Venlafaxine (VEN) is a serotonin-norepinephrine reuptake inhibitor (SNRI) marketed for the treatment of depression disorders.
VEN consists of a racemic mixture of R(+) and S(-) enantiomer. The ( R ) enantiomer has been shown to exhibit greater serotonin reuptake inhibition property, while the (S) enantiomer inhibits the reuptake of both monoamines [Articles:3790168, 7729333].
VEN is highly metabolized in humans with a urinary excretion of the unchanged compound between 1-10 % of an administered dose [Articles:8337893, 1487561]. Demethylation to O-desmethylvenlafaxine (ODV) is the primary route of the first pass metabolism of VEN. Cytochrome P450 2D6 (CYP2D6) is the major enzyme involved in ODV formation [Articles:8838442, 10192828]. ODV gets excreted unchanged and as its glucuronide [Article:8337893].
A few studies describe a possible stereoselective metabolism of VEN to ODV with either selection towards the (S) isoform [Articles:1487561, 8838442] or the ( R ) isoform [Articles:10855463, 21840145] but the majority of studies regarding VEN pharmacokinetics and antidepressant response in association with CYP2D6 metabolizer phenotype do not distinguish between the enantiomers.
ODV has antidepressant activity and desvenlafaxine succinate, a salt of ODV, is a FDA approved drug. Despite the predominate role of CYP2D6, ODV plasma concentrations are detectable in CYP2D6 poor metabolizer (PM) individuals who lack any CYP2D6 activity, which suggests that other cytochrome P450 enzymes might be involved in the ODV production to a minor extent [Article:10774634]. In-vitro experiments implicate the involvement of CYP2C19 in the formation of ODV in human liver microsomes [Article:10192828].
N-demethylation of VEN to N-desmethylvenlafaxine (NDV) is generally a minor metabolic pathway and catalyzed by CYP3A4 and CYP2C19 [Article:10192828]. NDV is found at about 1% in urine and has weak serotonin and norepinephrine reuptake inhibition properties in-vitro [Article:1487561]. Patients with the CYP2D6 PM phenotype show a higher level of NDV compared to CYP2D6 EM patients implicating an increase of flux via this route when ODV production is reduced [Articles:18214456, 16958828, 10780263, 10774634].
ODV and NDV are further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to N, O-didesmethylvenlafaxine (NODV), which is a minor metabolite with no known pharmacological effect [Articles:7729333, 19142106]. NODV is further metabolized into N, N, O-tridesmethylvenlafaxine or excreted as its glucuronide [Article:8337893]. To our knowledge, no studies have reported the UGT enzymes responsible for glucuronidation.
The effect of CYP2C19 in VEN metabolism has been investigated only limited to this point [Articles:10877013, 21099743] and further studies are needed. Since both PM and UM variations of CYP2C19 are present in most populations, it is reasonable to expect that these may have an impact on VEN metabolism, particularly in CYP2D6 PM and IMs.
The therapeutic range of VEN is between 125 and 400 microg/l [Articles:10774634, 12404307, 12503838]. However, a number of studies report a poor relationship between efficacy and plasma drug levels and more research on the relationship between plasma concentrations of VEN and clinical treatment outcome is needed [Articles:12503838, 14704834]. There is a correlation between early response and the sum of VEN + ODV concentration but comparing overall response and non-response at the end of the study suggests no effect of VEN pharmacokinetic on long-term response [Article:14704834].
VEN is a substrate of the multiple drug resistance protein 1 (MDR1, P-gp) encoded by ABCB1 as suggested in studies in knock-out mice [Articles:14550684, 20466523]. Further, in-vitro studies showed that VEN but not ODV is an inducer of drug efflux transporter expression ABCB1 and breast cancer resistance protein (BCRP)] [Article:21446053] and both only minimal inhibit MDR1 activity [Article:19629022].
Withdrawal syndrome has been reported after discontinuation of selective serotonin-reuptake inhibitors, especially paroxetine which has a relatively shorter half-life, but also VEN and tapering the drug dose gradually should be considered [Articles:8599410, 9326838, 8942467]. A placebo-controlled study shows a significantly greater number of adverse events after VEN treatment discontinuation than after discontinuation of a placebo [Article:9396960].
In case studies, adverse reactions are reported in association with very high VEN plasma concentration with the most common symptoms being neurotoxicity or cardiovascular toxicity [Articles:10372752, 10780263, 12663337, 19822698]. High VEN concentration were the result of either overdose of VEN and/or the patient carried a CYP2D6 PM genotype and/or the patient received several co-medication, some also metabolized by CYP2D6.
The pharmacokinetics of VEN is clearly affected by the CYP2D6 metabolizer phenotype and a correlation exists between the CYP2D6 genotype and the metabolic ratio of VEN to ODV shown in a number of studies [Articles:20441720, 20174590, 21288052, 21099743, 20446083, 19142106]. CYP2D6 poor metabolizers (PM) have higher VEN, lower ODV, and consequently higher NDV plasma concentrations [Articles:10774634, 16044105, 21099743].
Few studies investigated the effect of CYP2D6 variants on venlafaxine response or the risk of adverse reaction during VEN treatment, and the study sizes have been small (in the range of n=25-464) or are case studies. In general, little is known about the relationship between drug plasma level and efficacy or tolerability.
A study using VEN also as a phenotyping probe drug to classify PM and extensive metabolizers (EM) found an influence on VEN treatment efficacy [Article:20441720]. This study is a secondary analysis of the VEN and ODV plasma levels from the four double-blind, placebo controlled trails that were part of the VEN approval process. The results show that VEN is more effective than placebo in CYP2D6 EM but not in CYP2D6 PM [Article:20441720]. The finding suggests a decline in efficacy in PM duo to lower ODV levels, which might has a greater antidepressant profile. The discontinuation rate, side effect rate and VEN dose were not different between PM and EM, classified based on VEN as a probe drug [Article:20441720]. In general, an ODV/VEN ratio below 1 seems to map to genotypically PM subjects, although some genotypically EM subjects show an ODV/VEN ratio below 1 [Article:16958828].
An earlier study in a smaller cohort (n=33) showed that response was associated with a higher ODV/VEN ratio among EM (ODV/VEN ratio in responder: 3.7-8.9 and non-responder: 1.5-3.5) [Article:10774634]. The study only included 3 PM and 2 UM patients and due to the small number a significant relationship between higher VEN concentration and an increased likelihood of side effects or treatment response could not be established [Article:10774634]. In contrast, other studies were not able to link VEN response with ODV and VEN plasma levels or CYP2D6 genotype [Articles:16642541, 16958828, 20174590] but study sizes were small and CYP2D6 genotype or the genotype grouping was not always clear. An editorial proposes that CYP2D6 PM patients are less responsive to VEN also implicating an involvement of CYP2D6 in the metabolism of serotonin in the brain [Article:21346604].
Cases of severe arrhythmias have been reported in four patients treated with VEN who all were CYP2D6 PMs [Article:10780263]. A higher risk for side effects may exist in individuals lacking CYP2D6 activity and therefore having elevated VEN concentrations [Articles:16958828, 15168101]. The studies conclude that this might be due to pharmacological differences between VEN and ODV [Article:16958828], while others show no differences in side effect risk [Articles:16642541, 20441720]. Five patients with the intermediate CYP2D6 metabolizer phenotype (IM), who lack a fully active CYP2D6 allele, could not tolerate VEN doses above 75 mg/day and all except one discontinued the VEN treatment because of intolerable side effects [Article:17803873]. The clinical data for this study were retrieved from electronic clinical records and therefore no VEN and ODV plasma concentrations were available, furthermore therapeutic response and adverse side effects were recorded in a not standardized manner [Article:17803873].
Differences in the clinical efficacy of antidepressants that are substrates of MDR1 including VEN are associated with ABCB1 variations (rs2235067, rs4148740, rs10280101, rs7787082, rs2032583, rs4148739, rs11983225, rs10248420, rs2235040, rs12720067, and rs2235015) in a candidate gene association study [Article:18215618]. It is thought that this is due to a possible influence of these intronic SNPs on intronic regulatory elements of the gene and therefore may modulate the antidepressant accessibility into the brain. These findings need to be verified in further studies.
Only a few candidate gene studies investigate the influence of variants in pharmacodynamic genes such as catechol-O-methyltransferase (COMT) gene, serotonin receptor 2A (HTR2A) gene, brain-derived neurotrophic factor (BDNF) gene, FK506 binding protein 5 (FKBP5) gene, and dopamine transporter (SLC6A3) gene on the variability of treatment outcomes.
A cohort of 156 patients with generalized anxiety disorder, with a population composure of 112 European-American and 41 African-Americans and 3 others, was treated with VEN for 6-month with a flexible-dose of 75-225 mg/day as phase I of an 18-month relapse prevention study. The primary outcome analysis is based on response, defined as 50% or more reduction of the Hamilton Anxiety Scale (HAM-A) score at 6 month and remission with a HAM-A score of 7 or below. The secondary outcome measurement is the Clinical Global Impression of Improvement (CGI-I) score, with improvement defined as a CGI-I of 1 and 2 [Articles:22417933, 22006095, 21889574].
