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COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Over-reliance on symptom scales complicates the interpretation of research results for patients and clinicians. For future trials, it is crucial to prioritise primary outcomes that are relevant and understandable for patients

Background Missing outcome data can pose a serious threat to the validity of randomised clinical trial results. We aimed to study the extent of missing outcome data in randomised clinical trials of psychological interventions. Methods We performed a retrospective study of randomised clinical trial reports of psychological interventions published in World Psychiatry, JAMA Psychiatry, Lancet Psychiatry, American Journal of Psychiatry, British Journal of Psychiatry, or Psychotherapy and Psychosomatics from 2017 to 2022. We assessed the proportion of missing outcome data, whether missing data patterns differed between types of outcomes, participants, intervention lengths, and psychological intervention types, how missing outcome data were handled in the statistical analyses, and whether trialists discussed missing outcome data in the discussion section of the manuscript. Results We identified 182 randomised clinical trials (233 primary outcomes), of which 206 outcomes (88.4%) were assessed at high risk of bias due to missing data. The overall mean percentage of missing outcome data was 18.3% (95% confidence interval (CI): 16.7–20%) for all outcomes. The percentages of missing data were 18.9% (95% CI: 17.1–20.6%; 180 outcomes) for symptom severity scales and 1.8% (95% CI: 2.3–3.3%; 6 outcomes) for ‘hard’ binary outcomes. Trials including participants with borderline personality disorder had the highest percentage of missing outcome data (33.1%; 95% CI: 22.3–43.9%) compared with other psychiatric disorders. Fisher’s exact test showed that intervention lengths and psychological intervention types were associated with the proportion of missing outcome data ( p  < 0.001), but there were no clear patterns. Conclusion Missing outcome data is a considerable problem in randomised clinical trials of psychological interventions, and trialists should consider the corresponding methodological limitations in the design and analysis to reduce the risk of bias due to missing outcome data. Clinical trial registration number Not applicable.

Background Mirtazapine is used to treat depression worldwide, and the effects of mirtazapine on depression rating scales are well-known. Our primary objective was to assess the risks of adverse events with mirtazapine for major depressive disorder. Methods We searched relevant sources from inception to 7 March 2024 for randomised clinical trials comparing mirtazapine versus placebo in adults with major depressive disorder. The primary outcomes were suicides or suicide attempts, serious adverse events, and non-serious adverse events. Data were synthesised using meta-analysis and Trial Sequential Analysis. Results We included 17 trials randomising 2,131 participants to mirtazapine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. The included trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to determine the effects of mirtazapine on the risks of suicides or suicide attempts and serious adverse events. Meta-analyses showed that mirtazapine increased the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite but decreased the risk of headaches. Conclusions There is a lack of evidence on the effects of mirtazapine on suicides and serious adverse events. Mirtazapine increases the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite. Mirtazapine might decrease the risk of headaches. The long-term effects of mirtazapine are unknown. Prospero id CRD42022315395.

ObjectivesTo assess the beneficial and harmful effects of regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes.DesignSystematic review of randomised clinical trials with meta-analysis and trial sequential analysis.Data sourcesCENTRAL, MEDLINE, Embase, LILACS and other sources from inception to 30 January 2026.Study selectionRandomised clinical trials comparing regular human insulins versus rapid-acting insulin analogues (insulin aspart, lispro, glulisine) in children and adolescents with type 1 diabetes.AnalysesData were analysed using meta-analysis and trial sequential analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool, V.2, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Primary outcomesSevere hypoglycaemia, ketoacidosis and serious adverse events.Results10 trials randomising 1107 participants were included. The certainty of evidence was very low mainly due to high risk of bias and small sample sizes. Meta-analysis showed no evidence of a difference between regular human insulins and rapid-acting insulin analogues on severe hypoglycaemia (risk ratio (RR) 1.28, 95% CI 0.81 to 2.03; I2=0.0%; p=0.2851; nine trials), ketoacidosis (RR 0.88, 95% CI 0.26 to 2.93; I2=0.0%; p=0.8593; two trials) and serious adverse events (RR 1.00, 95% CI 0.44 to 2.25; I2=0.0%; p=0.9958; two trials). Trial sequential analysis showed that all meta-analyses of primary outcomes were underpowered.ConclusionsCurrent research shows no differential effects between regular human insulins and rapid-acting insulin analogues for children and adolescents with type 1 diabetes, but the evidence is very uncertain.PROSPERO registration numberCRD42024508625.

