scholarly journals Herbal Medicine (Sihogayonggolmoryeo-Tang or Chai-Hu-Jia-Long-Gu-Mu-Li-Tang) for Treating Hypertension:A Systematic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Boram Lee ◽  
Chan-Young Kwon

Introduction. For situations in which effective and safe natural-derived products to treat hypertension are needed, recent studies suggest that an herbal medicine, Sihogayonggolmoryeo-tang (SYM), can improve both hypertension and concurrent mood symptoms. We aimed to evaluate the effectiveness and safety of SYM in treating hypertension. Methods. Thirteen English, Korean, and Chinese databases were comprehensively searched from their inception to May 2020. Randomized controlled trials (RCTs) using SYM as a monotherapy or adjunctive therapy for hypertension were evaluated. The primary outcome was the systolic and diastolic blood pressure (BP). Descriptive analyses of the relevant data were conducted, and where appropriate data were available, a meta-analysis was performed, and the results were presented as a risk ratio or mean difference with 95% confidence intervals. The risk of bias was assessed using the Cochrane risk of bias tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results. Seven RCTs with 711 participants were included. Compared with placebo, SYM significantly lowered systolic and diastolic BP and concurrent depression. SYM significantly lowered systolic and diastolic BP compared with active controls; however, subgroup analysis revealed no differences between SYM and antihypertensives. In addition, SYM significantly decreased the level of concurrent depression compared with antidepressants. There was no consistent difference in BP reduction between SYM combined with antihypertensives and antihypertensives alone. No serious adverse events were reported following SYM administration. Most of the included studies had an unclear risk of bias, and the quality of evidence was generally rated “low.” Conclusion. Current evidence suggests that SYM may have the potential to lower hypertension and concurrent depressive symptoms without serious adverse events. Additional high-quality, placebo-controlled RCTs should be conducted to confirm the efficacy of SYM.

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ran Liu ◽  
Kun Zhang ◽  
Qiu-yu Tong ◽  
Guang-wei Cui ◽  
Wen Ma ◽  
...  

Abstract Background Acupuncture for post-stroke depression (PSD) has been evolving, but uncertainty remains. To assess the existing evidence from randomized clinical trials (RCTs) of acupuncture for PSD, we sought to draw conclusions by synthesizing RCTs. Methods An exhaustive literature search was conducted in seven electronic databases from their inception dates to April 19, 2020, to identify systematic reviews (SRs) and meta-analyses (MAs) on this topic. The primary RCTs included in the SRs/MAs were identified. We also conducted a supplementary search for RCTs published from January 1, 2015, to May 12, 2020. Two reviewers extracted data separately and pooled data using RevMan 5.3 software. The quality of evidence was critically appraised with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system. Results A total of 17 RCTs involving 1402 patients were included. Meta-analysis showed that participants who received a combination of acupuncture and conventional treatments exhibited significantly lower scores on the HAM-D17, HAM-D24 and HAM-D (MD, − 5.08 [95% CI, − 6.48 to − 3.67], I2 = 0%), (MD, − 9.72 [95% CI, − 14.54 to − 4.91], I2 = 65%) and (MD, − 2.72 [95% CI, − 3.61 to − 1.82], respectively) than those who received conventional treatment. However, there was no significant difference in acupuncture versus antidepressants in terms of the 17-item, 24-item and HAM-D scales (MD, − 0.43 [95% CI, − 1.61 to 0.75], I2 = 51%), (MD, − 3.09 [95% CI, − 10.81 to 4.63], I2 = 90%) and (MD, − 1.55 [95% CI, − 4.36 to 1.26], I2 = 95%, respectively). For adverse events, acupuncture was associated with fewer adverse events than antidepressants (RR, 0.16 [95% CI, 0.07 to 0.39], I2 = 35%), but there was no significant difference in the occurrence of adverse events between the combination of acupuncture and conventional treatments versus conventional treatments (RR, 0.63 [95% CI, 0.21 to 1.83], I2 = 38%). The quality of evidence was low to very low due to the substantial heterogeneity among the included studies. Conclusions The current review indicates that acupuncture has greater effect on PSD and better safety profile than antidepressants, but high-quality evidence evaluating acupuncture for PSD is still needed.


