Polygenic and familial contributions to antidepressant continuation, switching, discontinuation and augmentation in the All of Us and Pharmlines cohorts
- 1University of Oxford
Abstract
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.
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BibTeX
@misc{walker2026polygenic,
title = {{Polygenic and familial contributions to antidepressant continuation, switching, discontinuation and augmentation in the All of Us and Pharmlines cohorts}},
author = {A. Walker and X. Wang and J. Bos and T. Lin and F. Klont and I. Nolte and H. Snieder and R. Broekema and P. M. Visscher and A. K. Henders and C. Hartman and H. M. van Loo and M. Taquet and E. Hak and N. R. Wray},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.14.26360458},
url = {https://www.medrxiv.org/content/10.64898/2026.08.14.26360458v3},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Polygenic and familial contributions to antidepressant continuation, switching, discontinuation and augmentation in the All of Us and Pharmlines cohorts
AU - A. Walker
AU - X. Wang
AU - J. Bos
AU - T. Lin
AU - F. Klont
AU - I. Nolte
AU - H. Snieder
AU - R. Broekema
AU - P. M. Visscher
AU - A. K. Henders
AU - C. Hartman
AU - H. M. van Loo
AU - M. Taquet
AU - E. Hak
AU - N. R. Wray
PY - 2026
DA - 2026/08/14
PB - medRxiv
DO - 10.64898/2026.08.14.26360458
UR - https://www.medrxiv.org/content/10.64898/2026.08.14.26360458v3
AB - 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.
ER -