An open clinical study with 20 consecutive outpatients suffering from major depression with melancholia (DSM-III) was carried out. All patients were resistant to desipramine after at least six weeks of treatment. A significant improvement was found in 13 of the 20 patients when lithium carbonate was added. Among the responder patients, five improved in the first week of lithium augmentation, while eight others improved after one week of lithium. The mechanism of action of the lithium augmentation effect in tricyclic-resistant depressed patients is discussed in view of our findings. We suggest that the unified 5-HT/NE hypothesis used in affective disorder could be applied in drug refractory depression.