The Corticosteroid Receptor Hypothesis of Depression posits that impaired corticosteroid receptor (CR) signaling is a key mechanism in the pathogenesis of depression. This hypothesis is supported by clinical and preclinical data, including changes in the hypothalamic-pituitary-adrenocortical (HPA) system, elevated corticotropin-releasing hormone (CRH) levels, and altered CR signaling in the brain. Clinical observations have shown increased ACTH and cortisol secretory pulses, elevated CRH levels in cerebrospinal fluid, and reduced CRH binding sites in the frontal cortex. Neuroendocrine function tests, such as the dexamethasone suppression test and the dex/CRH test, have demonstrated that depressed patients have abnormal HPA regulation. Genetic studies suggest that inherited glucocorticoid resistance, possibly due to mutations in the GR gene, may contribute to depression. Preclinical studies using mouse genetics and molecular pharmacology have revealed that CRH and GR signaling are crucial in mediating stress-related hormonal and behavioral responses. Impaired CR signaling can lead to increased CRH production and secretion, which in turn can disrupt emotional behavior and cognitive functions. The hypothesis also highlights the importance of understanding the interaction between GR and mineralocorticoid receptors (MRs) in regulating HPA activity and the potential role of chaperones in modulating CR signaling. Overall, the Corticosteroid Receptor Hypothesis provides a comprehensive framework for understanding the pathophysiology of depression and suggests potential targets for future antidepressant development.The Corticosteroid Receptor Hypothesis of Depression posits that impaired corticosteroid receptor (CR) signaling is a key mechanism in the pathogenesis of depression. This hypothesis is supported by clinical and preclinical data, including changes in the hypothalamic-pituitary-adrenocortical (HPA) system, elevated corticotropin-releasing hormone (CRH) levels, and altered CR signaling in the brain. Clinical observations have shown increased ACTH and cortisol secretory pulses, elevated CRH levels in cerebrospinal fluid, and reduced CRH binding sites in the frontal cortex. Neuroendocrine function tests, such as the dexamethasone suppression test and the dex/CRH test, have demonstrated that depressed patients have abnormal HPA regulation. Genetic studies suggest that inherited glucocorticoid resistance, possibly due to mutations in the GR gene, may contribute to depression. Preclinical studies using mouse genetics and molecular pharmacology have revealed that CRH and GR signaling are crucial in mediating stress-related hormonal and behavioral responses. Impaired CR signaling can lead to increased CRH production and secretion, which in turn can disrupt emotional behavior and cognitive functions. The hypothesis also highlights the importance of understanding the interaction between GR and mineralocorticoid receptors (MRs) in regulating HPA activity and the potential role of chaperones in modulating CR signaling. Overall, the Corticosteroid Receptor Hypothesis provides a comprehensive framework for understanding the pathophysiology of depression and suggests potential targets for future antidepressant development.