[Concept of 2nd generation antidepressive agents]

Since the discovery of imipramine and iproniazide, the tricyclic antidepressants (TCA) have maintained a significant role in the pharmacotherapy of depression, whereas the MAO-inhibitors play a minor role because of toxicity problems. However, even the tricyclics present problems and the research to obtain a new "second generation" of less toxic and more efficacious antidepressants have been fully justified. This research has been based on biological models of depression and/or the experimental effects of existing antidepressants. In spite of the considerable investments over 30 years, the validity of prevailing biological depression-models is uncertain. Among the experimental effects of existing antidepressants, their ability to inhibit the reuptake of noradrenaline and serotonin has attracted most attention, resulting in the development of very selective compounds. Likewise, new selective and in particular reversible MAO-inhibitors have been developed. In light of the doubious validity of the experimental models, the clinical testing remains the crucial point. However, clinical trial methodology poses a number of problems, and there is much uncertainty concerning the efficacy of the heterogenous group of "second generation" antidepressants. Therefore, they are generally considered as antidepressants of second choice.