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Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.

Am J Psychiatry

June 2019

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Pardiñas, Nalmpanti, Pocklington, Legge, Medway, Zammit, Owen, O'Donovan, Walters); Magna Laboratories, Ross-on-Wye, U.K. (King); Leyden Delta, Nijmegen, the Netherlands (Jansen, Helthuis); the Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. (Zammit); the National Institute for Health Research, Biomedical Research Centre, University of Bristol, Bristol, U.K. (Zammit); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (MacCabe).

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia.

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