The prodromal phase and the early stages of the schizophrenia illness are associated with significant decreases in social and intellectual abilitie, with more modest declines seen with chronic disease. Meta-analyses have consistently identified a relationship between the longer duration of untreated psychosis (DUP), the duration between the onset of positive symptoms and treatment, and worse long term outcomes. However, the neurobiology of this phenomenon and its implications for response to antipsychotic medications remain poorly understood. Glutamatergic excess altering brain connectivity might provide an explanation for why those with longer DUP have worse clinical outcomes. We propose to use multimodal neuroimaging to study 67 first episode psychosis subjects before and after sixteen weeks of treatment with risperidone, a commonly prescribed antipsychotic. We will measure indices of (1) glutamate and (2) structural and functional brain connectivity and test the hypotheses that glutamatergic abnormalities are present in first episode patients and that longer DUP is associated with greater functional and structural connectivity abnormalities that set the stage for poor response to treatment. Our previous combined MR spectroscopy (1H-MRS), diffusion tensor imaging (DTI), and resting state functional MR (fMRI) studies have made progress in the understanding of abnormalities in the glutamate system and brain connectivity in unmedicated patients with schizophrenia and modulation of these by antipsychotic medication. We have identified two indices of glutamatergic dysfunction, elevated glutamate and a disturbance in the known correlation between N-acetyl-aspartate and glutamate, which is suggestive of glutamate/glutamine cycle abnormalities. While antipsychotic medications appear to modulate glutamate, the disturbance in the correlation between metabolites is not restored with treatment. In addition, we found that both structural and functional connectivity abnormalities in unmedicated patients with schizophrenia predict patients' subsequent response to treatment. To our knowledge, no other group has performed a study that uses a combination of complementary neuroimaging techniques that will allow generating a broad characterization of glutamatergic function and brain connectivity in first episode psychosis and their change with treatment. The results of proposed studies could suggest a mechanism by which DUP is associated with poor treatment response which might lead to new interventions to target DUP.
The prodromal phase and the early stages of the schizophrenia illness are associated with significant decreases in social and cognitive abilities, with longer duration of untreated psychosis related to worse treatment outcome. Glutamatergic excess altering brain connectivity might provide an explanation for why this occurs and why some patients do not improve with antipsychotic treatment. If successful, this study will provide biomarkers of this deterioration which could be used as targets for monitoring and treatment intervention in patients with schizophrenia and those at high risk of developing the disease.
