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Inflammation-Induced CNS Glutamate Changes in Depression

This study is currently recruiting participants.
Verified May 2017 by Andrew H Miller, Emory University
Sponsor:
ClinicalTrials.gov Identifier:
NCT03004443
First Posted: December 28, 2016
Last Update Posted: May 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Andrew H Miller, Emory University
  Purpose

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.


Condition Intervention Phase
Depression Drug: Infliximab Drug: Placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Inflammation-Induced CNS Glutamate Changes in Depression

Resource links provided by NLM:


Further study details as provided by Andrew H Miller, Emory University:

Primary Outcome Measures:
  • Change in CNS glutamate [ Time Frame: Baseline, Day 3, Week 2 ]
    Change is defined as the difference in basal ganglia glutamate as measured by magnetic resonance spectroscopy (MRS) from Baseline to Day 3 to Week 2.


Secondary Outcome Measures:
  • Change in Effort-Expenditure for Rewards Task (EEfRT) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The EEfRT task is a multi-trial game in which participants are given an opportunity on each trial to choose between two different task difficulty levels in order to obtain monetary rewards. For all trials, participants make repeated manual button presses within a short period of time. Each button press raises the level of a virtual ''bar'' viewed onscreen by the participant. Participants are eligible to win the money allotted for each trial if they raise the bar to the ''top'' within the prescribed time period.Lower proportions of hard task choices indicate decreased motivation.

  • Change in Snaith-Hamilton Pleasure Scale (SHAPS-C) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-administered, paper-pencil questionnaire with 14 items assessing four domains of pleasure response/hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink. Either of the Disagree responses receives a score of 1 and either of the Agree responses receives a score of 0. The SHAPS is scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of anhedonia. A cut-off score of 2 provides the best discrimination between "normal" and "abnormal" level of hedonic tone.

  • Change in Mood and Pleasure Scale (MAP) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The mood and pleasure questionnaire 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. A score of 5-9 is positive for Mild Depression. A score of 10-14 is positive or Moderate Depression. A score of 15 or more is positive for Severe Depression.

  • Change in Finger Tapping Task (FTT) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The FTT uses a specially adapted tapper that the subject taps as fast as possible using the index finger. The subject is given 5 consecutive 10-second trials for the preferred and non-preferred hands. The finger tapping score is the mean of 5 trials and is computed for each hand. 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.

  • Change in Reaction Time Task (RTT) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The RTT measures simple and choice movement and reaction time and is divided into 5 stages requiring increasingly complex chains of responses and providing distinction between reaction (or decision) time and movement latencies. A longer reaction time may indicate cognitive impairment.

  • Change in 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 graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor 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.

  • Change in 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. A longer time to finish may indicate cognitive impairment.

  • Change in Retardation Rating Scale a (RRS) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The RRS is a 14-item, clinician-administered scale used to assess psychomotor retardation.The items of the scale are either related to motility or mental activity. In factor analyses, items 1-8 have been specifically associated with motor retardation in elderly depressed patients.

  • Change in Multidimensional Fatigue Inventory (MFI) Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The MFI is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. A higher score indicates more fatigue.

  • Change in Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Item 20 Score [ Time Frame: Baseline, Day 3, Week 2 ]
    The IDS-SR is a 30-item self-report instrument designed to measure symptom constructs consistent with current DSM nosology and that has been widely used as a self-report outcome measure of depression. Total scores range from 0-84. A higher score indicates more severe depression.

  • Change in plasma inflammatory markers [ Time Frame: Baseline, Days 1 and 3, Weeks 1 and 2 ]
    C reactive protein (CRP), tumor necrosis factor (TNF), TNF receptor 2 (TNFR2), interleukin (IL)-1ra, IL-6, soluble IL-6 receptor (sIL-6R), IL-10, momocyte chemoattractant protein (MCP)-1, and mRNA as measured in peripheral blood

  • Correlation between basal ganglia glutamate and anhedonia and psychomotor speed [ Time Frame: Baseline, Day 3, Week 2 ]
    Correlation between change in basal ganglia glutamate and change in EEfRT Score, SHAPS-C Score, MAP Score, FTT Score, RTT Score, DSST Score, TMT-A Score, RRS Score, MFI Score and IDS-SR Score

  • Correlation between basal ganglia glutamate and plasma inflammatory markers [ Time Frame: Baseline, Days 1 and 3, Weeks 1 and 2 ]
    Correlation between change in basal ganglia glutamate as measured by MRS and change in CRP, TNFR2, IL-1ra, IL-6, sIL-6R, IL-10, MCP-1, mRNA as measured in peripheral blood

  • Cerebrospinal fluid (CSF) inflammatory markers [ Time Frame: Week 2 ]
    CRP, TNF, TNFR2, IL-1ra, IL-6, sIL-6R, IL-10, MCP-1, and mRNA as measured in CSF

  • Correlation between basal ganglia glutamate and CSF inflammatory markers [ Time Frame: Week 2 ]
    Correlation between basal ganglia glutamate as measured by MRS and CRP, TNF, TNFR2, IL-1ra, IL-6, sIL-6R, IL-10, and MCP-1 as measured in CSF


Estimated Enrollment: 200
Actual Study Start Date: May 15, 2017
Estimated Study Completion Date: November 2021
Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Saline solution

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   25 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willing and able to give written informed consent
  • Primary diagnosis of DSM-V MDD, current, or Bipolar, depressed type as diagnosed by the SCID-V
  • Score of ≥16 on the Quick Inventory of Depressive Symptomatology (QIDS)-SR-16
  • 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; e. history of recurrent viral or bacterial infections
  • History of any type of cancer; g. 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; 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 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
  • Highly treatment resistant depressed patients who score >5 on the MGH Antidepressant Treatment Response Questionnaire (ATRQ)

Due to the high co-morbidity between anxiety disorders and depression, investigators will include patients with anxiety disorders (excluding OCD and PTSD) as long as depression is the primary diagnosis.

Patients with stable medical conditions and on medications for those conditions will not be excluded.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03004443


Contacts
Contact: Bobbi J Woolwine, MSW 404-712-9620 bwoolwi@emory.edu
Contact: Andrew H Miller, MD 404-727-8260 amill02@emory.edu

Locations
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Bobbi Woolwine, LCSW    404-712-9620    bwoolwi@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Andrew H Miller, MD Emory University
Principal Investigator: Ebrahim Haroon, MD Emory University
  More Information

Responsible Party: Andrew H Miller, Professor, Emory University
ClinicalTrials.gov Identifier: NCT03004443     History of Changes
Other Study ID Numbers: IRB00090667
First Submitted: December 8, 2016
First Posted: December 28, 2016
Last Update Posted: May 30, 2017
Last Verified: May 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Andrew H Miller, Emory University:
Psychiatry

Additional relevant MeSH terms:
Depression
Depressive Disorder
Inflammation
Behavioral Symptoms
Mood Disorders
Mental Disorders
Pathologic Processes
Infliximab
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents