[Augmenting atypical antipsychotic medications with clozapin].

Typical antipsychotic medications have considerably improved clinical outcome of patients suffering from schizophrenic psychoses, but up to 40% of the cases show treatment resistant symptoms. Even therapy with atypical antipsychotic drugs such as risperidone, quetiapine, olanzapine, sulpiride, amisulpride, and ziprasidone often fails to reach complete remission due to resistant, positive or negative symptoms or dose-limiting side effects. As this also holds true in the case of monotherapy with clozapine, a substance known to be effective against treatment-resistant schizophrenia, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the use of clozapine combined with risperidone, olanzapine, quetiapine, sulpiride, amisulpride, or ziprasidone. Details on indication, methodology, and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride exists within a number of altogether 31 publications about 1182 treatments. Favorable effects on positive and/or negative symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases pharmacokinetic interactions or serious unfavorable effects occurred. In conclusion it might be accepted that most of the combination therapies follow a neurobiological rational. There a major differences in the level of evidence that they are safe, tolerable and effective. We discuss criteria for the indication for augmenting clozapine therapy and the differential indication for existing alternatives. Additional randomized prospective trials are needed in order to evaluate these strategies systematically.