Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective

@article{Legge2019GeneticsOC,
  title={Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective},
  author={Sophie E. Legge and James T. R. Walters},
  journal={Pharmacogenomics},
  year={2019},
  volume={20},
  pages={279 - 290}
}
  • S. LeggeJ. Walters
  • Published 15 February 2019
  • Psychology, Medicine, Biology
  • Pharmacogenomics
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1… 

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References

SHOWING 1-10 OF 94 REFERENCES

More than 25 years of genetic studies of clozapine-induced agranulocytosis

It is concluded that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance, and it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.

Clozapine-induced agranulocytosis and its genetic determinants.

Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in

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

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 and is essential for clinical utility, in particular in combination with a small high-risk group.

Gene polymorphisms potentially related to the pharmacokinetics of clozapine: a systematic review

More prospective longitudinal studies are needed to elucidate the possible role of the ABCB1 polymorphism and transmembrane transporters in clozapine pharmacokinetics and clinical response.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients.

Clozapine, agranulocytosis, and benign ethnic neutropenia

  • S. Rajagopal
  • Medicine, Psychology
    Postgraduate Medical Journal
  • 2005
This editorial looks at the important issues associated with agranulocytosis and BEN in patients receiving clozapine, a atypical antipsychotic effective in treatment resistant schizophrenia.

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles

Two loci in the major histocompatibility complex are independently associated with clozapine-induced agranulocytosis/granulocytopenia (CIAG), and these associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Drug-Induced Agranulocytosis: Impact of Different Fcγ Receptor Polymorphisms?

Fcγ receptors may not serve as a genetic marker to identify patients at risk for this life-threatening side effect of clozapine-induced agranulocytosis, and no further associations are found that underline an effect of polymorphisms in FcγRIIa, F cγRIIIa, and Fc�RIIIb genes.
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