Clozapine metabolism is associated with Absolute Neutrophil Count in individuals with treatment-resistant schizophrenia

AIM To investigate the relationship between clozapine concentration and neutrophils in a European cohort of long-term clozapine users. METHODS Pearson’s Correlation and Linear Regression analyses were applied to a subset of the CLOZUK2 dataset (N = 208) to assess the association between Absolute Neutrophil Count (ANC) and plasma clozapine concentration. Norclozapine and the metabolic ratio between clozapine and norclozapine were also investigated, along with SNPs associated with clozapine metabolism RESULTS Association between ANC and plasma clozapine concentration was found to be significant in a linear regression model (β = −1.41, p = 0.009), with a decrease in ANC of approximately 141 cells/mm3 for every 0.1 mg/litre increase in clozapine concentration. This association was attenuated by the addition of the metabolic ratio, which was significantly negatively correlated with ANC (β=-0.69, p=0.021). In a further regression model, three SNPs previously associated with norclozapine plasma concentrations and clozapine/norclozapine ratio were also found to be significantly associated with ANC: rs61750900 (β=-0.410, p=0.048), rs2011425 (β=0.450, p=0.026) and rs1126545 (β=0.330, p=0.039) CONCLUSION ANC was found to be significantly negatively associated with plasma clozapine concentration. Further investigation has suggested that the relationship is mediated by the clozapine/norclozapine ratio, and potentially moderated by genetic variants with effects on clozapine metabolism ### Competing Interest Statement Drs. Helthuis and Jansen are full-time employees of Leyden Delta. Dr. King is a full-time employee of Magna Laboratories. Drs. Owen, O'Donovan, and Walters are supported by a collaborative research grant from Takeda Pharmaceuticals (Takeda played no part in the conception, design, implementation, or interpretation of this study). The other authors report no financial relationships with commercial interests. ### Funding Statement Academy of Medical Sciences "Springboard" award to AFP (SBF005\1083). MRC Mental Health Data Pathfinder grant to JTRW (MC-PC-17212). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The CLOZUK study was reviewed and approved by the UK Multicentre Research Ethics Committee (ref. 10/WSE02/15). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes To comply with the ethical and regulatory framework of the CLOZUK project, access to individual-level data requires a collaboration agreement with Cardiff University. Requests to access data from this project should be directed to Prof. James T. R. Walters (WaltersJT@cardiff.ac.uk). Genome-wide summary statistics from the GWAS cited in this study can be found at the Data Availability Link.