The Hypothalamic-Pituitary-Adrenal Axis in Depression: Molecular Regulation, Pathophysiological Role, and Translational Implications

Abstract Major depression has long been recognized as a stress-related disease. The hypothalamic-pituitary-adrenocortical (HPA) axis is one of the main physiological systems to manage stressful life events. It consists of a fine-tuned cascade of stress hormones, with corticotropin-releasing hormone, adrenocorticotropic hormone, and glucocorticoids at its core. Dysbalanced HPA axis activity and regulation have frequently been observed in depressed patients. This chapter discusses the function and molecular regulation of the HPA axis, including its perturbance in major depression. Moreover, evidence from animal models for the contribution of the HPA axis to depression-like phenotypes is provided. Finally, the efforts to exploit this knowledge for the development of drugs targeting HPA axis dysfunction in major depression are presented.