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 typeas 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 humanimmunodeficiency virus infection;

3. history of any type of cancer requiring treatment with more than minor surgery;

4. unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologicdisease (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 heartfailure, stroke - controlled hypertension is OK),

9. major surgery within 8 weeks prior to screening or will require major surgery duringthe 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 orCNS involvement),

13. cirrhosis of the liver from any cause,

14. any of the following specific abnormalities on screening laboratory tests: ALT orAST >2 x upper limits of normal (ULN), alkaline phosphatase (ALP) ≥2 x ULN, totalbilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must havetotal 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 ofany type; substance abuse/dependence within 6 months of study entry (as determinedby standardized clinician interview);

17. active suicidal plan as determined by a score >3 on item #3 on the HAM-D; g. anactive eating disorder (except for patients with binge eating disorder in whombinging is clearly associated with worsening of mood symptoms);

18. history of a cognitive disorder or traumatic head injury involving loss ofconsciousness;

19. pregnancy or lactation,

20. use of gender affirming hormone therapy;

21. chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg ofaspirin), immunosuppressive (e.g., biologics), glucocorticoid containing medicationsor minocycline within 6 months, or non-prescription supplements with known orsuspected anti-inflammatory properties (e.g. fish oil supplements) within 2 weeks ofbaseline, 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'sability to fit comfortably in the MRI scanner.