Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients With Schizophrenia Using an Anti-Inflammatory Challenge.

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.