Common genetic variation in the indoleamine-2,3-dioxygenase genes and antidepressant treatment outcome in major depressive disorder

The essential amino acid tryptophan is the precursor to serotonin, but it can also be metabolized into kynurenine through indoleamine-2,3-dioxygenase (ID0). Increased immune activation has long been associated with symptoms of depression and has been shown to upregulate the expression of ID0. The presence of additional ID0 directs more tryptophan down the kynurenine pathway, leaving less available for synthesis of serotonin and its metabolites. Kynurenine can be metabolized through a series of enzymes to quinolinic acid, a potent N-methyl-D-aspartate receptor agonist with demonstrated neurotoxic effects. We tested the hypothesis that ID0 plays a role in outcome of treatment with the selective serotonin reuptake inhibitor, citalopram. Patients consisted of 1953 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). Genotypes corresponding to 94 single nucleotide polymorphisms (SNPs) in the genes ID01 and ID02, which encode ID0 and ID02, were extracted from a larger genome-wide set and analyzed using single marker tests to look for association with previously defined response, remission and QIDS-C score change phenotypes, with adequate correction for racial stratification and multiple testing. One SNP, rs2929115, showed evidence of association with citalopram response (OR = 0.64, p = 0.0005) after experiment-wide correction for multiple testing. Another closely associated marker, rs2929116 (OR = 0.64, p = 0.0006) had an experiment-wide significant result. Both implicated SNPs are located between 26 kb and 28 kb downstream of ID02. We conclude that common genetic variation in ID01 and ID02 may play a role in antidepressant treatment outcome. These results are modest in a genome-wide context and need to be replicated in an independent sample.