Escitalopram

Citalopram is a mixture of two mirror-image forms. Escitalopram is the pure S-form, which is at least 100 times more potent than the R-form at blocking serotonin reuptake. The usual dose is 10 mg once a day, with a maximum of 20 mg; for most older adults and people with liver impairment the label recommends 10 mg [1].

CYP3A4 and CYP2C19 are the main enzymes that break escitalopram down. Its metabolite, S-desmethylcitalopram, circulates at about a third of the parent level and is at least seven times weaker. The half-life is 27 to 32 hours, and steady state takes about a week. In the label's heart-rhythm study, the predicted QT increase at 20 mg was 6.6 milliseconds; a 30 mg dose, which gives blood levels similar to those expected in CYP2C19 poor metabolizers on 20 mg, increased it by 10.7 milliseconds compared with placebo [1].

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

The largest study comes from a drug-monitoring service in Oslo that measured escitalopram levels in 2,087 genotyped patients. Compared with *1/*1, levels were 3.3 times higher with two non-working alleles, 1.6 times higher with one, and 1.4 times higher with one non-working allele plus *17. They were 10% lower in *1/*17 carriers and 20% lower in *17/*17 carriers. Within a year, patients with two non-working alleles switched to another antidepressant 3.3 times as often as *1/*1 patients; the figures were 1.6 times for *1/*17 and 3.0 times for *17/*17 [2].

CPIC's review of the wider literature found the same pattern: ultrarapid metabolizers had lower exposure, may improve less and changed treatment more often, while poor metabolizers had higher levels and more side effects and treatment changes [3]. The FDA's Table of Pharmacogenetic Associations lists escitalopram in Section 3, for associations shown to affect pharmacokinetics only: CYP2C19 may alter systemic concentrations in ultrarapid, intermediate and poor metabolizers [5].

CPIC's 2023 guideline for serotonin reuptake inhibitor antidepressants, by Bousman and colleagues, covers escitalopram and citalopram in one table [3]. The CYP2C19 and escitalopram pair has CPIC level A, CPIC's highest level: genetic information should be used to change prescribing [6] [7].

The FDA label for citalopram limits CYP2C19 poor metabolizers to 20 mg a day because of QT prolongation. CPIC notes that the escitalopram label has no matching recommendation, although escitalopram may also carry a risk of QT prolongation. CPIC does not name particular alternatives; it does point out that citalopram, escitalopram and sertraline are all extensively metabolized by CYP2C19 [3].

Your result is most useful when escitalopram is being started, or when it has caused side effects or seemed not to work. Bring it to your prescriber, and 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 [3].

Medicines that change CYP2C19 activity

Because escitalopram is cleared by more than one enzyme, the label notes that blocking a single enzyme may not appreciably reduce its clearance; ritonavir, a strong CYP3A4 inhibitor, did not significantly change escitalopram levels [1]. Interactions still matter. CPIC describes phenoconversion, where an inhibitor or inducer makes a person's actual metabolism differ from what their genes predict, and notes that there is no agreed method for adjusting a phenotype for it [3]. The FDA lists fluconazole, fluoxetine, fluvoxamine and ticlopidine as strong CYP2C19 inhibitors [8].

Other factors

Age raises exposure independently of genotype: in people 65 and older, escitalopram exposure and half-life were both about 50% higher than in younger adults [1]. CPIC also lists diet, substance use, kidney and liver function and a person's past response to antidepressants among the factors to weigh [3].

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 result means none of the assessed CYP2C19 variants was found among the positions your data covers. Gene2Rx does not detect copy-number changes such as the rare CYP2C19 gene deletions, and CPIC notes that the CYP2C:TG haplotype, which is linked to higher CYP2C19 activity, is not tested by clinical genotyping platforms [3].

A genotype predicts drug levels, not how well an antidepressant will treat your symptoms. About half of adults with major depression do not respond adequately to their first antidepressant, and CPIC describes a genetic result as one of many pieces of clinical information [3].

Would citalopram be a better choice than escitalopram for my CYP2C19 result?

No. Escitalopram is the active form of citalopram, both depend on CYP2C19, and CPIC gives them the same recommendations [3]. For poor metabolizers, citalopram also carries the FDA's 20 mg limit (see the citalopram page).

Does CYP2D6 affect escitalopram?

Not in a way that changes prescribing. CPIC lists the CYP2D6 and escitalopram pair at level C, where no prescribing action is recommended [6] [7].

Do these recommendations apply to children and teenagers?

CPIC considers its citalopram, escitalopram and sertraline recommendations relevant to younger patients, because these drugs have the most pharmacogenetic data in children, and CYP2C19 activity reaches adult levels by early childhood [3].

1. Lexapro (escitalopram) tablets and oral solution: prescribing information. Allergan. DailyMed. Indications, dosing, QT data, metabolism and drug interactions.
2. Jukić MM, Haslemo T, Molden E, Ingelman-Sundberg M. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. Am J Psychiatry (2018). Escitalopram levels and treatment switching by CYP2C19 genotype.
3. 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). Recommendations for citalopram and escitalopram, evidence summary and test limitations.
4. CPIC. CYP2C19 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographical group.
5. U.S. Food and Drug Administration. Table of Pharmacogenetic Associations. Section 3 entry for escitalopram.
6. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). CPIC level for each gene and drug pair.
7. CPIC. Assignment of CPIC levels for genes/drugs. ClinPGx. What each CPIC level means.
8. U.S. Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2C19 inhibitors.