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

Verbelen, Moira; Collier, David A.; Cohen, Daniel; MacCabe, James H.; Lewis, Cathryn M.

doi:10.1038/tpj.2015.5

Cited by 22 publications

(15 citation statements)

References 33 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between CIA risk and the proportion of patients in the group with variant HLA alleles has been recently studied [26, 27]. Given the low incidence of CIA, to be clinically applicable, HLA allele testing must have a sensitivity of approximately 50%.…”

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine

et al. 2018

View full text Add to dashboard Cite

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotypeguided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotypeguided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

show abstract

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The genetic variants that have been identified to date for CIA and CIN as an adverse drug reaction (i.e., variants in HLA-DQB1 , HLA-B , and SLCO1B3/SLCO1B7 ) do not fulfill the criteria for a predictive genetic test [79]. Table 2 details the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of a potential pharmacogenetic test using these variants to predict CIN.…”

Section: Current Indications For Genetic Testingmentioning

confidence: 99%

“…A modeling study by Verbelen et al. demonstrated that high sensitivity is the critical factor for a successful genetic test for CIA [79]. Indeed, on the basis of the study by Athanasiou et al .…”

Section: Current Indications For Genetic Testingmentioning

confidence: 99%

Genetics of Clozapine-Associated Neutropenia: Recent Advances, Challenges and Future Perspective

Legge

Walters

2019

Pharmacogenomics

View full text Add to dashboard Cite

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 , HLA-B and SLCO1B3/SLCO1B7 . We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.

show abstract

“…Although the HLA-DQB1 locus may be implicated in CIA development, for the test to be clinically useful, it requires high sensitivity and specificity, and thus, the low sensitivity of the test has limited its use in clinical settings 71. This test gives a 1% (0.05×0.22) chance of identifying patients at risk of developing CIA, which is not very different from the risk for all patients treated with clozapine (0.8%) 71,72…”

Section: Pharmacogenomics and Clozapine Adverse Eventsmentioning

confidence: 99%

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

View full text Add to dashboard Cite

Up to 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics. They are said to have treatment-resistant schizophrenia (TRS). Clozapine is still the only effective treatment for TRS, although it is underused in clinical practice. Initial use is delayed, it can be hard for patients to tolerate, and clinicians can be uncertain as to when to use it. What if, at the start of treatment, we could identify those patients likely to respond to clozapine – and those likely to suffer adverse effects? It is likely that clinicians would feel less inhibited about using it, allowing clozapine to be used earlier and more appropriately. Genetic testing holds out the tantalizing possibility of being able to do just this, and hence the vital importance of pharmacogenomic studies. These can potentially identify genetic markers for both tolerance of and vulnerability to clozapine. We aim to summarize progress so far, possible clinical applications, limitations to the evidence, and problems in applying these findings to the management of TRS. Pharmacogenomic studies of clozapine response and tolerability have produced conflicting results. These are due, at least in part, to significant differences in the patient groups studied. The use of clinical pharmacogenomic testing – to personalize clozapine treatment and identify patients at high risk of treatment failure or of adverse events – has moved closer over the last 20 years. However, to develop such testing that could be used clinically will require larger, multicenter, prospective studies.

show abstract

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

Cited by 22 publications

References 33 publications

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine

Genetics of Clozapine-Associated Neutropenia: Recent Advances, Challenges and Future Perspective

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Contact Info

Product

Resources

About