PROJECT SUMMARY Schizophrenia spectrum disorders, among the most disabling of all psychiatric conditions, place a significant burden on the individuals who experience them, as well as their family members and society. Up to 35% of individuals with the disorders do not demonstrate an adequate response to antipsychotic treatment, and remain refractory to first-line therapies, which contributes to the burden and morbidity of the illness, often leaving patients unable to integrate with their communities. A limited understanding of the neurobiological mechanism underlying successful or unsuccessful antipsychotic treatment continues to hinder novel therapeutic development and optimization of our existing therapies for these disorders. While recent work has demonstrated the utility of functional and spectroscopic MR to elucidate the mechanisms underlying antipsychotic treatment, a more comprehensive understanding of molecular and neuronal changes associated with treatment efficacy is lacking. In this study, we address this knowledge gap by utilizing a multidimensional strategy with high-field, 7-Tesla neuroimaging to deconstruct the mechanism underlying antipsychotic response in a cohort of individuals with early schizophrenia. This project focuses on the cortical-basal ganglia system with several innovative approaches, including assays of (1) the dopamine system via neuromelanin-sensitive MRI; (2) magnetic resonance spectroscopic imaging of cortical γ-aminobutyric acid and glutamate functioning; and (3) both hypothesis and data-driven multivariate approaches to cortico-basal ganglia functional connectivity. Acutely psychotic patients with early schizophrenia spectrum illness will be examined in this naturalistic and prospective study. They will undergo scanning during treatment initiation, clinical assessments at 2-week intervals, and will be rescanned after 8 weeks of treatment. A group of healthy controls will also be examined to establish normal ranges of our neuroimaging measures. Results of this work will provide a more comprehensive foundation for our understanding of antipsychotic treatment-related neurobiology, which will facilitate biomarker development, mechanistic clinical trials, and the development of next-generation therapeutic strategies.