It has been suggested that hypothalamic-pituitary-adrenal (HPA) system dysregulation plays an important role in the pathophysiology of depression and that normalization of HPA axis hyperactivity precedes successful treatment with antidepressants. We report the case of a 61-year-old patient suffering from a major depressive episode who underwent the combined dexamethasone suppression/CRH stimulation test (DEX/CRH test) before and again after one week of mirtazapine treatment. While the patient showed a marked decrease of cortisol and ACTH secretion during the DEX/CRH test within one week, a pronounced and ongoing deterioration of depressive symptoms with suicidal thoughts occurred that was resistant to antidepressant medication and had to be treated with electroconvulsive therapy. Apparently, mirtazapine rapidly attenuates HPA axis hyperactivity in depressed patients via direct pharmacoendocrinological effects. However, this amelioration of HPA system dysregulation is not necessarily accompanied by clinical improvement.