Background Tirzepatide is a dual-acting glucagon-like peptide-1 analog and a glucose-dependent insulinotropic polypeptide analog. The disease-specific weight-reducing effects associated with tirzepatide use are well established, but its adverse effects have not been systematically assessed and may not be disease-specific. This systematic review aimed to assess the adverse effects associated with tirzepatide use compared with placebo in patients at increased risk of cardiovascular events. Methods We searched six electronic databases and other sources from inception to June 16, 2025. Randomized clinical trials comparing tirzepatide with placebo in patients at increased risk of cardiovascular events were eligible for inclusion. The literature search identified 8866 records after removal of duplicates. Two review authors screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with Cochrane Risk of Bias tool – version 2; an eight-step procedure was used to assess whether thresholds for statistical significance were crossed, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included non-serious adverse events (nsAEs). Results The analysis included 21 trials, randomizing 8043 participants to tirzepatide versus placebo. Beta-binomial regression showed no evidence of a difference when assessing all-cause mortality (odds ratio 1.02, 95% CI 0.57 to 1.81; p  = 0.95; 21 trials; TSA: underpowered meta-analysis; very low certainty of evidence) or SAEs (odds ratio 0.98, 95% CI 0.82 to 1.17; p  = 0.80; 21 trials; TSA: sufficiently powered meta-analysis; moderate certainty of evidence). Meta-analysis showed that tirzepatide increased the risk of several nsAEs, primarily gastrointestinal nsAEs such as nausea, diarrhea, decreased appetite, and vomiting. Conclusions Current evidence indicates that tirzepatide does not appear to influence the risk of serious adverse events. A meta-analysis of all-cause mortality showed no evidence of a difference; however, this finding was based on sparse data and is associated with very low certainty. Tirzepatide use is associated with an increased risk of several gastrointestinal nsAEs. Further trials designed for investigating the effects of tirzepatide compared with placebo on all-cause mortality are needed. Trial registration PROSPERO, CRD42024599035.

ObjectivesTo assess the beneficial and harmful effects of duloxetine versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder.DesignSystematic review with meta-analysis and trial sequential analysis of randomised trials.Data sourcesCochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and other relevant databases up until January 2023. We requested clinical study reports from 36 competent authorities.Eligibility criteria for selecting studiesAll randomised clinical trials comparing duloxetine versus placebo, ‘active placebo’ or no intervention, irrespective of publication type, publication status, publication year and language for treatment of major depressive disorder in adults.Data extraction and synthesisFive authors in pairs extracted data using a standardised data extraction sheet. A third review author was consulted for disagreements. Intervention effects were assessed by both random-effects and fixed-effect model meta-analyses, risk of bias assessments were performed by two independent review authors using Cochrane’s risk of bias tool V.2 and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation.ResultsWe included 28 trials randomising a total of 7872 participants. All results were at high risk of bias. The trials’ assessment time points were between 6 and 16 weeks after randomisation. Meta-analyses showed evidence of a beneficial effect of duloxetine on depressive symptoms (mean difference −1.81, Hamilton Depression Rating Scale (HDRS-17) points; 95% CI −2.34 to −1.28; heterogeneity I2=0.0%; 12 trials) and quality of life (mean difference −3.79 points, 95% CI −5.11 to −2.46; I2=0.0%; three trials), but the effect sizes were below our predefined minimal clinically important differences. Trial sequential analysis showed that we did not have enough information to assess the effects of duloxetine on serious adverse events (SAEs) (OR 0.67, 95% CI 0.44 to 1.02; I2=0.0%; 19 trials) or suicide or suicide attempts (OR 1.08, 95% CI 0.37 to 3.16; six trials). Duloxetine increased the risk of non-SAEs (risk ratio 1.27, 95% CI 1.22 to 1.32; I2=73.0%; 24 trials). The adverse events with the lowest number needed to harm (NNH) were nausea (NNH 6), dry mouth (NNH 13), somnolence (NNH 17), withdrawal syndrome (NNH 19), sweating (NNH 20), dizziness (NNH 21) and constipation (NNH 21).ConclusionsDuloxetine appears to reduce depressive symptom scores and improve quality of life scores in the short term, but the effect sizes are minimal and of questionable patient importance. The short- and long-term effects of duloxetine on risks of SAEs and suicidality are uncertain. Duloxetine increases the risks of several short-term adverse events. Systematic assessments of benefits and harms over longer periods are required.Trial registration numberPROSPERO 2016 CRD42016053931.

