CLEP_A_335584 1039..1049

s were not included. The methods and analysis of the present study were followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and prespecified and registered on the PROSPERO database (CRD42020152044). Data Extraction and Bias Risk Assessment During data extraction, publications describing the same trial were compiled into a single entry to prevent double counting patients. Extracted data included sample size, age, sex, disease diagnosis (bipolar type I or II), mood phase, intervention duration and protocols, and types and time points of the outcome assessments. Two independent reviewers (WY Chen and YC Cheng) performed both the screening and the data extraction, and any discrepancy between reviewers was resolved by a third independent reviewer. Bias risk assessment was conducted according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions. Outcome Selection and Network Development A feasibility assessment was performed to determine possible approaches for conducting NMA. Two approaches were considered: (1) Assessing studies evaluating the same cognitive test and (2) assessing studies evaluating the same cognitive domain, regardless of test. Although it is less prone to validity bias, we could not perform a meaningful NMA by using the first approach because of the large variety and seldom overlapping of cognitive tests used as endpoints among review studies. To overcome these problems, we used the second approach, in which the most commonly applied measurements together with other tests for each domain were evaluated. The priority of cognitive tests selected in each domain is summarized in Supplementary Table S1. Studies have suggested that episodes of acute depression or mania negatively affect cognitive function in patients with BD. Considering studies of patients with BD in euthymia with those of patients experiencing mood episodes was not appropriate. To avoid introducing bias into the effects of adjunct interventions, we analyzed studies of patients in the euthymic, depressive, or manic phase separately and provided NMA results for each domain by mood status. Statistical Analysis We performed NMA for each domain to simultaneously assess the effects of more than 2 treatments. A NMA synthesizes both direct and indirect evidence over an entire network of treatments within one analysis. Given the expected clinical and methodological heterogeneity among the studies, we used a random effects model but switched to using a fixed effects model if the number of included studies was insufficient to estimate the random effects robustly. The standardized mean difference (SMD) of cognitive measurements in the same domain in changes from baseline to the end of follow-up was the outcome variable. The ranking of treatment formats was estimated according to the surface under the cumulative ranking area (SUCRA), which was based on the estimated random effects models. All analyses were performed using the Network package in Stata, version 14. We further used partially ordered set to resolve possible conflicting rankings between cognitive outcomes. The Hasse diagram was used to graphically illustrate the partially ordered set. This statistical method revealed incomparability between treatment rankings or insufficient data for some outcomes. We first combined all the outcomes and then deleted them one by one until structured Hasse diagrams, constructed using the hasseDiagram package (version 0.1.3) in R software (version 3.6.1), were formed. Results Systematic Literature Review Figure 1 presents the PRISMA flowchart of studies through the systematic review process. Of the 1475 reference citations retrieved initially, 227 remained after duplicates and irrelevant citations were removed. First-stage screening of the citations identified 44 potentially relevant trials based on their abstracts. After the full texts were accessed for more detailed evaluation, 30 remained for extraction. However, detailed measurement data for 9 trials were inaccessible, leaving 21 RCTs for quantitative analysis. The 9 inaccessible trails were investigating adjunctive effect of N-acetylcysteine (NAC), melatonin, methylene blue, pramipexole, repetitive TMS (rTMS), docosahexaenoic acid (DHA), and atorvastatin among euthymic BD patients; and adjunctive tDCS, olanzapine, for depressed BD patients. Across these 21 trials for quantitative analysis, 42 