Inflammation Tied to Motivation Deficits in Schizophrenia

A new study from Emory University has identified a biological connection between inflammation and deficits in motivation in individuals with schizophrenia, offering new hope for treating symptoms that have long been resistant to existing therapies.

Published in Neuropsychopharmacology, a journal from the Nature Portfolio and official publication of the American College of Neuropsychopharmacology, the study found that higher levels of C-reactive protein — a blood biomarker of inflammation produced by the liver — were associated with reduced activity in brain circuits tied to reward and motivation. These brain changes, in turn, were linked to negative symptoms of schizophrenia specific to motivational deficits, such as difficulties in finding work, relationships or school. The inflammation was not associated with other schizophrenia symptoms such as hallucinations, delusions or depression.

The findings are significant because current antipsychotic medications do not address these motivational deficits and, in some cases, may even worsen them. These symptoms are also strongly associated with poor functional outcomes in patients with schizophrenia. Researchers focused on a key brain circuit involving the ventral striatum and the ventromedial prefrontal cortex — areas previously shown to be sensitive to inflammation in studies of depression.

“This is the first study in schizophrenia to link inflammation with both brain changes in reward circuits and specific motivational symptoms,” says David Goldsmith, MD, associate professor in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. “By identifying a biological mechanism underlying these symptoms, we are closer to developing targeted treatments that could offer real relief to patients.”

The study supports a precision medicine approach by suggesting treatments targeting inflammation may only benefit a specific group of patients — those with elevated inflammatory markers and significant motivational challenges. For example, previous studies of medications targeting inflammation in patients with schizophrenia have largely failed by not identifying which patients would benefit from these approaches.

The work helped lay the foundation for a current experimental-medicine trial at Emory testing the anti-inflammatory drug infliximab, commonly used to treat rheumatoid arthritis and inflammatory bowel disease, in patients with schizophrenia who have high inflammation and motivational deficits. This is the first study of infliximab in this patient population and designed to test whether the impact of inflammation on this circuit and these symptoms may be causal.

“There is an urgent need to develop new strategies to treat the negative symptoms of schizophrenia, which remains one of the greatest unmet needs in the field,” says Goldsmith. “We hope this line of research will change that. If we want to support recovery from schizophrenia, we must be able to treat these symptoms.”

Reference: Goldsmith DR, Ning CS, Strauss GP, et al. Inflammation is associated with avolition and reduced resting state functional connectivity in corticostriatal reward circuitry in patients with schizophrenia. Neuropsychopharmacol. 2025. doi: 10.1038/s41386-025-02114-2

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