Antidepressant agents: from tricyclics to serotonin uptake inhibitors

Background. The number of antidepressant drugs available in the market has grown rapidly in the last few years. The present paper underlines some of the pre-clinical and clinical problems that call close attention from the regulatory authorities when approving new drugs. Methods. We present here a review of the literature. Results. A wide heterogeneity in the action of the various antidepressants precludes any single theory about the pathogenesis and therapy of depression. Antidepressant activity, in fact, may be achieved by acting on a number of different monoaminergic mechanisms. The variety in the neurochemical effects of antidepressants is not reflected in clinical trials, which tend to stereotypy. In many cases clinical trials aim at demonstrating equivalence rather than differences in efficacy. Regulatory authorities should, therefore, pay attention in accepting the equivalence of effects of a new drug in relation to a reference one: most clinical trials of new antidepressant drugs do not have the power to detect clinically relevant differences. Conclusions. Unconventional new pre-clinical tests are needed to generate antidepressants with a different mechanism of action. Clinical studies are needed to promote objective comparative evaluation of the cost, benefits and toxic effects of new antidepressants.