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 depression, 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 showed the strongest association with being in a higher treatment-intensity category (continuation < switching < augmentation; ordinal OR=1.18 per SD, 95% CI 1.15–1.21), whereas schizophrenia and bipolar disorder PGS were selectively associated with augmentation. There was no evidence that PGS associations with switching differed across antidepressant classes. Familial aggregation in Pharmlines was detectable for continuation, including SSRI and SNRI continuation, but not for switching or discontinuation. Antidepressant switching was associated with greater depression polygenic liability and clinical severity, with little evidence that PGS associations differed across antidepressant classes. Augmentation was additionally associated with bipolar disorder and schizophrenia polygenic liability, while familial aggregation was confined to switch-free continuation.