Clozapine Pharmacogenetic Studies in Schizophrenia: Efficacy and Agranulocytosis

Numata, Shusuke; Umehara, Hiroki; Ohmori, Tetsuro; Hashimoto, Ryota

doi:10.3389/fphar.2018.01049

Cited by 28 publications

(18 citation statements)

References 132 publications

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“…HLA genetic diversity is also implicated in the modulation of treatment responses in psychiatric conditions, including in the regulation of adverse drug reaction (ADRs) and treatment efficacy. Both candidate gene studies and GWAS have shown that clozapine-induced agranulocytosis is partly mediated by class I and II HLA alleles ( Numataa et al, 2018 ). In a study of treatment response to antipsychotic, we showed that a double amino-acid change in the HLA-A peptide-binding groove was associated with a better response to treatment with Risperidone in patients with schizophrenia (LeClerc et al, 2015).…”

Section: Hla and Treatment Responsesmentioning

confidence: 99%

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

Tamouza¹,

Krishnamoorthy²,

Leboyer³

2021

Brain, Behavior, and Immunity

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Highlights Major psychiatric disorders are associated with genetically-determined immune dysfunctions. Human leukocyte antigen (HLA) molecules are prominent players of immune and neurodevelopmental processes. HLA molecules are encoded by polymorphic genes located in the major histocompatibility complex (MHC). Recent methodological approaches allowed understanding of the HLA genetic complexity and reconcile findings from GWAS in psychiatry. HLA haplotypes studies uncover protective and at risk markers for disease development or proxies of severity in schizophrenia, autism and bipolar disorders. Beyond disease risk, the HLA genetic diversity is associated with autoimmune encephalitis, treatment response, retrovirology and neurodevelopmental immunomodulation. HLA is also involved in anti-infections processes including against the coronavirus family

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Section: Hla and Treatment Responsesmentioning

confidence: 99%

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

Tamouza¹,

Krishnamoorthy²,

Leboyer³

2021

Brain, Behavior, and Immunity

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“…Due to the potential for agranulocytosis and a high risk of infection, patients taking clozapine require long-term hematology monitoring. A number of mechanisms for the clozapine-induced agranulocytosis have been explored [25,26]. In macrophages, clozapine affects adhesion, phagocytosis, and reactive oxygen species production [27].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine

Anderson

Gaffy

Weseli

et al. 2019

Viruses

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Epstein–Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine—desmethylclozapine—also inhibited EBV lytic reactivation, while another metabolite—clozapine-N-oxide—had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV.

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“…In spite of its evident clinical benefit, clozapine use is limited due to clozapine-induced agranulocytosis/granulocytopenia (CIAG). Significant pharmacogenetic studied have explored this phenomenon, as recently reviewed by Numata et al (2018). Several GWAS have been conducted, an initial effort by Goldstein et al, on 161 CIAG cases and 1196 controls of European descent, found genome-wide associations for variants in HLA-DQB1 and in HLA-B (Goldstein et al 2014).…”

Section: Clozapinementioning

confidence: 99%

Potential pharmacogenomic targets in bipolar disorder: considerations for current testing and the development of decision support tools to individualize treatment selection

Cuellar‐Barboza

McElroy

Veldić

et al. 2020

Int J Bipolar Disord

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Background: Treatment in bipolar disorder (BD) is commonly applied as a multimodal therapy based on decision algorithms that lack an integrative understanding of molecular mechanisms or a biomarker associated clinical outcome measure. Pharmacogenetics/genomics study the individual genetic variation associated with drug response. This selective review of pharmacogenomics and pharmacogenomic testing (PGT) in BD will focus on candidate genes and genome wide association studies of pharmacokinetic drug metabolism and pharmacodynamic drug response/ adverse event, and the potential role of decision support tools that incorporate multiple genotype/phenotype drug recommendations. Main body: We searched PubMed from January 2013 to May 2019, to identify studies reporting on BD and pharmacogenetics, pharmacogenomics and PGT. Studies were selected considering their contribution to the field. We summarize our findings in: targeted candidate genes of pharmacokinetic and pharmacodynamic pathways, genome-wide association studies and, PGT platforms, related to BD treatment. This field has grown from studies of metabolizing enzymes (i.e., pharmacokinetics) and drug transporters (i.e., pharmacodynamics), to untargeted investigations across the entire genome with the potential to merge genomic data with additional biological information. Conclusions: The complexity of BD genetics and, the heterogeneity in BD drug-related phenotypes, are important considerations for the design and interpretation of BD PGT. The clinical applicability of PGT in psychiatry is in its infancy and is far from reaching the robust impact it has in other medical disciplines. Nonetheless, promising findings are discovered with increasing frequency with remarkable relevance in neuroscience, pharmacology and biology.

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Clozapine Pharmacogenetic Studies in Schizophrenia: Efficacy and Agranulocytosis

Cited by 28 publications

References 132 publications

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine

Potential pharmacogenomic targets in bipolar disorder: considerations for current testing and the development of decision support tools to individualize treatment selection

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