Since the introduction of the newer atypical antipsychotics (AA) in the nineties global antipsychotic market sales are dramatically increased. Over the period 1993-2003 a tenfold increase occurred that was paralleled by a decrease of prescribed conventional antipsychotics without, however, a clearly demonstrated improvement of efficacy. The prescription of clozapine remained more or less stable. Moreover, there was a threefold increase in the prescription rate of combination antipsychotics. Shortly after the introduction of the first AA, the prevalence of antipsychotic polypharmacy in patients with schizophrenia tripled suggesting inadequate efficacy or treatment resistance. Remarkably, the prescription of clozapine did not increase. These trends are reflected by the number of publications about the rationale for augmentation strategies in case of lack of responsiveness to clozapine.

Over the past decade about 40 open studies have been published in which clozapine was augmented with one of the AA's, particularly risperidone and (ami)sulpride. Of these cases reports, nearly all described a positive outcome. Seven controlled studies have been published using augmentation of clozapine with sulpiride (n=1), amisulpride (n=1), amisulpride and quetiapine (n=1) and risperidone (n=4), including 266 schizophrenic patients, partially unresponsive to clozapine in a dialy dose of 400-550 mg. In only 3 of these studies the plasma concentration of clozapine was measured that ranged from 400-800 μg/l. None of these studies showed a relevant improvement. In the study with sulpiride a response of 21 % was noted.

There is no database to conclude that augmentation of clozapine with AA's is clinically relevant.