The application requests funding for a Research Scientist's Award. The basic theme behind the research proposed for the next five year period is to study the neural mechanisms that produce the abnormal mental phenomena observed in psychotic patients. The work proposed consists of two major types. One group of studies focuses on diagnoses and phenomenology; the second group involves the study of brain anatomy, metabolism and neurochemistry, using the tools of neuroimaging. The studies of diagnosis and phenomenology have emphasized instrument development and have produced a series of linked instruments that are suitable for providing a comprehensive assessment of diagnoses and phenomenology: the Comprehensive Assessment of Symptoms and History (CASH), Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms, (SANS and SAPS), and instruments suitable for longitudinal follow-up assessments (PSYCH-UP and CASH-UP). Thorough reliability and validity studies have been done with these instruments. They are currently being used on a prospective longitudinal study of first episode and 'young chronic' patients in order to monitor outcome and to identify predictors of good and poor outcome. Other studies include the evaluation of phenomenology and diagnosis in monozygotic and dizygotic twins in order to explore gene/environmental interactions as they shape clinical presentation. These various studies explore the possibility that schizophrenia is heterogeneous group of disorders and that rigorous evaluation of the clinical presentation may give us some leverage on separating patients into more homogeneous groups that may share an underlying pathophysiology or etiology. Studies using neuroimaging draw on the tools of magnetic resonance (MR), Single Photon Emission Computed Tomography (SPECT), and Positron Emission Tomography (PET). The image analysis component of the MR studies has led to the development of a variety of new techniques, including segmentation algorithms, methods for volumetric analysis and three-dimensional reconstruction, shape analysis, and techniques for overlaying structural and functional images. These techniques are being applied to a large, sample of schizophrenic patients and healthy volunteers in order to determine whether differences in grey and white matter structures exist and whether these evolve over time. Studies using SPECT have focused primarily on the prefrontal cortex; they use a variety of cognitive challenge tasks (e.g., the Tower of London, Wisconsin Card Sorting Test, Porteus Mazes, Continuous Performance Test) in order to study frontal executive functions in normal individuals, drug naive patients and chronic patients both on and off medications. A series of PET studies will be applied to the measurement of D2 receptor density in drug naive patients and in patients with tardive dyskinesia. The proposed studies will evaluate the relationship between drug dose, clinical response, and blood levels; they will also explore the phenomenon of receptor induction and super sensitivity. These studies are conducted within the context of the University of Iowa Mental Health Clinical Research Center; Dr. Andreasen serves as the principle investigator of this center. This center coordinates the efforts of 23 different investigators who conduct 18 different protocols. It also runs an active training program.