Blocking IL-6 with tocilizumab for depression

Neutralizing Interleukin (IL)-6 Signaling to Reverse Immune Related Anhedonia in Patients With Major Depressive Disorder

This study will test whether subcutaneous injections of the anti‑IL‑6 drug tocilizumab can improve reward‑related brain activity and depressive symptoms in adults with major depressive disorder who have high monocyte counts.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Icahn School of Medicine at Mount Sinai (Academic / other)
• Drugs / interventions: tocilizumab
• Locations: 1 site (New York, New York)
• Trial ID: NCT07493317 on ClinicalTrials.gov

What this trial studies

This open‑label, proof‑of‑concept Phase 2 trial will enroll up to 20 adults with major depressive disorder who meet an immune enrichment criterion (monocyte count ≥500 cells/μL) to receive subcutaneous tocilizumab 162 mg every two weeks for eight weeks (five total doses). A comparison group of 20 healthy volunteers will undergo baseline neuroimaging and blood biomarker sampling but will not receive the drug. The primary outcome is change in ventral striatal activation during reward processing on task‑based fMRI, with secondary outcomes including changes in anhedonia and depressive symptoms (SHAPS, MADRS, TEPS) and peripheral immune biomarkers. Safety and feasibility of the dosing schedule will also be monitored throughout the 8‑week treatment period.

Who should consider this trial

Good fit: Adults aged 18–70 with a DSM‑5 major depressive episode, elevated monocyte count (≥500 cells/μL), SHAPS ≥20, and stable antidepressant dosing for at least four weeks (plus agreement to contraception requirements) are the intended participants.

Not a fit: Patients without evidence of peripheral immune activation (low monocyte counts), those with depression driven by non‑inflammatory mechanisms, or those with contraindications to tocilizumab (e.g., active infection or significant immunosuppression) are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, this approach could reduce inflammation‑linked anhedonia and improve reward processing and depressive symptoms for patients with immune‑activated MDD.

How similar studies have performed: Targeting inflammation in depression is biologically plausible and has produced mixed but sometimes promising signals; IL‑6 blockade with tocilizumab is well established in autoimmune diseases but remains novel and unproven specifically for treating depression.

Eligibility criteria

Inclusion Criteria:

For MDD participants:

* Written informed consent;
* Ability to comply with the requirements of the study as determined by the PI;
* Ages 18-70 years;
* Any gender;
* DSM-5 diagnosis of MDD in a current Major Depressive Episode;
* Immune enrichment criterion: elevated monocyte count ≥ 500 cells/μL at screening;
* If patient is on antidepressant medication, they must be on a stable dose for ≥4 weeks prior to treatment;
* SHAPS score ≥20
* If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinence until 6 months after the last dose of study drug;
* Male patients, if heterosexually active with a partner who is female of childbearing potential, pregnant, or breastfeeding, must agree to barrier contraception for the treatment period and for at least 6 months after the last dose of the study drug. Female partners of male participants must use at least one form of highly effective contraception starting at least one cycle prior to male patient study drug initiation until 6 months after the last dose of study drug.
* Meet all MRI safety criteria.

For Healthy Volunteers:

* Written informed consent;
* Ability to comply with the requirements of the study as determined by the PI;
* Ages 18-70
* Any gender;
* No current or past DSM-5 psychiatric disorder;
* Meet all MRI safety criteria.

Exclusion Criteria:

For MDD Participants

* A primary DSM-5 psychiatric diagnosis other than MDD, with the exception of comorbid anxiety disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder, panic disorder) and post-traumatic stress disorder, which are permitted.
* History of schizophrenia, schizoaffective disorder, other psychotic disorder, MDD with psychotic features, or bipolar I or II disorder.
* Diagnosis of a major neurocognitive disorder.
* Moderate or severe substance use disorder within the past 6 months (excluding nicotine use disorder).
* Positive urine toxicology screen for illicit substances at screening.
* Serious or imminent risk of self-harm or violence, as determined by the PI, including:

  * Suicide attempt within the past 2 years, or
  * C-SSRS ideation score \>2 within the past month.
* Any contraindication to MRI, including claustrophobia, retained metallic foreign bodies, magnetic implants or pacemakers, or inability to tolerate MRI procedures.
* Clinically significant abnormalities on physical examination or laboratory testing.
* Unstable or clinically significant medical illness, including but not limited to hepatic, renal, gastrointestinal, respiratory, cardiovascular (including ischemic heart disease), endocrine, neurologic (including history of severe head injury), immunologic, or hematologic conditions.
* Evidence of active or untreated infection, including
* Active tuberculosis (TB) or untreated latent TB
* Positive QuantiFERON-TB Gold test at screening
* Known HIV infection
* Active Hepatitis B or Hepatitis C infection
* Current or recent (within an appropriate washout period) use of biologic therapies or other immunosuppressive agents (PRN NSAIDs permitted).
* Known hypersensitivity to tocilizumab or its excipients.
* Receipt of a live or live-attenuated vaccine within 30 days prior to first dose, or planned receipt during the study period.
* Pregnancy, breastfeeding, or unwillingness to use effective contraception during the study and for 6 months after the last dose.
* Any condition that, in the opinion of the PI, would compromise participant safety or data integrity.

For Healthy Volunteers

* Any current or unstable medical illness, including hepatic, renal, gastrointestinal, respiratory, cardiovascular (including ischemic heart disease), endocrine, neurologic (including history of severe head injury), immunologic, or hematologic disease.
* Use of biologic therapies or immunosuppressive agents (PRN NSAIDs permitted).
* Positive urine toxicology screen for illicit substances at screening.
* Pregnancy at the time of baseline assessments (e.g., MRI).

Where this trial is running

New York, New York

• Icahn School of Medicine at Mount Sinai — New York, New York, United States (Recruiting)

Study contacts

• Principal investigator: James Murrough — Icahn School of Medicine at Mount Sinai
• Study coordinator: Alexia Lizzano

Conditions Major Depressive Disorder; Depression; Monoclonal antibody; Healthy Volunteer; Tocilizumab; Interleukin-6; Anhedonia; fMRI