[Towards personalized treatment with clozapine]

Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate.

To personalize clozapine treatment, we investigated the efficacy of clozapine as first- or second-line treatment and investigated whether there are factors that were associated with efficacy and side effects.

We collected a unique cohort of over 800 clozapine users diagnosed with a schizophrenia spectrum disorder. We meta-analyzed factors that were associated with response during clozapine treatment. Additionally, we conducted genetic association analyses to investigate the relations between side effects and symptom severity during clozapinetreatment.

From our meta-analyses, we found that clozapine was more effective when used as a first- or second-line treatment. Furthermore, we found that younger age, less negative symptoms and the paranoid subtype of schizophreniawere associated with a better clozapine response. Several specific locations on genes (loci) were associated with clozapine-induced agranulocytosis and neutropenia, while polygenic risk scores were associated with symptom severity.

We found that clozapine could be effective earlier in treatment and identified factors that could aid the prediction of< response to clozapine treatment in the future. These finding could contribute to the start of a personalized clozapine treatment.