TY - JOUR
TI - Sex differences in the hypothalamic–pituitary–adrenal axis: An obstacle to antidepressant drug development?
AU - Kokras, N.
AU - Hodes, G.E.
AU - Bangasser, D.A.
AU - Dalla, C.
JO - British Journal of Pharmacology
PY - 2019
VL - 176
TODO - 21
SP - 4090-4106
PB - John Wiley and Sons Inc
SN - 0007-1188, 1476-5381
TODO - 10.1111/bph.14710
TODO - argipressin;  corticotropin releasing factor;  corticotropin releasing factor antagonist;  glucocorticoid;  glucocorticoid receptor;  mineralocorticoid receptor;  neuropeptide;  vasopressin;  antidepressant agent;  argipressin;  corticotropin releasing factor;  glucocorticoid receptor;  mineralocorticoid receptor, antidepressant activity;  clinical evaluation;  clinical study;  clinical trial (topic);  drug development;  human;  hypothalamus hypophysis adrenal system;  nonhuman;  personalized medicine;  preclinical study;  priority journal;  regulatory mechanism;  Review;  rodent;  sex difference;  treatment failure;  treatment response;  animal;  depression;  drug development;  hypophysis adrenal system;  hypothalamus hypophysis system;  metabolism;  sexual characteristics, Animals;  Antidepressive Agents;  Arginine Vasopressin;  Corticotropin-Releasing Hormone;  Depression;  Drug Development;  Humans;  Hypothalamo-Hypophyseal System;  Pituitary-Adrenal System;  Receptors, Glucocorticoid;  Receptors, Mineralocorticoid;  Sex Characteristics
TODO - Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has long been implicated in the pathophysiology of depression, and HPA axis-based compounds have served as potential new therapeutic targets, but with no success. This review details sex differences from animal and human studies in the function of HPA axis elements (glucocorticoids, corticotropin releasing factor, and vasopressin) and related compounds tested as candidate antidepressants. We propose that sex differences contribute to the failure of novel HPA axis-based drugs in clinical trials. Compounds studied preclinically in males were tested in clinical trials that recruited more, if not exclusively, women, and did not control, but rather adjusted, for potential sex differences. Indeed, clinical trials of antidepressants are usually not stratified by sex or other important factors, although preclinical and epidemiological data support such stratification. In conclusion, we suggest that clinical testing of HPA axis-related compounds creates an opportunity for targeted, personalized antidepressant treatments based on sex. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc. © 2019 The British Pharmacological Society
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