Even with appropriate antidepressant treatment, at least 10% of patients will fail to respond to successive trials and may experience refractory depressive illness. New therapeutic strategies including combined treatments are requested. The discovery and classification of monaminergic transporters, receptor types and subtypes have induced the development of new drugs. The new antidepressant mirtazapine probably acts by a potent presynaptic alpha-2 antagonistic activity consequently enhancing the release of noradrenaline and serotonin. This effect of alpha-2 blockade on noradrenaline could possibly be increased by blockade of noradrenergic re-uptake, the major effect of the tetracyclic antidepressant maprotiline. The latter additional effect could possibly be decreased by alpha-1 blockade, also induced by maprotiline.We report about the successful therapy of two patients with refractory depression, who showed only weak antidepressant effect after 6 weeks mirtazapine at high dosage (90 mg/day) and responded to additional treatment with maprotiline (case 1: 75 mg/day; case 2: 50 mg/day) The response occurred inbetween 14 days of maprotiline treatment.We cannot exclude the possibility of an effect of maprotiline alone, which could have taken place even without combination of mirtazapine. Further investigations are requested to prove our preliminary results.