Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response

Pharmacogenomics. 2010 Apr;11(4):537-46. doi: 10.2217/pgs.09.168.


Aims: The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response.

Materials & methods: A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers.

Results: The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A4*18 and CYP2C19*17 were too low to permit further subgroup analyses.

Conclusion: Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.

Trial registration: NCT00384020.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Second-Generation / administration & dosage
  • Antidepressive Agents, Second-Generation / blood
  • Antidepressive Agents, Second-Generation / pharmacokinetics*
  • Antidepressive Agents, Second-Generation / therapeutic use
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Biomarkers / analysis
  • Chromatography, High Pressure Liquid
  • Citalopram / administration & dosage
  • Citalopram / blood
  • Citalopram / pharmacokinetics*
  • Citalopram / therapeutic use
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP3A / genetics
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / enzymology*
  • Depressive Disorder, Major / genetics
  • Female
  • Gene Dosage
  • Gene Frequency
  • Humans
  • Male
  • Models, Genetic
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Treatment Outcome


  • Antidepressive Agents, Second-Generation
  • Biomarkers
  • Citalopram
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human

Associated data