Neutralizing Interleukin (IL)-6

Official title

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

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• Change in ventral stratal activation during reward processing (fMRI) [Time frame: at week 0 and week 10]

Secondary outcome measures (3)

• Change in Snaith-Hamilton Pleasure Scale (SHAPS) [Time frame: at week 0 and week 12]
• Change in Montgomery-Asberg Depression Rating Scale (MADRS) [Time frame: at week 0 and week 12]
• Change in Temporal Experience of Pleasure Scale (TEPS) [Time frame: at week 0 and week 12]

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Icahn School of Medicine at Mount Sinai — New York

Identifiers

NCT: NCT07493317 · STUDY-25-01000

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