JAK Signaling in Depression

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 3 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.