Clozapine metabolism is associated with Absolute Neutrophil Count in individuals with treatment-resistant schizophrenia
Isabella R Willcocks,
Sophie E Legge,
Michael J Owen,
Michael C O'Donovan,
James TR Walters,
Antonio F Pardiñas
Posted 03 Feb 2021
medRxiv DOI: 10.1101/2021.02.01.21250894
Posted 03 Feb 2021
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 (beta=-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 (beta=-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 (beta=-0.410, p=0.048), rs2011425 (beta=0.450, p=0.026) and rs1126545 (beta=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.
- Downloaded 790 times
- Download rankings, all-time:
- Site-wide: 54,793
- In pharmacology and therapeutics: 85
- Year to date:
- Site-wide: 14,597
- Since beginning of last month:
- Site-wide: 23,665
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!