Cortisol synthesis inhibition: a new treatment strategy for the clinical and endocrine manifestations of depression.

Evidence exists that oversecretion of cortisol may be responsible for the clinical manifestations and serotonergic abnormality in depressive illness. Using the cortisol synthesis inhibitor ketoconazole, we investigated the effects of directly lowering cortisol on the symptoms and the response of prolactin (PRL) to d-fenfluramine in eight patients suffering from major depression. Prolactin responses to d-fenfluramine were measured, and patients were treated with 400-600 mg of ketoconazole for 4 weeks, after which they were retested. Five patients treated with ketoconazole recovered from their depression, while the other three had decreases in their Hamilton Depression Rating Scale (HAMD) scores of < or = 50% and were deemed partial responders. Posttreatment prolactin responses to d-fenfluramine were higher than pretreatment values. Ketoconazole normalizes the blunted prolactin responses to d-fenfluramine and may be an effective method by which to treat depression. This implies that hypercortisolemia may be responsible for the clinical features and serotonergic subsensitivity observed in depression.