Clozapine-Induced Agranulocytosis and its Genetic Determinants

Opgen‐Rhein, Carolin; Dettling, Michael

doi:10.2217/14622416.9.8.1101

Cited by 48 publications

(32 citation statements)

References 68 publications

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“…11 Numerous association studies focusing on human leucocyte antigen (HLA) alleles, non-HLA alleles of the major histocompatibility complex (MHC) region, and non-MHC genes have been conducted leading to limited understanding of the genetic components of CAA. 8,12 Among the HLA sites investigated in the MHC region, the HLA-DQB1 66726G>C polymorphism was associated with CAA with an odds ratio of 16.9, 13 leading to the development of a commercial test using HLA-DQB1 6672G>C genotype to classify patients into high-and low-risk groups for CAA, yet this test's low sensitivity has limited its clinical use. 8 The major non-MHC candidate genes investigated in association with CAA are quinone oxidoreductase 2, myeloperoxidase, nicotinamide adenine dinucleotide phosphate oxidase, and P450 cytochrome enzymes.…”

mentioning

confidence: 99%

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

Yağcıoğlu

Yoca

Ayhan

et al. 2016

Journal of Clinical Psychopharmacology

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Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. 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. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

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confidence: 99%

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

Yağcıoğlu

Yoca

Ayhan

et al. 2016

Journal of Clinical Psychopharmacology

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“…15 There are also associations for genes that are not part of the MHC, for example, myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate-oxidase gene polymorphisms. 152,153 First steps toward a clinical use have been made by the temporary release of a commercial test-kit in 2007, that is, PGxPredict:CLOZAPINE (Clinical Data, Inc, New Haven, CT), which included the 6672G/C polymorphism in MHC, class II, DQ beta 1 (HLA-DQB1) for detection of high-risk patients carrying the C allele, with high specificity of 98.4% but a low of sensitivity of 21.5%. 41 Fu et al, 42 Patsopoulos et al 43 …”

Section: Agranulocytosismentioning

confidence: 99%

Pharmacogenetics of Antipsychotics

2014

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Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods:We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses.Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion:First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. W W W La pharmacogénétique des antipsychotiquesObjectif : Au cours des dernières décennies, des efforts croissants ont été déployés dans des études visant à percer l'influence des facteurs génétiques sur le dosage des antipsychotiques (AP), la réponse au traitement, et la survenue d'effets indésirables. Ces études voulaient améliorer les soins cliniques en prédisant le résultat du traitement par AP, et en donnant lieu ainsi à des stratégies de traitement individualisées. Nous présentons les résultats les plus importants obtenus par des études tant de gènes candidats que d'association pangénomique, notamment les facteurs pharmacocinétiques et pharmacodynamiques. Méthodes :Nous avons passé en revue les études sur la pharmacogénétique de la réponse aux AP et des effets indésirables publiées dans PubMed jusqu'au début de 2012. Vu le nombre élevé d'études publiées, notre revue a mis l'accent sur les résultats qui ont été reproduits dans des études indépendantes ou qui sont soutenus par des méta-analyses.

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“…This is a compelling argument to continue the search for possible genetic markers that alone or in combination may provide such information. Genetic tools, including whole exome and genome sequencing, as well as copy number variant analyses, may elucidate rare variations that may be useful in providing predictive measures to detect those patients who are more likely to develop this potentially fatal side effect [84]. The reported use of gene sequencing for the patient cohorts to discover the role of HLA-DQB1 highlights a key step forward in uncovering a genetic role in agranulocytosis [71].…”

Section: Discussionmentioning

confidence: 99%

“…One proposed mechanism is that the HLA alleles may induce cytotoxic effects in clozapine-treated patients [66]. However, the genetic mechanisms underlying CIA are likely multifaceted, and the role of these alleles may be interactive with other genetic sites.…”

Section: Overview Of Genetics Of Clozapine-induced Agranulocytosis (Mmentioning

confidence: 99%

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Chowdhury

Remington

Kennedy

2011

Curr Psychiatry Rep

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Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, 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.

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Clozapine-Induced Agranulocytosis and its Genetic Determinants

Cited by 48 publications

References 68 publications

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

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

Pharmacogenetics of Antipsychotics

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

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