2/7 Clozapine for the Prevention of Violence in Schizophrenia: a Randomized Clinical Trial

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While most people with psychosis are not dangerous and most violence is committed by non-psychotic people, people with psychotic disorders are at increased risk for violence, and violence is associated with worse outcomes and increased stigma. Therefore, decreasing violence risk in psychosis is clinically relevant and has important public health implications. Several clinical studies suggest that clozapine is superior to other antipsychotic medications in reducing violence or aggression. However, there were numerous limitations of these studies including that most of them were observational and non-randomized, included small sample sizes, or focused on hostility, non-physical aggression, or self-harm, rather than violent acts. Further, the majority of these trials were not generalizable to outpatient, community settings. No large effectiveness study has examined the effects of clozapine on violent behavior in community settings. We propose a randomized, parallel-group, 24-week, open-label, single (rater)-blind, 7-site clinical trial to examine the effects of treatment with clozapine vs. treatment as usual (TAU) on the risk of violent acts in 280 individuals with schizophrenia at high risk for violence. This trial will be a collaboration of 7 sites, coordinated by the New York State Psychiatric Institute. The 6 additional collaborating sites contribute unique expertise and will ensure an adequate sample size for this trial. Our primary effectiveness outcome is time to violent acts as measured by the MacArthur Community Violence Interview (MCVI). We will also explore the effects of clozapine on the Point Subtraction Aggression Paradigm. While many factors may contribute to violent behavior in individuals with schizophrenia, including positive symptoms, psychopathy, impulsivity, and substance use, evidence suggests that the final common pathway for many of these disparate causal influences likely runs through behaviors captured by the Excitement Factor of the Positive and Negative Syndrome Scale (i.e., a composite of the scores of excitement, uncooperativeness, poor impulse control, and hostility). Importantly, our target (the excitement factor of the PANSS) has been validated to measure excitement-like symptoms in clinical trials in schizophrenia, is sensitive to treatment, has been linked to the neurobiology of violence in spectroscopy and PET studies, and differentiates clozapine from other antipsychotic drugs. We will also explore the effects of clozapine vs. TAU on positive symptoms (e.g., persecutory delusions) and alcohol and substance use, and how these effects influence the risk for violent acts. To enhance the safe implementation of this study in this vulnerable population at risk of violent behaviors, we will implement clinical safety and treatment engagement protocols that rely upon standard personnel and that will be readily generalizable. This trial will provide guidance on the use of clozapine for violence in community settings and will definitively test hypotheses regarding mechanisms of its anti-violence effects. The results will be immediately relevant to practice and will impact public health because there is currently no standard approach for the treatment of violence in schizophrenia.