Association of neurotransmitter-based polygenic scores with antidepressant treatment outcomes in patients with major depressive disorder

Biologically informed polygenic scores (PGSs) may help interpret genetic associations with treatment outcomes. Here, we computed neurotransmitter-based PGSs ( NeuroPGSs ) for patients with major depressive disorder (MDD) and assessed their association with SSRI treatment outcomes. By targeting genetic variants involved in key neurotransmission pathways, we developed PGSs for serotonergic (5228), gamma-aminobutyric acid (GABA, 4103), dopaminergic (7061), and glutamatergic (5690) variants. We leveraged data from two cohorts of patients who received SSRIs for at least 4 weeks: the International SSRI Pharmacogenomics Consortium (ISPC) and the Pharmacogenomics Research Network Antidepressants Medication Pharmacogenomics Study (PGRN-AMPS). Treatment response was defined as ≥50% reduction from baseline depression symptoms, measured using 17-item Hamilton Rating Scale for Depression (HRSD-17) in ISPC and 16-item Quick Inventory of Depressive Symptomatology (QIDS-C16) in PGRN-AMPS. Remission was defined as HRSD-17 ≤7 (ISPC) or QIDS-C16≤5 (PGRN-AMPS). The association between each NeuroPGS and antidepressant response or remission was evaluated using logistic regression models, adjusting for age, sex and five genetic principal components, with statistical significance determined at Benjamini–Hochberg-adjusted p <0.05. The GABAergic-based PGS was associated with SSRI response (aOR per SD = 1.45, 95%CI: 1.14-1.85). Patients with the highest GABAergic PGS (10 ^th decile) had 2.59-fold higher odds of response (95%CI: 1.46-4.60) compared to those with the lowest decile (1 ^st decile). These exploratory findings support further evaluation of NeuroPGSs ; independent replication and assessment of incremental predictive value are needed before clinical application.