bilirubin <2 x ULN),
15. chronic kidney disease with eGFR <60 mL/min/1.73 m2,
16. history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry (as determined by standardized clinician interview);
17. 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);
18. history of a cognitive disorder or traumatic head injury involving loss of consciousness;
19. pregnancy or lactation,
20. use of gender affirming hormone therapy;
21. chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), immunosuppressive (e.g., biologics), glucocorticoid containing medications or minocycline within 6 months, or non-prescription supplements with known or suspected anti-inflammatory properties (e.g. fish oil supplements) within 2 weeks of baseline, or at any time during the study;
22. any contraindication for MRI scanning;
23. failure of more than 2 antidepressant trials (at least 6 weeks at recommended dose) in the current episode or 5 antidepressant trials lifetime; and
24. BMI >45 (to exclude severe obesity) or at the PI's discretion based on the patient's ability to fit comfortably in the MRI scanner.

All data will be de-identified prior to receipt by the repository, but the information needed to generate a global unique identifier for the NIMH Data Archive (NDA) will also be collected for each subject.

The research community will have access to data at the end of the grant award or when a publication has been submitted. Once the data are submitted to NDA, that archive will control the long-term persistence of the data set. Currently, NDA has no process for deleting or retiring data sets.

Data will be findable for the research community through the NDA Collection that will be established when this application is funded.

To request access of the data, researchers will use the standard processes at NDA, and the NDA Data Access Committee will decide which requests to grant. The standard NDA data access process allows access for one year and is renewable.