Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

Available evidence indicates that clozapine is the most effective antipsych otic currently used for the pharmacotherapy of schizophrenia. Unfortunately , clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageou s therapeutic properties of clozapine. Based on hypotheses that dopaminergi c and serotonergic receptor-blocking properties of clozapine account for it s clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclus ions regarding the efficacy of the newer 'atypical' antipsychotics in compa rison to clozapine, However, most published studies, and general clinical i mpressions, suggest that none of the newer drugs are as effective as clozap ine in treating patients resistant to typical antipsychotic drug therapy. T he present paper briefly reviews the clinical experience with the newer 'at ypical' antipsychotic drugs and then discusses clinical and preclinical dat a potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.