ABSTRACT
Antipsychotics were discovered by accident-as efforts to make better antihistaminics led to the synthesis of chlorpromazine. It was the work of Delay and Deniker (Delay et al, 1952) which established chlorpromazine’s efficacy as a ‘major tranquillizer’ against psychotic disorders, an effect we now tend to call ‘antipsychotic’ (King and Voruganti, 2002). That dopamine may have a critical role in antipsychotics was realized in the 1960s with the work of Carlsson et al (Carlsson and Lindqvist, 1963) and it was finally Seeman et al (1976) who established dopamine D2 blockade as central to antipsychotic efficacy. Over this period, hundreds of compounds with putative antipsychotic activity have been synthesized and dozens have made it to the clinic. The more recent agents have avoided the motor side effects of the earlier antipsychotics and are often called ‘atypical’ antipsychotics. Despite years of research several important questions remain: What is the most critical ingredient in optimal antipsychotic activity? What is the molecular basis of this activity? Why are antipsychotics anti-‘psychotic’? How do psychosis and antipsychotics fit into the larger context of schizophrenia?
