METABOLITES OF THE ANTIPSYCHOTIC AGENT CLOZAPINE INHIBIT THE REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Schizophrenia is a serious and often debilitating neuropsychiatric dis ease of worldwide importance, Current therapy relies on the use of typ ical antipsychotic medications, which specifically inhibit binding of ligand at the D2 dopamine receptor, and atypical medications which dis play little activity for this receptor interaction. While atypical ant ipsychotic agents have been shown to variably inhibit other neurorecep tor-ligand interactions, the exact mechanisms for the therapeutic effi cacy of these medications have not been completely defined. Clozapine, an atypical antipsychotic, and nine of its metabolites were studied i n vitro for possible antiviral activity against a model of a human neu rotropic virus, human immunodeficiency virus type 1 (HIV-1). In an ass ay for inhibition of virus-induced cytopathic effect (CPE) two metabol ites demonstrated antiviral activity (ID50 = 37-85 mu g/ml) (119-289 m u M), while other atypical or novel antipsychotics as well as typical medications had no effect, Based on an ELISA, four chemically similar metabolites inhibited the production of p24, the major internal antige n of HIV (ID50 = 11.6-15.7 mu g/ml) (38-51 mu M). These data suggest t hat the therapeutic efficacy of some antipsychotics may be due in part to an ability to inhibit viral replication. Antiviral agents may prov e to be effective adjuncts in the treatment of schizophrenia.