Early antidepressant efficacy modulation by glutamatergic gene variants in the STAR*D

The glutamatergic system has been suggested as a modulator of rapid antidepressant response. Thus, 44 glutamatergic genes were selected according to the literature and investigated in 1541 major depressive patients from the STAR*D genome wide dataset. Outcomes of interest were early response (2nd week) and late response (from the 4th to the 14th week) compared to non-response and stability of response through the STAR*D level 1. A complete agglomerative clustering, based on pairwise identity-by-state (IBS) matrix, was applied in order to control for genetic admixture. A chi-square test was employed as exploratory analysis and a logistic regression was employed to corroborate SNPs associated to the outcomes at p<0.001. Covariates were selected accordingly to their impact on phenotypes. A Bonferroni correction was applied. PLINK served for the analysis. About 1995 SNPs were available after quality control. Our results suggested that the rs1083801 within the GRM7 (glutamate receptor, metabotropic 7) gene was associated to early response under a recessive model (GG genotype observed in 14.34% of early responders vs 5.25% of late responders, OR=0.33, 95% CI=0.21-0.54, p=6.41e-06. GG genotype observed in 5.34% of non-responders, OR=0.33, 95% CI=0.20-0.56, p=4.07e-05). The result was confirmed in the white non-Hispanic group (GG genotype observed in 17.46% of early responders vs 5.81% of the rest of the sample, OR=0.29, 95% CI=0.18-0.46, p=2.04e-07). No marker predicted the stability of response. Glutamatergic genes may be useful markers of early antidepressant efficacy. This result may be relevant in further understanding the pathophysiology of the drug induced antidepressant effect.