Paroxetine

Like other SSRIs, paroxetine increases serotonin activity by blocking its reuptake into nerve cells [2]. The label's usual starting dose is 20 mg a day for depression, obsessive-compulsive disorder and post-traumatic stress disorder and 10 mg for panic disorder, raised by 10 mg a week if needed, to a maximum of 50 or 60 mg depending on the condition. Older adults and people with severe kidney or liver impairment start at 10 mg, with a maximum of 40 mg [1].

Paroxetine is extensively metabolized, and its metabolites have no more than a fiftieth of its potency at blocking serotonin uptake. CYP2D6 handles part of that metabolism and saturates at clinical doses. The result is unusual kinetics: at steady state, exposure was about 8 times what single-dose data predicted, and levels rise more than proportionally as the dose goes up. The half-life is about 21 hours [1].

The label calls paroxetine a strong CYP2D6 inhibitor, and its inhibition is irreversible [1]. CPIC explains what that means for the gene: paroxetine can convert normal metabolizers into intermediate or poor metabolizers, an effect that depends on dose and is greater at steady state. Normal and intermediate metabolizers may be more susceptible than ultrarapid metabolizers, and CPIC calls the effect minimal in poor metabolizers [2].

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].

CPIC summarizes the evidence by group. In several studies, ultrarapid metabolizers had low or even undetectable paroxetine levels, and people with undetectable or low levels were less likely to benefit, although a minimum effective level has not been defined. Poor metabolizers given similar doses had significantly greater exposure than normal metabolizers, and higher exposure raises the risk of dose-related side effects. Intermediate metabolizers have reduced metabolism when treatment starts or at low doses, but as paroxetine blocks the enzyme they may come to resemble poor metabolizers [2]. The label notes that paroxetine's pharmacokinetics have not been studied in CYP2D6 poor metabolizers [1].

In CPIC's frequency tables, about 6.5% of people of European ancestry are poor metabolizers, compared with 2% to 3% in most other groups and under 1% of people of East Asian ancestry; ultrarapid metabolizers range from under 1% to about 7% across most groups [4].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) covers paroxetine in its 2023 guideline on serotonin reuptake inhibitors, an update of its 2015 SSRI guideline [2]. Paroxetine and CYP2D6 are CPIC level A, CPIC's highest level: genetic information should be used to change prescribing [5]. CPIC rated the intermediate metabolizer advice optional after taking paroxetine's own inhibition of CYP2D6, and the phenoconversion it causes, into account [2].

An ultrarapid result requires extra copies of the gene, because every increased-function CYP2D6 allele is a gene duplication [3].

The FDA label gives no genotype-based doses. FDA's Table of Pharmacogenetic Associations lists paroxetine with CYP2D6 ultrarapid, intermediate and poor metabolizers in its section for effects on drug levels only [6]. The Dutch Pharmacogenetics Working Group (DPWG) differs from CPIC: its 2022 guideline advises avoiding paroxetine in CYP2D6 ultrarapid metabolizers but finds no action needed for poor or intermediate metabolizers [7]. Gene2Rx reports use the CPIC recommendations.

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

Paroxetine changes your other CYP2D6 results

While you take paroxetine, the CYP2D6 results in your report describe your genes, not how the enzyme is working. A drug that blocks an enzyme can make a person's metabolism differ from what the genes predict; this is called phenoconversion, and CPIC notes there is no agreed method for adjusting a predicted phenotype for it [2]. The label says paroxetine can raise levels of other CYP2D6 substrates, so their doses may need to come down; it contraindicates paroxetine with CYP2D6 substrates that prolong the QT interval of the heartbeat; and it advises an antidepressant with little or no CYP2D6 inhibition for people taking tamoxifen, whose activation depends on CYP2D6 [1]. The genotype-based advice in your report for other CYP2D6 medicines, such as amitriptyline or vortioxetine, does not account for this inhibition.

Other strong CYP2D6 inhibitors on FDA's list include bupropion, fluoxetine, quinidine and terbinafine [8].

Other factors

Age, kidney function and liver function change paroxetine dosing on their own [1], and CPIC lists age, kidney and liver function, diet and substance use 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.

CPIC notes that blood-level monitoring is uncommon for antidepressants [2].

My result is normal. Can paroxetine still behave as if I were a poor metabolizer?

Yes, at higher doses and over time, because paroxetine blocks the enzyme that clears it; see How paroxetine works.

Does CYP2C19 matter for paroxetine?

CPIC makes CYP2C19-based recommendations for citalopram, escitalopram and sertraline, but not for paroxetine [2].

1. Paxil (paroxetine) tablets (Apotex): prescribing information. DailyMed, US National Library of Medicine. Indications, dosing, CYP2D6 metabolism and inhibition, contraindications.
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. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
6. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
7. Brouwer JMJL et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet (2022). The Dutch SSRI recommendations.
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.