CYP2C19 variation and citalopram response

Abstract

Objective: Variations in cytochrome P450 (CYP) genes have been shown to be associated with both accelerated and delayed pharmacokinetic clearance of many psychotropic medications. Citalopram is metabolized by three CYP enzymes. CYP2C19 and CYP3A4 play a primary role in citalopram metabolism, whereas CYP2D6 plays a secondary role.

Methods: The Sequenced Treatment Alternatives to Relieve Depression sample was used to examine the relationship between variations in the CYP2C19 and CYP2D6 genes and remission of depressive symptoms and tolerance to treatment with citalopram. The primary analyses were of the White non-Hispanic patients adherent to the study protocol (n= 1074).

Results: Generally, patients who had CYP2C19 genotypes associated with decreased metabolism were less likely to tolerate citalopram than those with increased metabolism, although this difference was not statistically significant (P = 0.06). However, patients with the inactive 2C19*2 allele had significantly lower odds of tolerance (P = 0.02). Patients with the poor metabolism CYP2C19 genotype-based category who were classified as citalopram tolerant were more likely to experience remission (P = 0.03). No relationship between CYP2D6 genotype-based categories and either remission or tolerance was identified, although exploratory analyses identified a potential interaction between CYP2C19 and CYP2D6 effects.

Conclusion: Despite several limitations including the lack of serum drug levels, this study showed that variations in CYP2C19 were associated with tolerance and remission in a large sample of White non-Hispanic patients treated with citalopram.

Figures

Figure 1

CONSORT Diagram of Study Sample. Initial samples dropped from the genotype analysis included (1) five subjects missing clinical data, (2) three subjects who were duplicates, and (3) four subjects' whose DNA results did not match reported gender. To define the “remission analysis sample,” 411 additional subjects were excluded because (1) 61 were medication non-compliant, (2) 33 had a baseline QIDS-C16 <10, (3) 218 dropped out within the first six weeks, and (4) 99 were part of an ethnically diverse group. From reference [16] with permission.

Figure 2

Percentage of tolerant white non-Hispanic subjects who remitted shown by CYP2C19 activity genotype based category. Bars represent 95% CI. The overall remission rate in the study adherent tolerant white non-Hispanic subjects was 57.8% (405/872).

Figure 3

Methodology for defining combined CYP genotype based categories. Subjects with reduced activity genotype based categories for both enzymes were classified as having low combined activity. The group defined as having moderate combined activity consists of subjects with an extensive genotype based category for one enzyme paired with a reduced or extensive genotype based category for the other enzyme. Subjects with at least one ultra rapid genotype based category were classified into the high activity combined CYP genotype based category group.

Figure 4

White non-Hispanic remission rates for combined CYP genotype based categories (p = 0.01).