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

ABSTRACT: Elevated cortisol causes morbidity in chronic stress and mood disorders, 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 targetin

SUBMITTER: Tomer Milo 

PROVIDER: S-SCDT-10_1038-S44320-024-00083-0 | biostudies-other |

REPOSITORIES: biostudies-other