The corticosteroid receptor hypothesis of depression suggests that impaired corticosteroid receptor (CR) signaling in the central nervous system contributes to the pathophysiology of depression. This hypothesis is supported by clinical and preclinical evidence showing that depression is associated with altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis, including increased production and secretion of corticotropin-releasing hormone (CRH) in brain regions involved in depression. These changes are reflected in increased ACTH and cortisol secretion, elevated CRH levels in cerebrospinal fluid, and altered CRH receptor binding in the frontal cortex. Neuroendocrine function tests, such as the dexamethasone suppression test (DST) and the CRH stimulation test, have shown that patients with depression exhibit abnormal HPA responses, indicating impaired regulation of the HPA axis. These findings suggest that restoring a "normal" HPA setpoint is crucial for clinical improvement and that persistent HPA abnormalities increase the risk of relapse. Studies in animals and humans have shown that impaired corticosteroid signaling can lead to changes in hippocampal volume and function, which may contribute to depressive symptoms. Genetic studies have identified individuals with inherited glucocorticoid resistance, who may have polymorphisms or mutations in the glucocorticoid receptor (GR) gene. These individuals may be at increased risk for depression, although the relationship between GR mutations and depression is not fully understood. Mouse models have been used to investigate the role of CRH and corticosteroid signaling in depression, with findings indicating that CRH and its receptors play a key role in mediating stress-related behaviors. Transgenic mice with impaired GR function have shown altered anxiety-like behavior, impaired stress responses, and cognitive deficits, suggesting that GR dysfunction may contribute to the pathophysiology of depression. The interaction between GR and MR (mineralocorticoid receptor) in the brain is also important for regulating stress responses and behavior. The relative expression and activity of these receptors can influence the balance between pro- and anti-stress responses, with GR being more active under stress conditions. The role of corticosteroid signaling in depression is further complicated by the presence of other steroid receptors and the influence of environmental factors. Overall, the corticosteroid receptor hypothesis provides a framework for understanding the neurobiological mechanisms underlying depression and highlights the importance of HPA axis regulation in the pathogenesis of the disorder.The corticosteroid receptor hypothesis of depression suggests that impaired corticosteroid receptor (CR) signaling in the central nervous system contributes to the pathophysiology of depression. This hypothesis is supported by clinical and preclinical evidence showing that depression is associated with altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis, including increased production and secretion of corticotropin-releasing hormone (CRH) in brain regions involved in depression. These changes are reflected in increased ACTH and cortisol secretion, elevated CRH levels in cerebrospinal fluid, and altered CRH receptor binding in the frontal cortex. Neuroendocrine function tests, such as the dexamethasone suppression test (DST) and the CRH stimulation test, have shown that patients with depression exhibit abnormal HPA responses, indicating impaired regulation of the HPA axis. These findings suggest that restoring a "normal" HPA setpoint is crucial for clinical improvement and that persistent HPA abnormalities increase the risk of relapse. Studies in animals and humans have shown that impaired corticosteroid signaling can lead to changes in hippocampal volume and function, which may contribute to depressive symptoms. Genetic studies have identified individuals with inherited glucocorticoid resistance, who may have polymorphisms or mutations in the glucocorticoid receptor (GR) gene. These individuals may be at increased risk for depression, although the relationship between GR mutations and depression is not fully understood. Mouse models have been used to investigate the role of CRH and corticosteroid signaling in depression, with findings indicating that CRH and its receptors play a key role in mediating stress-related behaviors. Transgenic mice with impaired GR function have shown altered anxiety-like behavior, impaired stress responses, and cognitive deficits, suggesting that GR dysfunction may contribute to the pathophysiology of depression. The interaction between GR and MR (mineralocorticoid receptor) in the brain is also important for regulating stress responses and behavior. The relative expression and activity of these receptors can influence the balance between pro- and anti-stress responses, with GR being more active under stress conditions. The role of corticosteroid signaling in depression is further complicated by the presence of other steroid receptors and the influence of environmental factors. Overall, the corticosteroid receptor hypothesis provides a framework for understanding the neurobiological mechanisms underlying depression and highlights the importance of HPA axis regulation in the pathogenesis of the disorder.