Inflammation-Induced CNS Glutamate Changes in Depression
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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:
|
| 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:
|
Outcome Measures
Primary Outcome Measures
- Change in CNS glutamate [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 Snaith-Hamilton Pleasure Scale (SHAPS-C) Score [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 [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 [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 [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 [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 [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 Salpetriere Retardation Rating Scale (SRRS) Score [Baseline, Day 3, Week 2]
The SRRS 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 [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 [Baseline, Day 3, Week 2]
The 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. Total scores range from 0-84. A higher score indicates more severe depression.
- Change in plasma C reactive protein (CRP) [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. CRP increases when inflammation is present. Changes in plasma CRP will be compared between study arms.
- Change in plasma tumor necrosis factor (TNF)-α [Baseline, Day 3, Week 2]
This study is collecting 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. Changes in plasma TNF-α will be compared between study arms.
- Change in plasma TNF receptor 2 (TNFR2) [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma TNFR2 will be compared between study arms.
- Change in plasma interleukin (IL)-1ra [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma IL-1ra will be compared between study arms.
- Change in plasma IL-6 [Baseline, Day 3, Week 2]
This study is collecting 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). Changes in plasma IL-6 will be compared between study arms.
- Change in plasma soluble IL-6 receptor (sIL-6R) [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma sIL-6R will be compared between study arms.
- Change in plasma IL-10 [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma IL-10 will be compared between study arms.
- Change in plasma monocyte chemoattractant protein (MCP)-1 [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma MCP-1 will be compared between study arms.
- Change in plasma messenger ribonucleic acid (mRNA) [Baseline, Day 3, Week 2]
This study is collecting blood samples to assess inflammatory markers. Changes in plasma mRNA will be compared between study arms.
- Change in Columbia Suicide Severity Rating Scale (CSSRS) [Baseline, Day 3, Week 2]
The CSSRS asks respondents up to 6 questions, depending on the answers to certain questions. Respondents answer "yes" or "no" to questions about thoughts or plans of suicide. Rather than a total score, the survey results indicate if a person is feeling suicidal or not.
- Change in Hamilton Anxiety Rating Scale (HAM-A) Score [Baseline, Day 3, Week 2]
The HAM-A is a 14-item clinician-administered scale that assesses the severity of symptoms of anxiety on a 5-point scale where 0 = not present and 4 = very severe. Total scores range from 0 to 56 with higher scores indicating greater anxiety.
- Change in Beck Anxiety Inventory (BAI) Score [Baseline, Day 3, Week 2]
The BAI is a 21-item self-report measure of anxiety symptoms, rated on a 4-point Likert scale modified to be based on the patient's experience in the past week. Items are rated from 0 = not at all to 3 = severely. Total scores range from 0 to 63 and higher scores indicate greater anxiety.
- Change in PTSD Checklist for DSM-5 (PCL-5) Score [Baseline, Day 3, Week 2]
The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD, rated on a 5-point Likert scale modified to be based on the patient's experience in the past week where 0 = not at all and 4 = extremely. Total scores range from 0 to 80 with higher scores indicating greater symptoms of PTSD.
- Change in State-Trait Anxiety Inventory (STAI) State Scale Score [Baseline, Day 3, Week 2]
The STAI-State instrument is a 20-item self-report scale is used to measure current anxiety symptoms. Items are rated on a 4-point scale where 1 = not at all and 4 = very much. Total scores range from 20 to 80 where higher scores indicate greater symptoms of anxiety.
- Change in Gamble Task [Baseline, Week 2]
The Gamble Task will examine the relationship between chosen certain rewards the expected values of chosen gambles, the difference between experienced and predicted rewards and happiness. Participants will have the option of selecting between a certain choice and a gamble choice, with equal probabilities of the two outcomes. There will between 50 and 150 trials with an equal proportion of three trial types: mixed (a certain amount of $0 with a gain and loss amount), gain (with a certain gain or a gamble with $0 and a larger loss), and loss (with a certain loss or a gain of $0 and a greater loss). Further, participants will be asked to rate their current level of happiness after every three trials. Also, before and after the task is complete, participants will be asked to measure their life happiness. Previous studies have demonstrated that this technique can be used to establish a relationship between task earnings and happiness. This task takes between 10-20 minutes per session.
- Change in Go No-Go Variant Task [Baseline, Week 2]
One of four possible fractal images is briefly presented to the subject, each representing the combination between action (either "go" or "no-go", by button pressing or withholding button pressing), and valance at outcome (either win or lose). Action is required in response to a circle that follows the fractal image. In go trials, subjects will indicate which side of the screen the circle appeared on. In no-go trials, subjects will simply be asked to withhold any response. A green upward symbol indicates a win of $1, a red downward symbol indicates a loss of $1, and a horizontal bar indicates an absence of win or loss. In "go to win" trials, a correct button press is rewarded. In "go to avoid losing" trials, a correctly avoided button press avoids punishment. In "no-go to" win trials, withholding the button press leads to reward. In "no-go to avoid losing" trials, withholding a button press avoids punishment.
- Reinforcement Learning Task (RLT) [Baseline, Week 2]
Trials for this task involve a 1-3s cue presentation during which subjects choose between two abstract stimuli, and then a 3s feedback presentation with positive (monetary win), negative (monetary loss) or neutral outcomes. Behavioral responses will be analyzed by fitting a standard reinforcement learning (Q-learning) model to each subject's sequence of choices. Based on individual choices and outcomes for each trial, the Q-learning algorithm will compute the expected values (Q) of choosing a given stimulus: Qt = Qt-1 + alpha*RPEt, where RPEt = Rewardt - Qt-1 and alpha represents the learning rate. This task will include between 80-120 trials and will take approximately 10-15 minutes in length.
- Subjective Value Task (SLT) [Baseline, Week 2]
In this task, subjects will repeatedly choose between two options to obtain a monetary reward. Each option will consist of a horizontal bar (representing reward magnitude) with a percentage written underneath it (representing reward probability). Options will be presented then a question mark will appear, to prompt participants to press a button to indicate their choice. The outcome (reward or no reward) will be indicated by the bars turning green or red, respectively. Outcomes are then followed by an intertrial interval. A "prize bar" will be displayed between the options and will grow by the width of the reward bar when a subject options a reward. The subject's goal will be to move the prize bar across a target line to win a certain amount of money. Once this goal is achieved, the prize bar will be reset and the subject will begin again. This task will last a maximum of 20 minutes.
Eligibility Criteria
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 ≥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 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University | Atlanta | Georgia | United States | 30322 |
Sponsors and Collaborators
- Emory University
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Andrew H Miller, MD, Emory University
- Principal Investigator: Ebrahim Haroon, MD, Emory University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB00090667
- 1R01MH112076-01