Inflammation-Induced CNS Glutamate Changes in Depression
| Status: | Recruiting |
|---|---|
| Conditions: | Depression, Depression |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 25 - 60 |
| Updated: | 8/25/2018 |
| Start Date: | May 15, 2017 |
| End Date: | November 2021 |
| Contact: | Bobbi J Woolwine, MSW |
| Email: | bwoolwi@emory.edu |
| Phone: | 404-712-9620 |
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.
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.
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.
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.
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) as long as depression is the
primary diagnosis.
Patients with stable medical conditions and on medications for those conditions will not be
excluded.
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