MRP1 polymorphisms associated with citalopram response in patients with major depression

Abstract

Multidrug resistance protein 1 (MRP1, ABCC1) transports antidepressive agents in the endothelial cells of the blood-brain barrier. Therefore, polymorphisms in the MRP1 gene may affect the treatment response of antidepressants. This study was aimed to identify the association between genetic variations in MRP1/ABCC1 and the therapeutic response to the antidepressant citalopram. One hundred and twenty-three patients who had been treated with citalopram monotherapy to control their major depressive disorder were recruited, and genotype data from 64 patients who had completed their 8-week follow-up were evaluated together with those from 100 controls. Nine MRP1 single nucleotide polymorphisms (SNPs) showing more than 5% allele frequency in the Korean population were analyzed. The c.4002G>A, a synonymous SNP in exon 28, showed a strong association with the remission state at 8 weeks (P = 0.005, odds ratio [OR], 4.7, 95% confidence interval [CI], 1.5 approximately 14.7). The c.4002G>A forms a linkage disequilibrium block with 3 other SNPs including c.5462T>A in the 3' untranslated region. Accordingly, the haplotype showed a significant association with the remission state (P = 0.014). Subsequent molecular studies also supported the association between these MRP1 polymorphisms and the citalopram response. Thus, kinetic studies using MRP1-enriched membrane vesicles revealed that citalopram is a substrate of MRP1 (Km = 1.99 microM, Vmax = 137 pmol/min per milligram protein). In addition, individuals with c.4002G>A or c.5462T>A polymorphisms showed higher MRP1 mRNA levels in peripheral blood cells. These results suggest that MRP1 polymorphisms may be a predictive marker of citalopram treatment in major depression.