2019 ◽  
Vol 2 (22.2) ◽  
pp. E55-E70 ◽  
Author(s):  
Ian D. Coulter

Background: Mobilization and manipulation therapies are widely used by patients with chronic nonspecific neck pain; however, questions remain around efficacy, dosing, and safety, as well as how these approaches compare to other therapies. Objectives: Based on published trials, to determine the efficacy, effectiveness, and safety of various mobilization and manipulation therapies for treatment of chronic nonspecific neck pain. Study Design: A systematic literature review and meta-analysis. Methods: We identified studies published between January 2000 and September 2017, by searching multiple electronic databases, examining reference lists, and communicating with experts. We selected randomized controlled trials comparing manipulation and/or mobilization therapies to sham, no treatment, each other, and other active therapies, or when combined as multimodal therapeutic approaches. We assessed risk of bias by using the Scottish Intercollegiate Guidelines Network criteria. When possible, we pooled data using random-effects meta-analysis. Grading of Recommendations, Assessment, Development, and Evaluation was applied to determine the confidence in effect estimates. This project was funded by the National Center for Complementary and Integrative Health under award number U19AT007912 and ultimately used to inform an appropriateness panel. Results: A total of 47 randomized trials (47 unique trials in 53 publications) were included in the systematic review. These studies were rated as having low risk of bias and included a total of 4,460 patients with nonspecific chronic neck pain who were being treated by a practitioner using various types of manipulation and/or mobilization interventions. A total of 37 trials were categorized as unimodal approaches and involved thrust or nonthrust compared with sham, no treatment, or other active comparators. Of these, only 6 trials with similar intervention styles, comparators, and outcome measures/timepoints were pooled for meta-analysis at 1, 3, and 6 months, showing a small effect in favor of thrust plus exercise compared to an exercise regimen alone for a reduction in pain and disability. Multimodal approaches appeared to be effective at reducing pain and improving function from the 10 studies evaluated. Health-related quality of life was seldom reported. Some 22/47 studies did not report or mention adverse events. Of the 25 that did, either no or minor events occurred. Limitations: The current evidence is heterogeneous, and sample sizes are generally small. Conclusions: Studies published since January 2000 provide low-moderate quality evidence that various types of manipulation and/or mobilization will reduce pain and improve function for chronic nonspecific neck pain compared to other interventions. It appears that multimodal approaches, in which multiple treatment approaches are integrated, might have the greatest potential impact. The studies comparing to no treatment or sham were mostly testing the effect of a single dose, which may or may not be helpful to inform practice. According to the published trials reviewed, manipulation and mobilization appear safe. However, given the low rate of serious adverse events, other types of studies with much larger sample sizes would be required to fully describe the safety of manipulation and/or mobilization for nonspecific chronic neck pain. Key words: Chronic neck pain, nonspecific, chiropractic, manipulation, mobilization, systematic review, meta-analysis, appropriateness


RMD Open ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e001746
Author(s):  
Kedar Gautambhai Mehta ◽  
Tejas Patel ◽  
Paragkumar D Chavda ◽  
Parvati Patel

BackgroundColchicine, an anti-inflammatory drug is prescribed nowadays for COVID-19. In this meta-analysis, we evaluated efficacy and safety of colchicine in patients with COVID-19.MethodsWe searched databases for randomised controlled studies evaluating efficacy and/or safety of colchicine as compared with supportive care in patients with COVID-19. The efficacy outcomes were mortality, ventilatory support, intensive care unit (ICU) admission and length of hospital stay. The safety outcomes were adverse events, serious adverse events and diarrhoea. A meta-analytical summary was estimated using random effects model through Mantle-Hanzle method. An I2 test was used to assess heterogeneity. The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to assess quality of evidence for each outcome.ResultsOut of 69 full texts assessed, 6 studies (16148 patients with COVID-19) were included in meta-analysis. Patients receiving colchicine did not show significant reduction in mortality (risk difference, RD −0.00 (95% CI −0.01 to 0.01), I2=15%), ventilatory support (risk ratio, RR 0.67 (95% CI 0.38 to 1.21), I2=47%), ICU admission (RR 0.49 (95% CI 0.19 to 1.25), I2=34%), length of hospital stay (mean difference: −1.17 (95% CI −3.02 to 0.67), I2=77%) and serious adverse events (RD −0.01 (95% CI −0.02 to 0.00), I2=28%) than those who received supportive care only. Patients receiving colchicine had higher rates of adverse events (RR 1.58 (95% CI 1.07 to 2.33), I2=81%) and diarrhoea (RR 1.93 (95% CI 1.62 to 2.29), I2=0%) than supportive care treated patients. The GRADE quality of evidence was moderate for most outcomes.ConclusionThe moderate quality evidence suggests no benefit of addition of colchicine to the standard care regimen in patients with COVID-19.


