Background <p>Many people with depression do not respond well to the first antidepressant prescribed. Treatment Resistant Depression (TRD) refers to depression which does not respond to multiple subsequent antidepressant treatments. Identifying TRD in routinely-collected health records is challenging due to limited response-related data. Previous studies have used definitions based on the number of antidepressant switches observed. However, these do not account for other features clinically indicative of treatment resistance, such as augmentation of antidepressants with lithium or antipsychotics and switches between antidepressant classes. This study examined definitions of TRD and their impact on the resulting sample across three cohorts.</p> Methods <p>Across the DataLoch, UK Biobank, and Generation Scotland cohorts, we identified cases of depression from primary and secondary care record codes and extracted antidepressant treatment patterns from dispensing/prescribing records (<i>N</i> = 51,283, <i>N</i> = 10,556, and <i>N</i> = 649 respectively). We examined 9 TRD definitions that varied along two axes: the minimum number of switches required (1+, 2 + or 3 + switches), and the inclusion of other clinical features (augmentation and one or more between-class switches) as alternative routes to TRD. We contrasted sample size and characteristics between definitions, and examined factors associated with inclusion versus a reference definition of 2 + switches.</p> Results <p>The reference TRD definition included 10% of depression cases in the routine data collection, but substantially fewer cases (4%) in consented cohorts. More inclusive definitions that required fewer switches or included a between-class switch classified more individuals as TRD, but resulted in a proportionally older, more deprived sample with fewer depression-related health record codes, older age of depression onset, lower symptom severity, and greater use of first-line antidepressants. Requiring more switches (3 + switches) classified fewer individuals as TRD, but resulted in a proportionally younger sample, with more depression-related health record codes, younger age of depression onset, and greater use of antidepressants associated with later in the treatment line (e.g., Tricyclics). Definitions including augmentations resulted in a small increase in sample size without notable change in sample characteristics.</p> Conclusions <p>TRD is underrepresented in consented cohort studies. A definition of TRD that includes 2 + antidepressant switches or augmented antidepressant treatment as indicators balances sample size with depression severity, while incorporating features from real-world treatment journeys.</p> Clinical trial number <p>Not applicable.</p>