The CYP1A2 −163C&gt;A polymorphism is associated with super-refractory schizophrenia

Brito, Rodrigo Bernini de; Araújo, Leandro de Carvalho; Georg, Raphaela de Castro; Nabout, João Carlos; Vianelo, Rosana Pereira; Santos, Rodrigo da Silva; Cruz, Aldo Alfonso Alván De la; Ghedini, Paulo César

doi:10.1016/j.schres.2015.10.018

Cited by 8 publications

(10 citation statements)

References 7 publications

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“…A number of studies have provided evidence to suggest that the CYP1A2*1F allele is associated with clozapine response,46–48 with the response being linked to plasma concentration levels in the study by Eap et al Further studies have failed to identify an association between the CYP1A2 polymorphism and plasma clozapine concentrations, when controlling for clozapine dose and body weight 49. CYP1A2*1F polymorphisms were associated with a super-refractory schizophrenia group of patients, compared to controls, thus replicating previous work, and identifying this polymorphism as a moderator of clozapine response 50. However, as is the case in clozapine pharmacodynamic pharmacogenetic research, other studies have not replicated these findings in relation to CYP1A2 polymorphism and clozapine response 51,52.…”

Section: Pharmacogenomics and Clozapine Responsesupporting

confidence: 54%

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

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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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.

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Section: Pharmacogenomics and Clozapine Responsesupporting

confidence: 54%

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

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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“…Patients were classified as TRS (n = 63) or SRS (n = 45) following criteria described by Kane et al (1988) 4 and de Brito et al (2015). 9 Characteristics of the study population are shown ( Table 1).…”

Section: Materials and Methods Subjectsmentioning

confidence: 99%

“…[15][16][17] CYP3A4 and CYP1A2 are primarily responsible for the formation of N-desmethylclozapine, 18,19 with CYP2C19 playing a role and CYP2C9 and 2D6 playing more modest roles. 20 In light of these functions, our group previously observed CYP1A2*1F polymorphism associations with SRS, 9 thereby shedding some light on the relevance of CYP-genetic polymorphisms in CLZ responses. Although involvement of the CYP1A2*1F polymorphism in response to CLZ treatment has been shown, there are little data evaluating associations between CYP2C19 polymorphisms and TRS or SRS.…”

Section: Introductionmentioning

confidence: 96%

“…[4][5][6] Nevertheless, approximately 30% of TRS patients do not fully respond to CLZ as a monotherapy, meaning these patients are as known as CLZ non-responders or super-refractory schizophrenics (SRS). [7][8][9] For this condition, treatments are combined with CLZ and other antipsychotics, antidepressants or mood stabilizers. 10,11 Factors such as ethnicity, co-medication, age, gender, diet, as well as genetic variability to cellular receptors and drug metabolism, have been shown to affect CLZ responses.…”

Section: Introductionmentioning

confidence: 99%

“…25 Subjects with *2/*2 genotype are PM, those heterozygous for *1/*2 or *2/*17 are intermediate metabolizers (IM), and *1/*17 and *17/*17 are UM. 21,23,25 We recently identified a relationship between the CYP1A2*1F polymorphism and CLZ therapeutic outcomes; 9 however, there is a dearth of research investigating associations of CYP2C19 polymorphisms with refractoriness to CLZ responses. Therefore, this study sought to evaluate pharmacogenetic associations of CYP2C19*2 and CYP2C19*17 polymorphisms with TRS and SRS.…”

Section: Introductionmentioning

confidence: 99%

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<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

Rodrigues-Silva¹,

Semedo²,

Neri³

et al. 2020

NDT

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Introduction: Clozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism. Objective: The aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS. Methods: CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing. Results: CYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS. Conclusion: These results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.

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New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases

Shang

Zhong

et al. 2020

Acta Pharmaceutica Sinica B

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The CYP1A2 −163C>A polymorphism is associated with super-refractory schizophrenia

Cited by 8 publications

References 7 publications

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

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

<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases

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The CYP1A2 −163C>A polymorphism is associated with super-refractory schizophrenia

Cited by 8 publications

References 7 publications

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

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

<p>The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases

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<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>