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MDD may increase the risk for developing substance use disorders (SUD). The aim of this study was to investigate the risk for developing SUD among patients with TRD compared with other depressed patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Observational cohort study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Nation\u2010wide governmental health registers in Sweden.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>All patients aged 18\u201369\u00a0years with an MDD diagnosis in specialized health care who had received at least one antidepressant prescription during 2006\u201314 were identified. Patients with at least three treatment trials within a single depressive episode were classified with TRD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p>Patients with TRD were compared with the whole MDD cohort regarding risk for obtaining a SUD diagnosis or medication using survival analyses adjusted for socio\u2010demographics and comorbidities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>Of 121\u2009669 MDD patients, 13% were classified with TRD. Among the patients without any history of SUD, patients with TRD had a risk increase for any SUD both \u2264\u00a01 and &gt;\u00a01\u00a0year after antidepressant initiation [&gt;\u00a01\u00a0year hazard ratio (HR)\u00a0=\u00a01.4; 95% confidence interval (CI)\u00a0=\u00a01.3\u20131.5]. Risks were elevated for the subcategories of opioid (HR\u00a0=\u00a01.9, 95% CI\u00a0=\u00a01.4\u20132.5) and sedative SUD (HR\u00a0=\u00a02.7, 95% CI\u00a0=\u00a02.2\u20133.2). Patients with a history of SUD had a risk increase for any SUD \u2264\u00a01\u00a0year after start of treatment (HR = 1.2, 95% CI = 1.1\u20131.4), and both \u2264\u00a01\u00a0year and &gt;\u00a01\u00a0year for sedative (&gt;\u00a01\u00a0year HR\u00a0=\u00a02.0, 95% CI\u00a0=\u00a01.3\u20133.0) and multiple substance SUD (HR\u00a0=\u00a01.9, 95% CI\u00a0=\u00a01.4\u20132.5).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Patients with treatment\u2010resistant depression may be at greater risk for substance use disorders compared with other patients with major depressive disorder. Patterns may differ for patients with and without a history of substance use disorders, and for different categories of substance use disorder.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.14596","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T06:05:00Z","timestamp":1554185100000},"page":"1274-1282","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Treatment\u2010resistant depression as risk factor for substance use disorders\u2014a nation\u2010wide register\u2010based cohort study"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-6144","authenticated-orcid":false,"given":"Philip","family":"Brenner","sequence":"first","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Brandt","sequence":"additional","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"Janssen Research and Development LLC  Titusville NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allitia","family":"DiBernardo","sequence":"additional","affiliation":[{"name":"Janssen Research and Development LLC  Titusville NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2198-8842","authenticated-orcid":false,"given":"Robert","family":"Bod\u00e9n","sequence":"additional","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Neuroscience, Psychiatry Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1372-4262","authenticated-orcid":false,"given":"Johan","family":"Reutfors","sequence":"additional","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders (DSM\u20105\u00ae). 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