We searched Pub Med, Cochrane library, Scopus, CRD, Central Register of Controlled Trials to January 2015. Our searches will not be limited by language, publication status or setting. We also searched ClinicalTrials.gov, International depressive disorder Conference and the Anxiety Disorders and Depression Conference. For the reference lists of articles contact authors of included studies to acquire other data that may either be unpublished (Figure 1). Data collection, summary and analysis of the identification in this systematic review will be presented as a PRISMA [11] . Two review authors (Masoud. B, Meysam. B) will independently searched. First,

screening the titles and abstracts of RCTs, Secondly, (H.D, A.AS) review author will independently full text of all trials. Compared the contents of each review author’s list, and Conflicts were resolved by discussion.

Clinical trials testing the efficacy of Vortioxetine 20 mg for the short-term treatment (8 wks.) of major depressive disorder were eligible for inclusion. Included studies had to be RCTs comparing Vortioxetine 20 mg with placebo. Patients needed to meet the criteria for major depressive disorder used in the individual trials. Studies were excluded if the main outcome was prevention of relapse or if treatment outcomes based on rating scales of major depressive disorder were not available.

We collected data on participant characteristics, treatment details, study procedures, efficacy measures and Adverse Events (AEs). These data included, for example, group (treatment, placebo), size sample, age, sex, duration of treatment, baseline MADRS, doses and study location. Outcome data related to the characteristics of the individual trial and the reported results were extracted for each trial. For instance, the mean changes or reported numbers for Adverse Events were extracted from the individual study when appropriate. The efficacy measures were the mean change from baseline in on Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression Scale-Improvement (CGI-I), Sheehan Disability Scale (SDS) study [12] - [14] .

We will to assess the quality of studies, used Cochrane Collaboration “Risk of bias” assessment tool [15] , including Random sequence generation, Allocation concealment, Blinding of participants and personnel, Blinding of outcome assessment ,incomplete outcome data, Selective reporting and other bias (Figure 2).

The study quality was assessed with Jadad scores [16] . The Jadad score is an instrument used to assess the quality of randomized clinical trials (RCTs). It includes three items as follows: randomization, blindness and dropouts. The score standards and the results of our included studies are shown in Table 1, respectively. Were rated as providing good methodological quality based on a Jadad score of 1 - 5. So the total scores for all included articles indicated a high study quality.

In the review, we assessed values, Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression Scale-Improvement (CGI-I), Sheehan Disability Scale (SDS) and adverse effects randomized into the Vortioxetine 20 mg/day and placebo groups for each trial were statistically combined using the Mantel- Haenszel random effects model. The effects were expressed as Standard mean different ratios (SMD) with 95% confidence intervals (CIs) and P values. The incidence of adverse effects between the Vortioxetine 20 mg/day and placebo groups was also determined using the Mantel-Haenszel model, and the results were expressed as the Odds Ratio (ORs) with the 95% CI and P values. The heterogeneity across each effect size was evaluated with using the I² and Chi-squared tests statistic. This measure evaluates how much of the variance among studies can be attributed to the actual differences among the studies rather than to chance. A magnitude of considerable heterogeneity is usually I² = 75% - 100% [16] . A sensitivity analysis was performed to rule out the possibility that any single study strongly influenced the pooled effect. Publication bias was assessed by a funnel plot, Egger’s test [17] , and Begg’s rank correlation test [18] . All the statistical analyses were performed using Review Manager (Rev Man 5.3) software and Stata 12 software.

Overall, we found 4 articles met the inclusion criteria and were finally used for this meta-analysis (Table 2). This article consist Boulenger JP [19] , Mahableshwarkar AR [20] , Jacobsen PL [21] and trial no NCT01255787 [22] . A total of five studies with 1337 patients, 609 in the 20 mg/day Vortioxetine group and 728 patients in the placebo group. The standard mean different ratios (SMD) for Montgomery-Åsberg Depression Rating Scale (MADRS) with Vortioxetine 20 mg compared to placebo was −4.75 with 95% CI [−6.84, −2.65] and P value < 0.00001 and heterogeneity for MADRS scale was I² = 99%, The Standard mean different ratios (SMD) for Clinical Global Impression Scale-Improvement (CGI-I) was −4.34 with 95% CI [−6.41, −2.27] and P value < 0.00001 and heterogeneity for SMD was I² = 99% and Standard mean different ratios (SMD) for Sheehan Disability Scale (SDS) was −2.62 with 95% CI [−3.99, −1.25] and P value < 0.00001 and heterogeneity for SDS was I² = 98% (Figure 3).

^aThe Montgomery-Åsberg Depression Rating Scale (MADRS) is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression); ^bVortioxetine.

