Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients With Schizophrenia Using an Anti-Inflammatory Challenge.
Overview
- Phase
- Phase 4
- Intervention
- Infliximab
- Conditions
- Schizophrenia
- Sponsor
- Emory University
- Enrollment
- 20
- Locations
- 2
- Primary Endpoint
- Changes in Monetary Incentive Delay Task (MID)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This research project will explore negative symptoms of schizophrenia, such as motivational deficits, by examining the relationship between inflammation and reward-related brain regions. To accomplish this, we will administer a single infusion of either the anti-inflammatory medication infliximab or placebo (n=10 per group) to patients with high inflammation.
This study is important because schizophrenia can be a chronic and debilitating neuropsychiatric disorder and negative symptoms are some of the most difficult aspects of schizophrenia associated with worst functional outcomes. These symptoms do not typically respond to antipsychotic therapies, and as such, there are no current medications to treat negative symptoms.
Detailed Description
This research project will explore negative symptoms of schizophrenia, such as motivational deficits, by examining the relationship between inflammation and reward-related brain regions. To accomplish this, we will administer a single infusion of either the anti-inflammatory medication infliximab or placebo (n=10 per group) to patients with high inflammation. This study is important because schizophrenia can be a chronic and debilitating neuropsychiatric disorder and negative symptoms are some of the most difficult aspects of schizophrenia associated with worst functional outcomes. These symptoms do not typically respond to antipsychotic therapies, and as such, there are no current medications to treat negative symptoms. Study procedures include 9 separate visits as follows: 1. Pre-screening Visit which includes questions about mood and negative symptoms of schizophrenia, blood sampling to measure CRP which is a marker of inflammation, a urine drug screen (UDS) and urine testing for pregnancy in all biological women (approx. 1-2 hours). 2. Screening Visit which includes assessing for adverse events, more detailed questions about symptoms, a physical exam, blood draw for medical safety screening labs, magnetic resonance imaging (MRI) safety screening questionnaire, instruction and practice playing a computer game where the participant can earn money, and an electrocardiogram (EKG) to make sure the patient's heart is healthy. 3. Baseline Visit which includes assessing for adverse events, behavioral assessments, blood sampling for medical safety screening labs and research labs, functional magnetic resonance imaging (fMRI) scan where participant plays a computer game where s/he can earn extra money. Randomization to the study drug, Infliximab, or a placebo (approx. 5-6 hours). 4. Infusion Visit which includes assessing for adverse events, blood draw for safety screening labs, UDS and pregnancy testing, and infusion of the study drug, Infliximab, or a placebo (approx. 5 hours). 5. 24-hr Post Infusion Visit which includes behavioral assessments, vital signs, safety labs, and assessing for adverse events (approx. 1-2 hours). 6. 3-day Post Infusion Visit which includes assessing for adverse events, behavioral assessments, vital signs, safety labs (approx. 1-2 hours) 7. 7-day Post Infusion Visit which includes assessing for adverse events, behavioral assessments, vital signs and safety labs (approx. 1-2 hours) 8. 14-day Post Infusion Visit which includes assessing for adverse events, blood draw for safety labs, urine pregnancy and drug testing, fMRI scan and a lumbar puncture for cerebrospinal fluid (CSF)(approx. 6-7 hours) 9. One-month Follow-up Safety Check-in which includes a phone call to assess for adverse (approx. 10-15 minutes). Approximately 60 subjects will be consented and prescreened in order to obtain complete data on 20 medically stable, male, and female adult subjects with schizophrenia or schizoaffective disorder at the Grady Behavioral Health Clinic. Blood will be collected across multiple visits, some of which will be stored for future research use. Written informed consent will be obtained in a private office at the Grady Behavioral Health Clinic. All aspects of the study will be reviewed and a discussion will occur to make sure the participant is aware of all study details. Should a subject agree to study participation, s/he will be given a copy of the informed consent for their records. In addition, the process of informed consent will continue throughout the course of each study visit to be sure the participant is fully aware of all procedures. If the participant has a legally authorized representative (LAR), the LAR will be required to attend the initial prescreening visit and sign the informed consent.
Investigators
David Goldsmith
Assistant Professor
Emory University
Eligibility Criteria
Inclusion Criteria
- •Men or women, 18-45 years of age with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) schizophrenia or schizoaffective disorder;
- •Willing and able to give written informed consent;
- •Plasma CRP 3mg/L;
- •Significant motivational deficit as reflected by a score \>17 on the Motivation and Pleasure Domain of the Brief Negative Symptom Scale. Of note, for patients who exhibit CRP\>10mg/L, additional CRP testing will be conducted at 2-week intervals as per American Heart Association/ Center for Disease and Control Prevention guidelines to establish stability and rule out acute inflammation/infection (along with physical exam and laboratory testing).
- •Patients must also have a negative urine drug screen at all study visits.
