THE ATYPICAL NEUROLEPTIC CLOZAPINE (LEPON EX(R)) - STATE-OF-THE-ART AND RECENT CLINICAL ASPECTS

The dibenzoepine derivative clozapine is seen as a prototype of an aty pical neuroleptic, because clozapine has good antipsychotic efficacy b ut only minimal dopamine antagonistic properties in common animal para digms. The latter is reflected by the observation that extrapyramidal symptoms during clozapine are a rare phenomenon. Furthermore, recent s tudies in the USA demonstrated a superior efficacy of clozapine in sch izophrenic patients who are nonresponsive to classic neuroleptics. The refore, the introduction of clozapine in the USA was performed in 1990 despite the well-known risk of agranulocytosis (1-2% during the first year of treatment); however, under restricted conditions regarding th e mandatory weekly control of the white blood cell count. For the use of clozapine in Europe, it should be underlined that in 1992 the indic ation was restricted to ''acute and chronic forms of schizophrenia'' w hereas formerly it was permitted to treat several other neuroleptic re sistant syndromes with clozapine, e.g. severe psychotic excitement, ag gressive behavior or manic or atypical psychosis. The usage of clozapi ne in these indications is now only permitted under the restricted leg al conditions of a ''therapeutic trial'' in selected patients. However , several indications for which clozapine has been used successfully i n Europe are currently re-investigated in the USA, hopefully leading t o a redefinition and extension of the indication spectrum. On the othe r hand, the American multicenter trials lead to the conclusion that th e treatment with clozapine is not furthermore the treatment of last ch oice but a serious therapeutic alternative which should be available f or all schizophrenic patient in case of neuroleptic resistance or of s evere side effects of standard neuroleptics. Clozapine treatment leads to an improvement of the quality of life in one third of these schizo phrenics and moreover, results in a marked reduction of costs mainly b y reducing the rehospitalisation rates. On the other hand, the list of well-known side effects of clozapine (e.g. agranulocytosis, increased risk of seizures, initial sedation) has to be extended (e.g. transien t leucocytosis or eosinophilia, rare but severe complications like car diorespiratory arrest and ''sudden death'' during combination with ben zodiazepines, case reports of pericarditis, pancreatitis or polyserosi tis). On the background of possible cardiorespiratory complications we recommend to start the first treatment with clozapine in high risk pa tients (e.g, those in older age or in case of organic brain impairment ) only in restricted indications and only in centers with sufficient c lozapine experience.