Venlafaxine Metabolism as a Marker of Cytochrome P450 Enzyme 2D6 Metabolizer Status

Nichols, Alice I.; Lobello, Kasia; Guico-Pabia, Christine J.; Paul, Jeff; Preskorn, Sheldon

doi:10.1097/jcp.0b013e3181acc4dd

Cited by 45 publications

(30 citation statements)

References 19 publications

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“…11,23 In 4 studies investigating venlafaxine/O-desmethylvenlafaxine in a total of 196 patients, 96% of CYP2D6 PMs (23/24) had a metabolic ratio over 1. 14,24,26,27 The results of this study may be clinically useful in considering ongoing or future treatment with drugs metabolized by CYP2D6 to minimize the risk of adverse drug reactions and optimize therapeutic efficacy. In particular, a risperidone or venlafaxine result suggesting a PM genotype should serve as an indication for additional TDM to guide the dosing of other coprescribed drug substrates of CYP2D6 so as to avoid the risk of adverse drug reactions as reported in several clinical settings.…”

Section: Discussionmentioning

confidence: 96%

“…21,22 Cutoff levels of .1 and ,0.1 have been proposed for identification of individuals with a PM or UM CYP2D6 genotype (applicable both to risperidone and venlafaxine). 23,24 To evaluate these cutoff levels, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value. Confidence intervals (CIs) around respective ratio were calculated using VassarStats.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Mannheimer

Haslemo

Lindh

et al. 2016

Therapeutic Drug Monitoring

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Mannheimer

Haslemo

Lindh

et al. 2016

Therapeutic Drug Monitoring

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“…The metabolizing group of belonging shows a well-demonstrated correlation with antidepressant pharmacokinetics. In detail, numerous studies found a correlation between CYP2D6 metabolizing activity and the metabolism of several antidepressants: (a) venlafaxine [94][95][96][97][98][99][100], (b) fluoxetine [101][102][103][104], (c) paroxetine [101,105,106], and (d) nortriptyline [107][108][109][110]. The impact of CYP2C19 metabolizing status on antidepressant pharmacokinetics was also widely replicated for: (a) citalopram [111][112][113], (b) S-citalopram [44,[114][115][116][117], and (c) amitriptyline/nortriptyline [96,118,119].…”

Section: Individual Genes Involved In Antidepressant Responsementioning

confidence: 99%

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

Fabbri

Serretti

2015

Curr Psychiatry Rep

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The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.

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“…2 Using this approach to phenotype patients, Lobello and colleagues 1 conducted a secondary analysis of the registration trial data of VEN to treat major depressive disorder, reassessing the data after dividing the VEN-treated population into 2 groups: phenotypic CYP 2D6 EMs and PMs. The analysis was based on 4 large placebo-controlled, double-blind, efficacy trials of VEN in which a plasma level of VEN and ODV was measured at the time of the trial.…”

Section: Venlafaxine and Cyp 2d6mentioning

confidence: 99%

CYP 2D6 PM Status and Antidepressant Response to Nortriptyline and Venlafaxine

Macaluso

Preskorn

2011

Journal of Clinical Psychopharmacology

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W e propose that cytochrome P450 (CYP) 2D6 poor metabolizers (PMs) are inherently resistant to the beneficial effects of antidepressants that act by altering serotonin-norepinephrine neurotransmission and that this phenomenon is responsible for the curvilinear concentration-antidepressant response relationship observed with nortriptyline over 30 years ago.The impetus for this hypothesis was the recent finding by Lobello and colleagues 1 that CYP 2D6 PMs treated with venlafaxine (VEN) have low antidepressant response and remission rates: 2-to 3-fold lower than those achieved in CYP 2D6 extensive metabolizers (EMs) and comparable to rates seen in placebo-treated patients. The details concerning the work that lead to the finding of poor antidepressant response to VEN in CYP 2D6 PMs is summarized next. VENLAFAXINE AND CYP 2D6Venlafaxine is a model substrate of CYP 2D6, and the ratio of VEN to its major metabolite O-desmethylvenlafaxine (ODV) can be used to phenotype individuals as CYP 2D6 EMs or PMs as follows: ODV/VEN ratios greater than 1 predict EM status, whereas ratios less than 1 predict PM status. 2 Using this approach to phenotype patients, Lobello and colleagues 1 conducted a secondary analysis of the registration trial data of VEN to treat major depressive disorder, reassessing the data after dividing the VEN-treated population into 2 groups: phenotypic CYP 2D6 EMs and PMs. The analysis was based on 4 large placebo-controlled, double-blind, efficacy trials of VEN in which a plasma level of VEN and ODV was measured at the time of the trial. EMs had a 2-to 3-fold higher antidepressant response and remission rate on 4 of 5 efficacy measures when compared with PMs (P e 0.015). Both groups received the same average dose of VEN, achieved the same total concentration of VEN plus ODV, and had the same tolerability profile, ruling out differences in those parameters as an explanation for the differences in antidepressant efficacy observed. 1 Although the total concentration of VEN plus ODV was the same in both groups, the EMs achieved higher levels of ODV and lower levels of VEN, whereas the converse was true for the PMs. Of note, the finding by Lobello and colleagues was a replication of an earlier, smaller study by Borgherini and colleagues. 3 There are 2 possible explanations for the finding of poor antidepressant response to VEN in CYP 2D6 PMs. The first is VEN could be a prodrug that requires biotransformation to ODV to be an effective antidepressant. However, this explanation is inconsistent with the known pharmacology of VEN and ODV. The second is that CYP 2D6 PMs, for as yet unknown reasons, are less responsive to antidepressants, such as VEN, which are thought to work by affecting central serotonin and norepinephrine neurotransmission.Consistent with this second explanation, CYP 2D6 is expressed in the brain and is involved in the metabolism of serotonin. In addition, EMs and PMs are reported to differ in terms of personality type and to have differences in regional brain metabolism as determined using fu...

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Venlafaxine Metabolism as a Marker of Cytochrome P450 Enzyme 2D6 Metabolizer Status

Abstract: The ratio of ODV/VEN is an effective means of phenotyping individuals according to their CYP2D6 metabolizer status.

Cited by 45 publications

References 19 publications

Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

CYP 2D6 PM Status and Antidepressant Response to Nortriptyline and Venlafaxine

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