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Background: Depression is common in asthma and is associated with poor outcomes. However, antidepressant therapy in depressed patients with asthma has been the topic of little research., Objective: This study examined the impact of antidepressant treatment with escitalopram versus placebo on the Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self Report (IDS-SR), Asthma Control Questionnaire (ACQ), and oral corticosteroid use in patients with asthma and major depressive disorder (MDD)., Methods: Single-site 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of escitalopram (10 mg/d) was conducted in 139 outpatients with asthma and MDD. Randomization was stratified by oral corticosteroid use (≥3 bursts in past 12 months, yes or no) and baseline depressive symptom severity (HRSD score ≥ 20) (higher severity, n = 42) versus less than 3 bursts, HRSD score less than 20, or both (lower severity, n = 97). The primary data analysis was conducted using hierarchical linear modeling Version 7.01 on the higher and lower severity samples and post hoc was conducted on the combined sample., Results: Among the higher severity completers (n = 21), a significant reduction in the ACQ score (P = .04) and oral corticosteroid use (P = .04) was observed with escitalopram. In the combined sample, no significant differences were observed, but a trend toward greater reduction in the IDS-SR score was observed with escitalopram (P = .07). Side effects were comparable across groups., Conclusions: The findings suggest that patients with more severe asthma and depression symptomatology may have a positive response, in terms of both asthma and depressive symptom reduction, to antidepressant treatment., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)