Antipsychotic drug action: targets for drug discovery with neurochemical imaging

Abstract

Schizophrenia is a serious lifelong mental illness for which current treatments may only be partially effective. All antipsychotic medications available at present are thought to exert their main antipsychotic effect through antagonism of dopamine D₂ receptors. Clozapine is the most effective antipsychotic drug currently available, but it can cause serious side effects, including agranulocytosis and diabetes. Pharmacologic factors that distinguish clozapine from other antipsychotic drugs have been studied to try to develop safer drugs with similar efficacy to clozapine. These have met with limited success. Neurochemical imaging techniques, such as positron emission tomograpy, single photon emission tomography and magnetic resonance spectroscopy, have been used to study antipsychotic drug action in living human subjects. These techniques shed a great deal of light on the mechanisms of antipsychotic action and have revealed a number of novel targets for future drug development in schizophrenia. Next-generation antipsychotic medications will aim to improve on the efficacy and tolerability of currently available medications. The authors believe that they are likely to achieve this through drug action at non-D₂ sites. Future research and drug development, including the development of medications to prevent progression from the prepsychotic stage to schizophrenia, will rely heavily on neurochemical imaging methods at all stages in the drug-discovery pipeline.

Keywords::

• antipsychotic drug action
• antagonism
• blockade
• clozapine
• dopamine receptors
• magnetic resonance spectroscopy
• positron emission tomography
• schizophrenia
• single-emission tomography