Background and objectives: Quality of life and medication adherence worsen in untreated depressed individuals. Studies examining how vilazodone, escitalopram, and vortioxetine affect these factors are few and far between. Our study’s objectives were to determine the change in SF-36 at 12 weeks and the association between treatment outcome and medication adherence.Methods: This is an interim analysis of a randomized, open-label, three-arm ongoing study. The participants were evaluated at baseline, four, eight, and 12 weeks after being randomly assigned to take either vilazodone (20-40 mg/d), escitalopram (10-20 mg/d), or vortioxetine (5-20 mg/d). This study is registered with CTRI, 2022/07/043808.Results: Of 71 recruited participants, 49 (69%) completed the 12-week visit. The median scores of physical components of SF-36 for the three groups were 35.5, 35.0, and 35.0 at baseline (p=0.76) and 51.0, 49.5, and 53.0 (p<0.001) at 12 weeks respectively. Their corresponding median SF-36 scores for mental components were 43.0, 43.0, and 44.0 at baseline (p=0.34) and 66.0, 63.5, and 70.0 (p<0.001) at 12 weeks. The post hoc analysis yielded a significant difference (p<0.001) regarding SF-36 scores. MMAS-8 scores among the participants were similar (p=0.22) at 12 weeks. Higher medication adherence was associated with lesser depressive symptoms (r= -0.46, p=0.001).Conclusion: As per this interim analysis, vortioxetine substantially impacted the SF-36 scores, juxtaposed with vilazodone and escitalopram. The participants’ clinical improvements were reflected by their adherence levels. These effects need to be probed further.