A Poor Metabolizer for Cytochromes P450 2D6 and 2C19: <i>A Case Report on Antidepressant Treatment</i>

Johnson, Maria S.; Markham-Abedi, Courtney; Susce, Margaret T.; Murray-Carmichael, Elaina; McCollum, Stuart; León, José de

doi:10.1017/s1092852900014887

Cited by 24 publications

(9 citation statements)

References 14 publications

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“…For example, a CYP 2D6 poor metabolizer should not be administered codeine since the drug would have no effect. Conversely, a CYP 2D6 ultra-rapid metabolizer would likely suffer side effects from a normal dosage [31,32]. CYP 2D6 is a highly polymorphic CYP with at least 70 allelic variants [33] that can be categorized into four phenotypic classes.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy

et al. 2013

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The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.

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Section: Discussionmentioning

confidence: 99%

Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy

et al. 2013

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“…Very rare individuals (<1/1000) are PMs for both CYP2C19 and CYP2D6. These subjects, who are missing both CYPs, should have problems metabolizing TCAs and most of the newer antidepressants (Johnson et al 2006), but they should have no problem with mirtazapine (metabolized by multiple enzymes) or bupropion (metabolized by CYP2B6).…”

Section: Clinical Utility Of Cyp Genotyping In Psychiatrymentioning

confidence: 99%

Clinical applications of CYP genotyping in psychiatry

2014

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A critical review of the limited available evidence and the authors' experience and judgment are used to summarize the role of cytochrome P450 (CYP) genetic variants in the pharmacokinetics of and clinical response to psychotropic medications. CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 genetic polymorphisms and their contributions to the metabolism of psychotropic drugs are reviewed. CYP1A2, CYP2B6 and CYP3A4 genotyping have limited current clinical utility. CYP2C9 genotyping has no utility in psychiatry. Psychiatrists should master tricyclic antidepressant (TCA) prescription, and if they use TCAs, they should have expertise in CYP2D6 and CYP2C19 genotyping and in TCA therapeutic drug monitoring (TDM) to safely dose TCAs. Practice guidelines recommend dose changes, TDM or alternate drugs for (1) CYP2C19 ultrarapid metabolizers (UM) taking citalopram or escitalopram; (2) CYP2C19 poor metabolizers (PMs) taking sertraline; (3) CYP2D6 PMs taking venlafaxine, aripiprazole, haloperidol, risperidone or zuclopenthixol; and (4) CYP2D6 UMs taking venlafaxine, aripiprazole, haloperidol, risperidone, zuclopenthixol or atomoxetine. According to the prescribing information, CYP2D6 PMs should receive 75 % of the average long-acting aripiprazole dose and pimozide doses >4 mg/day should not be prescribed without CYP2D6 genotyping. In a situation of limited evidence, there is need to use the available pharmacological mechanistic information for better personalizing treatment in psychiatry. This is best done by combining CYP genotyping with TDM. Clozapine and risperidone concentration-to-dose ratios are provided as two examples of this approach of how to integrate CYP genotyping and TDM in psychiatry. New studies are needed to verify that CYP2C19 PM genotyping may have potential to identify clozapine PMs and explain the lower clozapine metabolic capacity in East Asians.

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“…If the outliers are so rare as to include less than 1% of the population, they are quite unlucky; it is very unlikely that well-designed studies using RCTs will ever be conducted in them. 70 If you are a pharmacologist interested in antidepressants and are trying to recruit 50 of these double poor metabolizers for a controlled clinical trial, you have the Herculean task of needing to screen 50,000 patients to identify 50 who meet the study criteria. 65 An example may clarify this: some very unlucky subjects do not have CYP2D6 and CYP2C19.…”

Section: Statistical Heterogeneity or Lack Of Homogeneity And Pmmentioning

confidence: 99%