2021 ◽  
pp. bmjebm-2021-111724
Author(s):  
Mathias Maagaard ◽  
Emil Eik Nielsen ◽  
Naqash Javaid Sethi ◽  
Ning Liang ◽  
Si-Hong Yang ◽  
...  

ObjectivesTo assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure.DesignA systematic review with meta-analysis and trial sequential analysis.Eligibility criteriaRandomised clinical trials comparing ivabradine and usual care with usual care (with or without) placebo in participants with heart failure.Information sourcesMedline, Embase, CENTRAL, LILACS, CNKI, VIP and other databases and trial registries up until 31 May 2021.Data extractionPrimary outcomes were all-cause mortality, serious adverse events and quality of life. Secondary outcomes were cardiovascular mortality, myocardial infarction and non-serious adverse events. We performed meta-analysis of all outcomes. We used trial sequential analysis to control risks of random errors, the Cochrane risk of bias tool to assess the risks of systematic errors and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence.ResultsWe included 109 randomised clinical trials with 26 567 participants. Two trials were at low risk of bias, although both trials were sponsored by the company that developed ivabradine. All other trials were at high risk of bias. Meta-analyses and trial sequential analyses showed that we could reject that ivabradine versus control reduced all-cause mortality (risk ratio (RR)=0.94; 95% CI 0.88 to 1.01; p=0.09; high certainty of evidence). Meta-analysis and trial sequential analysis showed that ivabradine seemed to reduce the risk of serious adverse events (RR=0.90; 95% CI 0.87 to 0.94; p<0.00001; number needed to treat (NNT)=26.2; low certainty of evidence). This was primarily due to a decrease in the risk of ‘cardiac failure’ (RR=0.83; 95% CI 0.71 to 0.97; p=0.02; NNT=43.9), ‘hospitalisations’ (RR=0.89; 95% CI 0.85 to 0.94; p<0.0001; NNT=36.4) and ‘ventricular tachycardia’ (RR=0.59; 95% CI 0.43 to 0.82; p=0.001; NNT=212.8). However, the trials did not describe how these outcomes were defined and assessed during follow-up. Meta-analyses showed that ivabradine increased the risk of atrial fibrillation (RR=1.19; 95% CI 1.04 to 1.35; p=0.008; number needed to harm (NNH)=116.3) and bradycardia (RR=3.95; 95% CI 1.88 to 8.29; p=0.0003; NNH=303). Ivabradine seemed to increase quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference (MD)=2.92; 95% CI 1.34 to 4.50; p=0.0003; low certainty of evidence), but the effect size was small and possibly without relevance to patients, and on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) (MD=−5.28; 95% CI −6.60 to −3.96; p<0.00001; very low certainty of evidence), but the effects were uncertain. Meta-analysis showed no evidence of a difference between ivabradine and control when assessing cardiovascular mortality and myocardial infarction. Ivabradine seemed to increase the risk of non-serious adverse events.Conclusion and relevanceHigh certainty evidence shows that ivabradine does not seem to affect the risks of all-cause mortality and cardiovascular mortality. The effects on quality of life were small and possibly without relevance to patients on the KCCQ and were very uncertain for the MLWHFQ. The effects on serious adverse events, myocardial infarction and hospitalisation are uncertain. Ivabradine seems to increase the risk of atrial fibrillation, bradycardia and non-serious adverse events.PROSPERO registration number: CRD42018112082.


Author(s):  
Alejandro Piscoya ◽  
Luis Ng-Sueng ◽  
Angela Parra del Riego ◽  
Renato Cerna-Viacava ◽  
Vinay Pasupuleti ◽  
...  

IntroductionWe systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients.Material and methodsRandomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events.ResultsFive RCTs (n = 1067) and 6 cohorts (n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33–1.10) or moderate (RR = 0.60, 95% CI: 0.09–3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49–0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47–1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48–1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82–1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes.ConclusionsIn comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients.


