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Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis

Molecular Psychiatry volume 19, pages 403–405 (2014)Cite this article

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Clozapine is a prototypical atypical antipsychotic drug. Its primary indication is for treatment-resistant schizophrenia and reduction of the risk for suicide.1 In spite of its efficacy, the use of clozapine is markedly curtailed by its side effects such as metabolic syndrome and agranulocytosis.2 Although metabolic syndrome is more common than agranulocytosis, it is the latter which is the major reason that clinicians and patients are reluctant to consider the use of clozapine. Clozapine-induced agranulocytosis (CIA) occurs in about 0.8% of clozapine-treated patients, generally within the first 18 weeks of treatment and is characterized by a decrease in absolute neutrophil count (ANC) below 500 cells mm−3. The etiologic mechanism of CIA is unknown although several hypotheses have been proposed. These include nitrenium ion-mediated apoptosis, mitochondrial oxidative stress-induced apoptosis or direct cytotoxicity against mesenchymal stromal cells in the bone marrow. In addition, an immune-mediated toxicity mechanism, based on reoccurrence of agranulocytosis within several days of reexposure to clozapine in patients who have had agranulocytosis, is considered to be a likely cause (reviewed in Chowdhury et al.2 and Opgen-Rhein and Dettling3).

Among the demographic risk factors for agranulocytosis are increased age and Asian or Finnish ancestry. Concordance of agranulocytosis has been reported in monozygotic twins and genetic polymorphisms, for example, in the major histocompatibility complex (HLA) genes (e.g. HLAB384 and HLA-DQB1 (6,672G>C)5) have been associated with CIA (reviewed in Chowdhury et al.2 and Opgen-Rhein and Dettling3).

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Acknowledgements

This study was supported by the Annual EVO Financing to JT (special government subsidies from the Ministry of Health and Welfare, Finland) and donations from Mr and Mrs Edward Hintz, Mr and Mrs Robert Peterson, and Mr and Mrs Robert Weisman to HYM. AKT is supported by the NARSAD 2010 young investigator award. CCZ is supported by American Foundation for Suicide Prevention Postdoctoral Fellowship and Eli Lilly, Canada. DJM is supported by CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia; OMHF New Investigator Fellowship and an Early Researcher Award by the Ministry of Research and Innovation of Ontario, Canada.

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Authors and Affiliations

  1. Neuroscience Department, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    A K Tiwari, C C Zai, N I Chowdhury, D J Müller & J L Kennedy

  2. Center for Human Genome Variation and Department of Medicine, Section of Medical Genetics, Duke University, Durham, NC, USA

    A C Need

  3. Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    F W Lohoff

  4. Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland

    A Putkonen, E Repo-Tiihonen, T Hallikainen & J Tiihonen

  5. Faculty of Medicine, Hacettepe University, Ankara, Turkey

    A E Anil Yağcıoğlu

  6. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden

    J Tiihonen

  7. Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    H Y Meltzer

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  1. A K Tiwari
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Correspondence to J L Kennedy.

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Competing interests

JLK has been a consultant to GSK, Sanofi-Aventis and Dainippon-Sumitomo. HYM has received grants, or payment for lectures, or is or was a consultant to: Abbott Labs, ACADIA, Alkemes, Bristol Myers Squibb, DaiNippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, Novartis, Roche, Sunovion, TEVA and BiolineRx. HYM is a shareholder of ACADIA, Glaxo Smith Kline and Suregene. HYM is a board member of Acadia, and is an advisor to Centerstone Research Institute. JT is a member of advisory board of AstraZeneca and Janssen-Cilag, and reports serving as a consultant to Lundbeck, Organon, Janssen-Cilag, Eli Lilly, AstraZeneca, F. Hoffman-La Roche, and Bristol-Myers Squibb. He has received fees for giving expert opinions to Bristol-Myers Squibb and GlaxoSmithKline, and lecture fees from Janssen-Cilag, Bristol Myers-Squibb, Eli Lilly, Pfizer, Lundbeck, GlaxoSmithKline, Novartis, and Astra Zeneca. AKT/ACN/FWL/CCZ/NIC/DJM/AP/ERT/AEAY declare no conflict of interest.

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Tiwari, A., Need, A., Lohoff, F. et al. Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis. Mol Psychiatry 19, 403–405 (2014). https://doi.org/10.1038/mp.2013.74

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