Cognitive Dysfunction and Inflammation in Depression: Experimental Inhibition Via Infliximab

The Role of Inflammation in Cognitive Dysfunction in Acute Depression as Determined by Experimental Inhibition of Tumor Necrosis Factor-alpha Signaling in a Randomized Controlled Trial.

This study is a mechanistic randomized controlled trial that investigates whether inhibition of tumor necrosis factor signaling via intravenous infusion of infliximab improves psychomotor speed and executive functioning in depressed individuals who exhibit an inflammatory phenotype.

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Depressive Disorder, Major
• Intervention / Treatment: Drug: Infliximab; Other: Placebo

Detailed Description

In this mechanistic RCT, depressed adults who exhibit a pro-inflammatory phenotype (C reactive protein ≥3mg/L) will be randomized on a 1:1 allocation to receive a TNF inhibitor (infliximab) or placebo. Over a two-week follow-up, participants will remotely complete brief, daily assessments of depressive symptoms and psychomotor speed/executive functioning using a mobile-based platform (TestMyBrain) in addition to in-person clinician-rated assessment of depressive symptom severity (Hamilton Depression Rating Scale), anhedonia (Dimensional Anhedonia Rating Scale), and more comprehensive computerized batteries assessing cognitive function (TestMyBrain). Blood will be drawn at baseline and week 1 to assess immune biomarkers (C reactive protein, tumor necrosis factor- alpha and its soluble receptors). Specifically, the study will determine whether randomization to infliximab is associated with improvement in psychomotor speed and executive function.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Naoise Mac Giollabhui, PhD; Phone Number: 6177241000; Email: nmacgiollabhui@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Naoise Mac Giollabhui, PhD; Phone Number: 6177241000; Email: nmacgiollabhui@mgh.harvard.edu
      • Principal Investigator: Naoise Mac Giollabhui, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 25-50 years
2. Able to read and understand English and willing to provide informed consent/comply with the study protocol
3. Willingness to complete intravenous infusion and have blood drawn
4. Exhibit circulating blood level of C reactive protein ≥ 3mg/L
5. Diagnosed with Major Depressive Disorder
6. Moderate depressive symptom severity, as indicated by score ≥15 on the Hamilton Depression Rating Scale
7. Antidepressant treatment free for at least 4 weeks prior to study entry or be on a fixed treatment regimen for at least 4 weeks; willingness to continue treatment status (i.e., change/begin new treatment) until study termination
8. Willingness not to begin/change therapies until study termination (maximum of three weeks following screening)

9. Be of non-childbearing potential per the following specific criteria:

   a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or b. Childbearing potential and meets the following criteria: i. A negative serum pregnancy test within thirty days of infusion (may be repeated closer to infusion date at the discretion of the PI or study staff) and abstinent after the negative serum pregnancy test and prior to infusion; or ii. Using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent; iii. Continuously use one of the following methods of birth control over the last six months: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence.

Exclusion Criteria:

1. Medical conditions that could confound interpretation or increase participant risk, as indicated via medical history or laboratory testing; exclusionary medical conditions will include:

   i. acute injury/infection within one week of study initiation or infection within one month of study initiation that required antibiotic/antiviral treatment ii. chronic infection (e.g., hepatitis B or C or HIV) or history of Covid 19 infection within the past 6 months or with persisting symptoms.

   iii. latent infection (e.g., tuberculosis, fungal infections), or history of recurrent infections, iv. uncontrolled cardiovascular, endocrine, hematologic, hepatic, renal or neurologic disease (as determined by medical history, physical exam and laboratory testing) v. cancer history vi. autoimmune conditions; neurologic conditions (controlled) that are known to substantially impact cognitive function (e.g., stroke).

   Of note, stable medical conditions such as diabetes and cardiovascular disease, will be allowed in the study as they can contribute to endogenous inflammation.

2. Active antipsychotic and anticonvulsant medication use (that interact with infliximab)
3. Prior use of a TNF antagonist or use of systemic corticosteroids or anti-proliferative agents within one year of study entry
4. History of liver abnormalities
5. Major cognitive impairment as determined by study investigators
6. Active restrictive eating disorder or obsessive compulsive disorder deemed by study investigators to be primary cause of depressive disorder
7. History of a psychotic disorder or Bipolar disorder type I/II
8. Current substance use disorder (i.e., present in last six months), of greater than mild severity
9. Suicidal ideation based on a score ≥3 on the Columbia-Suicide Severity Rating Scale
10. Electroconvulsive therapy (ECT)/deep brain stimulation (DBS) within the last year, or report of persistent negative cognitive effects of ECT/DBS
11. Presence of a transplanted solid organ

12. Medication use affecting immune or cognitive function:

    i. Chronic use (>1 month) of a benzodiazepine more than the equivalent of 2 mg of lorazepam ii. Use of anti-inflammatory agents during the study: non-steroidal anti-inflammatory agents (NSAIDs) (excluding 81mg of aspirin), glucocorticoid containing medicines or statins, or cyclooxygenase-2 (COX-2) inhibitors

13. Considered by the study investigators to be inappropriate for the study due to safety concerns or to be unlikely to complete the protocol
14. History of allergic response to murine products

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Infliximab; Participants in this arm will receive 5 mg/kg of infliximab via an in-dwelling catheter.	Drug: Infliximab; Intravenous infusion of infliximab
Placebo Comparator: Placebo; Participants in this arm will receive saline as placebo via an in-dwelling catheter.	Other: Placebo; Intravenous infusion of saline solution (matching in color and consistency in infliximab)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psychomotor Speed (TestMyBrain: Simple Reaction Time)	Faster within-person psychomotor speed (i.e. median response time)	Repeated measures over two weeks
Executive Function (TestMyBrain: Choice Reaction Time)	Better within-person executive function performance (i.e. accuracy-adjusted response speed)	Repeated measures over two weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression Rating Scale (17-item; range 0-54)	Reduced depressive symptoms severity	Week 2
Dimensional Anhedonia Rating Scale (17-item; range 0-68)	Reduced anhedonia	Week 2
Concentrations of circulating C reactive protein	Reduced circulating C reactive protein	Week 1

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2025
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): January 31, 2029

Study Registration Dates

• First Submitted: November 13, 2023
• First Submitted That Met QC Criteria: November 13, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 7, 2025
• Last Update Submitted That Met QC Criteria: May 6, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Depression; Major Depressive Disorder; Infliximab; Cognitive Dysfunction
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Behavioral Symptoms; Neurocognitive Disorders; Cognition Disorders; Mood Disorders; Cognitive Dysfunction; Depression; Depressive Disorder; Inflammation; Depressive Disorder, Major; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Gastrointestinal Agents; Antirheumatic Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: 2023p002988

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes