An important breakthrough in the development of novel neuroleptics arose over 25 years ago with the discovery of the dibenzazepine neuroleptic clozapine. This neuroleptic was novel because it attenuated both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects or elevating serum prolactin concentrations, effects which characterize most typical neuroleptics such as chlorpromazine and haloperidol.
Despite its novel therapeutic profile, it was soon evident that clozapine occasionally caused agranulocytosis, a potentially fatal immune condition, in approximately 3% of patients. The use of clozapine was therefore restricted largely to patients who suffered severe side effects with the typical neuroleptics, who were resistant to conventional neuroleptics or who had a high proportion of negative symptoms. Thus, clozapine has served as a useful prototype for the development of new neuroleptics and these will be briefly described.
Clozapine binds with a high affinity (in the nanomolar range) to D4 and D2 receptors and with lower affinity for the D1, D3 and D5 receptors. The finding that clozapine had a high affinity for the D4 receptors was particularly exciting when it was discovered that an elevated expression of D4 receptors occurred in the brains of schizophrenic patients. However, more recent studies have shown that clozapine also binds with a high affinity to the short form of the D2 receptor. Further evidence for the relative lack of specificity of clozapine, not only for different types of dopamine receptors but also for 5-HT, muscarinic, adrenergic and histaminergic receptors, suggests that it is a neuroleptic with a very broad basis of action. However, the beneficial effects of clozapine (and other atypical neuroleptics such as risperidone, seroquel and sertindole) may be due to its selective effects on mesolimbic and mesocortical dopaminergic neurons. Clinical and experimental studies suggest that such atypical neuroleptics decrease the negative symptoms of schizophrenia by enhancing prefrontal dopaminergic activity while decreasing the activity of this transmitter in the mesolimbic
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