Overall, no significant association between the primary outcome measure and the Val158Met variant (rs4680) in the COMT gene could be established in the 112 European-American patients of this cohort [Article:22417933]. However, a slight dominant effect of the A-allele (Met) compared to the G-allele (Val) is showed when the CGI-I scale is used as secondary outcome measure [Article:22417933].
In same cohort of 156 anxious patients, the frequency of the HTR2A rs7997012 G-allele differed significantly between responders (70%) and nonresponders (56%) at 6 months (p=0.05) using the HAM-A score as described above [Article:22006095]. Furthermore, the G-allele was associated with improvement using the CGI-I as the secondary outcome measure (p=0.001, odds ratio=4.72) [Article:22006095].
Earlier, treatment response in association with the functional variant rs6265 (Val66Met) in the BDNF gene was assessed in 111 of the European-American patients and no significant correlation was found [Article:21889574].
Unfortunately, a combined effect of the variants was not studied since each individual study only focused on a single gene even though the same clinical study cohort was used.
In studies that investigated predictors of the response to antidepressant therapy included VEN among other antidepressants such as selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) [Articles:16702979, 18597649]. Carriage of the FKBP5 variants rs 3800373 and rs1360780, which are in linkage, related to a trend towards a higher response chance (p=0.004; OR 1.8; 95% Cl: 0.98-3.3) mainly in the subgroups of patients receiving antidepressant combinations or VEN [Article:18597649]. The SLC6A3 3' UTR variable number of tandem repeats (VNTR) SNP influenced rapid response to antidepressant therapy (39 patients out of 190 were treated with VEN). The study participants were either homozygous carrier for 9 or 10 repeat genotype or heterozygous carrier for 9 and 10 repeat genotype [Article:16702979]. The rapid improvement of depression symptoms was greater in patients carrying the 10-repeat allele compared to homozygous carriers of the 9-repeat allele [Article:16702979]. This effect was significant combining all antidepressants (p=0.0037). The analyses of the individual drug groups only reached statistically significance for the patients receiving SSRIs [Article:16702979].
The drug response to VEN treatment varies among patients. An influence of CYP2D6 variations on the pharmacokinetic parameters of VEN is clearly demonstrated in a large number of studies. The higher VEN and reduced ODV concentrations in CYP2D6 PM subjects seems to translate into reduced response and a higher risk of side effects compared to EM carriers. However the studies on VEN treatment outcome are limited in sample size and conflicting results exist. Larger studies are needed to enroll sufficient numbers of PM, IM and UM to determine if the effect of CYP2D6 variations on VEN and ODV plasma levels translate into an increased risk for non-response and side effects. Furthermore, the inclusion of the CYP2C19 genotype might help to understand the variability in venlafaxine response. Additionally, further investigation regarding VEN and ODV mechanism of action and binding preferences of the respective enantiomers might explain pharmacological differences. A preference of CYP2D6 for the S or R form might also shape the overall monoamine re-uptake profile. Further research about the selectivity of CYP2D6 might aid in the understanding of the complex issue of VEN drug response and side effect profile.
Sangkuhl Katrin, Stingl Julia C, Turpeinen Miia, Altman Russ B, Klein Teri E . "PharmGKB summary: venlafaxine pathway" Pharmacogenetics and genomics (2013).
Entities in the Pathway
Drugs/Drug Classes (1)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|N, O-didesmethyl venlafaxine||N, N, O-tridesmethyl venlafaxine||8337893|
|N, O-didesmethyl venlafaxine||N, O-didesmethyl venlafaxine glucuronide||8337893|
|N-desmethyl venlafaxine||N, O-didesmethyl venlafaxine||CYP2C19, CYP2D6||21099743|
|O-desmethyl venlafaxine||N, O-didesmethyl venlafaxine||CYP2C19, CYP3A4||19142106, 21099743|
|O-desmethyl venlafaxine||O-desmethyl venlafaxine glucuronide||8337893|
|SLC6A2||SLC6A2||O-desmethyl venlafaxine, venlafaxine||11098412, 7729333|
|SLC6A4||SLC6A4||O-desmethyl venlafaxine, venlafaxine||11098412, 7729333|
|venlafaxine||N-desmethyl venlafaxine||CYP2C19, CYP3A4||10192828, 10877013|
|venlafaxine||O-desmethyl venlafaxine||CYP2C19, CYP2D6||10192828, 10774634, 8838442|
Download data in TSV format . Other formats are available on the Downloads/LinkOuts tab.