title: HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions.
abstract: Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is one of the most prominent neurobiological findings in major depressive disorder (MDD). The relationship of regional brain metabolism to HPA axis dysfunction in depressed patients, however, is still unclear. In this study, to examine the clinical pharmacotherapeutic effects on HPA axis function and brain metabolism in MDD patients, we performed the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test on 24 antidepressant-free patients with MDD a few days after positron emission tomography (PET) with a radiotracer, [(18)F]-fluorodeoxyglucose (FDG). Moreover, 10 patients who responded to pharmacotherapy were re-tested. 75% of unmedicated MDD patients exhibited a heightened cortisol response to the DEX/CRH test, and thus were defined as non-suppressors. Non-suppressors showed a marked hypometabolism in the medial prefrontal cortex as compared with suppressors. After successful pharmacotherapy, enhanced cortisol responsiveness normalized. Prior to treatment of the unmedicated MDD, a significant hypometabolism in various frontal regions and a significant hypermetabolism in the right hippocampus and parahippocampal gyrus were observed compared with controls. Metabolic activity in treatment responders showed a normalizing pattern in almost all the areas that had been characterized by metabolic abnormality at baseline except for the medial prefrontal cortex. These results indicate that depressed patients remitted with antidepressant treatment were accompanied by resolution of HPA dysregulation and alteration of regional glucose metabolism in the prefrontal cortical, limbic and paralimbic regions.
authors.affiliation: Department of Psychiatry and Human Behavior, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Aihara
authors.forename: Itsuro
authors.initials: I
authors.lastname: Ida
authors.forename: Naoya
authors.initials: N
authors.lastname: Yuuki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kumano
authors.forename: Keisuke
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masato
authors.initials: M
authors.lastname: Fukuda
authors.forename: Noboru
authors.initials: N
authors.lastname: Oriuchi
authors.forename: Keigo
authors.initials: K
authors.lastname: Endo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mikuni
mesh_terms: D000328:Adult; D000368:Aged; D003346:Corticotropin-Releasing Hormone; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology*; D003907:Dexamethasone; D005260:Female; D019788:Fluorodeoxyglucose F18; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D008032:Limbic System / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000378:metabolism / Q000503:physiopathology*; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology*; D019275:Radiopharmaceuticals
chemical_list: D005938:Glucocorticoids; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone