Depression and anxiety are among the most prevalent of all psychiatric disorders. In recent years it has become increasingly apparent that depression and anxiety are highly comorbid. The comorbidity of Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) is particularly pernicious: compared to non-comorbid individuals, persons with this pattern of comorbidity report higher levels of suffering, greater severity of avoidance behavior, greater impairment in social and occupational functioning, and higher risk of suicide. Despite the high co-occurrence of MDD and SAD, few studies have examined the nature of this comorbidity. We do not know, for example, how comorbid patients differ from their diagnostically purer, or non-comorbid, counterparts. It is also unclear whether relapse rates differ for comorbid and non-comorbid patients, or whether the factors that have been found to predict the course of anxiety and depressive disorders are also relevant for understanding their comorbidity. And most important for the purposes of this proposal, we know little about the genetics, or the psychological and biological dysfunctions that are associated with comorbidity. The constructs of stress reactivity, stress recovery, and emotion dysregulation all have been implicated, albeit separately, in understanding the nature of MDD and SAD;we postulate that these constructs are critical in also understanding the comorbidity of these disorders. Thus, in this project we propose to examine and integrate self-report measures, cognitive measures, indicators of hypothalamic-pituitary-adrenal axis functioning, neural responses to emotional stimuli and emotion regulation, and a genetic polymorphism in participants diagnosed with non-comorbid MDD, with non-comorbid SAD, with comorbid MDD/SAD, and with no history of psychiatric disorder. More specifically, we propose to examine in a single project with carefully diagnosed comorbid and non-comorbid participants the roles of: (a) orienting towards and disengaging from negative stimuli;(b) neuroendocrine responses to and recovery from a psychological stressor;(c) patterns of neural activation in response to emotional stimuli;(d) responsivity to, and utilization of, positive material to regulate negative affect;and (e) allele polymorphism on the serotonin transporter gene. Findings from this project will represent important contributions to the development of an integrative psychobiological theory of the comorbidity of depression and anxiety, and promise to elucidate the interplay of stress reactivity, neuroendocrine functioning, emotion regulation, cognitive processes, genetics, and patterns of neural reactivity in comorbid MDD and SAD, and to identify critical areas of dysfunction as targets for intervention programs for this debilitating condition. PUBLIC HEALTH RELEVANCE: Depression and anxiety are among the most prevalent of all psychiatric disorders. In recent years it has become increasingly apparent both that depression and anxiety are highly comorbid, and that this comorbidity is associated with significant adverse outcomes, including a high risk of suicide. This project is proposed to examine the interplay of stress reactivity, neuroendocrine functioning, emotion regulation, cognitive processes, and patterns of brain function in comorbid depression and anxiety. Findings from this project promise to identify critical areas of dysfunction as targets for intervention programs for this debilitating condition.