title: [The hypothalamic-pituitary-adrenal axis and depressive disorder: recent progress].
abstract: Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders.
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo, 187-8502 Japan. hkunugi@ncnp.go.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hori
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
authors.forename: Miho
authors.initials: M
authors.lastname: Ota
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy*; D003907:Dexamethasone / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone