Hormone circuit explains why most HPA drugs fail for mood disorders and predicts the few that work

• Published in: Molecular systems biology Vol. 21; no. 3; pp. 254 - 273
• Main Authors: Milo, Tomer, Nir Halber, Shiraz, Raz, Moriya, Danan, Dor, Mayo, Avi, Alon, Uri
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2025; Springer Nature
• Subjects: Adrenal Glands - drug effects; Adrenal Glands - metabolism; Biomedical and Life Sciences; Computer Simulation; Corticotropin-Releasing Hormone - antagonists & inhibitors; Corticotropin-Releasing Hormone - metabolism; Dynamic Compensation; EMBO10; HPA Axis; Humans; Hydrocortisone - blood; Hydrocortisone - metabolism; Life Sciences; Models, Biological; Molecular Targeted Therapy - methods; Mood Disorders; Mood Disorders - blood; Mood Disorders - drug therapy; Mood Disorders - metabolism; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Stress, Psychological - blood; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; Stress, Psychological - psychology; Systems Biology; Systems Endocrinology; Systems Pharmacology; Systems Pharmacology; HPA Axis; Dynamic Compensation; Systems Endocrinology; Mood Disorders
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/s44320-024-00083-0

Elevated cortisol in chronic stress and mood disorders causes morbidity including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic–pituitary–adrenal (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’s 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. Synopsis A mathematical model suggests that existing HPA-targeting drugs failed in clinical trials for mood disorders because the endocrine glands change their functional mass. The model predicts CRH-targeting interventions as effective alternatives. A mathematical model of the stress axis suggests that drugs lowering cortisol in Cushing syndrome fail in chronic stress and mood disorders, as their effects are fully compensated by changes in endocrine gland functional mass. CRH-targeting drugs are predicted to lower cortisol in chronic stress and mood disorders. CRH-synthesis inhibitors and neutralizing antibodies are predicted to normalize all HPA hormones and glands and to maintain a proper acute stress response. Existing HPA-targeting drugs are effective in Cushing syndromes because the hormone-secreting tumors in these conditions are not subject to compensatory feedback mechanisms. A mathematical model suggests that existing HPA-targeting drugs failed in clinical trials for mood disorders because the endocrine glands change their functional mass. The model predicts CRH-targeting interventions as effective alternatives.