Molecular Psychiatry (1999) 4, 418–428  1999 Stockton Press All rights reserved 1359–4184/99 $15.00 MECHANISMS OF DRUG ACTION Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia GE Duncan 1 , S Zorn 2 and JA Lieberman 1 1 Department of Psychiatry and UNC Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599; 2 NS Discovery, Pfizer Inc, Central Research Division, Pfizer Inc, Groton, CT 06340, USA Available evidence indicates that clozapine is the most effective antipsychotic 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 advan- tageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and ser- otonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer ‘atypical’ antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resist- ant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experi- ence with the newer ‘atypical’ antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia. Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia; dopamine; NMDA The introduction of clozapine for the pharmacotherapy of schizophrenia represented a significant advance in the treatment of this devastating mental illness. Cloza- pine is superior to typical neuroleptic drugs (eg haloperidol) in treating positive and negative symp- toms, and is effective in many patients who are refrac- tory to typical antipsychotics. 1–3 In addition, clozapine does not induce the extrapyramidal side effects (EPS) commonly caused by the typical agents. Because of these properties, clozapine was termed atypical and represents the prototype drug of this class. Although clozapine is the most efficacious antipsychotic cur- rently available, serious side effects induced by the drug, including agranulocytosis, impose substantial limitations on its use. Concerted research and develop- ment efforts have been made to produce an antipsy- chotic drug with the therapeutic advantages of cloza- pine, without the properties contributing to its serious side effects. However, the specific pharmacological characteristics of clozapine that confer its therapeutic properties are poorly understood. Clozapine binds to a diverse number of neurotransmitter receptors (see Correspondence: GE Duncan, PhD, Neuroscience Center, CB # 7250, University of North Carolina School of Medicine, Chapel Hill, NC 27599–7250, USA. E-mail: gduncanKcss.unc.edu Received 3 March 1999; revised and accepted 10 May 1999 Table 1) but it is unclear whether actions at specific serotonin, dopamine, or adrenergic receptors, alone or in combination, account for its clinical efficacy. A number of specific hypotheses concerning mech- anisms of action of clozapine have directed drug dis- covery efforts and led to clinical trials of drugs with widely different receptor-binding characteristics. The clinical experience with drugs whose development was inspired by clozapine will be briefly reviewed and then actions of clozapine and other antipsychotic drugs will be addressed in the context of the NMDA hypo- function hypothesis of schizophrenia. Clinical experience with clozapine-inspired putative antipsychotics in relation to therapeutic mechanisms of action One of the earliest hypotheses of clozapine’s mech- anism of action related to the D1 dopamine antagon- istic properties of the drug. 4 Clozapine binds to D1 receptors in vitro with modest affinity (see Table 1) and at therapeutic doses occupies approximately 40–50% of D1 receptors in humans. 5 Based on the hypothesis that the D1 antagonistic properties of clozapine dis- tinguished it from the typical antipsychotic drugs, selective D1 antagonists were developed as potential antipsychotic agents. Unfortunately, such drugs were not effective and there were indications that selective