Letter to the Editor regarding ‘Homicide associated with psychotic illness: What global temporal trends tell us about the association between mental illness and violence’

Can clozapine reduce violent crime in patients with schizophrenia?

Patients with psychosis are 4–10 times more likely to commit homicide, compared with the general population and 2–8 times more likely to commit violence as compared to non-affected members of the general population (Simpson et al., 2021). Worldwide trends of homicide rates for patients with psychosis have been largely unchanged for several decades. While total homicide rates reduced by 50% in Australia between 1993 and 2013, homicide rates for patients with severe mental illness were essentially unchanged (Simpson et al., 2021).

In this correspondence, we respond to the viewpoint by Simpson et al. (2021) on ‘Homicide associated with psychotic illness: What temporal trends tell us about the association between mental illness and violence’. We specifically suggest increasing clozapine utilisation for patients with schizophrenia, to potentially reduce rates of incarceration, violent crime and possibly homicide.

To assess the potential differential anti-aggressive effect of clozapine, compared to other antipsychotic medication it is important to analyse results from large-scale observational studies as they are more likely to reflect actual real-world settings. Sariaslan et al. (2021), using a Swedish registry cohort, evaluated the relative benefit of antipsychotic medication for 74,925 individuals in reducing overall crime rates and violent crime. The relative risks of all crime outcomes were substantially reduced during periods when the patients were prescribed antipsychotic medication as compared with periods when they were not (adjusted rate ratio range [aRR]: 0.50–0.67), based on a within individual analysis. Within antipsychotic medications, clozapine was associated with the lowest risk of overall arrest and conviction risk among all antipsychotic medications, with an aRR of 0.28–0.44, comparing favourably with olanzapine (aRR: 0.46–0.72), risperidone (aRR: 0.53–0.64), quetiapine (aRR: 0.68–0.84) and haloperidol (aRR: 0.67–0.77). Importantly, while all antipsychotic medications were associated with lower rates of violent crime arrest, clozapine was associated with the highest adjusted risk reduction among all antipsychotic medications, (aRR: 0.38, 95% confidence interval [CI] = [0.29, 0.49]) and quetiapine with the lowest adjusted risk reduction (aRR: 0.84, 95% CI = [0.79, 0.90]).

Krakowski et al. (2021) recently published the outcomes of 99 patients with physically assaultive schizophrenia. In a 12-week double-blind trial, patients were randomly assigned to receive either clozapine, olanzapine or haloperidol. Clozapine was significantly superior in reducing overall assaults compared to both haloperidol and olanzapine (olanzapine was more effective than haloperidol on this measure). Clozapine’s differential anti-aggressive effect (compared with both haloperidol and olanzapine) was also noted in patients with and without a history of conduct disorder. In patients with conduct disorder, clozapine was four times more likely than haloperidol to result in lower violence and in patients without conduct disorder, it was three times more likely to do so (Krakowski et al., 2021). The authors suggested that clozapine should be considered potentially as a primary treatment in patients with both schizophrenia associated with violence, and a history of conduct disorder.

Clozapine is considered to have anti-aggressive effects independent of its antipsychotic effects, possibly related to its unique multi-receptor binding profile (Krakowski et al., 2021; Sariaslan et al., 2021). This differential anti-aggressive effect, compared to all other antipsychotic medication has been evidenced in both real-world settings and in short-term randomised controlled clinical trials (Krakowski et al., 2021; Sariaslan et al., 2021). However, clozapine is largely underutilised and this may therefore be an important factor partially contributing to the unchanging worldwide homicide rates in patients with schizophrenia. It is likely that increasing worldwide clozapine prescription rates would reduce violent crime and associated incarceration rates in patients with schizophrenia, based on the available evidence. We should bear in mind that part of the reduction in violence seen with clozapine prescription may also relate to the tight monthly monitoring requirements in place for this medication. The US Food and Drug Administration have previously approved a specific indication for clozapine in the setting of suicidality and schizophrenia. It would be important to conduct further well-designed clozapine cohort and long-term clinical trials, specifically assessing its differential anti-aggressive properties compared to other antipsychotic medication. This may lead to a further clinical indication for clozapine in the setting of schizophrenia associated with significant violence. It is our view that for patients with treatment resistant schizophrenia and significant accompanying violence, clozapine will likely be effective in reducing psychotic symptoms, violent crime and incarceration rates.