Atypical Antipsychotics

Abstract

Neuroleptic action was first discovered and defined in 1952 with the clinical use of chlorpromazine, known before as an antihistamine (Delay et al. 1952). The identification of dopamine as a neurotransmitter in the brain and neurochemical and pharmacological studies revealed that neuroleptic activity involved dopamine antagonism (Carlsson and Lindqvist 1963; Van Rossum 1966). The butyrophenone, haloperidol, discovered in 1958, became the prototype of a neuroleptic with selective dopamine antagonistic action (Divry et al. 1958; Janssen et al. 1959). Following these discoveries, a first generation of neuroleptics was developed between the 1960s and mid-1980s, which were designed to be dopamine antagonists. Over 70 neuroleptics, belonging to more than 10 different chemical classes, were brought to the European market (Leysen and Niemegeers 1985). All these compounds appeared to block dopamine D₂ receptors in the brain and a correlation was shown between their affinity for D₂ receptors and dosages used for treating positive symptoms of schizophrenia (Creese et al. 1976; Seeman et al. 1976). However, a direct relationship also exists between blockade of D₂ receptors and the induction of extrapyramidal symptoms and the elevation of plasma prolactin levels (Van Wielinck and Leysen 1983; Kuenstler et al. 1999).