Independent Replication and Drug-specificity of an Antidepressant Response Polygenic Risk Score

Abstract

We here examine associations of a recently published polygenic risk score of antidepressant response (PRS-AR) with antidepressant treatment outcomes (remission and depression score change) in an independent clinical trial. We not only replicate the PRS-AR for escitalopram, but also find antidepressant interaction effects, suggesting drug-specificity of PRS-AR. We therefore also tested the utility of this PRS-AR to stratify between antidepressants and demonstrate a 14% increase in remission rate (from 43.6% to 49.7%), relative to the randomized remission rate.

Decoding complexity

“…Pharmacogenomic studies have focused on genetic biomarkers of antidepressant treatment response in MDD, resulting in a PRS (or PGS) of antidepressant response (PRS-AR) (Pain et al 2020). The usefulness of PRS-AR was validated by Lin et al in an independent dataset that was not part of the initial GWAS (Lin et al 2022). In the first two studies included in this thesis (chapter 2 and 3), we have used the PRS-AR as an intermediate step for the selection of brain networks that likely have a biological basis.…”

“…We used PRS-AR (Pain et al 2020) to guide the selection of functional brain networks for subsequent response prediction, thus combining genetics with neurophysiology approaches. The usefulness of PRS-AR was recently validated in an independent dataset of pharmacotherapy response, that was not included in the original GWAS (Lin et al 2022). Here, we show one functional network that is significantly associated with polygenic liability to antidepressant response in men.…”