On the feasibility of designing new antidepressants

Modern antidepressants lack many of the side-effects and much of the toxici ty of the first generation tricyclics and monoamine oxidase inhibitors. Kno wledge of the receptor interactions that are responsible for poor tolerabil ity and potential lethality in overdosage has enabled the design of agents that have low or no affinity for such receptors. Nevertheless, even the sec ond generation selective serotonin reuptake inhibitors (SSRIs), the seroton in noradrenaline reuptake inhibitors (SNRIs) and the noradrenaline and sero tonin specific antidepressants (NaSSAs) have not substantially improved upo n the efficacy of the older agents. They still take some time to be effecti ve, although venlafaxine and mirtazapine may be faster in onset than SSRIs, and they leave a substantial minority of patients unaffected. Innovative new antidepressants may be based upon a variety of mechanisms, i ncluding receptors, G-proteins, second messengers, gene transcription facto rs and the hypothalamic-pituitary-adrenal axis, but their availability may be hindered by recent advances in pharmaceutical research technology. Thus, the creation of large chemical libraries containing millions of new entiti es has increased structural diversity, but pharmacological evaluation has n arrowed down to simple assays in high-throughput screening systems. Such as says depend to a major extent on how well they reflect the biological aetio logy of the disease under study. While new antidepressant moieties will und oubtedly emerge, optimal use of the new research tools will necessitate a m ore sophisticated level of knowledge about the true causes of depression. C opyright (C) 2001 John Wiley & Sons, Ltd.