Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens

Dettling, Michael; Cascorbi, Ingolf; Opgen‐Rhein, Carolin; Schaub, Rainer T.

doi:10.1038/sj.tpj.6500423

Cited by 60 publications

(32 citation statements)

References 32 publications

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“…For HLA class II alleles, HLA-DQB-0502, -DRB1-0101, and -DRB3-0202 were found to be associated with CIA, but in contrast to previous findings, no significant association was found between CIA and the HLA-B38 allele [63]. More recently, Dettling et al [64] identified a significant association with CIA for two Cw-7-related two-locus haplotypes with HLA-Cw7-B18 and HLACw7-B39; one HLA class II two-locus haplotype with HLA-DRB5-0201-DRB4; and a three-locus haplotype with HLACw7drb5, HLA-Cw7-B39-DRB5, and HLA-Cw7-B44-DRB5. The authors concluded that combinations and possibly epistasis of alleles or haplotypes at several HLA class I loci, spanning from MHC-I over MHC-III to MHC-II, may be [65].…”

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

confidence: 73%

“…Loci highlighted as significant in the GWAS included HLA-DQB1, granulocyte-colony stimulating factor receptor (G-CSFR), and dopamine receptor D1. The investigators also found that a variant in HLA-DQB1, 6672G>C, was associated with risk of CIA, reporting a 16.9 times increased risk for carriers of this marker [64]. A commercial test was marketed in 2007 based on data from 136 patients in the cohorts utilizing the HLA-DQB1 6672G>C genotype to classify patients as "lower risk" or "higher risk" for CIA.…”

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

confidence: 99%

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

confidence: 73%

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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“…African Caribbeans were also more likely to have a diminished baseline WBC count and neutrophil count when compared with White counterparts. Dettling et al (2007) focused on specific genetics during their research on 42 non-Jewish Whites. Human leukocyte class 1 and class 2 antigens were found to have a link with clozapine-induced blood dyscrasias.…”

Section: Review Of Literaturementioning

confidence: 99%

Maximizing clozapine utilization while minimizing blood dyscrasias

Demler

Morabito

Meyer

et al. 2016

International Clinical Psychopharmacology

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The aim of this study was to determine whether patient characteristics such as age, sex, race/ethnicity, and frequency of monitoring play a role in clozapine-related blood dyscrasias. This study examined all neutropenic events to identify any potential demographic qualities that may pose increased risk to individuals receiving clozapine treatment in accordance with the FDA guidelines released in 2005. These guidelines required the addition of absolute neutrophil count (ANC) tests in addition to white blood cell (WBC) counts to regular monitoring and a reduction in the frequency of testing to once monthly after 1 year of satisfactory WBC counts and ANCs. The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely. This is a retrospective, closed chart review of all patients who received clozapine at the State Psychiatric Center and experienced a leukopenic/neutropenic event and/or who had a substantial drop in WBC/ANC from January 2009 to December 2011. A subset of patients who were identified as achieving 'non-rechallengeable' status with either an ANC and/or WBC threshold value from 2001 to 2014 were also examined. This protocol was approved by the New York State Psychiatric Institute Institutional Review Board. A total of 193 patients were included in the study. Males experienced more total events at 6.4 events per person compared with 5.2 events per woman. White patients had 6.5 total events per person compared with 4.2 total events per Black patient; however, Black patients experienced more moderate leukopenia/granulocytopenia events compared with Whites. Regardless of race or ethnicity, patients in the 40-49-year age range had the most events at 8.1 events per person and also presented with the highest number of moderate leukopenia/granulocytopenia events as did those scheduled for weekly monitoring. Conversely, the majority of patients with no recorded events were female and either 20-29 or 60-69 years of age. In total, 16 patients were exclusively designated as non-rechallengeable from 2001 to 2014 and only had one single blood event prompting this clozapine monitoring status. Of these 16 patient events, seven were White males, eight were White females, and one was a Black female with roughly 40% of those patients in the 50-59-year age group. Currently published predictions on possible demographic risk groups may not reflect clinical experience and may pose unnecessary treatment barriers in the provision of clozapine. Although the healthcare team should be aware of the possible demographic predictors of blood dyscrasias when using clozapine, treatment goals and monitoring strategies must be individualized to ensure successful clozapine therapy.

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“…Haplotypes in HLA-DQB1, HLA-C, NTSR1, DRD1 and CSF2RB were significant with a permutation test adjusted P < 0.05. Methods: We attempted to replicate the findings from four of these genes in an independently collected cohort of 49 cases and 78 controls (Mosyagin et al, 2005;Dettling et al, 2006). Cases were patients with an ANC < 500 during clozapine treatment and controls were treated with clozapine for at least 2 years without an adverse effect on the WBC or ANC.…”

Section: P 088 High Frequency Of Cyp2d6 Pms In the Faroe Islands A Rimentioning

confidence: 99%

Poster presentation: Wednesday 29 August 2007

2007

Basic Clin Pharma Tox

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Introduction: Neuropathic pain is common in rheumatological practice, although often associated with nociceptive mechanisms. It is caused by lesions of the nervous system, and the usual treatments with analgesics or anti-inflammatory drugs are most often ineffective. Antiepileptic drugs (AEDs) have proven effective in relieving neuropathic pain. AEDs are hardly used by rheumatologists since only recently has attention been drawn to the importance of neuropathic pain in rheumatological conditions. The CEDR (Cercle dEtude de la Douleur en Rhumatologie), a specific interest group of the French Society of Rheumatology that focuses on rheumatic pain, aimed to develop recommendations for the use of AEDs in Rheumatology. Methods: A systematic review of the published literature was performed by a working group of seven experts from the CEDR. The search was conducted using electronic databases with no limitation on the type of publications. All studies were scored for quality. A list of questions about the prescription of AEDs in rheumatic pains was validated by the group and served to structure the recommendations. Based on the literature and the clinical experience, the recommendations were elaborated with the Delphi method. Results: The trials are scarce. We identified only nine randomized and controlled studies and six open and observational studies. These few trials, the guidelines published for neuropathic pain treatment and the clinical experience of each expert were used to develop eleven recommendations about the use of AEDS in painful rheumatic conditions. Conclusion: These recommendations represent only a guideline for the physicians meanwhile disposing more scientific evidences. . The aim of this study was to compare the cost, efficacy, and tolerability of Nimulid Ò and Tenaprost Ò . Methodology: From 06 to 11/2004, a prospective, randomized doubleblinded phase four clinical trial was conducted at the Institute of Rheumatology, the School of Medicine at the University of Belgrade. Sixty out-patients with symptomatic gonarthrosis or lumbal syndrome were randomized to receive Tenaprost Ò or Nimulid Ò (100 mg 2·/day for 20 days) according to their year of birth. In order to be eligible to participate in the study, patients had to require treatment with an analgesic or an anti-inflammatory agent. The intensity of pain, joint stiffness, and physical activity were evaluated according to the 100 mm Visual Analogue Scale (VAS). In those patients with gonarthrosis, a knee circumference (measured in cm across the middle of the patella), motion (flexion/extension) degree in grades, and a sensitivity of tendons to a palpation were assessed. In those patients with low back pain syndrome muscular spasm, sagital mobility (finger-floor distance in grades) and the Lequesne functional index were estimated. Adverse events reported by the patient or observed by the investigator during clinical trial were recorded. Results: At the end of treatment with Tenaprost Ò and Nimulid Ò , reduction in the pain level (P < 0.001) and knee c...

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Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens

Cited by 60 publications

References 32 publications

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Maximizing clozapine utilization while minimizing blood dyscrasias

Poster presentation: Wednesday 29 August 2007

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