Polygenic Risk Score Analysis of Antidepressant Treatment Outcomes: A CAN-BIND-1 Study Report: Analyse des résultats du traitement antidépresseur à l’aide des scores de risque polygéniques : Rapport sur l’étude CAN-BIND-1

ObjectiveThe genetic architecture of antidepressant response is poorly understood. This study investigated whether polygenic risk scores (PRSs) for major psychiatric disorders and a personality trait (neuroticism) are associated with antidepressant treatment outcomes.MethodsWe analysed 148 participants with major depressive disorder (MDD) from the Canadian Biomarker Integration Network for Depression-1 (CAN-BIND-1) cohort. Participants initially received escitalopram (ESC) monotherapy for 8 weeks. Nonresponders at week 8 received augmentation with aripiprazole (ARI), while responders continued ESC until week 16. Primary outcomes were remission status and symptom improvement measured at weeks 8 and 16. At week 16, post-hoc stratified analyses were performed by treatment arm (ESC-only vs. ESC + ARI). Eleven PRSs derived from genome-wide association studies of psychiatric disorders (e.g., MDD and post-traumatic stress syndrome (PTSD)) and neuroticism, were analysed for associations with these outcomes using logistic and linear regression models.ResultsAt week 8, a higher PRS for PTSD was nominally associated with a lower probability of remission (odds ratio (OR) = 0.08 [0.014-0.42], empirical p-value = 0.017) and reduced symptom improvement (beta (standard error) = -29.15 (9.76), empirical p-value = 0.019). Similarly, a higher PRS for MDD was nominally associated with decreased remission probability (OR = 0.38 [0.18-0.78], empirical p-value = 0.044). However, none of the results survived multiple testing corrections. At week 16, the stratified analysis for the ESC-only group revealed that a higher PRS for MDD was associated with increased remission probability (empirical p-value = 0.034) and greater symptom improvement (empirical p-value = 0.02). In contrast, higher PRSs for schizophrenia (empirical p-value = 0.013) and attention-deficit hyperactivity disorder (empirical p-value = 0.032) were associated with lower symptom improvement. No significant associations were observed in the ESC + ARI group.ConclusionsThese findings suggest that PRSs may influence treatment outcomes, particularly in ESC monotherapy. Replication in larger studies is needed to validate these observations.