Dopaminergic and serotonergic effects of clozapine. Implications for a unique clinical profile

The clinical profile of clozapine (CAS 5786-21-0) is characterized by superior efficacy in reducing the positive and negative symptoms of schizophrenia and a greatly reduced propensity to elicit acute extrapyramidal symptoms (e.g., Parkinsonian symptoms), long-term effects (e.g., tardive dyskinesia) and hyperprolactinemia. For these reasons clozapine is considered the prototypic atypical antipsychotic. The failure of clozapine to elevate serum prolactin concentrations may be related to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons and/or the failure of clozapine to achieve effective blockade of pituitary dopamine D2 receptors. The lack of acute blockade of striatal D2 receptors by clozapine and the failure of chronic clozapine treatment to suppress striatal dopamine release, relative to that produced by typical antipsychotic agents, may account for the lack of acute extrapyramidal symptoms and tardive dyskinesia, respectively, associated with the use of clozapine. Although the neurochemical substrates that subserve the unique preclinical and clinical profile of clozapine have not been determined unequivocally, clozapine and other purported atypical antipsychotic agents produce a greater antagonism of 5-HT2 receptors relative to D2 receptors than is the case for typical antipsychotics. Clozapine also exerts antagonism of D1 receptors. It is proposed that the selective interaction of clozapine among D2, D1, D4 and 5-HT2 receptors results in a distinctive alteration in the function of pre- and post-synaptic dopamine elements.