Augmentation of Clozapine with Atypical Antipsychotic Substances

The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved with typical antipsychotic drugs, however, up to 40 % of the cases show treatment resistant symptoms. Even therapy with atypical substances such as risperidone, olanzapine, quetiapine, sulpiride, amisulpride, and ziprasidone often fails in reaching complete remission due to resistant schizophrenic symptoms or dose-limiting side effects. As this also holds true for monotherapy with clozapine, a substance with proved efficacy in formerly resistant cases, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the combined application of clozapine with other atypical antipsychotic drugs. Details about indication, methodology and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride was found in a total number of 34 publications, encompassing a total of 1250 patients. Favorable effects on psychotic symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases, pharmacokinetic interactions or serious unfavorable effects were reported. In conclusion, most of the combination therapies follow a neurobiological rationale. There are major differences in the level of evidence regarding their safety, tolerability and effectiveness. We discuss criteria for the indication of a clozapine augmentation and differential indication for existing alternatives. Additional randomized prospective trials are needed in order to systematically evaluate these strategies.