Exclusion Criteria
- •Any autoimmune disorder (as confirmed by laboratory testing);
- •History of tuberculosis infection as determined by QuantiFERON Gold or high risk of tuberculosis exposure;
- •Active hepatitis B or C infection or human immunodeficiency virus infection (as established by laboratory testing);
- •History of any type of cancer;
- •History of fungal infection;
- •History of recurrent viral or bacterial infections;
- •Unstable cardiovascular (including evidence of congestive heart failure as determined by physical examination and laboratory testing), endocrinologic, hematologic, hepatic, renal, and neurological disease (as determined by physical examination and laboratory testing);
- •Demyelinating brain disease and/or a concerning structural abnormality seen on MRI;
- •Substance abuse/dependence within 6 months of study entry (as determined by MINI and urine drug screen);
- •Primary diagnosis of mood or anxiety disorder (i.e., major depressive disorder, bipolar disorder, post-traumatic stress disorder) as determined by the International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders (MINI).
Arms & Interventions
Infliximab
Subjects will be stratified by sex and randomized prior to this visit in preparation for the infusion. Vitals and safety labs will be drawn at this visit as well as urine testing for drugs of abuse and pregnancy testing for all biological females. Patients will receive breakfast followed by a double-blinded infusion of infliximab (5mg/kg body weight) in the GCSTA Clinical Research Center at Emory University Hospital. The infusion will last 3 hours, and subjects will be monitored during the infusion and for one hour after completion for the possible development of anaphylaxis, which occurs in less than 1% of patients receiving an initial dose of infliximab
Intervention: Infliximab
Placebo
Subjects will be stratified by sex and randomized prior to this visit in preparation for the infusion. Vitals and safety labs will be drawn at this visit as well as urine testing for drugs of abuse and pregnancy testing for all biological females. Patients will receive breakfast followed by a double-blinded infusion of saline in the GCSTA Clinical Research Center at Emory University Hospital. The infusion will last 3 hours, and subjects will be monitored during the infusion and for one hour after completion for the possible development of anaphylaxis, which occurs in less than 1% of patients receiving an initial dose of infliximab
Intervention: Placebo
Outcomes
Primary Outcomes
Changes in Monetary Incentive Delay Task (MID)
Time Frame: Study visits: 1-3 days before intervention and 6 weeks post-intervention
Change in Bold Oxygen Level Dependent (BOLD) Activation in the Ventral Striatum during "Win" Monetary Incentive Delay (MID) Task between Infliximab and Placebo (time frame: 1-3 days between first scan and intervention and then 2 weeks between intervention and repeat scan). Activation response in ventral striatum in response to reward anticipation: Infliximab (vs placebo)-treated patients will exhibit a) increased activation in ventral striatum in response to reward. Mixed-effects models for repeated measures (MMRM) will first be employed to examine effects of group (infliximab vs. placebo), time and their interaction on blood oxygenation level-dependent (BOLD) signals (an index of regional brain activation) using a Region-of-Interest (ROI) approach.
Changes in Effort Based Decision Making Task (EBDM)
Time Frame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
Changes in BOLD Activation response in anterior insula in response to increasing effort between Infliximab and Placebo (time frame: 1-3 days between first scan and intervention and then 2 weeks between intervention and repeat scan). Activation response in insula in response to increasing effort: Infliximab (vs placebo)-treated patients will exhibit a) decreased activation in anterior insula in response to effort. Mixed-effects models for repeated measures (MMRM) will first be employed to examine effects of group (infliximab vs. placebo), time and their interaction on BOLD signals (an index of regional brain activation) using a Region-of-Interest (ROI) approach.
Changes in C-Reactive Protein (CRP)
Time Frame: Study Visits :1-3 days before intervention, immediately after the intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention
30ml study bloods per visit will be collected by venipuncture into EDTA-containing vacutainer tubes using standard sterile technique. Plasma for the evaluation of plasma concentrations of CRP will be obtained by centrifugation of whole blood at 1000 x g for 10 minutes at 4 C. Plasma CRP will be assessed with a high sensitivity turbidimetric assay. Assay sensitivity is rated at 0.18 mg/L, range of measure is 0.2 to 80 mg/L and functional sensitivity (at 20% CV) is 0.2 mg/L.
Changes in Brief Negative Symptom Scale (BNSS)
Time Frame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
Infliximab (vs placebo) -treated patients will record their performance on the BNSS Motivation and Pleasure domain score. The BNSS is a 13-item scale designed for research studies in response to the 2005 National Institute of Mental Health (NIMH) consensus development conference on negative symptoms of schizophrenia.The BNSS measures the five commonly accepted domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and avolition. Items are scored on a 0 to 6 scale, with 0 indicating the symptom is absent and 6 indicating the symptom is severe. Items are summed for a total score that ranges between 0 and 78.
Secondary Outcomes
- Changes in Performance on the Effort Expenditure for Reward Task(Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention)
- Changes in Positive and Negative Syndrome Scale (PANSS)(Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention)
- Changes in Motivation and Pleasure Scale (MAPS-SR)(Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention)
- Changes in Calgary Depression Scale for Schizophrenia (CDSS)(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: sTNFR2(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in The Calgary Depression Scale for Schizophrenia (CDSS)(Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention)
- Changes in WHO Disability Assessment Schedule (WHODAS)(Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: IL-1(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: IL-6(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: IL-10(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: Soluble IL-6R(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: Tumor necrosis factor (TNF)(Study Visits :1-3 days before intervention, immediately after the intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Inflammatory markers changes: monocyte chemoattractant protein (MCP)-1(Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention)
- Changes in Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form(Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention)