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We conducted a population-based cohort study using seven linked administrative health databases from Newfoundland and Labrador, Canada. Adults (\u226518 years) with a first hospitalization for MDD between June 2017 and March 2023 and a post-discharge antidepressant prescription of \u226530 days were included. The primary outcome was reinitiation of antidepressant pharmacotherapy following a\u2009\u2265\u20096-month treatment gap. Antidepressant treatment groups were defined as SSRI monotherapy (reference), SNRI monotherapy, other monotherapy, two-medication combination therapy, and three or more medication combinations. Time-varying Cox regression models were used to assess associations with reinitiation risk, adjusted for age, sex, socioeconomic status (SES), and length of hospital stay. Sensitivity and exploratory age-stratified analyses were conducted. Among 2,734 patients, 61% reinitiated antidepressant treatment after a\u2009\u2265\u20096-month gap. SSRI monotherapy was the most common initial regimen (34.3%), followed by 2-medication combinations (18.1%). Combination therapy was associated with lower reinitiation risk compared to SSRIs: HR\u2009=\u20090.67 (95% CI: 0.50\u20130.90) for 2-medication combinations and HR\u2009=\u20090.49 (95% CI: 0.40\u20130.60) for 3\u2009+\u2009medication combinations. SNRI monotherapy conferred modest protection (HR\u2009=\u20090.84, 95% CI: 0.72\u20130.99). Age, sex, and SES were independently associated with reinitiation. Younger adults, males, and individuals in both high and low-income quintiles were at increased risk. Reinitiation of antidepressants after a\u2009\u2265\u20096-month gap was common following hospitalization for MDD. Combination therapy maybe associated with reduced reinitiation risk compared to SSRI monotherapy, with age-specific treatment effects, although residual confounding cannot be excluded. Further research, ideally RCTs, is needed before informing clinical decision-making.<\/jats:p>","DOI":"10.1371\/journal.pmen.0000427","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:32:31Z","timestamp":1774459951000},"page":"e0000427","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reinitiation of antidepressant pharmacotherapy among patients discharged from the hospital: A population-based cohort study"],"prefix":"10.1371","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4130-5962","authenticated-orcid":true,"given":"Waseem","family":"Abu-Ashour","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6891-8721","authenticated-orcid":true,"given":"John-Michael","family":"Gamble","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-5538","authenticated-orcid":true,"given":"John","family":"Hawboldt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0389-3038","authenticated-orcid":true,"given":"Joanna E. 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