Decoding the CRH system from clinical failures to therapeutic translation

The corticotropin-releasing hormone (CRH) system orchestrates stress adaptation, integrating neuroendocrine, autonomic, immune, and behavioural responses to internal and external challenges. For over 2 decades, CRH receptor type 1 (CRH-R1) has been pursued as a therapeutic target for neuropsychiatric disorders. Despite compelling biological rationale and extensive preclinical validation, most CRH-R1 antagonist programmes have failed in depression, anxiety, post-traumatic stress disorder, and alcohol use disorder. In contrast, CRH-R1 antagonism has demonstrated clinical proof-of-concept in congenital adrenal hyperplasia, and CRH receptor type 2 agonism is attracting growing translational interest in cardiovascular and metabolic diseases. This review reassesses CRH-system therapeutics, extracting generalisable lessons from both failure and success and outlining a roadmap for future drug development.