The article presents a case of a long-term mental disorder in a 35-year-old woman with a persistent laboratory-confirmed increase in cortisol levels, without clinical manifestations of hypercortisolism. The first signs of mental illness appeared at the age of 14; over the past 8 years, the disease has been continuous and manifests itself in the form of a predominantly depressive state with increasing severity and complication of symptoms. Throughout all the years of the disease, active psychopharmacotherapy was carried out, combinations of antidepressants with antipsychotics and mood stabilizers were used, but no pronounced effect was achieved. Inpatient treatment in the clinic of the Mental Health Research Center for 5 months using several methods of enhancing antidepressant therapy had a good therapeutic effect and made it possible to achieve complete remission of the disease. There was a normalization of laboratory parameters of cortisol along with a decrease in the severity of pathopsychological symptoms, which indicates the genesis of hypercortisolism secondary to mental illness and its functional nature. It is assumed that hypercortisolism in this patient contributed to the formation of atypical clinical symptoms and resistance to antidepressant therapy. The discussion substantiates the need to consult a psychiatrist in case of persistent hypercortisolism in the absence of clinical manifestations of Cushing’s syndrome. The detection of persistent hypercortisolism in patients with depression determines the advisability of active therapy using several tactics to enhance the effect of antidepressants.