PROJECT SUMMARY Psychotic disorders are often characterized by recurrent relapses over the course of illness. Relapses impact occupational and social functioning, may endanger the patient and others, and often require inpatient hospitalization, driving up healthcare costs. In fact, the cumulative effect of relapses plays a major role in the quality of life of individuals with psychotic disorders in the long run. The pathophysiology of psychosis relapse has not been well captured in most previous research, as few studies account for the confounder of antipsychotic drug non-adherence, which affects most patients with psychosis at some point during treatment and is often unnoticed. In this proposal, we aim to study the neurobiological mechanisms of psychosis relapse in individuals treated with long acting injectable (LAI) antipsychotics, for whom medication adherence at the time of relapse can be reliably quantified. We will focus on striatal functioning, given its critical role in the pathophysiology of psychosis and as a target of antipsychotic drugs. Specifically, we will conduct MRI assessment of striatal functioning at rest (Aim 1) and during reward processing (Aim 2), as well as of meso- striatal dopamine transmission using neuromelanin sensitive MRI (Aim 3). We will compare these measures in a cross-sectional design between individuals with psychosis relapse during treatment with LAI antipsychotics (n=44), individuals who are symptomatically stable during treatment with LAI antipsychotics (n=44) and healthy controls (n=32). Our general hypothesis is that individuals experiencing relapse will show greater degree of aberrant striatal functioning compared with clinically stable individuals on LAI treatment. If successful, this project will generate data about the pathophysiology of psychosis relapse unbiased for treatment adherence. Such data are critical to develop much needed prognostic biomarkers for relapse prevention in psychosis.