New antipsychotic agents and the future

In the absence of knowledge about the etiology of the diseases being treated and of adequate animal models, the future design of antipsychotic agents must rely largely on a pragmatic extension from the drugs already known to be useful. The property of dopamine receptor antagonism has proved a reliable predictor of antipsychotic effect. It may be argued that further therapeutic gains through development of more selective and more potent dopamine antagonists are unlikely. A general limitation of receptor-active drugs is the phenomenon of reactive change in receptor numbers. For long-term maintenance treatment, it may be sensible to search for a neuroleptic equivalent of lithium, which has no direct effect on membrane receptors. The two most pressing clinical issues are 1) persuading clinicians to use the minimum effective clinical dose for the shortest time, and 2) developing an effective treatment for the schizophrenic defect state, its possible association with cerebral atrophy notwithstanding.