Drop-out rates in placebo-controlled trials of antidepressant drugs: A systematic review and meta-analysis based on clinical study reports

2019 ◽  
Vol 30 (4) ◽  
pp. 217-232 ◽  
Author(s):  
Tarang Sharma ◽  
Louise Schow Guski ◽  
Nanna Freund ◽  
Dina Muscat Meng ◽  
Peter C. Gøtzsche
BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e024886 ◽  
Author(s):  
Klaus Munkholm ◽  
Asger Sand Paludan-Müller ◽  
Kim Boesen

ObjectivesTo investigate whether the conclusion of a recent systematic review and network meta-analysis (Ciprianiet al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence.DesignReanalysis of a systematic review, with meta-analyses.Data sources522 trials (116 477 participants) as reported in the systematic review by Ciprianiet aland clinical study reports for 19 of these trials.AnalysisWe used the Cochrane Handbook’s risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses.ResultsSeveral methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Ciprianiet al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a ‘placebo run-in’ study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Ciprianiet aldiffered from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0–52 points) was 1.97 points (95% CI 1.74 to 2.21).ConclusionsThe evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.


2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Lars Jørgensen ◽  
Peter C. Gøtzsche ◽  
Tom Jefferson

Abstract Background No study has looked at differences of pooled estimates—such as meta-analyses—of corresponding study documents of the same intervention. In this study, we compared meta-analyses of human papillomavirus (HPV) vaccine trial data from clinical study reports with trial data from corresponding trial register entries and journal publications. Methods We obtained clinical study reports from the European Medicines Agency and GlaxoSmithKline, corresponding trial register entries from ClinicalTrials.gov and corresponding journal publications via the Cochrane Collaboration’s Central Register of Controlled Trials, Google Scholar and PubMed. Two researchers extracted data. We compared reporting of trial design aspects and 20 prespecified benefit and harm outcomes extracted from each study document type. Risk ratios were calculated with the random effects inverse variance method. Results We included study documents from 22 randomized clinical trials and 2 follow-up studies with 95,670 healthy participants and non-HPV vaccine comparators (placebo, HPV vaccine adjuvants and hepatitis vaccines). We obtained 24 clinical study reports, 24 corresponding trial register entries and 23 corresponding journal publications; the median number of pages was 1351 (range 357 to 11,456), 32 (range 11 to 167) and 11 (range 7 to 83), respectively. All 24 (100%) clinical study reports, no (0%) trial register entries and 9 (39%) journal publications reported on all six major design-related biases defined by the Cochrane Handbook version 2011. The clinical study reports reported more inclusion criteria (mean 7.0 vs. 5.8 [trial register entries] and 4.0 [journal publications]) and exclusion criteria (mean 17.8 vs. 11.7 and 5.0) but fewer primary outcomes (mean 1.6 vs. 3.5 and 1.2) and secondary outcomes (mean 8.8 vs. 13.0 and 3.2) than the trial register entries. Results were posted for 19 trial register entries (79%). Compared to the clinical study reports, the trial register entries and journal publications contained 3% and 44% of the seven assessed benefit data points (6879 vs. 230 and 3015) and 38% and 31% of the 13 assessed harm data points (167,550 vs. 64,143 and 51,899). No meta-analysis estimate differed significantly when we compared pooled risk ratio estimates of corresponding study document data as ratios of relative risk. Conclusion There were no significant differences in the meta-analysis estimates of the assessed outcomes from corresponding study documents. The clinical study reports were the superior study documents in terms of the quantity and the quality of the data they contained and should be used as primary data sources in systematic reviews. Systematic review registration The protocol for our comparison is registered on PROSPERO as an addendum to our systematic review of the benefits and harms of the HPV vaccines: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20180320.pdf: CRD42017056093. Our systematic review protocol was registered on PROSPERO on January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews on January 2018: 10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: 10.1136/bmj.k3694.


