The search for novel antipsychotics: pharmacological and molecular targets

There can be little doubt that the newer, atypical, antipsychotic drugs provide improved treatment for many patients suffering from schizophrenia. However, the significant gains in tolerability produced by these drugs have not generally been accompanied by major advances in clinical efficacy. In particular, negative and cognitive symptoms, which may represent the core deficit of the disease, remain inadequately treated. There is, therefore, a pressing need for more effective drugs. A number of drug discovery and development programmes are currently underway in parallel with significant research into the basic neurobiology of the disease. All antipsychotic drugs currently used in the clinic are antagonists at dopamine D2 receptors, and dopamine neurotransmission seems likely to remain a major biological target for research. However, novel approaches to modulate dopaminergic neurotransmission selectively in relevant brain regions may be required. In addition, a range of non-dopaminergic targets including glutamate, serotonin, neurokinins and acetylcholine are also of major interest. It is likely, however, that the importance of many of these targets may lie in their relationships to and interactions with dopaminergic mechanisms. Finally, advances in genetics and molecular biology are identifying genes associated with a susceptibility to develop schizophrenia. It remains to be seen whether or not these genes and their associated proteins will provide molecular targets for successful drug discovery.