We acknowledge Leyden Delta and Magna Laboratories for supporting the CLOZUK2 sample collection, anonymisation and data preparation (Andy Walker and Anouschka Colson). We acknowledge deCODE genetics (Hreinn Stefansson) for genotyping of the CLOZUK2 sample. We acknowledge Cardiff University MRC Centre Core Team (Lucinda Hopkins, Lesley Bates, and Catherine Bresner) for laboratory sample management. We acknowledge Cardiff University MRC Centre HPC team (Mark Einon), and Cardiff University Advanced Research Computing division (Wayne Lawrence), for support with the use and setup of computational infrastructures. Competing Financial Interests M. H. and J. J. are full-time employees of Leyden Delta B.V.; A.K. is a full-time employee of Magna Laboratories Ltd. The remaining authors declare no conflicts of interest.

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Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

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