Inflammation-Induced CNS Glutamate Changes in Depression

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03004443

Enrollment

Registered

2016-12-28

Start date

2017-05-15

Completion date

2019-11-27

Last updated

2023-10-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Depression

Keywords

Psychiatry

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.

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.

Interventions

DRUGInfliximab

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

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to 65 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Central Nervous System (CNS) Glutamate	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.

Secondary

Measure	Time frame	Description
Mood and Pleasure Scale - Self Report (MAP-SR) Score	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.
Finger Tapping Task (FTT) Score	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.
Digit Symbol Substitution Task (DSST) Score	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.
Trails Making Test A (TMT-A) Score	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.
Multidimensional Fatigue Inventory (MFI) Score	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.
Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score	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.
Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score	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.
Plasma Concentrations of Tumor Necrosis Factor Alpha (TNF-α)	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.
Plasma Concentrations of Tumor Necrosis Factor (TNF) Receptor 2 (TNFR2)	Baseline, Day 3, Week 2	This study collected blood samples to assess inflammatory markers. TNFR2 has proinflammatory effects and has strong anti-inflammatory activities.
Plasma Concentrations of Interleukin-1 Receptor Antagonist (IL-1Ra)	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.
Plasma Concentrations of IL-6	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).
Plasma Concentrations of Soluble IL-6 Receptor (sIL-6R)	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.
Plasma Concentrations of High-sensitivity C-reactive Protein (Hs-CRP)	Baseline, Day 3, Week 2	This study collected blood samples to assess inflammatory markers. Increases in hsCRP are seen when inflammation is present.

Countries

United States

Participant flow

Recruitment details

Participants were recruited from Emory University Hospitals and Clinics in Atlanta, Georgia, USA. Participant enrollment began May 15, 2017 and the final follow-up assessment occurred November 27, 2019. The study was suspended in March 2020 during the coronavirus disease 2019 (COVID-19) pandemic. Due to the intervention being an immune suppressant it was not safe to reopen the study to enrollment and the decision was made to terminate the study in March 2023.

Participants by arm

Arm	Count
Infliximab Participants randomized to receive one intravenous (IV) infusion of infliximab.	11
Placebo Participants will be randomized to receive one intravenous (IV) infusion of placebo.	11
Total	22

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Pregnancy	0	1

Baseline characteristics

Characteristic	Infliximab	Total	Placebo
Age, Continuous	44.6 years STANDARD_DEVIATION 12.8	38.6 years STANDARD_DEVIATION 12.54	33.3 years STANDARD_DEVIATION 9.9
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	4 Participants	10 Participants	6 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	6 Participants	11 Participants	5 Participants
Region of Enrollment United States	11 Participants	22 Participants	11 Participants
Sex: Female, Male Female	9 Participants	19 Participants	10 Participants
Sex: Female, Male Male	2 Participants	3 Participants	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 11	0 / 11
other Total, other adverse events	6 / 11	8 / 11
serious Total, serious adverse events	1 / 11	0 / 11

Outcome results

Primary

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.