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There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis. However, several promising HPA-modulating drugs have failed to reduce long-term cortisol in mood disorders, despite effectiveness in other hypercortisolism conditions such as Cushing\u2019s syndrome. The reasons for these failures remain unclear. Here, we use a mathematical model of the HPA axis to demonstrate that the pituitary and adrenal glands compensate for drug effects by adjusting their functional mass, a feedback mechanism absent in Cushing tumors. Our systematic in silico analysis identifies two interventions targeting corticotropin-releasing hormone (CRH) as effective for lowering long-term cortisol. Other targets either fail due to gland mass compensation or harm other aspects of the HPA axis. We propose CRH-neutralizing antibodies and CRH-synthesis inhibitors as potential targets for reducing long-term cortisol in mood disorders and chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial to prioritize drug targets.<\/jats:p>","DOI":"10.1038\/s44320-024-00083-0","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T04:55:35Z","timestamp":1737608135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hormone circuit explains why most HPA drugs fail for mood disorders and predicts the few that work"],"prefix":"10.1038","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4493-7244","authenticated-orcid":false,"given":"Tomer","family":"Milo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9539-1359","authenticated-orcid":false,"given":"Shiraz","family":"Nir Halber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moriya","family":"Raz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dor","family":"Danan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-3423","authenticated-orcid":false,"given":"Avi","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1121-5907","authenticated-orcid":false,"given":"Uri","family":"Alon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"83_CR1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0079-6123(08)00403-2","volume":"170","author":"G Aguilera","year":"2008","unstructured":"Aguilera G, Subburaju S, Young S, Chen J (2008) The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress. 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