Pharmacological and molecular targets in the search for novel antipsychotics

The recent enthusiasm among clinicians for the so-called 'atypical antipsychotics' has both improved treatment for schizophrenic patients and provided a welcome stimulus for basic research on antipsychotic mechanisms. Even the newer drugs have shortcomings, and research is underway aimed at identifying novel agents with greater efficacy and safety. Much of this effort is directed towards compounds which, in addition to blocking dopamine receptors, also act on other neurotransmitter receptors such as 5-HT2, 5-HT1A and alpha2-adrenergic receptors. However, there is also a large amount of scientific activity seeking to discover and develop selective dopamine receptor subtype antagonists (including compounds which specifically block D3 or D4 receptors) or drugs that specifically target the dopamine autoreceptor. Finally, a number of drug development programmes are searching for non-dopaminergic antipsychotics. Drugs that do not have affinity for dopamine receptors but act through neurotensin, sigma or cannabinoid CB1 receptors or glutamatergic mechanisms are currently being evaluated. If any of these agents prove to have clinical efficacy this may lead to a third generation of antipsychotics. It is likely, however, that the mechanisms of action of such drugs will nevertheless imply the intimate involvement of dopaminergic pathways.