Background Semaglutide’s disease-specific weight-reducing effects are well established, but its adverse effects, which may not be disease-specific, have not been systematically assessed. The aim of this review was to assess the adverse effects associated with semaglutide use compared with placebo in patients at increased risk of cardiovascular events. Methods We searched six electronic databases and other sources from inception to 31/03/2025. Randomized trials comparing semaglutide (oral or subcutaneous) with placebo in patients at increased risk of cardiovascular events were eligible. The search identified 8370 records. Two review authors independently screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with the Cochrane Risk of Bias tool – version 2; our eight-step procedure was used to assess if the thresholds for statistical significance were crossed, and the certainty of the evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included myocardial infarction and non-serious adverse events (AEs). Results The analysis included 50 trials, with a total of 54,972 participants randomized. Nineteen (38%) enrolled participants with type 2 diabetes (T2DM), 17 (34%) with overweight, 5 (10%) with T2DM and chronic kidney disease, 5 (10%) with T2DM and overweight, and 4 (8%) involved other patient populations. Meta-analysis and TSA showed evidence of beneficial effects of semaglutide on all-cause mortality (relative risk (RR) 0.85; 95% CI 0.79 to 0.91; I 2  = 0.0%; p  < 0.01) and myocardial infarction (RR 0.77, 95% CI 0.69 to 0.85; I 2  = 0.0%; p  < 0.01). None of these analyses showed signs of heterogeneity, and the evidence was of high certainty. Meta-analysis showed that semaglutide decreased the risk of SAEs (RR 0.93, 95% CI 0.88 to 0.98; I 2  = 24.1%; p  < 0.01), but increased the risk of several non-serious gastrointestinal AEs including nausea (RR 3.00, 95% CI 2.63 to 3.42), vomiting (RR 4.12, 95% CI 3.47 to 4.90), and diarrhea (RR 1.88, 95% CI 1.68 to 2.11). Conclusions In patients at increased risk of cardiovascular events, semaglutide reduced the risk of mortality, SAEs, and myocardial infarction but increased the risk of several non-serious gastrointestinal AEs. Registration PROSPERO, CRD42024499511.

IntroductionCardiovascular diseases remain the leading cause of mortality worldwide. Tirzepatide is approved for the treatment of type 2 diabetes mellitus and overweight and is increasingly used. The adverse effects with tirzepatide may not be disease-specific and have not been assessed previously.Methods and analysisWe will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index—Science (CPCI-S)) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in January 2025. Two review authors will independently extract data and perform risk of bias assessments. We will include randomised clinical trials comparing tirzepatide versus placebo or no intervention in all patient groups with an increased risk of cardiovascular events. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and Trial Sequential Analysis, risk of bias will be assessed with the Cochrane Risk of Bias tool—version 2. We will systematically assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations.Ethics and disseminationThis protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration numberCRD42024599035.