Baricitinib to block JAK signaling in people with depression and high inflammation

Janus Kinase (JAK) Signaling in Depression

This trial will test whether the anti-inflammatory pill baricitinib can improve motivation, motor speed, and reward-circuit brain function in adults (25–55) with major depression, anhedonia, and high C-reactive protein.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 25 Years to 55 Years
• Sex: All
• Sponsor: Emory University (Academic / other)
• Drugs / interventions: baricitinib
• Locations: 1 site (Atlanta, Georgia)
• Trial ID: NCT07003997 on ClinicalTrials.gov

What this trial studies

This randomized, placebo-controlled Phase 2 trial enrolls adults 25–55 with major depressive symptoms, significant anhedonia, and CRP ≥3 mg/L who are off psychotropic medications. Approximately 100 participants will be screened to randomize about 60 subjects to 8 weeks of baricitinib or matching placebo, with at least eight study visits over 2–3 months. Outcomes include blood inflammatory markers, clinician and self-reported depression measures, computerized tests of motivation and motor speed, and functional brain imaging of reward and motor circuits. Collected blood, imaging, and behavioral data will be stored for future research with consent.

Who should consider this trial

Good fit: Adults aged 25–55 with DSM-V major depressive episode or bipolar depressed type who have anhedonia, PHQ-9 anhedonia score ≥2, PHQ-9 >14 and HAM-D ≥18, CRP ≥3 mg/L, and who are off psychotropic medications for the required washout period.

Not a fit: Patients without elevated inflammation (CRP <3 mg/L), those with autoimmune disease, active hepatitis/HIV, recent cancer treatment, or unstable medical conditions are unlikely to benefit or are excluded.

Why it matters

Potential benefit: If successful, this approach could provide a new anti-inflammatory treatment option that improves motivation and motor symptoms in people with inflammation-linked depression.

How similar studies have performed: Broadly, anti-inflammatory approaches in depression have had mixed results, and specifically targeting JAK signaling with baricitinib for depression is a relatively novel and limitedly tested strategy.

Eligibility criteria

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.

Where this trial is running

Atlanta, Georgia

• Emory University — Atlanta, Georgia, United States (Recruiting)

Study contacts

• Principal investigator: Jennifer Felger, PhD — Emory University
• Study coordinator: Jennifer Felger, PhD

Conditions Major Depressive Disorder