Anti-Inflammatory Challenge in Schizophrenia

Phase 4RecruitingNCT05823532

Emory University60 enrolled

Overview

This study aims to illuminate the biological underpinnings of negative symptoms in schizophrenia-particularly motivational impairments-by probing the link between systemic inflammation and neural activity in reward-related brain circuits. The primary goal of this study is to determine: * Ventral Striatum Activation: Assess how reward anticipation engages the ventral striatum in individuals with schizophrenia, both before and after an anti-inflammatory intervention. * Anterior Insula Activation: Examine how increasing effort demands modulate activity in the anterior insula under the same conditions.

Schizophrenia is a chronic and disabling mental illness that affects over 20 million people globally. One of its most debilitating aspects is a group of symptoms known as negative symptoms, which include reduced motivation, pleasure, and social engagement. Among these, amotivation-or the lack of drive to pursue rewarding activities-is particularly damaging, as it contributes to poor quality of life and limited recovery. Current medications do not effectively treat these symptoms, underscoring the urgent need for new therapeutic approaches. Emerging research suggests that inflammation may play a key role in disrupting brain circuits related to motivation and reward. Specifically, inflammation appears to affect two critical brain regions-the ventral striatum and the anterior insula-leading to decreased motivation and impaired effort-based decision-making. The proposed study aims to test whether reducing inflammation can improve motivation in individuals with schizophrenia. Researchers will recruit patients who exhibit both high levels of inflammation, measured by C-reactive protein (CRP) in the blood, and significant motivational deficits. Participants will be randomly assigned to receive either infliximab, a drug that blocks the inflammatory molecule TNF, or a placebo. Brain activity will be measured using functional magnetic resonance imaging (fMRI), and motivation will be assessed through behavioral tasks and questionnaires. The study will examine whether infliximab increases activity in the ventral striatum-making rewards feel more exciting-and decreases activity in the anterior insula-making effort feel less overwhelming-ultimately improving motivation and pleasure. Study procedures include eleven separate visits. The pre-screening visit involves questions about mood and symptoms, CRP blood testing, urine drug screening, and pregnancy testing for biological women. The screening visit includes a physical exam, safety labs, MRI safety screening, and practice with a computer game designed to measure reward processing. The baseline visit includes behavioral assessments, an EKG, blood sampling, an fMRI scan during the reward game, and randomization to either infliximab or placebo. The infusion visit involves drug administration and safety checks. Follow-up visits occur at 24 hours, 3 days, 7 days, and 14 days post-infusion, with assessments of adverse events, behavioral performance, and vital signs. The 14-day visit also includes a second fMRI scan. A final one-month follow-up is conducted via phone to monitor safety. Approximately 250 subjects will be prescreened to obtain complete data on 60 medically stable adult participants with schizophrenia or schizoaffective disorder, recruited from the Grady Behavioral Health Clinic. Blood samples will be collected across multiple visits, with some stored for future research. This study is innovative in its direct investigation of the link between inflammation and brain function in schizophrenia. By focusing on patients with elevated inflammation and using precise neuroimaging and behavioral measures, the research could pave the way for personalized treatments targeting the biological roots of motivational deficits. If successful, it may lead to new therapies for symptoms that currently lack effective medication, improve patient quality of life, and help clinicians identify individuals most likely to benefit from anti-inflammatory interventions.

Interventions

InfliximabDRUG

Infliximab has FDA approval for the treatment of rheumatoid arthritis and inflammatory bowel syndrome. The current proposal represents the use of infliximab as an experimental tool to dissect the role of inflammatory processes leading to changes in brain reward circuitry and changes in specific symptom domains. Double-blinded infusions of infliximab will be administered in the GCTSA Clinical Research Center, located at Emory University Hospital. Independent pharmacists will dispense either infliximab or placebo in a 250ml saline bag according to a computer-generated randomization list provided by the study pharmacist.

PlaceboDRUG

Double-blinded infusions of saline will be administered in the GCTSA Clinical Research Center, located at Emory University Hospital. Independent pharmacists will dispense either infliximab or placebo in a 250ml saline bag according to a computer-generated randomization list provided by the study pharmacist.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Men or women, 18-55 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 ≥2 mg/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.

