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Objective To assess the effect of antidepressants on functional post-stroke recovery, we conducted a retrospective analysis among acute ischemic stroke patients with a subgroup analysis of severe stroke cases, assessing outcomes through 18 months. Methods A retrospectively gathered ischemic stroke population was obtained from an institutional database. Grouping was via intention-to-treat with antidepressant use post-stroke or lack thereof. Patients with severe stroke (NIHSS ≥ 21) were further analyzed independently. The primary and secondary outcomes were modified Rankin scale (mRS) and survival over 18 months, respectively. Patient demographics and NIHSS were obtained. Data were analyzed in R using adjusted logarithmic-multivariate models. Adjusted Cox proportional hazards models were used to estimate associations between survival and antidepressants. Results Eight-hundred six patients (52 severe strokes) received antidepressants post-stroke while 948 (56 severe) did not. The antidepressant group was more female (56% to 43.5%) and had significantly better survival rates (88% vs. 79%, HR 0.62, p < 0.01) but not mRS scores (2.13 vs 2.24, p = 0.262) by the end of the study period. Among severe stroke cases, those receiving antidepressants showed better survival rates (79% vs. 60%, HR 0.36, p=0.026) and most recent mRS score (3.9 vs 5, p < 0.01). The analysis controlling for demographics variables retained significance. Conclusion Antidepressant use post-stroke may improve functional outcomes in patients suffering from severe stroke and may decrease all-cause mortality for strokes of any severity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Heiberger et al.)