Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?
BACKGROUND
Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating. Selective serotonin reuptake inhibitors are commonly prescribed to treat depression, but may not be as effective for more severe or persistent depression.


METHODS
The authors review data concerning the effects of corticosteroid synthesis inhibitors (CSIs) in the management of depressive disorders, present a hypothesis as to their possible mechanisms of action based on recent data suggesting synergistic effects of glucocorticoids on extrahypothalamic corticotropin-releasing hormone (CRH), and consider alternative hypotheses. Published reports evaluating the efficacy of CSIs in treating depression are reviewed and presented in light of recent findings regarding actions of glucocorticoids on the central CRH system.


RESULTS
Results from open label and double-blind studies by several groups have indicated that CSIs may be efficacious or of adjunctive value in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production.


CONCLUSIONS
The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs on glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features.
Kling
Mitchel A
MA
Department of Clinical Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, USA.
Coleman
Victoria H
VH
Schulkin
Jay
J
D000311:Adrenal Glands / Q000378:metabolism; D000616:Aminoglutethimide / Q000494:pharmacology* / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology* / Q000627:therapeutic use*; D008797:Metyrapone / Q000494:pharmacology* / Q000627:therapeutic use*; D015735:Mifepristone / Q000494:pharmacology* / Q000627:therapeutic use*; D012720:Severity of Illness Index
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D000616:Aminoglutethimide; D015735:Mifepristone; D003346:Corticotropin-Releasing Hormone; D007654:Ketoconazole; D006854:Hydrocortisone; D008797:Metyrapone