Inflammation-Induced CNS Glutamate Changes in Depression

October 12, 2023 updated by: Andrew H Miller, Emory University

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This study aims to test the hypothesis that increased inflammation causes increased basal ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two pathways that have received increasing attention regarding the pathophysiology of neuropsychiatric disease including mood disorders. Patients with depression exhibit increased peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block either inflammation or glutamate signaling can reverse depressive symptoms, especially in depressed patients with treatment resistance.

Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release from astrocytes, and glutamate antagonists have been shown to block inflammation-induced depressive-like behavior in mice. Moreover, using MRS, data has shown that administration of the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In addition, increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is correlated with increased basal ganglia glutamate in association with decreased motivation and psychomotor speed in patients with MDD. Nevertheless, the data to date has been correlational, and whether increased inflammation causes increased glutamate in the basal ganglia, which in turn contributes to behavioral changes in patients with depression has not been established.

To test this hypothesis, investigators plan to determine the cause and effect relationship between increased inflammation and increased CNS glutamate by blocking inflammation in depressed patients with high inflammation (CRP>3mg/L) using the highly specific tumor necrosis factor (TNF) antagonist infliximab (n=30) versus placebo (n=30). In addition, the study team will examine whether changes in basal ganglia glutamate are linked to changes in behaviors related to the basal ganglia including anhedonia and psychomotor retardation.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
22

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

21 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  • Chronic use of non-steroidal anti-inflammatory agents (NSAIDS), glucocorticoid containing medications or statins
  • Use of NSAIDS, glucocorticoids, or statins at any time during the study
  • Contraindication to MRI
  • Previous organ transplant
  • History of CNS trauma or active seizure disorder
  • Highly treatment resistant depressed patients who score >5 on the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) for current episode

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Infliximab
Participants will be randomized to receive one intravenous (IV) infusion of infliximab.
Drug: Infliximab
Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period.
Other Names:
  • Remicade
Placebo Comparator: Placebo
Participants will be randomized to receive one intravenous (IV) infusion of placebo.
Drug: Placebo
Saline solution will be administered intravenously over a 2 to 2.5 hour period.
Other Names:
  • Saline solution

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Central Nervous System (CNS) Glutamate
Time Frame: Baseline, Day 3, Week 2
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score
Time Frame: Baseline, Day 3, Week 2
The SHAPS-C is a 14-item, clinician-administered instrument assessing pleasure response/hedonic experience. Responses are scored as 1 = lots of pleasure, 2 = average/usual pleasure, 3 = some pleasure, and 4 = no pleasure. Total scores range from 14 to 56 where higher scores indicate increasing severity of anhedonia.
Baseline, Day 3, Week 2
Finger Tapping Task (FTT) Score
Time Frame: Baseline, Day 3, Week 2
The FTT uses a specially adapted tapper that the participant taps as fast as possible using the index finger. The participant is given 5 consecutive 10-second trials for the dominant hands. The finger tapping score is the mean of 5 trials. The FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders and lesions. A lower score indicates motor impairment.
Baseline, Day 3, Week 2
Trails Making Test A (TMT-A) Score
Time Frame: Baseline, Day 3, Week 2
The scale measures cognitive processing speed using a series of non-sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring to numerical order as quickly as possible. The score is the time time it takes to complete the task, measured in seconds. A longer time to finish may indicate cognitive impairment.
Baseline, Day 3, Week 2
Multidimensional Fatigue Inventory (MFI) Score
Time Frame: Baseline, Day 3, Week 2
The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions of General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Participants respond to fatigue related statements using a 5-point scale where 1 = "yes, that is true" and 5 = "no, that is not true". Total scores range from 20 to 100 and higher scores indicate greater fatigue.
Baseline, Day 3, Week 2
Mood and Pleasure Scale - Self Report (MAP-SR) Score
Time Frame: Baseline, Day 3, Week 2
The Mood and Pleasure Scale is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. Responses are given on a 5-point Likert scale where 0 = no pleasure/not at all and 4 = extreme pleasure/very often. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.
Baseline, Day 3, Week 2
Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score
Time Frame: Baseline, Day 3, Week 2
The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item self-report instrument designed to measure symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that has been widely used as a self-report outcome measure of depression. Participants complete 28 of the 30 items, depending on if they experienced an increase or decrease in appetite and weight. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.
Baseline, Day 3, Week 2
Digit Symbol Substitution Task (DSST) Score
Time Frame: Baseline, Day 3, Week 2
The DSST is a subtest of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphomotor speed, visual scanning and memory, with about half of the variance being accounted for by graphomotor speed, a third by visual scanning and 4-5% by memory. Performance on the DSST has been found to correlate with subcortical atrophy in disorders involving basal ganglia.The DSST is scored as the number of correct responses in 120 seconds, with higher scores indicating better performance.
Baseline, Day 3, Week 2
Plasma Concentrations of High-sensitivity C-reactive Protein (Hs-CRP)
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. Increases in hsCRP are seen when inflammation is present.
Baseline, Day 3, Week 2
Plasma Concentrations of Tumor Necrosis Factor Alpha (TNF-α)
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. TNF-α is elevated in patients experiencing inflammation and a decrease in serum TNF-α is an indication of effective treatment.
Baseline, Day 3, Week 2
Plasma Concentrations of Tumor Necrosis Factor (TNF) Receptor 2 (TNFR2)
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. TNFR2 has proinflammatory effects and has strong anti-inflammatory activities.
Baseline, Day 3, Week 2
Plasma Concentrations of Interleukin-1 Receptor Antagonist (IL-1Ra)
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. IL-1Ra is an anti-inflammatory protein secreted by immune cells, epithelial cells, and adipocytes.
Baseline, Day 3, Week 2
Plasma Concentrations of IL-6
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL).
Baseline, Day 3, Week 2
Plasma Concentrations of Soluble IL-6 Receptor (sIL-6R)
Time Frame: Baseline, Day 3, Week 2
This study collected blood samples to assess inflammatory markers. Working with the pro-inflammatory cytokine IL-6, sIL-6R regulates pro-inflammatory reactions.
Baseline, Day 3, Week 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Emory University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Mental Health (NIMH)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Andrew H Miller, MD, Emory University
  • Principal Investigator: Ebrahim Haroon, MD, Emory University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 15, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 27, 2019

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 27, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 8, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 27, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 28, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 27, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 12, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB00090667
  • 1R01MH112076-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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