Rolipram improves signal transmission in central noradrenergic neurones at a pre- and postsynaptic level, and is thus a novel approach in antidepressant therapy. In order to prove efficacy, tolerance, and safety, several controlled studies are underway. Results of a randomized double-blind comparative trial versus imipramine involving 64 in-patients with Major Depressive Disorder (DSM III) in six independent centers will be presented and discussed. The chosen biometric model provided evidence that towards the end of the study imipramine was superior to Rolipram. The particular clinical relevance of this difference is discussed. As regards tolerance, nausea emerged as the typical side-effect of Rolipram, whereas imipramine precipitated mainly anticholinergic side-effects.