Prediction of antidepressant side effects in the Genetic Link to Anxiety and Depression Study

Antidepressants are the most common treatment for moderate or severe depression. Side effects are crucial indicators for antidepressants, but their occurrence varies widely among individuals. In this study, we leveraged genetic and medical data from self-reported questionnaires in the Genetic Links to Anxiety and Depression (GLAD) study to build prediction models of side effects and subsequent discontinuation across three antidepressant classes (SSRI, SNRI, tricyclic antidepressant (TCA)) at the first and the last (most recent) year of prescription. We included 259 predictors spanning genetic, clinical, illness, demographic, and antidepressant information. Six prediction models were trained, and their performance was compared. The final dataset comprised 4,354 individuals taking SSRI in the first prescription and 3,414 taking SSRI, SNRI or TCA in the last year of prescription. In the first year, the best area under the receiver operating characteristic curve (AUROC) for predicting SSRI discontinuation and side effects were 0.65 and 0.60. In the last year of SSRI prescription, the highest AUROC reached 0.73 for discontinuation and 0.87 for side effects. Models for predicting discontinuation and side effects of SNRI and TCA showed comparable performance. The history of side effects and discontinuation of antidepressant use were the most influential predictors of the outcomes in the last year of prescription. When examining 30 common antidepressant side effect symptoms, most of them were differentially prevalent between antidepressant classes. Our findings suggested the feasibility of predicting antidepressant side effects using a self-reported questionnaire, particularly for the last prescription. These results could contribute valuable insights for the development of clinical decisions aimed at optimising treatment selection with enhanced tolerability but require replication in medical record linkage or prospective data. ### Competing Interest Statement Prof Breen has received honoraria, research or conference grants and consulting fees from Illumina, Otsuka, and COMPASS Pathfinder Ltd. Prof Hotopf is the principal investigator of the RADAR-CNS consortium, an IMI public private partnership, and as such receives research funding from Janssen, UCB, Biogen, Lundbeck and MSD. Prof McIntosh has received research support from Eli Lilly, Janssen, and the Sackler Foundation, and has also received speaker fees from Illumina and Janssen. ### Funding Statement This work was supported by the National Institute for Health and Care Research (NIHR) BioResource [RG94028, RG85445], NIHR Biomedical Research Centre [IS-BRC-1215-20018], HSC R&D Division, Public Health Agency [COM/5516/18], MRC Mental Health Data Pathfinder Award (MC\_PC\_17,217), and the National Centre for Mental Health funding through Health and Care Research Wales. Dr Hubel acknowledges funding from Lundbeckfonden (R276-2018-4581). Johan Kallberg Zvrskovec acknowledges funding from the National Institute for Health and Care Research (NIHR) Biomedical Research Centre and Guy's and St Thomas' NHS Foundation Trust. Prof McIntosh received funding from the Wellcome Trust (226770/Z/22/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Genetic Links to Anxiety and Depression (GLAD) Study received ethical approval from the London - Fulham Research Ethics Committee (REC reference: 18/LO/1218), while the NIHR BioResource obtained approval from the East of England - Cambridge Central Committee (REC reference: 17/EE/0025). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GLAD study data are available via a data request application to the NIHR BioResource (). [1]: http://ClinicalTrials.gov