Early adverse experiences, such as childhood abuse, neglect and parental loss, have been firmly established as risk factors for the development of depression, certain anxiety disorders, and perhaps other disorders, in adulthood. We demonstrated during the previous funding period that women with a history of childhood sexual or physical abuse exhibit markedly increased hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses to psychosocial laboratory stress and this effect was most pronounced in those abused women who suffered from current depression. We subsequently demonstrated alterations at multiple levels of the HPA axis, including the CNS, which together likely contribute to the increased sensitivity to stress and the manifestation of psychopathology, particularly in response to additional stress exposure. The objective of this proposed project is to confirm and extend these findings with a focus on the further characterization of the neurobiological consequences of ELS, identification of factors that might moderate or mediate increased vulnerability to stress after ELS in humans, and to expand our sample to include male subjects. We will determine whether age at the time of the ELS, and characteristics of the ELS influence responsiveness to a standardized psychosocial laboratory stressor and to a standard neuroendocrine challenge test in individuals with and without MDD. We will further determine whether the interaction of ELS and adolescent/adulthood trauma stress influences neuroendocrine reactivity in these subjects. We will also determine whether there are sex differences in the effects of ELS on neuroendocrine reactivity and whether the effects of ELS are moderated by polymorphisms of genes that are known to influence the manifestation of psychopathology in relation to life stress. The specificity of our previous observations in patients with depression will also be expanded by assessing neuroendocrine function in patients with social anxiety disorder (SAD) with and without a history of ELS, and by comparing these results to those of a new cohort of patients with major depression with and without ELS. Finally, because cognitive dysfunction in depression remains a largely unexplored research area, we will seek to determine the impact of ELS in patients with and without depression or SAD on cognitive function, i.e. perception, attention, memory, and problem solving, and whether the severity of cognitive impairment is related to HPA axis reactivity, as well as the timing and type of ELS, adulthood trauma, gender and psychopathology. This project will also serve as a human subjects core for the identification and description of individuals that will undergo assessments in Projects 0009 (Miller,PI), 0006 (Davis, PI), 0012 (Mayberg, PI) and 0013 (Kilts, PI).
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