Why do we need new and better antidepressants?

The range of available antidepressants is reviewed in relation to mechanisms of action and the evidence of efficacy in general and efficacy in severe depression in particular. In studies investigating efficacy in major depressive disorder, not all antidepressants have been shown to have clear-cut efficacy in severe depression. Here, the minimum standards for the necessary methodology to investigate efficacy in severe depression are reviewed and the methods that are needed to establish efficacy as a superior antidepressant or as an antidepressant with a faster than expected response are suggested. A review of the mechanisms of action of different antidepressants is accompanied by a critical review of the properties of an antidepressant likely to achieve either efficacy in severe depression or the status of a superior antidepressant.