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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200951,283,\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200910,556, and\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009649 respectively). We examined 9 TRD definitions that varied along two axes: the minimum number of switches required (1+, 2\u2009+\u2009or 3\u2009+\u2009switches), 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\u2009+\u2009switches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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\u2009+\u2009switches) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TRD is underrepresented in consented cohort studies. A definition of TRD that includes 2\u2009+\u2009antidepressant switches or augmented antidepressant treatment as indicators balances sample size with depression severity, while incorporating features from real-world treatment journeys.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12888-026-08085-y","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:15:55Z","timestamp":1777029355000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Treatment resistant depression in electronic health records: definitions matter"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7242-0456","authenticated-orcid":false,"given":"Matthew H.","family":"Iveson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-9581","authenticated-orcid":false,"given":"Emily L.","family":"Ball","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3219-8942","authenticated-orcid":false,"given":"Chris Wai Hang","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7649-6251","authenticated-orcid":false,"given":"Mat\u00fa\u0161","family":"Falis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-8476","authenticated-orcid":false,"given":"Cathryn M.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4505-8869","authenticated-orcid":false,"given":"Heather C.","family":"Whalley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"issue":"3","key":"8085_CR1","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.cell.2024.12.002","volume":"188","author":"MJ Adams","year":"2025","unstructured":"Adams MJ, Streit F, Meng X, Awasthi S, Adey BN, Choi KW, Chundru VK, Coleman JRI, Ferwerda B, Foo JC, Gerring ZF, Giannakopoulou O, Gupta P, Hall ASM, Harder A, Howard DM, H\u00fcbel C, Kwong ASF, Levey DF, McIntosh AM. 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Article 2.","DOI":"10.1038\/s41397-019-0067-3"}],"container-title":["BMC Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12888-026-08085-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12888-026-08085-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12888-026-08085-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:40:30Z","timestamp":1781649630000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12888-026-08085-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,24]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8085"],"URL":"https:\/\/doi.org\/10.1186\/s12888-026-08085-y","relation":{},"ISSN":["1471-244X"],"issn-type":[{"value":"1471-244X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,24]]},"assertion":[{"value":"16 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was submitted to and approved by the Edinburgh Medical School Research Ethics Committee at The University of Edinburgh (23-EMREC-035) and by the DataLoch generic Research Ethics Committee (22\/NN\/0093). This study was conducted with human data in compliance with the Declaration of Helsinki and in accordance with relevant guidelines and regulations. For DataLoch, de-identified data was accessed and analysed by accredited researchers within a Trusted Research Environment according to DataLoch protocol and under UK GDPR article 6(1)(e): a task carried out in the public interest. For UK Biobank and Generation Scotland, individuals consented to participating in the cohort studies, and to sharing their data for research projects approved by the respective Access Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"CML sits on the Scientific Advisory Board of Myriad Neuroscience.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"453"}}