The search for biological correlates of endogenous depression (ED) has been on for several years. Anomalous regulation of the hypothalamo-pituitary-adrenal (HPA) axis has been implicated using the Dexamethasone Suppression Test (DST). While there is active debate concerning the clinical usefulness of the DST, there is general agreement that some ED patients show defective HPA regulation, especially as seen in their baseline plasma cortisol and the lack of suppression after dexamethasone (DEX). In our previous funding period, we studied the pituitary component of the HPA axis in ED patients by measuring the peptide products from the ACTH/endorphin precursor. We have shown substantial pituitary regulation defects as reflected by plasma beta-endorphin (BE) assays in ED patients when compared to psychiatric controls. These studies revealed a partial concordance between BE and cortisol dysregulation. The combination of both measures after DEX reveals abnormalities in 70% of the ED patients. Based on the peptide and steroid measures we are proposing the possible existence of 4 subgroups of ED patients with different patterns of HPA dysfunction. The present proposal is aimed at testing these notions and further exploring the nature of the HPA defect. Studies on the effect of age, sex and time of testing in normals and psychiatric subjects will further explore variables contributing to the different patterns of response post DEX. Studies with CRF-induced release of ACTH and BE, metyrapone, cortisol fast feedback and biochemical characterization of the released peptides will be conducted to elucidate the locus and nature of the dysregulation. Finally, we will study patients in remission whose DST has normalized to determine if other HPA correlates reveal continuing abnormalities.
