Dopamine and Schizophrenia: A Reappraisal in the Light of Clinical Studies with Clozapine

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Abstract
In this paper we review the results of our clinical evaluation of a novel antipsychotic drug, clozapine, and discuss some fundamental issues in the neuropharmacology of schizophrenia, in the light of the results. Nineteen hospitalized chronic schizophrenic patients were treated with clozapine. The drug was administered according to a fixed changing dosage schedule, ranging from 75 mg to 800 mg daily. There was a highly significant improvement as measured by the Brief Psychiatric Rating Scale. At the same time no evidence of Parkinsonism or other extrapyramidal side effects was noted in these patients during the drug administration. For some time now, drug effect on the extrapyramidal system mediated through the nigrostriatal dopaminergic pathway was considered necessary for therapeutic effects in schizophrenic patients. But the recent discovery of the mesolimbic dopaminergic system raises the possibility that the therapeutic action of antipsychotic drugs could be mediated through this pathway without necessarily affecting the nigrostriatal pathway. This is further supported by the fact that these two dopaminergic systems have somewhat different pharmacological properties in relation to DA turnover and DA receptor blockade. The present study clearly demonstrates the antipsychotic property of clozapine. It is equally clear that it induces no extrapyramidal effects. These findings tend to support the hypothesis that clozapine may be selectively blocking dopaminergic receptors in the limbic system. The pharmacological evidence from the literature for this selectivity is presented to support the hypothesis that schizophrenic symptoms are related to excessive dopaminergic activity in the limbic system. In conclusion it can be stated that clozapine represents a significant advance in the investigation of the neuropharmacology and pathophysiology of schizophrenia.