cognitive tests were used to assess intervention effects on the 8 domains. A summary of the tests applied to each domain Clinical Epidemiology 2021:13 https://doi.org/10.2147/CLEP.S335584 DovePress 1041 Dovepress Chen et al Powered by TCPDF (www.tcpdf.org) and details on all 21 RCTs are presented in Supplementary Table S1 and Table S2, respectively. Cognitive Outcomes for Network Development in Euthymic BD Thirteen of the 21 RCTs reported results related to euthymic BD. Ten out of the 13 trials, comparing for adjunctive interventions, including memantine, rTMS, lurasidone, NAC, tDCS, quetiapine, erythropoietin (EPO), Withania somnifera, intranasal insulin, and galantamine to TAU. Three studies, which compared monotherapies of quetiapine or lithium with placebo, were excluded from the network plot, because of the absence of a common link with other interventions, leaving 10 studies with TAU as the control condition. Except trial for memantine, other 9 studies evaluated processing speed; 9 evaluated verbal learning (adjunctive rTMS, lurasidone, NAC, quetiapine, EPO, Withania somnifera, intranasal insulin, memantine and galantamine); 7 evaluated executive function (adjunctive lurasidone, NAC, tDCS, quetiapine, EPO, intranasal insulin, and galantamine); 6 evaluated working memory (adjunctive rTMS, lurasidone, NAC, quetiapine, EPO, Withania somnifera); 5 evaluated visual learning (adjunctive rTMS, lurasidone, tDCS, memantine and intranasal insulin) and attention (adjunctive rTMS, lurasidone, memantine, quetiapine, EPO); 2 evaluated social cognition (adjunctive rTMS and Withania somnifera), and 1 evaluated problem-solving (adjunctive rTMS). Among the 10 adjunctive trials, the number of patients, mean age, and percentage of male patients in each study ranged between 13 and 175, 28 and 49 years, and 32.4% and 60%, respectively. The timing of cognitive assessment varied between 2 and 24 weeks after baseline assessment. The widely used criteria defining euthymic BD among the studies were Young Maria Rating Score (YMRS) ≦ 14 or Montgomery A° sberg Depression Rating Scale (MADRS) ≦ 18. Figure 2 shows that positive outcomes were observed for working memory, verbal learning, and attention. The forest plots present the SMD for each study compared with TAU. Out of the interventions used in the 6 studies (209 patients) that evaluated working memory, Withania somnifera was the only one to demonstrate significant benefits in this domain relative to TAU (SMD = 0.58, 95% CI = 0.03– Records identified through PsycInfo (n = 180) Records identified through PubMed (n = 202) Records screened by title and abstract (n = 227) Records excluded duplication and irrelevant with title or abstract (n = 1248) Excluded based on inclusion and exclusion criteria (n = 183) Ongoing trials Not relevant Background discussion Foreign language 4 Full-text articles assessed (n = 44)) Articles included in qualitative review (n =30) Excluded with reasons (n = 14) No clear comparison group (9) Outcomes unavailable (4) Review (1) Records identified through Cochrane trials (n = 834)) Records identified through EMBASE (n = 259) Articles included for synthesis (n = 21) Euthymic group n = 13 Depressive group n = 6 Manic group n = 2 Lack of detailed data (n= 9) Total Potentially relevant Record (n = 1475) Figure 1 Flow diagram of study identification and selection. https://doi.org/10.2147/CLEP.S335584 DovePress Clinical Epidemiology 2021:13 1042 Chen et al Dovepress Powered by TCPDF (www.tcpdf.org) 1.13; Figure 2A). Out of the interventions used in the 9 studies (443 patients) that evaluated verbal learning, adjunctive galantamine was the only one to demonstrate benefits in this domain relative to TAU (SMD = 1.22, 95% CI = 0.10–2.35; Figure 2B). Out of the interventions used in the 5 studies (314 patients) that evaluated attention, only adjunctive EPO suggested improvements (SMD = 0.61, 95% CI = 0.00–1.23; Figure 2C) in this domain relative to TAU. According to the SUCRA results for the remaining domains (processing speed, visual learning, problem-solving, social cognition, and executive function), we revealed the potential benefit of Withania somnifera and EPO in processing speed and executive function, respectively. In addition, rTMS also ranked highly in visual learning domain. However, for these five cognitive domains, none exhibited significant effects compared with TAU (Supplementary Figure S1 and