Recent advances in potential atypical antipsychotics: Past, present and future hopes - Preclinical and clinical considerations

The development of new and better antipsychotics has been hampered, unexpectedly enough, by the dopamine (DA) hypothesis of schizophrenia. The persuasive power of this has meant that preclinical models in most cases have been fine-tuned to reflect substances that work only via the DA system thus excluding by definition subtances working via new mechanisms. The so called atypical antipsychotics represent modifications of the DA hypothesis, modifications that have utilized, for example, our increasing knowledge of how neurotransmitters modulate each other in the brain. Thus, the D₂-5HT₂ development is based largely on the receptor profile of clozapine and, in part, on studies that indicate that 5-HT₂ receptors modulate mesolimbic DA neuron function. The development of sertindole has also utilized this D₂-5HT₂ interaction together with the observation that certain atypical antipsychotics preferentially affect mesolimbic DA neurons when administered chronically. It is the authors' opinion, however, that a breakthrough in this area will only occur when the DA hypothesis no longer steers development. We cannot, in this short review, cover all aspects of the field. Instead, we will concentrate on some of the hottest areas in the literature today and discuss some potential new ways to develop new and better antipsychotic agents.