Outcomes

Primary Outcomes

Changes in Monetary Incentive Delay Task (MID)

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 before intervention and 2 weeks post intervention (MID occurs during scans). 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.

Time frame: Study visits: 1-3 days before intervention and 2 weeks post-intervention ]

Changes in Effort Based Decision Making Task (EBDM)

Changes in BOLD Activation response in anterior insula in response to increasing effort between Infliximab and Placebo (time frame:1-3 days before intervention and 2 weeks post intervention (EBDM occurs during scans) ). 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.

Time frame: 1-3 days before intervention, 2 weeks post intervention

Changes in C-Reactive Protein (CRP)

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.

Time frame: Study Visits :1-3 days before intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention

Changes in Brief Negative Symptom Scale (BNSS)

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.

Time frame: 1-3 days before intervention, 1 day, 3 days, 1 week, and 2 weeks post intervention

Changes in Performance on the Effort Expenditure for Reward Task (EEfRT)

Infliximab (vs placebo) -treated patients will be evaluated on their performance on the EEfRT. Assessment of reward motivation will be accomplished using an fMRI-adapted version of the EEfRT task. During each trial, subjects are presented with a choice between two levels of task difficulty, a High Effort option and a Low Effort option, which require different amounts of speeded manual button pressing for differing levels of monetary reward. The reward magnitude for a No Effort option remains constant , while the reward magnitude for the High Effort option will vary between 20%, 50%, 80%, and 100% of the subjects max effort (set for each individual prior to scan). The task will use a rapid event-related design with an exponential jitter between trials drawn in order to optimize hemodynamic response function estimation. Responses will be made using MRI-compatible button-boxes and images will be presented on a rear projection screen visible with a mirror mounted on the head coil.

Time frame: Study Visits :1-3 days before intervention and 2 weeks post intervention

Secondary Outcomes

Changes in Positive and Negative Syndrome Scale (PANSS)

Infliximab (vs placebo) -treated patients will record their performance on the Positive and Negative Syndrome Scale (PANSS) The PANSS is the most commonly used measure of assessing the symptoms of schizophrenia. Seven items measure positive symptoms, seven measure negative symptoms, and sixteen measure general psychopathology symptoms. PANSS items are rated on a 7-point scale (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, and 7=extreme); because the absence of symptoms is equal to 1 point, the lowest possible total score on both PANSS scales is 7.

Time frame: Study Visits :1-3 days before intervention, 1 day, 3 days, 1 week, and 2 weeks post intervention

Changes in Motivation and Pleasure Scale (MAPS-SR)

The MAPS-SR is a 15-item self-report scale that has demonstrated good convergent validity with the clinician-rated Motivation and Pleasure scale of the Clinical Assessment Interview for Negative Symptoms (CAINS). The scale has four subscales that include ratings of social pleasure, recreational or work pleasure, feelings and motivations about close, caring relationships, and motivation and effort to engage in activities, corresponding to the CAINS subscales of deficits in motivation and pleasure and deficits of expression. (MAP-SR) Six items tap consummatory and anticipatory pleasure related to social and recreational or work domains. Six items tap feelings and motivations to be around family, romantic partners, and friends. The remaining six items tap motivation and effort to engage in activities. All items are rated on a 5-point Likert scale; higher scores reflect greater pathology after reverse scoring for items 8, 10, and 12.

Time frame: Study Visits : 1-3 days before intervention and 2 weeks post intervention

Changes in Calgary Depression Scale for Schizophrenia (CDSS)

The CDSS is a clinician-administered, 9-item rating scale designed for the assessment of depressive symptoms in schizophrenia. Depressive symptoms are highly prevalent in patients with schizophrenia and may lead to a higher burden of disease. It is reliable, valid, and able to distinguish depressive symptoms from negative symptoms and extrapyramidal symptoms.

Time frame: Study Visits : 1-3 days before intervention and 2 weeks post intervention

Changes in Inflammatory markers changes: IL-1