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.

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.

Phenotypic, biomarker, and neuroimaging data may be shared by request to the PI two years after publication of the primary study results.

Two years after publication of the primary study results with no specified end date

Access criteria decisions will be made by the PI, via communication with him.