Contribution of Glutamate Excess and Inflammation to Progressive White Matter Changes in Psychosis

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Schizophrenia is a complex disorder associated with subtle white matter abnormalities that progress over time. Alterations are associated with disease severity across symptom dimensions and worse overall outcomes, but no strategies exist to attenuate white matter disease progression. This is largely because the underlying pathophysiological processes remain unknown. Glutamate excess and inflammation may be contributing factors, but we do not know if there is a period early in the illness where these affect white matter or if they alter white matter across illness stages. We propose to use multimodal neuroimaging to study 60 unmedicated first-episode psychosis patients, 60 unmedicated chronic psychosis patients, and 120 matched healthy controls. We will use (1) advanced diffusion weighted imaging to measure white matter structural integrity, (2) Magnetic Resonance Spectroscopy to measure glutamatergic and inflammatory markers in white matter, and (3) blood samples to measure peripheral inflammatory and glutamatergic markers to test the hypothesis that white matter integrity deficits increase as a function of illness stage and that glutamate excess and inflammation contribute to white matter pathology. Identification of factors that contribute to progressive white matter deficits holds the promise to transform our mechanistic understanding and inform biomarkers for targeted drug development investigating the potential of glutamatergic or anti-inflammatory agents delaying or attenuating white matter decline in schizophrenia.