- CRH-R1 antagonists, despite strong biological rationale and preclinical support, largely failed in depression, anxiety, PTSD and alcohol use disorder.
- CRH-R1 antagonism achieved clinical proof of concept in congenital adrenal hyperplasia, validating indication-specific efficacy.
- CRH-R2 agonism offers translational promise for cardiovascular and metabolic diseases, prompting a roadmap for refined drug development strategies.
Trends Endocrinol Metab. 2026 Aug 28:S1043-2760(26)00206-7. doi: 10.1016/j.tem.2026.08.002. Online ahead of print.
ABSTRACT
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.
PMID:42665478 | DOI:10.1016/j.tem.2026.08.002
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