No abstract

Preliminary results of a non-blinded prospective study of the effect of clozapine on symptomatology and social function in 51 treatment-resistant schizophrenic patients are reported. The mean duration of treatment at the time of this report was 10.3 +/- 8.1 months, median 7.6 months. Overall, 3/51 patients (60.8%) showed at least a 20% decrease in total BPRS, a criterion of improvement in the study of Kane et al. (1988). Four of 51 (7.8%) had at least a 50% decrease in total BPRS. Improvements in both positive and negative symptoms were noted. Marked improvements in social function were noted within the first 6 months of treatment. Improvement was first noted at all time points, with only 45.2% of improvers being identified after 6 weeks of treatment. These results suggest a 6-12-month trial may be desirable before deciding to discontinue clozapine because of insufficient response. Higher total Brief Psychiatric Rating Scale (BPRS) score and higher ratings on the Paranoid Disturbance subscales of the BPRS were factors which discriminated clozapine responders from non-responders.

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Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic-resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT2 receptor, producing a high 5-HT2/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2DA receptors and a potent inhibitory effect on 5-HT2 receptors, as well as its ability to increase DA and 5-HT2 release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission.