Citalopram

Monopgraph

Therapeutic action

Antidepressant that acts as an inhibitor of serotonin reuptake inhibitors (SSRIs), with serotonin enhancing action. It is more given to depressed patients with tardive dyskinesia than tricyclic antidepressants. It is also effective to reduce the consumption of ethanol in alcoholic patients.

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Additional information

As a purely indicative suggestion, when initiating treatment, CYP2C19 poor metabolisers (PMs) could start with approximately 60% of the standard dose, while intermediate metabolisers (IMs) could start with approximately 80%.

In patients who are poor metabolisers for both CYP2D6 and CYP2C19, the dose should be reduced to less than 50% of the standard dose, or an alternative drug such as mirtazapine should be considered.

Dose adjustment is not generally expected to be necessary in CYP2D6 poor metabolisers, although it may be required depending on drug interactions, particularly inhibition of CYP3A4 or CYP2C19.

Metabolism

Citalopram exists as two enantiomers: S-citalopram and R-citalopram. It is rapidly absorbed from the intestine, reaches peak plasma concentration after approximately 4 hours and has a half-life of around 35 hours.

It is demethylated mainly by CYP2D6 and CYP2C19, with CYP3A4 also contributing, to form R- and S-desmethylcitalopram.

The only active forms are S-citalopram and S-desmethylcitalopram, which are approximately 167 and 6 times more active, respectively, than R-citalopram and R-desmethylcitalopram. The desmethyl metabolites cross the blood–brain barrier only to a limited extent.

Further demethylation is mediated exclusively by CYP2D6.

CYP2D6 also catalyses the formation of oxidised metabolites, which have practically no pharmacological activity. Therefore, the polymorphisms most likely to affect citalopram plasma concentrations are those involving CYP2C19 and CYP2D6.

Citalopram plasma concentrations appear to be affected mainly in CYP2C19 poor metabolisers, who may have concentrations approximately twice those observed in normal metabolisers.

A similar effect may occur in CYP2D6 poor metabolisers. However, no significant differences in citalopram metabolism have been described in CYP2D6 poor metabolisers who retain normal activity in the other enzymes involved, suggesting that alternative pathways may compensate.

The CYP2D6 poor metaboliser phenotype is more likely to affect citalopram metabolism in the presence of CYP2C19 or CYP3A4 inhibitors, or in patients with intermediate or deficient CYP2C19 activity.

Patients who are poor metabolisers for both enzymes may therefore have a high risk of adverse reactions due to excessive drug exposure. In these cases, it may be preferable to use an antidepressant that does not depend on these cytochromes, such as bupropion or mirtazapine.

Mirtazapine has been shown to be effective in patients who are poor metabolisers for both enzymes and intolerant to other medicines.

The metabolites that increase in poor metabolisers correspond to the S-enantiomers rather than the R-enantiomers.

Patients with CYP2D6 ultrarapid metaboliser genotypes or the CYP2C19*17 allele may have lower-than-expected concentrations and may therefore require a higher dose.

In ultrarapid metabolisers, the standard dose could be administered every 12 hours instead of every 24 hours. The patient’s clinical response should be monitored closely.

Other factors to consider

Citalopram is absorbed in the small intestine through the ABCB1 transporter protein. However, the practical relevance of ABCB1 SNPs for dose adjustment remains uncertain because the available results are not yet conclusive.

The EGAPP Working Group (Evaluation of Genomic Applications in Practice and Prevention) developed recommendations regarding the usefulness of CYP450 SNP testing for monitoring SSRIs. Its conclusions were as follows:

1.- There is a clear correlation between drug plasma concentrations and the patient’s EM, IM or PM phenotype. Therefore, this information may be useful for dose adjustment according to the patient’s phenotype.

2.- However, in most studies, no clear differences in clinical response were observed among patients with different phenotypes. This suggests that drug plasma concentrations do not predict the potential clinical response.

3.- Regarding adverse reactions, these were observed mainly in CYP2D6 poor metabolisers, particularly in the form of nausea and gastrointestinal disorders. In the specific case of citalopram, CYP2C19 poor metaboliser status appears to have an even greater influence.

These recommendations were published in Genet Med 2007;9(12):819–825, and a LINK is provided in the “Additional information” section.

The report concludes that CYP450 SNP testing is not indicated at the start of treatment. However, testing may be appropriate if the patient presents adverse effects, poor response and, particularly, if other drugs metabolised by CYP2D6 or CYP2C19 are being administered concomitantly.

The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is contraindicated because of the high risk of serotonin syndrome.

Conclusions

Like many drugs acting on the central nervous system, citalopram is metabolised through saturable CYP pathways that are shared by numerous medicines.

Competitive inhibition between these drugs may complicate dose adjustment, even when pharmacogenetic information is available and even in normal metabolisers. Close clinical monitoring of patients is therefore essential.

Bibliography

• Fudio S et al. (2010). Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol. 626(2-3):200-4.
• Rudberg I et al. (2008) Impact of the ultrarapid CYP2C19*17 allele on serum concentrations of escitaloproam in psychiatric patients. Clin Pharmacol Ther; 83(2): 322-7.
• Johnson M. et al. (2006). A Poor Metabolizer for Cytochromes P450 2D6 and 2C19: A Case Report on Antidepressant Treatment. CNS Spectr. 11(10):757-760
• Bank.Ning Yu et al. (2003) Pharmacokinetics of citalopram in relation to genetic polymorphism of CY2C19. Drug Metabolism and Disposition; 31: 1255-59.
• Herrlin K et al. (2003) Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. J Clin Pharmacol; 56: 415-21

Marc Cendrós Bertran Licenciado en Biología Master en Asesoramiento Genético