Major Depressive Disorder: Potential Biomarkers for Antidepressant Treatment

A study in Translational Psychiatry has identified two genetic variations — single nucleotide polymorphisms – that may predict response to antidepressant drugs in Korean patients suffering from major depressive disorder (MDD).

This isn’t the first study attempting to identify candidate genes related to antidepressant response, considered by many to be the “Holy Grail” of genetic research related to depression. Initial antidepressant treatments fail in at least one-third of patients, and there are currently no known biomarkers of treatment response. “Selecting candidate genes related to antidepressant response is difficult because of our limited knowledge of the underlying biology,” the study authors noted. “In addition, most pharmacogenetic studies that have focused on a few candidate genes (for example, serotonin transporter gene, SLC6A4) have shown results that lack sufficient predictive power to be useful in clinical practice…These failures underscore the heterogeneous phenotype and the complex nature of clinical depression.”

In the current study, the researchers conducted a genome-wide pharmacogenetic study in ethnically homogeneous patients, with careful quality control. The discovery phase was conducted in a single, experienced clinical research site. The resulting findings were then validated in an independent, ethnically identical sample.

The study involved a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in a sample of Korean patients with untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1).

Then, in a focused replication study of 230 SSRI-treated patients, two of the four SNP candidates were confirmed (Stage 2): rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. The AUTS2 gene has multiple known linkages to human psychological functions and neurobehavioral disorders, including autism and developmental delay, as well as significant associations with nicotine dependence, cannabis dependence, alcohol sensitivity, and antisocial personality.

Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10^-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset, and baseline severity.

“Similar to previous GWAS studies for antidepressant response, our study was a naturalistic one; therefore, it did not have a placebo-treated group,” the authors explained. “Further studies with placebo-treated groups or groups treated with non-pharmacological interventions will be helpful to clarify this issue.”

Limitations include small sample size as well as that the study design allowed for clinical judgment to enter into the choice of drug used for treatment, along with the fact that because the study participants were mostly elderly, the generalizability of the results to depressed patients in other age groups may be limited. “Further studies in a variety of ethnic populations will be required,” the researchers concluded.