We carried out an open clinical study with 60 consecutive patients suffering from major depression with melancholia who were resistant to anti-depressants. After at least 6 weeks of desipramine (DMI) or fluoxetine (FX) without improvement, lithium carbonate was added to the anti-depressant. Semistructured clinical interviews using the 7-point Clinical Global Impression Scale and 90-item Symptom Checklist were done at baseline and weeks 1, 6 and 14. Following the addition of lithium, more patients on FX improved within the first week than those on DMI. However, with FX, 6 relapses occurred during the 2 months of follow-up and none with DMI. The unified serotonergic and noradrenergic hypothesis for the antidepressant action could be relevant in drug-refractory depression and should be studied further.