Clozapine is gold standard, but questions remain

Abstract

In their recent publication, Frogley and colleagues have reviewed the evidence indicating that clozapine treatment reduces aggressive behaviour in patients with schizophrenia, and perhaps with other disorders as well (Frogley et al. 2012). Although randomized controlled trials testing this anti-aggressive effect are relatively scarce, the evidence based on many studies supports it. There is general agreement on the superiority of clozapine's anti-aggressive effect in schizophrenia, as reflected for example in published expert consensus guidelines (Kane et al. 2003, p. 38) and in standard textbooks (Volavka et al. 2012). However, there are issues that are not quite as clear. Failure to respond to clozapine is one of these issues. In the general population of schizophrenia patients with treatment-resistant illness, only about 50% of patients respond to clozapine (Lieberman et al. 1994). The proportion of responders to clozapine in the treatment of aggression in schizophrenia has not been reliably established, but it is clear that not all patients will respond. The data published by Krakowski et al. (2006) probably represent the most robust support for the anti-aggressive superiority of clozapine over other antipsychotics in schizophrenia. The statistical analyses used in that paper (Krakowski et al. 2006) were not designed to define the outcome in dichotomous terms (response vs. non-response). However, the published interquartile ranges strongly suggest that non-responders to clozapine were present. Similar variability of response to clozapine was observed in other studies. The causes of this variability of response are not well understood. In a follow-up paper, Krakowski & Czobor (2012) demonstrated that the superiority of clozapine was probably not due to its effect on executive functioning. The variability of response is therefore apparently attributable to other factors than cognitive performance. One reason for this variability is that aggressive behaviour in schizophrenia is …