The Association Between Cytochrome P450 2D6 Genotype and Prescription Patterns of Antipsychotic and Antidepressant Drugs in Hospitalized Psychiatric Patients

Mulder, Hans; Wilmink, Frederik W.; Beumer, Tim L.; Tamminga, Wim J.; Jedema, J. N.; Egberts, Toine C. G.

doi:10.1097/01.jcp.0000155832.79777.b5

Cited by 31 publications

(21 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, other studies have also shown that CYP2D6 EMs [genotyping (two active alleles; *1, *2, *33, *35) or phenotyping (ODV/VEN ratio) determined] experienced a better clinical response to VEN than PMs; these findings suggest that the metabolism of VEN to ODV is a determinant factor for the clinical outcome [28,100,101]. Perhaps in CYP2D6 PMs the alternative metabolic pathway of VEN (N-demethylation mediated through CYP3A4, CYP2C9, and CYP2C19) may assume greater importance, which yields pharmacologically inactive or less-active metabolites.…”

Section: Genetic Biomarkers and Metabolic Phenotypesmentioning

confidence: 94%

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

Magalhães¹,

Alves²,

LLerena

et al. 2014

Drug Metabolism and Drug Interactions

View full text Add to dashboard Cite

Venlafaxine (VEN) is one of the safest and most effective drugs used in the treatment of selective serotonin reuptake inhibitors-resistant depression, and thereby it is nowadays one of the most commonly prescribed antidepressants. Nevertheless, patients treated with antidepressant drugs including VEN have exhibited large inter-individual variability in drug outcomes, possibly due to the influence of genetic and nongenetic factors on the drug pharmacokinetics and/or pharmacodynamics. Among them, an increased interest has emerged over the last few years on the genetic and/or phenotypic profile for drug-metabolizing cytochrome P450 isoenzymes and drug transporters such as potential predictive pharmacokinetic-based biomarkers of the variability found in drug biodisposition and antidepressant response. The integration of some of these key therapeutic biomarkers with classic therapeutic drug monitoring constitutes a promising way to individualization of VEN's pharmacotherapy, offering to clinicians the ability to better predict and manage pharmacological treatments to maximize the drug effectiveness. Thus, this review provides an extensive discussion of the pharmacokinetics of VEN focusing in particular on metabolism issues, without forgetting the clinically relevant sources of pharmacokinetics variability (mainly the genetic sources) and aiming on the identification of phenotypic and/or genetic biomarkers for therapy optimization.

show abstract

Section: Genetic Biomarkers and Metabolic Phenotypesmentioning

confidence: 94%

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

Magalhães¹,

Alves²,

LLerena

et al. 2014

Drug Metabolism and Drug Interactions

View full text Add to dashboard Cite

show abstract

“…Further work on this phenomenon is important because the literature regarding antidepressant efficacy and tolerability in CYP 2D6 PMs is limited principally to retrospective analyses 1,15 and small, prospective, studies 16 16 demonstrated that subjects heterozygous for 1 reduced-functioning allele had higher levels of S-mianserin, which was accompanied by a greater likelihood of treatment response. In this case, CYP 2D6 PMs had a greater treatment response than did CYP 2D6 EMs.…”

Section: The Case For Nortriptylinementioning

confidence: 97%

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

Macaluso

Preskorn

2011

Journal of Clinical Psychopharmacology

View full text Add to dashboard Cite

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...

show abstract

“…Several pharmacogenetic studies on antidepressant induced side effects (mouth dryness, nausea, and restlessness) reported that CPY2D6 poor metabolizers had an increased frequency and severity of concentration-dependent side effects due to slow elimination (Rau et al, 2004; D'Empaire et al, 2011). A retrospective follow-up study of depressed inpatients found that CYP2D6 poor metabolizers had more frequent switches (RR 3.50, 95% CI 1.52-8.10), and more dosage modifications (RR 2.18, 95% CI 1.36-2.95), which was indicative of an overall expression of unsatisfactory response to treatment including both treatment failure and unacceptable side effects (Mulder et al, 2005). …”

Section: Discussionmentioning

confidence: 99%

“…Severity of depression, maternal age, marital status (living alone or cohabiting), education level (≤12 or >12 years), race (Caucasian vs. others), body mass index (BMI, kg/m 2 ), vitamin supplement intake, and smoking status were considered as potential confounders if crude estimates resulted in p -values of less than 0.10. “Duration of antidepressant use” and “reasons for discontinuation” were not considered in the analyses given that they are intermediate variables in the causal pathway between the exposure and the outcome (Rau et al, 2004; Mulder et al, 2005; Bijl et al, 2008), and not sharing a common cause with CYP2D6 genotype (Shenfield, 2004; D'Empaire et al, 2011). …”

Section: Methodsmentioning

confidence: 99%

Association between CYP2D6 Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy

et al. 2017

View full text Add to dashboard Cite

Importance: Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by CYP2D6 genotype.Objective: To investigate the association between CYP2D6 genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal CYP2D6, Antidepressants, Depression during pregnancy.Setting: Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006–2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic.Main Outcomes and Measures: Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for CYP2D6 genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals.Results: A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, n = 204, 83%); 3.3% (n = 8) were ultrarapid metabolizers (UM), 5.7% (n = 14) poor metabolizers (PM), and 8.1% (n = 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptom in the first trimester (19.81 vs. 5.88%, P = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM).Conclusions and Relevance: Prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.

show abstract

The Association Between Cytochrome P450 2D6 Genotype and Prescription Patterns of Antipsychotic and Antidepressant Drugs in Hospitalized Psychiatric Patients

Abstract: Mrs P, a 46-year-old married woman with a 9-year history of recurrent depressive illness, presented with depressed mood, 194

Cited by 31 publications

References 9 publications

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

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

Association between CYP2D6 Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy

Contact Info

Product

Resources

About