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  • This meta-analysis was performed according to the protocol provided as supporting material(S1 File), and was reported as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17](S2 File). Two review authors (Xinyuan Li, Lijun Zhu) independently searched the PubMed, Embase, Web of Science, Cochrane Center Register of Controlled Trials (CENTRAL), and ClinicalTrials databases from inception to October 4, 2017 using the search terms (duloxetine OR LY248686 OR cymbalta) AND (generalized anxiety disorder OR GAD).The detailed search strategy was available (S3 File). Searches were limited to RCTs and publications in the English language. Manual searches of the reference lists for all relevant articles were conducted, and corresponding authors of some trials were contacted for missing information. The search was updated on November 10, 2017 using the same strategy. Inclusion criteria were: (1) population: ≥18 years of age with a diagnosis of GAD according to the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [18]; (2) study design: placebo-controlled RCTs; (3) intervention: duloxetine or duloxetine plus other antipsychotics for<6 months; (4) outcomes: efficacy and tolerability outcomes. Trials were excluded if they included patients with: (1) DSM-IV diagnosis of major depressive disorder, bipolar disorder, or other psychotic disorders within the past 6 months; (2) use of any neuroleptic, antidepressant, or anxiolytic agent in the two weeks before data collection at baseline; (3) history of alcohol or any psychoactive substance abuse or dependence (as defined by DSM-IV) within the past 6 months; (4) risk of suicide; (5) previous treatment with duloxetine before randomization. Trials were also excluded if they did not report HAM-A psychic and somatic anxiety factor scores. Two review authors (Xinyuan Li, Lijun Zhu) independently assessed eligible trials. The full text of potentially relevant trials was examined and the following data were extracted: first author’s name, year of publication, study design, patient population, sample, age, sex distribution, intervention, treatment duration, and efficacy and tolerability outcomes using the last-observation-carried-forward (LOCF) approach. Disagreements were resolved by discussion with a third review author until consensus was reached. The primary efficacy outcome was mean change in the Hospital Anxiety and Depression Scale(HADS) anxiety subscale score from baseline to endpoint. The key secondary efficacy outcomes were mean changes in HAM-A psychic and somatic anxiety factor scores. Other secondary efficacy outcomes were response and remission rates. The response was defined as ≥50% reduction from baseline in the HAM-A total score and remission was defined as HAM-A total score ≤7 at endpoint. Tolerability outcomes were discontinuation rate due to AEs and commonly reported TEAEs including nausea, constipation, dry mouth, dizziness, and somnolence. Two review authors (Xinyuan Li, Lijun Zhu) independently assessed the risk of bias in included trials using the Cochrane Collaboration’s Risk of Bias Tool [19]. Reviewers examined seven domains including: random sequence generation, allocation concealment, blinding of outcome assessment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other bias. Risk of bias was categorized as low, high, or unclear. Disagreements about quality assessment were resolved by discussion with a third review author until consensus was reached. Statistical analysis was performed using Review Manager 5.3 (Cochrane Collaboration, London, UK). All analyses were conducted on the intent-to-treat (ITT) populations. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous variables, and odds ratios (ORs) with 95% CIs were calculated for dichotomous variables. A random-effects model was used to pool studies with substantial heterogeneity, as determined by the chi-squared test (P<0.05) and the inconsistency index (I2 ≥ 50%) [20–21]. Publication bias was assessed with funnel plots and the Begg’s/Egger’s test[22–23] using Stata 12.0 software. We also conducted sensitivity analyses to evaluate the stability of the outcomes. The significance of the pooled estimates was determined by the Z statistic; statistical significance was set at P<0.05[24].
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