Vortioxetine

The label says the antidepressant effect is not fully understood but is thought to come from blocking serotonin reuptake. Vortioxetine also blocks 5-HT3, 5-HT1D and 5-HT7 receptors, partly activates 5-HT1B and activates 5-HT1A receptors, though how much these actions add is not established. In imaging studies it occupied about 50% of serotonin transporters at 5 mg a day, 65% at 10 mg and 80% at 20 mg [1].

The usual starting dose is 10 mg once a day, increased to 20 mg as tolerated; 5 mg can be used by people who do not tolerate higher doses. Nausea is the most common side effect and is dose-related; 15% to 20% of patients had nausea after one or two days. People stopping 15 or 20 mg a day are advised to take 10 mg for a week first [1].

The activity comes from the parent drug. Vortioxetine is metabolized by several CYP enzymes (CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6) and then conjugated, but CYP2D6 is the main enzyme forming its major, inactive metabolite. Its kinetics are proportional to dose, about 75% of a dose reaches the bloodstream, and the half-life is about 66 hours, so steady state takes about two weeks [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][3].

Poor metabolizers have approximately twice the vortioxetine concentration of people with normal CYP2D6 activity [1]. CPIC cites a study in which ultrarapid metabolizers had low or undetectable levels compared with normal metabolizers, and notes that lower exposure decreases the probability of benefit [2]. Intermediate metabolizers have somewhat higher levels, which CPIC does not consider a reason to change the starting dose [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 [4].

The FDA label is direct: the maximum recommended dose is 10 mg a day in known CYP2D6 poor metabolizers, because they have higher vortioxetine levels [1]. FDA's Table of Pharmacogenetic Associations lists the pair in its first section, for associations where the data support therapeutic management recommendations [5].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) covers vortioxetine in its 2023 guideline on serotonin reuptake inhibitors, and vortioxetine and CYP2D6 are CPIC level A, CPIC's highest level: genetic information should be used to change prescribing [2][6]. CPIC derived its 50% starting dose for poor metabolizers from the differences in drug exposure between groups [2].

For a poor metabolizer, the report shows both sources: the label's 10 mg maximum and CPIC's lower starting dose. An ultrarapid result requires extra copies of the gene, because every increased-function CYP2D6 allele is a gene duplication [3].

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 vortioxetine because of a genetic result without talking to your prescriber.

Medicines that change the dose

The label builds phenoconversion into its dosing. It tells prescribers to halve the vortioxetine dose when a strong CYP2D6 inhibitor, such as bupropion, fluoxetine, paroxetine or quinidine, is added, and to return to the original dose when the inhibitor is stopped. With strong inducers of several CYP enzymes, such as rifampin, carbamazepine or phenytoin, it suggests considering a higher dose, up to three times the original [1]. Vortioxetine itself is unlikely to change the metabolism of other drugs [1].

Other factors

Mild to severe liver or kidney impairment did not change vortioxetine clearance in the label's studies [1]. CPIC lists age, other medicines and past response among the factors to weigh alongside genotype [2].

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.

My report says poor metabolizer. Is 20 mg off limits?

The label's maximum for known CYP2D6 poor metabolizers is 10 mg a day; see What the guidelines recommend [1]. Your prescriber decides how that applies to you.

Is vortioxetine an SSRI?

CPIC groups it with the serotonin modulators that have SSRI-like properties, because it blocks serotonin reuptake and also acts on serotonin receptors [2].

1. Trintellix (vortioxetine) tablets (Takeda): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, the CYP2D6 poor metabolizer maximum dose and interactions.
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. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
4. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
5. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
6. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.