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Pharmacogenomics J. 2015 Oct;15(5):461-6. doi: 10.1038/tpj.2015.5. Epub 2015 Mar 3.

Establishing the characteristics of an effective pharmacogenetic test for clozapine-induced agranulocytosis.

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SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Discovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research Laboratories, Erl Wood Manor, Surrey, UK.
Department of Severe Mental Illness, Mental Health Care Organization North-Holland North, Heerhugowaard, The Netherlands.
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Department of Medical and Molecular Genetics, King's College London, London, UK.


Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high-risk and a low-risk group, we explore the relationship between test sensitivity, group size and agranulocytosis risk. High sensitivity minimizes the agranulocytosis risk in the low-risk group and is essential for clinical utility, in particular in combination with a small high-risk group.

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