Clinical trial NCT05823532: Anti-Inflammatory Challenge in Schizophrenia
Official title: Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients With Schizophrenia Using an Anti-Inflammatory Challenge.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Schizophrenia
Keywords: Inflammation
Reward-related Brain Regions
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2023-04-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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).
* Active suicidal ideation or plan;
* An active eating disorder;
* A history of cognitive disorder or Mini-Mental State Exam (MMSE) \< 24 (indicating cognitive impairment);
* Pregnancy or lactation;
* Treatment with clozapine (given increased risk of neutropenia/agranulocytosis);
* Women of childbearing potential who are not using a medically accepted means of contraception;
* Known allergy to murine products or other biologic therapies;
* Previous organ transplant;
* Administration of any modified live virus vaccine within one month of study entry, during the study, and for at least one month after the final study visit;
* Oral glucocorticoids, immunosuppressive drugs (e.g. anti-cytokine therapies or methotrexate), or any other drugs targeting the immune system within 6 months of baseline;
* Chronic use of non-steroidal anti-inflammatory agents (NSAIDs; excluding 81mg of aspirin), glucocorticoid-containing medications, or minocycline or non-prescription supplements with known or suspected anti-inflammatory properties (e.g. fish oil supplements, curcumin, pre- or probiotics) within 2 weeks of baseline or at any time during the study;
* Use of non-steroidal anti-inflammatory agents (NSAIDs), and glucocorticoid medications at any time during the study;
* Any contraindication to MRI. Due to the high co-morbidity between schizophrenia and mood/anxiety disorders, the study team plans to include patients with these diagnoses as long as schizophrenia is the primary diagnosis.
* Subjects may be taking psychotropic medications at the time of the study (including antipsychotics, antidepressants, mood stabilizers, and benzodiazepines) but may have no psychotropic medication changes for one month before study enrollment or during participation in the study. Patients with stable medical conditions and on medications for those conditions will not be excluded. No patient will be removed from antipsychotic treatment for this study.

Primary outcomes:
measure: Changes in Monetary Incentive Delay Task (MID)
timeFrame: Study visits: 1-3 days before intervention and 6 weeks post-intervention
measure: Changes in Effort Based Decision Making Task (EBDM)
timeFrame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
measure: Changes in C-Reactive Protein (CRP)
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Brief Negative Symptom Scale (BNSS)
timeFrame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
Secondary outcomes:
measure: Changes in Performance on the Effort Expenditure for Reward Task
timeFrame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
measure: Changes in Positive and Negative Syndrome Scale (PANSS)
timeFrame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
measure: Changes in Motivation and Pleasure Scale (MAPS-SR)
timeFrame: Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention
measure: Changes in Calgary Depression Scale for Schizophrenia (CDSS)
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: IL-1
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: IL-6
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: IL-10
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: Soluble IL-6R
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: Tumor necrosis factor (TNF)
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: sTNFR2
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Inflammatory markers changes: monocyte chemoattractant protein (MCP)-1
timeFrame: Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention
measure: Changes in Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form
timeFrame: Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention
measure: Changes in The Calgary Depression Scale for Schizophrenia (CDSS)
timeFrame: Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention
measure: Changes in WHO Disability Assessment Schedule (WHODAS)
timeFrame: Study Visits :1-3 days before intervention, 1 week and 2 weeks post-intervention
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
Study officials:
affiliation: Assistant Professor
name: David R Goldsmith, MD
role: PRINCIPAL_INVESTIGATOR
References: