Description (from grant):
Schizophrenia is a heterogeneous disorder that likely involves multiple underlying pathological mechanisms, which has plagued attempts to identify rational therapeutic targets. Current treatments only work for a limited number of patients. All available antipsychotic drugs (APD) are dopamine receptor antagonists, but clinical response is variable, with a third of patients being partial responders, and a third non-responders. Arguably, those who respond well to APD have primarily dopaminergic abnormalities but it is crucial to characterize the specific underlying pathologies in those with poor response in order to unravel the heterogeneity of psychosis and effectively develop new treatments. We will longitudinally follow treatment response to APD for eight months in medication-naïve first episode psychosis (FEP) subjects using brain imaging. We already have identified provisional markers for several different pathophysiological mechanisms underlying psychosis, including abnormalities in glutamate and brain connectivity. We propose to study the changes that occur in the brain in early versus delayed treatment responders and changes that occur over time in response to treatment. By characterizing treatment trajectories and their relationship to baseline pathophysiologic alterations, we will further our mechanistic understanding of the heterogeneity of psychosis, which is needed to identify new therapeutic targets.