This Program Project Grant is a multidisciplinary attempt to deal with the complexities of the anxiety disorders. Our original effort to validate the DSM-III disorders in terms of physioloqy, response to provocation, and family study, is now extended to deal also with the complex issue of cross sectional and developmental co-morbidity. Our team now includes Rachel Gittelman Klein and Myrna Weissman; experts in the developmental and longitudinal study of clinical samples, family studies, and epidemiological samples. Rachel Klein will pursue the systematic study of the offspring of patients with panic disorder, social phobia, agoraphobia, simple phobia and normals. Myrna Weissman will study the already gathered ECA data, which is now ready for complete cross-site analyses, thus applying the variables of epidemiological aggregation and risk factors to the problem of syndromal validation. Jack Gorman's project grant on hyperventilation and carbon dioxide sensitivity in panic disorders is amplified by this grant to include social phobics and obsessive compulsives. Thirty-five percent carbon dioxide challenges allow for yet further study of the carbon dioxide dose response curve in patients with panic disorder, social phobia, obsessive compulsive disorder and normal controls. To control for cognitive and expectation effects a comparison with increased airway resistance will be conducted. The family study will pursue the issue of comorbidity and heterogeneity in panic disorder, social phobia, agoraphobia, simple phobia and two classes of normals (acquaintances and relatives of normal acquaintances). Blind followup of first degree relatives of anxiety disorders will provide information concerning onset of this high risk group as well as the natural history of untreated sick people. DNA analyses of selected pedigrees will be conducted in collaboration with James Gusella and Jurg Ott.