Converging evidence from perceptual asymmetry, electrophysiologic, and neuroimaging studies support the hypothesis that depressive disorders involve both left prefrontal and right temporoparietal hypoactivation. Perceptual and electrophysiologic asymmetries are related to important clinical features of depression, i.e., diagnostic subtype, comorbidity with anxiety, and responsiveness to antidepressants. The major focus of the next project period will be on development and evaluation of behavioral, EEG and event-related potential (ERP) measures for predicting clinical response to antidepressants. One aim is to evaluate hypothesized differences in hemispheric asymmetry between patients who respond to a selective serotonin reuptake inhibitor (SSRI) and those who do not. ERPs will be recorded during continuous recognition memory tests with word and face stimuli to provide physiologic measures of lateralized medial temporal and frontal function. Regional measures Df EEG hemispheric asymmetry will be examined not only in a resting state but also during psychometrically matched verbal and spatial tasks. We will also continue to use dichotic word and complex tone tests for assessing perceptual asymmetries. A second aim is to evaluate alternative hypotheses relating antidepressant response to bilateral frontal lobe function, particularly to dorsolateral and medial frontal function. For this purpose ERPs will be recorded during a novelty oddball paradigm, which provides a physiologic probe of frontal function, i.e., the novelty P3. Neuropsychological tests will be independently performed to assess frontal lobe function. Testing a large sample of depressed patients will allow further evaluation of these behavioral and electrophysiologic tests as predictors of therapeutic response to antidepressants and will provide a more definitive determination of gender effects. We will also take advantage of ongoing crossover studies to begin to examine the potential of these tests for predicting response to alternative treatments for SSRI non-responders. These aims contribute to the long range goal of identifying more homogeneous subtypes of depression with distinctive clinical features and characteristic alterations of regional brain asymmetry.