Abstract 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 non-responders. Methods In 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. Results In UKB, 5,133 (13.2 %) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days. Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree compared to no qualifications: 0.727 [0.666-0.794]) 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. The heritability (h2) of SSRI switching was approximately 4% on the observed scale. Conclusion This study identified SSRI switching as a proxy of drug non-response, scalable across biobanks, capturing demographic and genetics of treatment non-response, and independent of the genetics of MDD.

CL sits on the Scientific Advisory Board for Myriad Neuroscience and has received consultancy fees from UCB. OP provides consultancy services for UCB. AHY is the editor of Journal of Psychopharmacology and the Deputy Editor of BJPsych Open. AHY received paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Neurocentrx. He is the Principal Investigator in the Restore-Life VNS registry study funded by LivaNova, the Principal Investigator on ESKETINTRD3004: 'An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.', Principal Investigator on 'The Effects of Psilocybin on Cognitive Function in Healthy Participants' and 'The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)' studies, including:'A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy.', 'An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD).' , 'A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy.', and ' A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR.' AHY is also the UK Chief Investigator for Compass COMP006 & COMP007 studies, and Novartis MDD study MIJ821A12201. He has received grant fundings (past and present) from the following organisations: NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020. AHY has no shareholdings in pharmaceutical companies. All other authors have no competing interests to disclose.

This research was funded by Wellcome Mental Health Award (226770/Z/22/Z) and part-funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). GS:SFHS was funded by a grant from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award 'STratifying Resilience and Depression Longitudinally' Reference 104036/Z/14/Z). CF was partly supported by #NEXTGENERATIONEU (NGEU), funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). OP is supported by a Sir Henry Wellcome Postdoctoral Fellowship [222811/Z/21/Z]. MHI is supported by the HDR UK DATAMIND hub, which is funded by the UK Research and Innovation grant MR/W014386/1, by the Wellcome Trust (220857/Z/20/Z; 226770/Z/22/Z, 104036/Z/14/Z; 216767/Z/19/Z) and by a Research Data Scotland Accelerator Award (RAS-24-2). AHY is funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UK Biobank has research ethics approval from the North West Multi-center Research Ethics Committee (MREC; approval number 11/NW/0382) covering the United Kingdom. This current study has received approval to be conducted using the UK Biobank resource, under the project application number 82087. Ethical guidelines have been followed during analysis of this study.

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The UK Biobank data was accessed via project 82087. Please visit https://www.ukbiobank.ac.uk/enable-your-research for access. Generation Scotland data are available on reasonable request. Researchers may request access to Generation Scotland data through https://www.ed.ac.uk/generation-scotland/for-researchers.