MADRS:

Drug safety evaluation for symptoms that have been observed in studies for was meta-analysis. The most common side effects were diarrhea, dry mouth, dizziness, fatigue, headache and nausea.

Results the 20 mg/day Vortioxetine compared to placebo showed for diarrhea OR = 0.92 with 95% CI [0.46, 1.83], P value = 0.09, for dry mouth OR = 1.74 with 95% CI [1.07, 2.83], P value = 0.80, for dizziness OR = 1.62 with 95% CI [0.72, 3.66], P value = 0.05, for fatigue OR = 1.17 with 95% CI [0.34, 4.08], P value = 0.07, for headache OR = 1.28 with 95% CI [0.91, 1.79], P value = 0.60 and for nausea OR = 4.78 with 95% CI [3.43, 6.67], P value = 0.61 (Figure 4).

Sensitivity analysis not found that the pooled remission rate was significantly influenced when we excluded the study from .trial no NCT01255787.

Analysis for publication bias showed, no publication bias was observed for MADRS, CGI-I and SDS (Egger’s test: P = 0.006, P = 0.010, P = 0.105 respectively, and Begg’s test: P = 0.042, P = 0.174, P = 0.174, respectively). Results showed no publication bias was observed for Adverse Events contain Diarrhea, Dry mouth, Dizziness, Fatigue, Headache and Nausea in the included studies (Egger’s test: P = 0.823, P = 0.257, P =0.617, P = 0.149, P = 0.227, P = 0.205, P = 0.197 respectively and Begg’s test: P = 1.000, P = 0.174, P = 0.497, P = 0.174, P = 0.174, P = 0.174, respectively).

This study evaluated the efficacy, safety of Vortioxetine 20 mg/d compared with placebo treatment in patients with major depressive disorder. We identified four RCTs examining the efficacy of Vortioxetine 20 mg/d versus placebo for treatment major depressive disorder. The present meta-analysis demonstrated the superior efficacy of Vortioxetine compared with placebo for the treatment of major depressive disorder in terms of mean change MADRS scale (SMD = −4.75). Our results showed that the treatment of the Vortioxetine 20 mg/day group based on both depression rating SDS (SMD = −2.62) and CGI-H (SMD = −4.34) was greater than the placebo group. The decrease in depression symptoms seems too associated with 20 mg/d of Vortioxetine versus placebo. Vortioxetine 20 mg/d were statistically significantly superior to placebo in three scales. Efficacy has been replicated at the 20 m/g doses in adults, demonstrated efficacy in study Boulenger et al., Mahableshwarker et al., Jacobsen et al. and trial NCT01255787. In the studies Alvarez et al. [23] , Mahableshwarkar et al. [24] , Jain et al. [25] , Katona et al. [26] , and Henigsberg et al. [27] showed Vortioxetine efficacy. Improve symptoms in patient by major depressive disorder Obtained in these studies. Results of Adverse Events (AEs) showed a significant for dry mouth OR = 1.74 [1.07 - 2.83] and nausea OR = 4.78 [3.43 - 6.67]. But no significant differences were observed for the other four adverse effects. AEs discontinuation rates were generally low. It suggested that the negative results in previous double-blind, random-controlled studies may have been due to an inadequate sample size, which can be overcome by the meta-analytic method. These findings indicate that compared to placebo, 20 mg/d mg/day Vortioxetine significantly improved depressive symptoms in patients with major depressive disorder. In the randomized clinical analyzed, the common adverse effects of Vortioxetine include diarrhea, dizziness, dry mouth, nausea, headache and fatigue.

The limitations of this meta-analysis include the following: the inclusion of patients only during the acute phase, which did not enable us to analyze the long-term efficacy and safety of Vortioxetine in treating major depressive disorder. The included studies did not include data on the onset time of Vortioxetine’s efficacy, and thus, we did not compare the onset time between 20 mg/d Vortioxetine and placebo. All included trials were supported by the Takeda company, Ltd. All included studies did not include the efficacy and adverse effects based on sex; thus, we could not evaluate gender differences. Due to the limited number of the published articles, we did not analyze the efficacy and safety of different doses of Vortioxetine in the treatment of major depressive disorder. The small number of included studies and the relatively small sample size, which may influence the reliability of the results. However, depression is frequently associated with coronary heart diseases [28] , diabetes mellitus [29] , stroke [30] , pregnancy, and the postpartum period [31] . Thus, the use of Vortioxetine should also benefit the physical state of these patients. Due to the small number of trials in our meta-analysis, our results warrant additional studies to verify these findings. In the future, additional large-scale and well-designed Studies are needed to determine the optimal dose, the most appropriate treatment group, and the efficacy and safety of Vortioxetine combined with other antidepressants in treating depression [32] .