Inflammation-Induced CNS Glutamate Changes in Depression

NCT03004443 | Terminated Phase 4 Results DMC FDA Drug

• 2 other identifiers: IRB000906671R01MH112076-01
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Increased inflammation has been implicated in the pathophysiology of a number of neuropsychiatric illnesses including mood disorders, which affect almost 30 million adults in the United States alone. One mechanism by which inflammation may alter behavior is through increasing brain glutamate, a neurotransmitter that in excess has been implicated in neuronal toxicity and resistance to conventional antidepressant therapy. The goal of the proposed research is to test the hypothesis that inflammation alters behavior through increasing glutamate in specific brain regions, ultimately leading to behavioral changes. The proposed research is designed to determine the cause and effect relationship between inflammation and CNS glutamate as well as the relationship between CNS glutamate and specific symptoms. To accomplish these aims, investigators will administer a single infusion of either the tumor necrosis factor (TNF) antagonist infliximab or placebo (n=30 per group) to patients with high inflammation (CRP\>3mg/L). A CRP\>3mg/L was chosen because it is considered high inflammation according to guidelines by the American Heart Association. Moreover, a CRP\>3mg/L is associated with significantly increased basal ganglia glutamate and with a clinical response to infliximab. Inflammatory biomarkers, basal ganglia glutamate as measured by MRS, and motivation and psychomotor activity will be assessed at baseline and days 1 and 3 and weeks 1 and 2 following infliximab or placebo administration.

Conditions

Depression

Keywords

Psychiatry

Outcome Measures

Primary Outcomes (1)

• Central Nervous System (CNS) Glutamate

  Left basal ganglia glutamate was measured by magnetic resonance spectroscopy (MRS). Left basal ganglia glutamate tends to be increased during inflammation and is also associated with an increase in depressive symptoms.

  Baseline, Day 3, Week 2

Secondary Outcomes (13)

• Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score

  Baseline, Day 3, Week 2

• Mood and Pleasure Scale - Self Report (MAP-SR) Score

  Baseline, Day 3, Week 2

• Finger Tapping Task (FTT) Score

  Baseline, Day 3, Week 2

• Digit Symbol Substitution Task (DSST) Score

  Baseline, Day 3, Week 2

• Trails Making Test A (TMT-A) Score

  Baseline, Day 3, Week 2

Study Arms (2)

Infliximab

EXPERIMENTAL

Participants will be randomized to receive one intravenous (IV) infusion of infliximab.

Drug: Infliximab

Placebo

PLACEBO COMPARATOR

Participants will be randomized to receive one intravenous (IV) infusion of placebo.

Drug: Placebo

Interventions

Infliximab DRUG

Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period.

Also known as: Remicade

Infliximab

Placebo DRUG

Saline solution will be administered intravenously over a 2 to 2.5 hour period.

Also known as: Saline solution

Placebo

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give written informed consent
• Primary diagnosis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) MDD, current, or Bipolar, depressed type as diagnosed by the SCID-V
• Score of ≥14 on the Quick Inventory of Depressive Symptomatology (QIDS-SR-16) or score ≥ 15 on the Patient Health Questionnaire 9 item (PHQ-9)
• Absence of significant suicidal ideation defined using the Columbia Suicide Severity Rating Scale - Screen Version (CSSRS)
• Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to the baseline visit (8 weeks for fluoxetine). No patients will be removed from their psychotropic medications for the sole purpose of participating in the study.

You may not qualify if:

• Autoimmune disorder (as confirmed by laboratory testing)
• History of tuberculosis (by history or as discovered by chest X-ray, skin testing or blood testing) or high risk of tuberculosis exposure
• Hepatitis B or C infection or human immunodeficiency virus infection (as established by laboratory testing)
• History of fungal infection
• History of recurrent viral or bacterial infections
• History of any type of cancer
• Unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination and laboratory testing)
• History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; antisocial personality disorder as determined by a clinician; substance abuse/dependence within 6 months of study entry (as determined by SCID)
• Active suicidal plan as determined by a score \>3 on item #3 on the Hamilton Depression Rating Scale (HAM-D)
• Active eating disorder
• History of a cognitive disorder or ≤28 on the Mini-Mental State Exam
• Pregnancy or lactation
• Women of child bearing potential who are not using a medically accepted means of contraception
• Heterosexual males and their partners who do not agree to practice appropriate birth control
• Known allergy to murine products or other biologic therapies

Sponsors & Collaborators

• Emory University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Emory University

Atlanta, Georgia, 30322, United States

Location

Related Publications (1)

• Lee Y, Subramaniapillai M, Brietzke E, Mansur RB, Ho RC, Yim SJ, McIntyre RS. Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression. Ther Adv Psychopharmacol. 2018 Nov 19;8(12):337-348. doi: 10.1177/2045125318791944. eCollection 2018 Dec.

  PMID: 30524702 DERIVED

MeSH Terms

Conditions

Depression

Interventions

Infliximab; Saline Solution

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Andrew H. Miller, MD
• Organization: Emory University

amill02@emory.edu

404-727-8260

Study Officials

• Andrew H Miller, MD

  Emory University

  PRINCIPAL INVESTIGATOR

• Ebrahim Haroon, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 8, 2016
• First Posted: December 28, 2016
• Study Start: May 15, 2017
• Primary Completion: November 27, 2019
• Study Completion: November 27, 2019
• Last Updated: October 27, 2023
• Results First Posted: June 7, 2023

Record last verified: 2023-10

Locations

US (1)