Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder

Abstract

Objective: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the mu-opioid receptor gene may influence population variation in response to citalopram treatment.

Method: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission.

Results: Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the mu-opioid receptor-1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intracellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected.

Conclusions: These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the mu-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.

Trial registration: ClinicalTrials.gov NCT00021528.

FIGURE 1. Location and Phenotype Association of 48 Single Nucleotide Polymorphisms (SNPs) Genotyped in the OPRM1 Region in a Sample of Depressed Patientsa

^a The top image depicts the μ-opioid receptor-X and -1 transcripts. The relative positions of the SNPs are shown horizontally by physical position. A single, distant SNP was placed near the final exon of the μ-opioid receptor-10 transcript. The bottom graph illustrates pairwise linkage disequilibrium measures for SNPs <50 kb apart, with greater shades of red indicating increasing D′. Phenotype shown is specific response.