Who and how to screen for endogenous hypercortisolism in patients with mood disorders.

A strict association exists between mood disorders and endogenous hypercortisolism, namely Cushing's syndrome (CS). Indeed, CS is characterized by a wide range of mood disorders, such as major depression, generalized anxiety, panic disorders, bipolar disorders up to psychosis, with major depression being the most frequent, with a prevalence of 50-80%, and potentially representing the clinical onset of disease. Despite this observation, the exact prevalence of hypercortisolism in patients with mood disorders is unknown and who/how to screen for endogenous hypercortisolism among patients with mood disorders is still unclear. In this context, an accurate anamnestic and clinical examination are crucial in order to identify those patients who may benefit from CS screening. In particular, the presence of specific signs and symptoms of CS, comorbidities typically associated with CS, and lack of improvement of depressive symptoms with standard treatments can further guide the decision to screen for CS. Anyhow, it is noteworthy that mood disorders represent a cause of functional activation of hypothalamic-pituitary-adrenal (HPA) axis, a condition formerly known as non-neoplastic hypercortisolism (NNH). The differential diagnosis between CS and NNH is challenging. Beyond anamnestic and clinical features, various tests, including measurement of daily urinary cortisol and late-night salivary cortisol, together with low dose-dexamethasone suppression test, are used for initial screening. However, considering their low accuracy, a definitive diagnosis may require a longitudinal follow-up along with second-line dynamic tests like combined dexamethasone-CRH test and desmopressin test. In conclusion, available data suggest the need for a comprehensive assessment and follow-up of individuals with mood disorders to detect possible underlying CS, considering the pitfalls in diagnosis and the overlap of symptoms with other conditions like NNH. Specialized centers with expertise in CS diagnosis and differential testing are recommended for accurate evaluation and management of these patients.