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

Legge, Sophie E.; Walters, James

doi:10.2217/pgs-2018-0188

Cited by 50 publications

(57 citation statements)

References 86 publications

(117 reference statements)

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“…Although CLZ can interact with genetic factors to evoke rare but potentially fatal complications such as agranulocytosis and neutropenia 42 , CLZ is currently one of the most commonly used atypical antipsychotic drugs for treatment-resistant schizophrenia 10 . As CLZ readily crosses the blood-brain barrier, it can be used reliably to activate DREADD receptors in a variety of chemogenetic experiments, replacing CNO.…”

Section: Discussionmentioning

confidence: 99%

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Cho

Ryu

Lee

et al. 2020

Sci Rep

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clozapine (cLZ) has been proposed as an agonist for Designer Receptors exclusively Activated by Designer Drugs (DREADDs), to replace Clozapine-N-oxide (CNO); however, there are no reliable guidelines for the use of cLZ for chemogenetic neuromodulation. We titrated the optimal dose of cLZ required to evoke changes in neural activity whilst avoiding off-target effects. We also performed [ 18 f] fluoro-deoxy-glucose micro positron emission tomography (fDG-micropet) scans to determine the global effect of CLZ-induced hM3D(Gq) DREADD activation in the rat brain. Our results show that low doses of CLZ (0.1 and 0.01 mg/kg) successfully induced neural responses without off-target effects. CLZ at 1 mg/kg evoked a stronger and longer-lasting neural response but produced off-target effects, observed as changes in locomotor behavior and FDG-microPET imaging. Unexpectedly, FDG-microPET imaging failed to demonstrate an increase in regional glucose metabolism in the stimulated cortex during CLZ chemogenetic neuromodulation. Therefore, caution should be used when interpreting FDGpet images in the context of cortical chemogenetic activation.

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Section: Discussionmentioning

confidence: 99%

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Cho

Ryu

Lee

et al. 2020

Sci Rep

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“…Genetic aetiology of neutropenia/agranulocytosis induced by CZP is complex and is likely to involve variants of several genes including HLA-DQB1, HLA-B, and SLCO1B3/ SLCO1B7 [26]. Further studies are required to separate causal variants from association signals and to improve our understanding of mechanisms underlying these associations.…”

Section: Risk Factors and Geneticsmentioning

confidence: 99%

Clozapine-induced agranulocytosis

Mijović

MacCabe

2020

Ann Hematol

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Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.

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“…The clozapine literature could be improved by taking that approach, particularly when attempting to improve our understanding of the aetiologies of these difficult adverse events. As described by Legge we hope that a wider understanding of the role of the Duffynull genotype in BEN in general and in low neutrophil counts in patients taking clozapine in particular (and potentially other psychotropic drugs with a risk of neutropenia) will translate in to an easily obtainable pharmacogenetic test (9). Duffy typing can be performed following a routine laboratory request for a blood group.…”

Section: Discussionmentioning

confidence: 99%

“…The Duffy Null polymorphism which protects against some types of malaria is predicative of BEN (24) and can be determined simply by a request an extended blood type. It has recently been shown to be associated with the development of clozapine induced neutropenia and withdrawal in clozapine treated UK patients of African genetic ancestry (9) to the extent that there may be the potential to use this readily available genetic investigation in combination with other clinical information, the presence of a fluctuating neutropenia in the absence of infection or other pathology in an affected group, to adjust neutrophil thresholds (25). Since 2002 clozapine monitoring services in the UK have reference ranges 0.5 x 10 9 /L lower for patients with haematologically confirmed BEN (see Table 1) (26).…”

Section: Benign Ethnic Neutropeniamentioning

confidence: 99%

Clozapine Re-Challenge and Initiation Despite Neutropenia and Outcomes from 14 Patients

Silva

Higgins

Hammer

et al. 2019

Preprint

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Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia. But its use is limited because of the risk of neutropenia and agranulocytosis. In the absence of effective alternatives its use after blood dyscrasias is possible. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using routinely collected clinical data we describe the patient characteristics, causes of neutropenia, the strategies used and outcomes. Results: Previous neutropaenia was due to varying aetiologies: benign ethnic neutropaenia; clozapine induced; other medication; autoimmune. A range of risk mitigation strategies were used to prevent neutropaenia on clozapine rechallenge: G-CSF; lithium; watch and wait. There were no serious adverse events associated with clozapine or risk mitigation treatments. At follow up during 2019, half of the original 14 patients had improved sufficiently to transfer to conditions of lesser security. Conclusion: With careful planning and monitoring, taking into account what is known about neutrophil biology, clozapine can be successfully reinitiated following CIN or in the face of preexisting neutropenia resulting in significant benefits for patients.

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

Cited by 50 publications

References 86 publications

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Clozapine-induced agranulocytosis

Clozapine Re-Challenge and Initiation Despite Neutropenia and Outcomes from 14 Patients

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