Multireceptor atypical antipsychotic drugs

Abstract

The atypical antipsychotic drugs are those antipsychotic agents which produce fewer extrapyramidal side-effects (EPS) at clinically effective anti-psychotic doses than do the typical neuroleptic drugs [23]. This definition of an atypical antipsychotic drug is still controversial [3]. Various authorities have suggested that the term be dropped completely and some other general name be used, e.g. novel antipsychotics, while others propose that the definition be broadened to include features beyond antipsychotic efficacy and low EPS, e.g. specific pharmacological features such as multi-receptor activity, efficacy in treatment-resistant schizophrenia, and ability to improve negative symptoms [3 4]. Clozapine is the prototypical atypical antipsychotic drug [5]. It was designated as an atypical anti-psychotic because it differed from the neuroleptic agents that were available at the time of its introduction in 1960 in that the neuroleptics produced catalepsy in rodents and EPS in man at clinically relevant doses and clozapine did not [6]. This term was widely used by preclinical investigators to refer to clozapine in their efforts to understand the biological basis for the difference between it and the prototypical typical neuroleptic drug, haloperidol, with regard to their effects on the limbic and nigrostriatal dopaminergic systems, the probable sites of antipsychotic action and EPS, respectively [7]. Thus, there has been much historical precedent to the definition of atypicality that focuses on the extrapyramidal system differences between antipsychotic drugs. Furthermore, acute and chronic EPS are the most significant side-effects of the first generation of antipsychotic drugs because of their influence upon compliance, and its effect, in turn upon relapse and rehospitalization [8], as well as the sometimes fatal neuroleptic malignant syndrome, and the ability to cause tardive dyskinesia [9]. What has complicated the issue of the essence of an atypical antipsychotic is the discovery of the many advantages of clozapine other than low EPS, including no known ability to cause tardive dyskinesia, efficacy in treatment-resistant schizophrenia, improvement in negative symptoms, decreased risk of suicide, and improvement in cognition, to name the most important [10] (see Naber et al., this volume].