The applicant will continue to pursue her research on three major topics: neurobiological correlates and the classification of schizophrenia, family studies and the classification of affective disorders, and phenomenology and instrument development. The overall purpose of this work is to develop improved definitions of the major psychoses, with the long-term goal of defining illnesses that are distinct in terms of pathophysiology and ethiology. This goal is pursued from several vantage points. The work on schizophrenia involves the use of various types of brain imaging (CT, NMR, and eventually regional blood flow), neuropsychological testing, and detailed phenomenological description in order to attempt to determine whether different symptom pictures of this complex illness reflect different types of brain abnormality. Work on schizophrenia using multiplex families collected in Iowa and the Twin Registry of the Maudsley will further enlarge the perspective. The work on family studies and classification in depression is done in the context of the NIMH Collaborative Study of the Psychobiology of Depression, in which the applicant has been the principal investigator for many years. This study has many aspects. The applicant has assumed major responsibility for those aspects that use family studies as an independent validator of nosological classes. The final aspect of the study, phenomenology and instrument development, involves developing new improved techniques for evaluating particularly difficult aspects of psychopathology, such as thought disorder, effect, and negative symptoms. In addition, the applicant is currently developing a new structured interview for use in the major psychoses, the Comprehensive Assessment of Symptoms and History (CASH), which permits a flexible approach to making diagnoses using many different systems.