Polygenic and familial contributions to antidepressant continuation, switching, discontinuation and augmentation in the All of Us and Pharmlines cohorts

Predicting antidepressant response remains a major challenge, and it is unclear whether reported polygenic associations reflect drug-specific non-response or a broader propensity for treatment modification. We analysed participants with at least one antidepressant monotherapy episode of [≥]28 days in the All of Us (AoU; n=98,357) and Pharmlines (Lifelines linked to IADB.nl; n=12,884) cohorts, comparing continuation with switching, discontinuation and augmentation (atypical antipsychotic or lithium) in relation to polygenic scores (PGS). Among individuals with recorded major depressive disorder, switching, but not discontinuation, was associated with anxiety, higher depression symptom count and stress-related measures in both cohorts. Depression PGS was associated with switching in AoU (OR=1.16 per SD, 95% CI 1.12-1.20), with a concordant nominally significant estimate in Pharmlines (OR=1.11, 1.01-1.22). In AoU, depression PGS increased progressively from continuation to switching to augmentation (per-step OR=1.18, 1.15-1.21), whereas schizophrenia and bipolar disorder PGS were selectively associated with augmentation. No PGS showed drug-class-specific associations with switching. Familial aggregation in Pharmlines was detectable for continuation, including SSRI and SNRI continuation, but not for switching or discontinuation. Antidepressant switching therefore partly indexes depression severity rather than drug-specific non-response alone, whereas augmentation captures cross-disorder psychiatric complexity, and familial aggregation was confined to sustained, switch-free continuation.