2021 ◽  
Author(s):  
Hyunjoo Oh ◽  
Seungwon Shin ◽  
Euiju Lee ◽  
Won-Seok Chung

Abstract Background: Herbal medicines (HMs) have been widely used in the treatment of cervicogenic dizziness (CGD) based on their empirical effectiveness and safety. Herein, we reviewed and evaluated the clinical evidence on the efficacy and safety of HM for CGD. Methods: Among the relevant studies published up to December 2019 in 11 electronic databases, only randomised controlled trials (RCTs) were included. The studies’ methodological quality was assessed using the revised Cochrane risk-of-bias tool for randomised trials, and the strength of evidence for the main findings was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results: All 17 included RCTs with 1,797 participants were conducted with six types of modified HM prescriptions and three types of active controls. More than half of the included studies were of low quality because of the high risk of bias due to deviations from the intended intervention. HMs plus active controls were more effective in CGD treatment than active controls alone. HMs plus antivertigo drugs, HMs plus manual therapy, and HMs plus acupuncture therapy were all effective in CGD treatment, with HMs plus antivertigo drugs showing the most reliable effect. All HM prescriptions were effective for specific patterns of CGD when administered with active controls, with Banxia Baizhu Tianma tang and Dingxuan tang demonstrating the most reliable effect. No serious adverse events were reported in all included studies. Conclusions: The current evidence suggests that HMs may enhance the treatment effect on CGD when combined with other treatments without serious adverse events. Further high-quality evidence is needed to draw a definite conclusion.Systematic review registration: PROSPERO (registration number: CRD42020199222), and the Research Registry (Review Registry Unique Identifying Number: reviewregistry1036)


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chan-Young Kwon ◽  
Boram Lee ◽  
Sun-Yong Chung ◽  
Jong Woo Kim ◽  
Aesook Shin ◽  
...  

Abstract This systematic review and meta-analysis aimed to analyze the efficacy and safety of Sihogayonggolmoryeo-tang (SGYMT), a classical herbal medicine consisting of 11 herbs, for treatment of post-stroke depression (PSD). Thirteen databases were comprehensively searched from their inception dates until July 2019. Only randomized controlled trials (RCTs) using SGYMT as a monotherapy or adjunctive therapy for PSD patients were included. Where appropriate data were available, meta-analysis was performed and presented as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). We assessed the quality of RCTs using the Cochrane risk of bias tool and the Jadad scale. The quality of evidence for each main outcome was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Twenty-one RCTs with 1,644 participants were included. In the comparison between the SGYMT and antidepressants groups, the SGYMT group scored significantly lower on both the Hamilton Depression Scale (HAMD) (8 studies; MD −2.08, 95% CI −2.62 to −1.53, I2 = 34%) and the National Institutes of Health Stroke Scale (NIHSS) (2 studies; MD −0.84, 95% CI −1.40 to −0.29, I2 = 19%), and significantly higher on the Barthel index (3 studies; MD 4.30, 95% CI 2.04 to 6.57, I2 = 66%). Moreover, the SGYMT group was associated with significantly fewer adverse events (6 studies; RR 0.13, 95% CI 0.05 to 0.37, I2 = 0%) than the antidepressants group. In the subgroup analysis, SGYMT treatment consistently reduced HAMD scores within the first 8 weeks of treatment, but thereafter this difference between groups disappeared. Comparisons between SGYMT combined with antidepressants, and antidepressants alone, showed significantly lower scores in the combination group for both HAMD (7 studies; MD = −6.72, 95% CI = −11.42 to −2.01, I2 = 98%) and NIHSS scores (4 studies; MD −3.03, 95% CI −3.60 to −2.45, I2 = 87%). In the subgroup analysis, the reductions of HAMD scores in the SGYMT combined with antidepressants group were consistent within 4 weeks of treatment, but disappeared thereafter. The quality of RCTs was generally low and the quality of evidence evaluated by the GRADE approach was rated mostly “Very low” to “Moderate.” The main causes of low quality ratings were the high risk of bias and imprecision of results. Current evidence suggests that SGYMT, used either as a monotherapy or an adjuvant therapy to antidepressants, might have potential benefits for the treatment of PSD, including short-term reduction of depressive symptoms, improvement of neurological symptoms, and few adverse events. However, since the methodological quality of the included studies was generally low and there were no large placebo trials to ensure reliability, it remains difficult to draw definitive conclusions on this topic. Further well-designed RCTs addressing these shortcomings are needed to confirm our results.


2018 ◽  
Vol 73 (5) ◽  
pp. 294-305 ◽  
Author(s):  
Сhavdar S. Pavlov ◽  
Daria L. Varganova ◽  
Marianna C. Semenistaia ◽  
Ekatherina A. Kuznetsova ◽  
Anna A. Usanova ◽  
...  

