Milnacipran is a new antidepressant which possesses potent and doubly selective action in that it inhibits both the re-uptake of serotonin and noradrenaline without any effect on other neurotransmitter systems. The almost equipotent inhibition of serotonin and noradrenaline by milnacipran is functionally reflected in the several-fold and long-lasting increase of the levels of these monoamines in the brain and in antidepressant-like effects in animals. In man, milnacipran distinguishes itself from many other antidepressants by its simple pharmacokinetics. It shows linear dose-concentration relationship over a dose range of 25-200 mg/day. It is rapidly and extensively absorbed and almost completely eliminated after 12 h (t1/2 approx. 8 h). Steady-state plasma levels are reached within 32-48 h after twice daily oral administration. Milnacipran is highly bioavailable (>85 per cent) and its metabolism does not involve the cytochrome P450 enzyme system. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs and superior to that of placebo. At the optimum dose of 100 mg/day, after 4-8 weeks of treatment, 60-64 per cent of in- or out-patients with major depression improve (>/=50 per cent reduction of HAMD and MADRS score) and about 32-39 per cent of them achieve full remission (HAMD score</=7). Milnacipran has proved to be a very safe drug with a benign adverse event profile clearly superior to that of TCAs and, to a certain extent, that of SSRIs. Only about 10 per cent of patients experience side-effects and only dysuria occurred more frequently (2 per cent) with milnacipran than with TCAs or SSRIs. Milnacipran appears therefore to be an antidepressant with a very favourable benefit/risk ratio. Copyright 2000 John Wiley & Sons, Ltd.