Backgrounds: Antidepressants are widely used to treat major depressive disorder. First-line treatments with antidepressants are only successful in one-third of patients; however, evidence from randomized controlled trials on second-line treatments is limited. Moreover, recently acceptability is suggested to be a good indicator of overall treatment success. Methods: This is a multi-center two-arm, three-phased randomized controlled trial performed in Japan from December 2013 to March 2017 comparing the acceptability of escitalopram and duloxetine as a second-line drug. Patients, who failed to respond to antidepressants such as sertraline, paroxetine, fluvoxamine, milnacipran or mirtazapine for at least 3 weeks, were randomized to either escitalopram (Group A) or duloxetine (Group B) in Step 1 (8 weeks). In Step 2 (8 weeks), the drug was switched to the other if the first drug failed. The discontinuation rate at the end of Step 1 was the primary endpoint and non-inferiority of escitalopram vs duloxetine was tested. In addition, change in clinical measures from baseline were also assessed at the end of Step 1, 2 and up to 52 weeks. Results: At the end of Step 1, Group A (n = 82) was significantly superior to Group B (n = 78) in discontinuation rate (4.9% to 19.2%, P = 0.007). The change in clinical indices from baseline were not different between the groups at either timepoint. Limitations: As the major reason for discontinuation in Group B was the “withdrawal of consent” the concrete reason could not be verified. Conclusions: As a second-line treatment drug, escitalopram was suggested to be non-inferior to duloxetine in acceptability. Trial registration: UMIN[sbnd]CTR(UMIN000012367), registered on December 1st, 2013 and last updated on April 4th, 2017.
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