2020 ◽  
Vol 86 (4) ◽  
pp. 646-667 ◽  
Author(s):  
Igho J. Onakpoya ◽  
Joseph J. Lee ◽  
Kamal R. Mahtani ◽  
Jeffrey K. Aronson ◽  
Carl J. Heneghan

2020 ◽  
Author(s):  
Tommaso Boldrini ◽  
Viola Ghiandoni ◽  
Elisa Mancinelli ◽  
Silvia Salcuni ◽  
Marco Solmi

Abstract:Objectives. Disruptive behaviour disorders (DBDs) are common reason for referral among children/adolescents. The present meta-analysis aims to estimate the efficacy of psychosocial treatments for adolescents with DBDs. Method. PRISMA-compliant systematic review, MEDLINE/PubMED/PsycINFO/Cochrane Central Register of Controlled Trials, last search April 5th, 2020. Eligible were randomized controlled trials (RCTs) administering psychosocial interventions to adolescents with symptoms of/full- blown DBDs. Out of 6,006 initial hits, random-effect meta-analysis (with sensitivity, subgroup and meta-regression analyses) was conducted on 18 cohorts, in 17 RCTs from 16 publications. Primary outcome: externalizing behaviors at RCT endpoint (standardized mean difference [SMD]). Secondary outcome: acceptability (drop-out odds ratio [OR]). Risk of bias was assessed with Risk of Bias Tool 2. Results. Seventeen RCTs, including 1,954 adolescents, were included. Mean age was 14.09 (DS 1.33), 61% were male. Mean duration of RCT was 12 weeks, and of follow-up eight (DS 3.98) months. Some concern on risk of bias emerged in twelve studies, high in six. In main analyses, psychosocial interventions had a large effect size at RCT endpoint (SMD=0.98, 95%CI -0.55 to -1.38, k=18), and were acceptable (drop-out OR=1.29, 95%CI 0.62 to 2.70, k=13). Such beneficial effect did not persist at follow-up (SMD=-0.36, 95%CI 0.06 to -0.78, k=10). Family format was the most effective. No clinically significant moderator was found. Conclusion. In conclusion, psychosocial interventions involving family of adolescents with DBDs symptoms/disorders are effective, and acceptable in the short term, but not effective at follow-up. Future studies should focus on strategies to maintain short-term efficacy of psychosocial interventions in DBDs.


2018 ◽  
Author(s):  
Joao Ricardo Nickenig Vissoci

BackgroundHarmful alcohol use leads to a large burden of disease and disability which disportionately impacts LMICs. The World Health Organization and the Lancet have issued calls for this burden to be addressed, but issues remain, primarily due to gaps in information. While a variety of interventions have been shown to be effective at reducing alcohol use in HICs, their efficacy in LMICs have yet to be assessed. This systematic review describes the current published literature on alcohol interventions in LMICs and conducts a meta analysis of clinical trials evaluating interventions to reduce alcohol use and harms in LMICs.MethodsIn accordance with PRISMA guidelines we searched the electronic databases Pubmed, EMBASE, Scopus,Web of Science, Cochrane, and Psych Info. Articles were eligible if they evaluated an intervention targeting alcohol-related harm in LMICs. After a reference and citation analysis, we conducted a quality assessment per PRISMA protocol. A meta-analysis was performed on the 39 randomized controlled trials that evaluated an alcohol-related outcome.ResultsOf the 3,801 articles from the literature search, 87 articles from 25 LMICs fit the eligibility and inclusion criteria. Of these studies, 39 randomized controlled trials were included in the meta-analysis. Nine of these studies focused specifically on medication, while the others focused on brief motivational intervention, brain stimulation, AUDIT-based brief interventions, WHO ASSIST-based interventions, group based education, basic screening and interventions, brief psychological or counseling, dyadic relapse prevention, group counseling, CBT, motivational + PTSD based interview, and health promotion/awareness. Conclusion Issues in determining feasible options specific to LMICs arise from unstandardized interventions, unequal geographic distribution of intervention implementation, and uncertain effectiveness over time. Current research shows that brain stimulation, psychotherapy, and brief motivational interviews have the potential to be effective in LMIC settings, but further feasibility testing and efforts to standardize results are necessary to accurately assess their effectiveness.


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