Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics

C. W. H. Lo; A. C. Gillett; M. H. Iveson; M. Kamp; C. Fabbri; W. L. E. Wong; D. Handley; O. Pain; E. Vassos; N. R. Wray; H. C. Whalley; D. Li; A. H. Young; A. M. McIntosh; null AMBER Research Team; Cathryn M Lewis

doi:10.1101/2024.11.09.24316987

Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics

C. W. H. Lo, A. C. Gillett, M. H. Iveson, M. Kamp, C. Fabbri, W. L. E. Wong, D. Handley, O. Pain, E. Vassos, N. R. Wray, H. C. Whalley, D. Li, A. H. Young, A. M. McIntosh, AMBER Research Team, Cathryn M Lewis^*

^*Corresponding author for this work

Research output: Working paper/Preprint › Preprint

Abstract

BackgroundSelective 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 non-responders. MethodsIn UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a [≤] 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with [≥] 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. ResultsIn UKB, 5,133 (13.2%) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days (IQR: 17-49). Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree: 0.73 [0.67-0.79], compared to no qualifications) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p=0.007). MDD PGS and family history of depression were not significantly associated with switching. Using GCTB, the heritability of SSRI switching was approximately 4% (SE: 0.016) on the observed scale. ConclusionThis study identified SSRI switching as a proxy of non-response, scalable across biobanks with EHR, capturing demographic and genetics of treatment non-response, and independent of MDD genetics.

Original language	English
DOIs	https://doi.org/10.1101/2024.11.09.24316987
Publication status	Published - 2025

Keywords

psychiatry and clinical psychology

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Lo, C. W. H., Gillett, A. C., Iveson, M. H., Kamp, M., Fabbri, C., Wong, W. L. E., Handley, D., Pain, O., Vassos, E., Wray, N. R., Whalley, H. C., Li, D., Young, A. H., McIntosh, A. M., AMBER Research Team, & Lewis, C. M. (2025). Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics. https://doi.org/10.1101/2024.11.09.24316987

@techreport{4195ed58cf2c445697bff8072910b352,

title = "Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics",

abstract = "BackgroundSelective 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 non-responders. MethodsIn UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a [≤] 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with [≥] 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. ResultsIn UKB, 5,133 (13.2%) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days (IQR: 17-49). Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree: 0.73 [0.67-0.79], compared to no qualifications) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p=0.007). MDD PGS and family history of depression were not significantly associated with switching. Using GCTB, the heritability of SSRI switching was approximately 4% (SE: 0.016) on the observed scale. ConclusionThis study identified SSRI switching as a proxy of non-response, scalable across biobanks with EHR, capturing demographic and genetics of treatment non-response, and independent of MDD genetics.",

keywords = "psychiatry and clinical psychology",

author = "Lo, {C. W. H.} and Gillett, {A. C.} and Iveson, {M. H.} and M. Kamp and C. Fabbri and Wong, {W. L. E.} and D. Handley and O. Pain and E. Vassos and Wray, {N. R.} and Whalley, {H. C.} and D. Li and Young, {A. H.} and McIntosh, {A. M.} and {AMBER Research Team} and Lewis, {Cathryn M}",

year = "2025",

doi = "10.1101/2024.11.09.24316987",

language = "English",

type = "WorkingPaper",

}

Lo, CWH , Gillett, AC, Iveson, MH, Kamp, M , Fabbri, C , Wong, WLE , Handley, D , Pain, O , Vassos, E, Wray, NR, Whalley, HC, Li, D , Young, AH, McIntosh, AM, AMBER Research Team, & Lewis, CM 2025 'Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics'. https://doi.org/10.1101/2024.11.09.24316987

TY - UNPB

T1 - Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics

AU - Lo, C. W. H.

AU - Gillett, A. C.

AU - Iveson, M. H.

AU - Kamp, M.

AU - Fabbri, C.

AU - Wong, W. L. E.

AU - Handley, D.

AU - Pain, O.

AU - Vassos, E.

AU - Wray, N. R.

AU - Whalley, H. C.

AU - Li, D.

AU - Young, A. H.

AU - McIntosh, A. M.

AU - AMBER Research Team, null

AU - Lewis, Cathryn M

PY - 2025

Y1 - 2025

N2 - BackgroundSelective 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 non-responders. MethodsIn UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a [≤] 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with [≥] 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. ResultsIn UKB, 5,133 (13.2%) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days (IQR: 17-49). Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree: 0.73 [0.67-0.79], compared to no qualifications) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p=0.007). MDD PGS and family history of depression were not significantly associated with switching. Using GCTB, the heritability of SSRI switching was approximately 4% (SE: 0.016) on the observed scale. ConclusionThis study identified SSRI switching as a proxy of non-response, scalable across biobanks with EHR, capturing demographic and genetics of treatment non-response, and independent of MDD genetics.

AB - BackgroundSelective 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 non-responders. MethodsIn UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a [≤] 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with [≥] 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. ResultsIn UKB, 5,133 (13.2%) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days (IQR: 17-49). Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree: 0.73 [0.67-0.79], compared to no qualifications) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p=0.007). MDD PGS and family history of depression were not significantly associated with switching. Using GCTB, the heritability of SSRI switching was approximately 4% (SE: 0.016) on the observed scale. ConclusionThis study identified SSRI switching as a proxy of non-response, scalable across biobanks with EHR, capturing demographic and genetics of treatment non-response, and independent of MDD genetics.

KW - psychiatry and clinical psychology

U2 - 10.1101/2024.11.09.24316987

DO - 10.1101/2024.11.09.24316987

M3 - Preprint

BT - Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics

ER -

Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics

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