Вackground: Non-alcoholic liver disease (NAFLD) is a widely spread disease that needs an effective and safe treatment strategy. One of pharmacological treatments for people with NAFLD is ursodeoxycholic acid (UDCA). The use of UDCA is pathogenetically justified because of its cytoprotective, antiapoptotic, antioxidant, and hypoglycemic properties. Aim: Our meta-analysis (M-A) aimed to assess the benefits and harms of UDCA in people with NAFLD. Material and methods: We identified trials through electronic searches in the Cochrane Hepato-Biliary (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, SCI, LILACS, eLibrary (May 2018). We considered for inclusion randomised clinical trials (RCTs) assessing URSO versus placebo/no intervention in adult participants with NAFLD. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis to perform meta-analysis (M-A), assessed bias risk of the trials, quality of evidence using GRADE. Results: Four RCT, at high bias risk, low quality of evidence, provided data for analysis: 254 participants at different stages of NAFLD received oral UDCA (median of 18 months), 256 ― placebo/no intervention; age 18 to 75 years. We found no evidence of effect on mortality (there were no deaths) and on histological parameters such as steatosis (MD -0.13; CI -0.40−0.13; participants 323; trials 3; I2=43%), fibrosis (MD 0.00; CI -0.00−0.22; participants 323; trials 3; I2=0%), and inflammation (MD -0.05; CI -0.20−0.10; participants 325; trials 3; I2=0%). Also we found no evidence for significant influence of UDCA on occurrence of serious adverse events (RR 1.45, 95% CI 0.65−3.21; participants 292; trials 2; I2=0%), adverse events (RR 1.52, 95% CI 0.73−3.16; participants 510; trials 4; I2=36%) neither with traditional M-A (random-effects), nor with TSA SAE (CI 0.56−2.91; participants 292; trials 2; I2=0%, D2=0%), AE (CI 0.77–2.21; participants 510; trials 4; I2=0%, D2=0%). There was no evidence of effect on cytolysis, but beneficial effect of UDCA on cholestasis (GGTP) (data from two trials only) (р0.0001). We found no data on quality of life. All the trials were funded by the industry. Conclusion: Based on the small number of trials at high risk of bias, low quality, despite the safety profile observed with our M-A, we can neither recommend nor reject the use of UDCA for people with NAFLD. Further trials with low risk of bias and high quality are required to assess the benefits and harms of UDCA. 


2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yuan-Bin Chen ◽  
Johannah L Shergis ◽  
Zhen-Hu Wu ◽  
Xin-Feng Guo ◽  
Anthony L Zhang ◽  
...  

Introduction. Herbal medicine is commonly used by patients with chronic cough, but the role of herbal medicine for cough variant asthma (CVA) has not yet been clearly defined. For the first time, we performed a meta-analysis to integrate the current evidence of randomized controlled trials (RCTs) on this topic and assess the efficacy of herbal medicine in adults with CVA. Methods. A comprehensive search was conducted in electronic databases to identify RCTs of herbal medicine for adult CVA. Cochrane systematic review methods were followed, and the Grading of Recommendations Assessment, Development, and Evaluation was performed to evaluate the quality of evidence. Results. Twenty-eight RCTs were included. Compared with placebo, moderate-quality evidence from two studies showed that herbal medicine was associated with reduced cough symptom score (CSS) (MD −1.15 points; 95% CI, −1.67 to −0.63) and visual analogue scale (VAS) (MD −1.76 points; 95% CI, −2.66 to −0.86). Compared with montelukast, low- to moderate-quality evidence from 11 studies indicated that herbal medicine was associated with improved Leicester Cough Questionnaire (LCQ) (MD 2.38 points; 95% CI, 1.32 to 3.44), reduced CSS (SMD −0.81 points; 95% CI, −1.09 to −0.53), and VAS (MD −1.34 points; 95% CI, −1.82 to −0.86). There were no significant differences between herbal medicine and ICS plus bronchodilator. Conclusions. In adults with CVA, herbal medicine may result in improved quality of life and reduced cough frequency and severity scores compared with placebo or montelukast. Herbal medicine was not better than ICS plus a bronchodilator but the evidence is very uncertain.


2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Sophie Juul ◽  
Faiza Siddiqui ◽  
Marija Barbateskovic ◽  
Caroline Kamp Jørgensen ◽  
Michael Pascal Hengartner ◽  
...  

Abstract Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. Methods/design A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events. Discussion As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder. Systematic review registration PROSPERO CRD42020220279


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