Current trends in the development of new antidepressants

Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are effective because they enhance eit her noradrenergic or serotonergic mechanisms, or both. Unfortunately, these compounds block cholinergic, histaminergic and proportional to 1-adrenergi c receptor sites, interact with a number of other medications and bring abo ut numerous undesirable side effects. Several chemically unrelated agents h ave been developed and introduced in the past decade to supplement the earl y antidepressants. These include selective inhibitors of the reuptake of se rotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenal ine (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as d rugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. All these newer compounds are the results of ra tional developmental strategies to find drugs that were as effective as the TCAs but of higher safety and tolerability profile. In spite of the remark able structural diversity, most currently introduced antidepressants are 'm onoamin based' and modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research. It must be emphasised, howev er, that these newer antidepressants are far from the ideal ones, also resu lting in undesirable side effects and requiring 2-6 weeks of treatment to p roduce therapeutic effect. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoamine rgic synapse. The results of recent novel developmental approaches have sug gested that modulation of N-methyl-D-aspartate (NMDA), neuropeptide (substa nce P and corticotrophin-releasing factor) receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic t argets. This paper discusses the advances from monoamine-based treatment st rategies and looks at the future developments in the treatment of depressio n.