Citalopram

Citalopram blocks the reuptake of serotonin by nerve cells in the brain, which is thought to explain its antidepressant effect. Treatment usually starts at 20 mg once a day, with a maximum of 40 mg. The label advises against higher doses because of QT prolongation, a change on the electrocardiogram that has been associated with dangerous heart rhythms [1].

The liver clears citalopram mainly by N-demethylation, carried out chiefly by CYP3A4 and CYP2C19. Its main metabolite, demethylcitalopram, is at least eight times weaker at blocking serotonin reuptake, so the parent drug does most of the work. Citalopram has a half-life of about 35 hours and reaches steady state in about a week. The QT effect rises with dose: in a study of 119 healthy volunteers, the largest average increase over placebo was 8.5 milliseconds at 20 mg and 18.5 milliseconds at 60 mg [1]. Anything that raises citalopram levels, including a slow CYP2C19 enzyme, adds to that effect.

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

For citalopram, a slower enzyme means more drug. In CYP2C19 poor metabolizers, the label reports that steady-state peak levels and total exposure (AUC) rose by 68% and 107% [1]. CPIC's evidence review found that poor metabolizers had higher concentrations and, in a growing body of studies, worse outcomes, including more side effects and more switching or stopping of treatment. At the other end, ultrarapid metabolizers had significantly lower citalopram exposure, may improve less, and switched or stopped more often. The effects in rapid metabolizers were smaller than in ultrarapid metabolizers, and intermediate metabolizers may have somewhat higher levels than normal [2].

CYP2D6 does not change the picture. Citalopram levels did not differ significantly between CYP2D6 poor and extensive metabolizers [1], and CPIC lists the CYP2D6 and citalopram pair at level C, a level at which no prescribing action is recommended [4] [5].

CPIC's 2023 guideline for serotonin reuptake inhibitor antidepressants, by Bousman and colleagues, replaced its 2015 SSRI guideline and gives one table for citalopram and escitalopram together [2]. The CYP2C19 and citalopram pair has CPIC level A, CPIC's highest level: genetic information should be used to change prescribing [4] [5]. The guideline explains how to use a genotype that is already known; which patients to test is outside its scope [2].

CPIC rates the poor metabolizer advice strong because of the risk of arrhythmia and because the FDA gives a specific dose limit. CPIC does not name particular alternatives, but it notes that citalopram, escitalopram and sertraline are all extensively metabolized by CYP2C19 [2], so switching among those three does not take the gene out of the picture.

What the FDA label says

The label sets 20 mg a day as the maximum dose for CYP2C19 poor metabolizers, and also for people over 60, people with liver impairment and anyone taking a CYP2C19 inhibitor such as cimetidine (Sections 2.3, 2.4 and 5.2) [1]. The FDA's Table of Pharmacogenetic Associations lists citalopram in Section 1, for associations where the data support therapeutic management recommendations: poor metabolizers have higher systemic concentrations and a higher risk of adverse reactions (QT prolongation), and the maximum recommended dose is 20 mg [6].

If you are about to start citalopram, or have had side effects or little benefit from it, raise your result with your prescriber. Do not start, stop or change an antidepressant on the strength of a genetic result. CPIC also points out that people on a stable, effective dose without troublesome side effects may not benefit from changes based on genotype [2].

Medicines that change CYP2C19 activity

Other drugs can raise citalopram levels whatever your genotype. The label names omeprazole and cimetidine as CYP2C19 inhibitors that may reduce citalopram clearance; cimetidine raised citalopram exposure by 43% [1]. The FDA lists fluconazole, fluoxetine, fluvoxamine and ticlopidine as strong CYP2C19 inhibitors [7]. With any CYP2C19 inhibitor, the label's 20 mg maximum applies. CPIC notes that there is no agreed method for adjusting a predicted phenotype for such interactions [2].

Other factors

Age and liver function also raise exposure. In the label's studies of people 60 and older, citalopram exposure was 23 to 30% higher and its half-life 30 to 50% longer, and liver impairment cut clearance by 37%. The label advises avoiding citalopram in people with congenital long QT syndrome, low potassium or magnesium, a recent heart attack or uncompensated heart failure, and with other drugs that prolong the QT interval, unless the benefits outweigh the risks [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. A normal result therefore means none of the assessed CYP2C19 variants was found among the positions your data covers. Gene2Rx also does not detect copy-number changes, such as the rare CYP2C19 gene deletions.

CPIC describes a variant pattern near CYP2C19, the CYP2C:TG haplotype, that is associated with higher CYP2C19 activity in some people who carry *1. It sits in the neighboring CYP2C18 gene and is not tested by clinical genotyping platforms [2]. A genotype also says nothing about how severe your depression is, whether citalopram suits you in other ways, or how your heart rhythm behaves; an electrocardiogram measures the QT interval directly.

Can a CYP2C19 poor metabolizer take citalopram?

Possibly, at a limited dose. The label's maximum for poor metabolizers is 20 mg a day [1]. CPIC suggests considering an antidepressant not mainly metabolized by CYP2C19 or, if citalopram is used, a lower starting dose, slower titration and half the usual maintenance dose [2].

Is escitalopram a better choice for a poor metabolizer?

Not for CYP2C19 reasons. CPIC gives escitalopram the same recommendations as citalopram. Its label has no matching 20 mg limit, but CPIC notes that escitalopram may also carry a risk of QT prolongation [2]. The escitalopram page has the details.

My result says rapid metabolizer. Will citalopram work for me?

It may. CPIC's advice for rapid metabolizers is optional: start at the usual dose, and consider a higher maintenance dose or a switch only if the response is inadequate. The effects seen in rapid metabolizers are smaller than in ultrarapid metabolizers [2].

1. Celexa (citalopram) tablets: prescribing information. Allergan, revised October 2023. DailyMed. Dose limits (Sections 2.3 and 2.4), QT warning (Section 5.2) and pharmacokinetics in CYP2C19 poor metabolizers (Section 12.3).
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). Recommendations for citalopram and escitalopram, evidence summary and test limitations.
3. CPIC. CYP2C19 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographical group.
4. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). CPIC level for each gene and drug pair.
5. CPIC. Assignment of CPIC levels for genes/drugs. ClinPGx. What each CPIC level means.
6. U.S. Food and Drug Administration. Table of Pharmacogenetic Associations. Section 1 entry for citalopram and CYP2C19 poor metabolizers.
7. U.S. Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2C19 inhibitors.