Continuous treatment with antipsychotic medications is the foundation on which all other interventions for schizophrenia rest. Nonadherence with medication has repeatedly been shown to increase the frequency and severity of relapse in schizophrenia, nevertheless there is evidence that a substantial portion of patients relapse during continuous treatment with long-acting injectable antipsychotics. Relapse in schizophrenia may have devastating effects over and above the uncontrolled psychosis, including distress for family and caregivers, harmful or suicidal behaviors, rehospitalization, and functional deterioration with loss of independence. Its public health significance is undeniable, and there is a compelling need to identify vulnerabilities to relapse. Preliminary data has shown an association between genetic variation and rapid relapse in schizophrenia and there is a growing literature showing that genetic variation affects outcome with antipsychotic treatment. The recently funded NIMH multi-center relapse prevention trial "Relapse Prevention: Long Acting Atypical Antipsychotics" provides a timely platform for examining the pharmacogenetics of relapse over an extended period of time. We propose to examine whether genetic variations can predict which patients are at highest risk for psychotic relapse during antipsychotic treatment. Blood samples will provide DNA to detect variations in genes that code for a serotonin transporter, dopamine receptors, and P-glycoprotein transporter (transports lipophilic medications including antipsychotics into the CMS) in 304 patients, who will have comprehensive evaluations of relapse, symptoms, functionality, and tolerability over two and a half years of treatment with long-acting risperidone injections or oral second generation antipsychotics (SGAs). Our primary hypothesis is that genetic differences in the serotonin transporter, dopamine receptors and/or Pglycoprotein transporter will be associated with the likelihood of relapse during long-term antipsychotic therapy. If there are differences in efficacy to prevent relapse between the treatment groups, we will adjust for these differences in the final genetic analyses. This pharmacogenetics study will advance our ability to detect the role that genetics play in relapse and provide important new data to inform the clinical use of SGAs in the long-term treatment of schizophrenia. An understanding of the genetic factors involved in relapse may allow clinicians to identify patients who are at a high risk for relapse and modify their treatment plan accordingly, which may significantly reduce the public health burden of schizophrenia. [unreadable] [unreadable] [unreadable]