Neutralizing Interleukin (IL)-6

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

The proposed study aims to establish the feasibility and safety of subcutaneous tocilizumab, a monoclonal antibody (mAb) against interleukin (IL)-6 receptor, in adults with Major Depressive Disorder (MDD) and evidence of peripheral immune activation. IL-6 is a pro-inflammatory cytokine implicated in the pathophysiology of depression. The investigators hypothesize that neutralizing peripheral immune signaling via IL-6 receptor blockade with tocilizumab will improve neural and behavioral measures of reward processing. This is an open-label, proof-of concept, trial in which up to N=20 adults with MDD meeting a specific immune enrichment criterion will receive open-label tocilizumab over 8 weeks. A healthy control (HC) group (N=20) will undergo baseline neuroimaging and blood-based biomarker assessment without receiving the study drug to aid interpretation of findings. Blood-based immune markers and brain MRI scans (including task-based reward activation and resting-state functional connectivity) will be assessed at baseline for all participants and again post treatment for the MDD group.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Tocilizumab

Detailed Description

This open-label, proof-of-concept interventional study is designed to evaluate the feasibility and safety of IL-6 receptor blockade using subcutaneous tocilizumab in adults with MDD and evidence of peripheral immune activation.

Participants with MDD (N=20) meeting immune enrichment criteria (elevated monocyte count) will receive tocilizumab 162 mg administered subcutaneously every 2 weeks for 8 weeks (5 total doses).

A comparison group of healthy volunteers (N=20) will undergo baseline neuroimaging and blood sampling but will not receive study drug.

The primary objective is to assess change in neural reward circuitry function, measured by ventral striatal activation during reward processing tasks using functional MRI.

Secondary objectives include evaluating changes in anhedonia and depressive symptoms using validated clinical scales (SHAPS, MADRS, TEPS), as well as changes in peripheral immune biomarkers.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alexia Lizzano; Phone Number: 3322437059; Email: alexia.lizzano@mssm.edu
• Study Contact Backup: Name: Mackenzie Hargrove; Phone Number: 3322437052; Email: mackenzie.brown@mssm.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • ICAHN School of Medicine at Mount Sinai
      • Principal Investigator: James Murrough
      • Contact: Mackenzie Hargrove; Phone Number: 332-243-7052; Email: mackenzie.brown@mssm.edu
      • Contact: Matthew Dobbs; Phone Number: 332-243-7055; Email: matthew.dobbs@mssm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants with MDD; MDD participants will receive 5 doses of tocilizumab 162 mg administered via subcutaneous injection every 2 weeks over an 8-week period.	Drug: Tocilizumab; One treatment condition in an open-label study design: subcutaneous injection of tocilizumab 162 mg at weeks 0, 2, 4, 6, and 8.
No Intervention: Healthy Control; Healthy controls will serve as a baseline comparison group for neuroimaging and biomarker analyses only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ventral stratal activation during reward processing (fMRI)	Change in ventral stratal activation (brain response) during reward processing (fMRI)	at week 0 and week 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Snaith-Hamilton Pleasure Scale (SHAPS)	Changes in the following scales from baseline to end of treatment: Snaith-Hamilton Pleasure Scale (SHAPS): SHAPS total score ranges from 14 to 56, with higher scores indicating greater anhedonia.	at week 0 and week 12
Change in Montgomery-Asberg Depression Rating Scale (MADRS)	Changes in the following scales from baseline to end of treatment: Montgomery-Asberg Depression Rating Scale (MADRS): MADRS total score ranges from 0 to 60, with higher scores indicating greater depression severity.	at week 0 and week 12
Change in Temporal Experience of Pleasure Scale (TEPS)	Changes in the following scales from baseline to end of treatment: Temporal Experience of Pleasure Scale (TEPS): TEPS total score ranges from 25 to 120, with lower scores indicating greater anhedonia severity.	at week 0 and week 12

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: James Murrough, ICAHN School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2026
• Primary Completion (Estimated): February 6, 2031
• Study Completion (Estimated): February 6, 2031

Study Registration Dates

• First Submitted: March 20, 2026
• First Submitted That Met QC Criteria: March 20, 2026
• First Posted (Actual): March 25, 2026

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Monoclonal antibody; Healthy Volunteer; fMRI; Tocilizumab; Anhedonia; Interleukin-6
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Behavioral Symptoms; Neurobehavioral Manifestations; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Depression; Depressive Disorder, Major; Anhedonia; tocilizumab
• Other Study ID Numbers: STUDY-25-01000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared due to privacy concerns related to sensitive psychiatric and neuroimaging data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No