The HPA Axis as Target for Depression

Curr Neuropharmacol. 2024;22(5):904-915. doi: 10.2174/1570159X21666230811141557.


Major depressive disorder (MDD) is a stress-related mental disorder with a lifetime prevalence of 20% and, thus, is one of the most prevalent mental health disorders worldwide. Many studies with a large number of patients support the notion that abnormalities of the hypothalamus-pituitaryadrenal (HPA) axis are crucial for the development of MDD. Therefore, a number of strategies and drugs have been investigated to target different components of the HPA axis: 1) corticotrophinreleasing hormone (CRH) 1 receptor antagonists; 2) vasopressin V1B receptor antagonists, 3) glucocorticoid receptor antagonists, and 4) FKBP5 antagonists. Until now, V1B receptor antagonists and GR antagonists have provided the most promising results. Preclinical data also support antagonists of FKBP5, which seem to be partly responsible for the effects exerted by ketamine. However, as HPA axis alterations occur only in a subset of patients, specific treatment approaches that target only single components of the HPA axis will be effective only in this subset of patients. Companion tests that measure the function of the HPA axis and identify patients with an impaired HPA axis, such as the dexamethasone-corticotrophin-releasing hormone (dex-CRH) test or the molecular dexamethasonesuppression (mDST) test, may match the patient with an effective treatment to enable patient-tailored treatments in terms of a precision medicine approach.

Keywords: CRH1; FKBP5; HPA axis; SSR149415; V1B receptor antagonist; antidepressants; biomarkers; depression; glucocorticoid receptor.; precision medicine; stress; vasopressin.

MeSH terms

  • Corticotropin-Releasing Hormone / metabolism
  • Corticotropin-Releasing Hormone / pharmacology
  • Corticotropin-Releasing Hormone / therapeutic use
  • Depression
  • Depressive Disorder, Major* / drug therapy
  • Humans
  • Hypothalamo-Hypophyseal System / metabolism
  • Pituitary-Adrenal System / metabolism


  • Corticotropin-Releasing Hormone