Antidepressant Switching as a Proxy Phenotype for Drug Nonresponse: Investigating Clinical, Demographic, and Genetic Characteristics
Background: Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Biological Psychiatry Global Open Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667174325000564 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Background: Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI nonresponders. Methods: In the UK Biobank (UKB) (N = 38,813) and Generation Scotland (N = 1777) datasets, SSRI switching was defined using ≤90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Nonswitchers were participants with ≥3 consecutive prescriptions for an SSRI. In the UKB, clinical, demographic, and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. Results: In the UKB, 5133 (13.2%) SSRI switchers and 33,680 nonswitchers were defined. The mean time to switch was 28 days (interquartile range, 17–49). Switching patterns were consistent across the UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (odds ratio [OR] [95% CI] for a university degree, 0.73 [0.67–0.79] compared with no qualifications) were associated with lower levels of switching. PGSs for nonremission, based on clinical studies, were associated with increased risk of switching (OR, 1.07 [1.02–1.12], p = .007). MDD PGSs and family history of depression were not significantly associated with switching. Using genome-wide complex trait Bayesian, the single nucleotide polymorphism–based heritability was approximately 4% (SE 0.016) on the observed scale. Conclusions: This study identified SSRI switching as a proxy for nonresponse, scalable across biobanks with electronic health records, capturing demographics and genetics of treatment nonresponse, and independent of MDD genetics. |
|---|---|
| ISSN: | 2667-1743 |