The overall aim of this high risk longitudinal (a decade) study has been: 1) to understand the nature and familial patterns of psychiatric problems in offspring at high and low risk for major depression (MDD) from childhood, adolescence and through young adulthood; 2) to determine the psychiatric status of the next generation (the grandchildren). The first aim is completed. The grandchildren were young at the last interview but any who were at that time age 6 or over (N=90) were assessed. Preliminary findings show the same pattern of illness in the high risk grandchildren as seen in their parents and grandparents including a prepubertal onset MDD, often comorbid with anxiety disorders, with onset of anxiety as young as age 6. This pattern transmits across the generations. The aim of this renewal is to conduct a more comprehensive assessment of an expended sample of grandchildren. Sufficient time has passed for the sample to have aged into the period of risk and the additional grandchildren will increase power so that we will be able: 1) to determine if the grandchildren demonstrate the same depressive features, impairment, medical, and behavioral problems as their parents and; 2) to add psychophysiologic measures as potential biological markers of a familial diathesis for depressive and anxiety disorders. We will measure quantitative electroencephalographic (qEEG) measures at rest, and startle responses, as well as autonomic nervous system measures, during adverse stimulation, in both grandchildren and their parents. In the context of a multi-generational high risk study such measures may: 1) simplify phenotypes through the reduction of heterogeneity; and 2) identify markers for latent, potentially genetic risk. The strength of this proposal is the availability and careful assessment of three generations of persons at high risk for MDD. This will provide a database on the magnitude, risk and sequence of psychiatric disorders which can ultimately be used to develop preventive intervention strategies and more focused treatments. Moreover, the biological markers will offer another tool for refining the phenotype for genetic and other studies and for identifying high risk offspring.