Cohort Profile: Investigating Antidepressant Response within Generation Scotland

Abstract

BackgroundThe Antidepressant Medications: Biology, Exposure & Response (AMBER) research programme was established to investigate the biological mechanisms underlying antidepressant action and variability in treatment response. Generation Scotland holds detailed genomic, clinical, and health information with recontacting consent, making this cohort ideal for investigating these aims. MethodsWe deployed a questionnaire, developed with input from a Lived Experience panel, to the Generation Scotland cohort to gather data on their depressive symptoms, medication history, efficacy, and side effects to develop clinically meaningful phenotypes of antidepressant response. Invitations were sent to 15,117 Generation Scotland participants who were 18 years or older and consented to be recontacted. Between July and November 2025, 1,180 participants with a history of antidepressant treatment for depression completed the questionnaire. ResultsThe sample was predominantly female (78.1%), self-identified as White (98.6%), and older (median age 57 years) than the wider Generation Scotland cohort (median 49 years) and Scottish population (median 41.3 years). Participants reported heterogeneous depressive symptom profiles spanning mood, anxiety, cognitive, sleep, behavioural, and physical domains. One-third of participants (31.1%) had taken three or more different antidepressants. Selective serotonin reuptake inhibitors (SSRIs) were the most common class (89.1%). Using self-reported treatment duration, discontinuation patterns, and efficacy, we developed a stringent classification system to capture treatment response extremes, where 23.8% were classified as responders and 1.5% as non-responders, with the majority unclassified. ConclusionsQuestionnaire data will be linked with electronic health records to validate antidepressant response classifications. Following validation, 25 responders and 25 non-responders will provide biological samples for DNA methylation profiling and generation of patient-derived cell lines. These models will be exposed to SSRIs to identify gene expression signatures and biological pathways distinguishing treatment response, integrating with genomic and clinical data across the AMBER project. These findings will provide a valuable resource for future antidepressant response research. Plain Language SummaryDepression is a common mental health condition affecting millions of people worldwide. Antidepressant medications are the primary medication treatment, but response is highly variable with only about one-third of individuals achieving full symptom remission after their first medication trial. We dont fully understand why some people respond well while others dont. To help answer this question, the Antidepressant Medications: Biology, Exposure & Response (AMBER) research programme was established. This study utilised the Generation Scotland cohort, a large health study in Scotland. Between July and November 2025, we invited 15,117 Generation Scotland participants to complete a detailed questionnaire about their experiences with antidepressant medications. A total of 1,180 participants answered detailed questions about their depression symptoms, which medications they tried, how long they were on a medication, how well the medications worked, and what side effects they experienced. We found that peoples experiences with depression and antidepressants varied considerably. About one-third had tried three or more different antidepressants. Using strict criteria based on treatment duration, effectiveness ratings, and medication changes, we identified 281 people (24%) who responded very well to SSRIs (the most common type of antidepressant) and 18 people (1.5%) who did not respond despite trying multiple SSRIs. A key limitation is that all information was self-reported, so we will validate findings by linking questionnaire responses with medical records. In the future, we will collect blood samples from some participants to study the biological differences between responders and non-responders. This research will help us better understand why antidepressants work for some people but not others, which could lead to more personalised treatment approaches for depression.