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… 
View PDF
30 Citations
Highly Influential Citations
2
Background Citations
9

Tables from this paper

30 Citations

Clozapine-induced agranulocytosis

A review of the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA is presented.

Neutropenia in Patients With Clozapine-Treated Schizophrenia: An Effect of Clozapine or a Consequence of SARS-CoV-2 Infection? A Systematic Review

Clozapine treatment in COVID-19–positive patients may be associated with a transient reduction of absolute neutrophils count, in some cases reaching neutropenia levels, and needs to be continued whenever possible, with dose adjustments in relation to blood test results.

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis

Pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, and these data support the working hypothesis that oxidation of clozAPine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozabine.

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK

Owing to its cost-effectiveness, pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment is proposed for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozAPine treatment schedule under the safety consideration.

Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital

Even in this extreme group of patients with treatment resistant schizophrenia, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients, according to a case series of 14 consecutive patients rechallenged in a high-secure psychiatric hospital.

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19

Clozapine doses should be personalized for each patient based on pharmacogenetics testing when available and the genetic vulnerability postulates predictors of adverse reactions’ severity; patients with a lower genetic risk could have less frequent hematological monitoring.

Clozapine. Pharmacodynamic Mechanisms, Potential Pharmacogenetic Biomarkers, and Risks in Schizophrenia. Particularities in the Context of Covid-19. An Updated Overview

The genetic vulnerability postulates predictors of severity so clozapine doses should be personalises for each patient based on pharmacogenetic testing, and patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule.

Therapeutic drug monitoring of clozapine in adults with schizophrenia: a review of challenges and strategies

  • E. Molden
  • Medicine, Psychology
    Expert opinion on drug metabolism & toxicology
  • 2021
Development of advanced TDM methods, including biomarkers predicting the risk of granulocyte toxicity might extend TDM to be a tool for deciding which patients that can be treated safely with CLZ, potentially increasing its utility beyond TRS.

Characterization of Clozapine-Responsive Human T Cells

Data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells and bind in a similar conformation to the P4–P6 peptide binding pockets, whereas clozAPine N-oxide, which did not activate the TCC, bound in a different conformation.

Drug-Induced Idiosyncratic Agranulocytosis - Infrequent but Dangerous

The chemical, the biotransformation-related, the mechanistic and the therapeutic basis of this clinically relevant and undesirable side effect of drug-induced idiosyncratic agranulocytosis are discussed.

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.

Agranulocytosis related to clozapine in monozygotic twins and association with allelic variants of multidrug resistance gene MDR1.

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.
...