[Leponex, 10 years after -- a clinical review]

Clozapine was one of the major advances in the treatment of schizophrenia since the introduction of the classic antipsychotic agent chlorpromazine in the 1950s. Over the past 10 years, clozapine has become the reference compound for the development of new antipsychotics, and new drugs have been developed which have also claimed atypical status. The indications of clozapine were recently extended to Psychosis in Parkinson's disease and harmonized in the European Union. This provides the opportunity to update the data on clozapine in the treatment of schizophrenia. In this article we review current clinical evidence in schizophrenia to address the following issues: 1) Efficacy in refractory/positive symptoms: a systematic and critical analysis of 14 double-blind clinical trials in comparison with both standard and novel antipsychotics show consistent findings in favour of clozapine, with all but three of the reports demonstrating superiority. The review of studies allow us to say little about the predictors of treatment response, time to clozapine response and about the impact of clozapine on the quality of patients'life and longer-term outcome. Treatment options for clozapine non-responders are reviewed. 2) Risk of EPS: clozapine is considered to have a minimal risk of EPS and in all studies where a valid methodology was used, a clear superiority over the other neuroleptics is demonstrated. It is pointed out that, if the prevalence and incidence of EPS with clozapine is low, it is not zero. All the studies assessing clozapine treatment for TD have major methodological limitations, so no final conclusion can be drawn. 3) Efficacy for primary and secondary negative symptoms and neurocognitive effects: the data of clinical studies where negative symptoms scales were used favour clozapine in terms of improvement. However most of the studies were carried out in populations with predominantly positive symptoms. With regard to the need to distinguish primary and secondary symptoms, data are conflicting regarding the benefit of clozapine. Due to the lack of studies with a valid methodology, no definitive conclusion can be drawn about the efficacy on clozapine on the deficit syndrome and on neurocognitive disorders. 4) Impact on suicide risk: 4 out of 6 retrospective studies provide evidence for the ability of clozapine therapy to reduce suicidal behaviour. The results of a recent randomized, parallel-group study designed to compare clozapine versus olanzapine in preventing suicide attempts seems to confirm this hypothesis. We also address the tolerability and safety data, especially haematologic, comitial, cardiovascular and metabolic side-effects. The effectiveness of blood monitoring for the management of neutropenia and agranulocytosis demands that the recommendations are strictly followed. The use of clozapine at doses higher than 600 mg daily should follow published recommendations, in order to minimize the risk of seizures; these include anticonvulsant regimens based on blood levels. With regard to the cardiovascular mortality, if clozapine therapy has negligible effects on QT interval, its association with potential fatal myocarditis cannot be excluded in young patients who should be investigated if they develop cardiac symptoms in the first weeks of treatment. Available data support the notion that the frequency of bodyweight gain is high with several new antipsychotics, including clozapine. Potential long term effects of bodyweight gain on mortality and morbidity have to be taken into consideration. The pharmacological mechanisms underlying the "unique clozapine profile" is discussed. Clozapine remains the only antipsychotic with efficacy at relatively low D2 receptor occupancy. The pharmacogenetic and pharmacokinetic aspects are also reviewed. Finally, the place of clozapine in the current treatment of schizophrenia is highlighted to inform the development of guidelines for clinical management.