Sertraline

Sertraline blocks serotonin reuptake in the brain. Adults with depression usually start at 50 mg a day, and the dose can rise in steps of 25 to 50 mg once a week up to 200 mg; the label sets the weekly interval because the half-life is about a day. Sertraline undergoes extensive first-pass metabolism, mainly by N-demethylation to N-desmethylsertraline, which is substantially less active and lingers longer, with a half-life of 62 to 104 hours [1].

Several cytochrome P450 enzymes take part, including CYP2D6, CYP2C19 and CYP2B6. Pharmacokinetic studies point to CYP2C19 as the major pathway, and there is evidence that CYP2B6 variation affects sertraline exposure, whereas CYP2D6 genotype has shown little or no effect [2].

CYP2C19 alleles fall into four function groups: normal (*1), decreased (such as *9), no function (such as *2 and *3) and increased (*17), and the two copies a person carries give a metabolizer phenotype from ultrarapid to poor [2]. Intermediate metabolizers make up about a quarter of people of European ancestry and nearly half of people of East Asian ancestry; poor metabolizers about 2% and 13% [4]. The CYP2C19 gene page has more detail.

In 1,202 patients whose sertraline levels were measured in routine care in Oslo, levels were 1.38 times higher in CYP2C19 intermediate metabolizers and 2.68 times higher in poor metabolizers than in normal metabolizers, and about 10% lower in ultrarapid metabolizers. Poor metabolizers had 8.7 times the odds of a level above the therapeutic reference range [3].

CYP2B6 is the second route. Its alleles are grouped the same way: normal function (*1), decreased function (*6 and *9), no function (*18) and increased function (*4) [2]. *6 is common. It makes up about 23% of CYP2B6 alleles in European populations, 32% in African American/Afro-Caribbean populations and 17% in East Asian populations. An estimated 7%, 16% and 4% of those groups are CYP2B6 poor metabolizers [5].

A second Oslo study of 840 patients looked at both genes. Sertraline exposure was 128% higher in CYP2C19 poor metabolizers and about 20% lower in people with two increased-function variants than in *1/*1 patients, and 189% higher in people who were poor metabolizers for both CYP2C19 and CYP2B6. The CYP2B6 *4, *6 and *9 alleles also had significant effects [6]. CPIC classes its CYP2B6 advice as optional because it rests on two pharmacokinetic studies without outcome data [2].

CPIC's 2023 guideline for serotonin reuptake inhibitor antidepressants, by Bousman and colleagues, gives three sets of sertraline recommendations: for CYP2C19 alone, for CYP2B6 alone, and for both genes together [2]. The CYP2C19 and sertraline pair has CPIC level A, CPIC's highest level: genetic information should be used to change prescribing. The CYP2B6 pair has level B: genetic information could be used to change prescribing, because alternative dosing or drugs are extremely likely to be as effective and as safe [7] [8]. When both genes have a phenotype, the Gene2Rx report shows CPIC's combined recommendation; if either gene is Indeterminate or not available, it shows each gene's own recommendation.

CYP2C19 alone

CYP2B6 alone

Both genes together

CPIC notes that a combination of non-normal results can call for a change even when neither gene alone does. Its combined table is based on how far sertraline exposure differed from normal metabolizers in the Oslo data [2].

CPIC does not name particular alternatives. It does note that citalopram and escitalopram are also extensively metabolized by CYP2C19 [2], so they do not avoid the gene.

Raise your result with your prescriber when sertraline is being started, or if it has caused side effects or seemed not to work. Do not start, stop or change an antidepressant on the strength of a genetic result. CPIC notes that people on a stable, effective dose without troublesome side effects may not benefit from changes based on genotype [2].

Medicines that change enzyme activity

Other drugs can shift sertraline levels whatever your genotype. In the label, cimetidine raised sertraline exposure by 50% [1]. The FDA lists fluconazole, fluoxetine, fluvoxamine and ticlopidine as strong CYP2C19 inhibitors, and rifampin as a strong CYP2C19 inducer that also moderately induces CYP2B6 [9]. CPIC notes that there is no agreed method for adjusting a predicted phenotype for these interactions [2]. Sertraline also affects other drugs: it inhibits CYP2D6, and the label advises lowering the dose of a CYP2D6-metabolized drug if needed when the two are combined [1].

Other factors

Liver function has a large effect. In mild liver impairment, sertraline exposure was about three times higher, so the label recommends half the usual dose; it does not recommend sertraline in moderate or severe impairment [1].

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions in the genome. 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 CYP2C19 or CYP2B6 result means none of the assessed variants was found among the positions your data covers. Gene2Rx does not detect copy-number changes such as rare gene deletions.

CPIC adds that different laboratory tests examine different sets of variants and can assign different phenotypes, and that metabolism can also depend on age, diet, illness, smoking, pregnancy and other medicines [2]. A genotype predicts drug levels; it does not measure how well sertraline will treat your symptoms.

Is sertraline a good choice if citalopram did not suit my CYP2C19 result?

Not automatically. Sertraline is also extensively metabolized by CYP2C19 and has its own recommendations for poor metabolizers [2]. The citalopram and escitalopram pages cover those drugs.

Does CYP2D6 matter for sertraline?

Not for prescribing. CPIC lists the CYP2D6 and sertraline pair at level C, a level at which no prescribing action is recommended [7] [8].

1. Zoloft (sertraline) tablets and oral solution: prescribing information. Viatris, revised August 2023. DailyMed. Indications, dosing, metabolism and drug interactions.
2. Bousman CA, Stevenson JM, Ramsey LB, 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). Sertraline recommendations for CYP2C19, CYP2B6 and both genes together (Tables 3b, 4 and 5).
3. Bråten LS, Haslemo T, Jukic MM, Ingelman-Sundberg M, Molden E, Kringen MK. Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. Neuropsychopharmacology (2020). Sertraline levels by CYP2C19 phenotype.
4. CPIC. CYP2C19 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographical group.
5. CPIC. CYP2B6 frequency table (spreadsheet). Estimated allele and phenotype frequencies by biogeographical group.
6. Bråten LS, Ingelman-Sundberg M, Jukic MM, Molden E, Kringen MK. Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population. Clin Transl Sci (2022). Sertraline exposure by CYP2C19 and CYP2B6 genotype.
7. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). CPIC level for each gene and drug pair.
8. CPIC. Assignment of CPIC levels for genes/drugs. ClinPGx. What each CPIC level means.
9. U.S. Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. CYP2C19 and CYP2B6 inhibitors and inducers.