Venlafaxine

Venlafaxine and its metabolite ODV are both potent, selective inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake, with no significant affinity for muscarinic, histamine or alpha-adrenergic receptors [1]. For depression, Effexor XR usually starts at 75 mg once a day, or 37.5 mg for 4 to 7 days before that, and can be raised in steps of up to 75 mg, at least 4 days apart, to a maximum of 225 mg a day [1].

Venlafaxine is extensively metabolized on its first pass through the liver, mainly to ODV. Laboratory studies show CYP2D6 forms ODV, and a clinical study confirmed that CYP2D6 poor metabolizers had more venlafaxine and less ODV than people with normal activity. The half-life is about 5 hours for venlafaxine and 11 hours for ODV, and steady state is reached within 3 days. About 87% of a dose appears in the urine within 48 hours: 5% as unchanged venlafaxine, 55% as ODV and 27% as minor inactive metabolites [1].

A CYP2D6 result is an activity score: each copy of the gene gets a value (1 for normal function, 0.5 or 0.25 for decreased function, 0 for no function) and the two are added. A score of 0 means poor metabolizer, 0.25 to 1 intermediate, 1.25 to 2.25 normal and above 2.25 ultrarapid [2][4].

Because both compounds are active, a change in the ratio does not simply mean more or less drug. CPIC found insufficient evidence that the higher ODV-to-venlafaxine ratio in ultrarapid metabolizers, or the lower ratio in intermediate metabolizers, changes outcomes. In poor metabolizers the ratio is greatly decreased; the clinical impact is unclear, but poor metabolizer status has been associated with side effects, and data suggest more concentration-dependent side effects in this group [2].

In CPIC's frequency tables, about 6.5% of people of European ancestry are CYP2D6 poor metabolizers, compared with 2% to 3% in most other groups and under 1% of people of East Asian ancestry [5].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) covers venlafaxine in its 2023 guideline on serotonin reuptake inhibitors [2]. Venlafaxine and CYP2D6 are CPIC level B: genetic information could be used to change prescribing, because alternative therapy or dosing is extremely likely to be as effective and safe as non-genetic dosing [6]. CPIC rated its poor metabolizer advice optional because prospective studies are few, blood-level monitoring of antidepressants is uncommon, and lowering the dose could make the drug less effective [2].

The FDA view appears in the report too. FDA's Table of Pharmacogenetic Associations lists venlafaxine with CYP2D6 poor metabolizers in its first section, for associations where the data support therapeutic management recommendations: the gene "alters systemic parent drug and metabolite concentrations," and FDA says to consider dosage reductions [3]. The Effexor XR label shows the effect in poor metabolizers but does not set a genotype-specific dose [1]. So for a poor metabolizer the report carries two sources: CPIC's suggestion to consider another drug and FDA's suggestion to consider a lower dose. Both are options for the prescriber to weigh.

An ultrarapid result requires extra copies of the gene, because every increased-function CYP2D6 allele is a gene duplication [4]; neither source recommends a change for that group.

Bring the report to your prescriber or pharmacist with a list of everything you take. CPIC notes that people who are stable on an effective dose without troublesome side effects may not benefit from genotype-based changes [2]. Do not start, stop or change venlafaxine because of a genetic result without talking to your prescriber; the label reports discontinuation symptoms after abrupt stopping or dose reduction and recommends tapering [1].

Medicines that change the picture

Phenoconversion is common with venlafaxine. In a study of 900 adults being treated with venlafaxine for depression, 4% were CYP2D6 poor metabolizers by genotype, but 27% had ODV-to-venlafaxine ratios typical of poor metabolizers [7]. The label notes that strong CYP2D6 inhibitors are expected to have a similar effect to poor metabolizer status [1]; FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [8]. CYP3A inhibitors raise both venlafaxine and ODV, and the label suggests considering a lower venlafaxine dose with them. Venlafaxine in turn raises levels of other CYP2D6 substrates [1].

Other factors

The label reduces the dose by 50% in mild to moderate liver impairment and by 25% to 50% in mild to moderate kidney impairment. Venlafaxine raised blood pressure in a dose-related way in trials, so blood pressure is checked before and during treatment [1].

Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use. They read fixed positions and can miss rare variants. Array processing uses imputation to infer some variants that were not measured directly, but a variant at a position the data does not cover cannot be seen, so a normal result means none of the assessed variants was found among the positions your data covers. "Indeterminate" means the alleles found could not be assigned a function. A genotype from GeneSight, Genomind or another lab can be entered for a Panel Report.

Is desvenlafaxine affected by CYP2D6?

CPIC describes desvenlafaxine as metabolized by CYP3A4 and not affected by CYP2D6 or CYP2C19, so it assigned no CPIC level or recommendation for it [2].

Why does the report show two sources for venlafaxine?

Gene2Rx includes both CPIC's recommendation and FDA's summary; for poor metabolizers they suggest different actions, as explained under What the guidelines recommend.

1. Effexor XR (venlafaxine extended-release capsules) (Viatris): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing, metabolism to desvenlafaxine and CYP2D6 effects.
2. Bousman CA et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther (2023). CPIC recommendations and the evidence behind them.
3. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
4. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
5. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
6. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
7. Preskorn SH et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry (2013). How often measured CYP2D6 activity differs from genotype in practice.
8. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.