On the feasibility of designing new antidepressants.

Modern antidepressants lack many of the side-effects and much of the toxicity of the first generation tricyclics and monoamine oxidase inhibitors. Knowledge of the receptor interactions that are responsible for poor tolerability and potential lethality in overdosage has enabled the design of agents that have low or no affinity for such receptors. Nevertheless, even the second generation selective serotonin reuptake inhibitors (SSRIs), the serotonin noradrenaline reuptake inhibitors (SNRIs) and the noradrenaline and serotonin specific antidepressants (NaSSAs) have not substantially improved upon the efficacy of the older agents. They still take some time to be effective, 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, including receptors, G-proteins, second messengers, gene transcription factors 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 entities has increased structural diversity, but pharmacological evaluation has narrowed down to simple assays in high-throughput screening systems. Such assays depend to a major extent on how well they reflect the biological aetiology of the disease under study. While new antidepressant moieties will undoubtedly emerge, optimal use of the new research tools will necessitate a more sophisticated level of knowledge about the true causes of depression. Copyright 2001 John Wiley & Sons, Ltd.