The cytochrome P450 CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic patients

Kootstra‐Ros, Jenny E.; Smallegoor, Windy; Weide, Jan van der

doi:10.1258/0004563053857798

Cited by 45 publications

(30 citation statements)

References 6 publications

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“…17 Yet this independent effect was not observed in a clinical trial on clozapine concentrations, another CYP1A2 substrate. 37 On the contrary, an effect of the CYP1A2*1F genotype alone was detected in a previous study on the risk for tardive dyskinesia, a severe and potentially irreversible side effect, under treatment with typical antipsychotics such as haloperidol which is also a CYP1A2 substrate. The risk was lower for CYP1A2*1F carriers in general and was most pronounced in CYP1A2*1F carriers who were smokers.…”

Section: -Htr2c C-759tmentioning

confidence: 90%

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

et al. 2009

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Section: -Htr2c C-759tmentioning

confidence: 90%

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

et al. 2009

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“…67,68 In addition, smoking seriously affects the activity of CYP1A2, with smokers displaying a higher metabolic rate, 69 in particular those with *1C and *1D variants. 70 However, CYP1A2 polymorphisms did not significantly influence individuals' clozapine metabolic capacity, 71 although delays in response to clozapine have been observed in individuals with the UM phenotype. 72,73 Also a combination of high inducibility CYP1A2 alleles and smoking may result in higher metabolic ratios and reduced clozapine plasma levels.…”

Section: Pharmacokinetic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…The genetic studies of clozapine drug response are supported by the identification of multiple functional variants in CYP1A244,45 with well-defined effects on clozapine metabolism. 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.…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

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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The cytochrome P450 CYP1A2 genetic polymorphisms 1F and 1D do not affect clozapine clearance in a group of schizophrenic patients

Cited by 45 publications

References 6 publications

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

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

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