Search

Background: Depression drugs can be difficult to come off due to withdrawal symptoms. Gradual tapering with tapering support is needed to help patients withdraw safely., Objective: To review the withdrawal success rates, using any intervention, and the effects on relapse/recurrence rates, symptom severity, quality of life, and withdrawal symptoms., Methods: Systematic review based on PubMed and Embase searches (last search 4 October 2022) of randomised trials with one or more treatment arms aimed at helping patients withdraw from a depression drug, regardless of indication for treatment. We calculated the mean and median success rates and the risk difference of depressive relapse when discontinuing or continuing depression drugs., Results: We included 13 studies (2085 participants). Three compared two withdrawal interventions and ten compared drug discontinuation vs. continuation. The success rates varied hugely between the trials (9% to 80%), with a weighted mean of 47% (95% confidence interval 38% to 57%) and a median of 50% (interquartile range 29% to 65%). A meta-regression showed that the length of taper was highly predictive for the risk of relapse (P = 0.00001). All the studies we reviewed confounded withdrawal symptoms with relapse; did not use hyperbolic tapering; withdrew the depression drug too fast; and stopped it entirely when receptor occupancy was still high., Conclusion: The true proportion of patients on depression drugs who can stop safely without relapse is likely considerably higher than the 50% we found.

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from NACTRC for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Anonymous sources are used by journalists when it is important to protect whistleblowers from repercussions. Healthcare is heavily influenced by vested interests which are often financial, but academic prestige and protection of guild interests also play a major role. If anonymous authorship is not allowed, many potential whistleblowers would prefer to keep quiet, even though their stepping forward would serve the public interest and might save many lives, particularly by reducing prescription drug deaths. This is especially important since drugs are the third leading cause of death in the Western world.

It has been widely suspected that SARS-CoV-2, the coronavirus that caused the Covid-19 pandemic, escaped from the Wuhan Institute of Virology because of sloppy safety procedures and that it was man-made as part of the so-called gain-of-function research at the institute [1]. If this is the case, it makes China responsible for over 5 million deaths so far and the United States complicit, as it funded the highly dangerous research [1]. The public has been misled about the likely origins of the pandemic right from the start [2].

Objectives: To assess whether drug regulatory agencies decided on applications for extended-release methylphenidate for use in adult ADHD based on select samples of trials., Study Design and Setting: Case series of publicly available regulatory documents. We matched an index of extended-release methylphenidate trials for adult ADHD with trials appearing in regulatory documents of extended-release methylphenidate applications. Trials and regulatory documents were identified as part of this systematic review (https://doi.org/10.1002/14651858.CD012857). We sought to identify missing trials in the regulatory documents and to clarify regulatory submission requirements., Results: We indexed 18 trials and matched those with 13 drug applications (11 approved, 2 rejected) published by 7 agencies. There were trials missing in 7 (54%) of 13 applications, median 4 trials (range 1-6). The median proportion of missing trial participants was 45% (range 23% - 72%). Regulators seemingly require that all trials must be included in new drug applications, but wording is ambiguous., Conclusion: In this sample of extended-release methylphenidate drug applications for adult ADHD, 7 of 13 regulatory decisions were missing entire trials according to public documents, even though regulatory requirements seem to stipulate that all available trials should be included in drug applications., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first-line pharmacological treatment is central nervous system (CNS) stimulants, such as methylphenidate, but uncertainty remains about its benefits and harms., Objectives: To assess the beneficial and harmful effects of extended-release formulations of methylphenidate in adults diagnosed with ADHD., Search Methods: We searched CENTRAL, MEDLINE, Embase, nine other databases and four clinical trial registries up to February 2021. We searched 12 drug regulatory databases for clinical trial data up to 13 May 2020. In addition, we cross-referenced all available trial identifiers, handsearched reference lists, searched pharmaceutical company databases, and contacted trial authors., Selection Criteria: Randomised, double-blind, parallel-group trials comparing extended-release methylphenidate formulations at any dose versus placebo and other ADHD medications in adults diagnosed with ADHD., Data Collection and Analysis: Two review authors independently extracted data. We assessed dichotomous outcomes as risk ratios (RRs), and rating scales and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We meta-analysed the data using a random-effects model. We assessed three design characteristics that may impair the trial results' 'generalisability'; exclusion of participants with psychiatric comorbidity; responder selection based on previous experience with CNS stimulants; and risk of withdrawal effects. Our prespecified primary outcomes were functional outcomes, self-rated ADHD symptoms, and serious adverse events. Our secondary outcomes included quality of life, ADHD symptoms rated by investigators and by peers such as family members, cardiovascular variables, severe psychiatric adverse events, and other adverse events., Main Results: We included 24 trials (5066 participants), of which 21 reported outcome data for this review. We also identified one ongoing study. We included documents from six drug regulatory agencies covering eight trials. Twenty-one trials had an outpatient setting and three were conducted in prisons. They were primarily conducted in North America and Europe. The median participant age was 36 years. Twelve trials (76% of participants) were industry-sponsored, four (14% of participants) were publicly funded with industry involvement, seven (10% of participants) were publicly funded, and one had unclear funding. The median trial duration was eight weeks. One trial was rated at overall unclear risk of bias and 20 trials were rated at overall high risk of bias, primarily due to unclear blinding of participants and investigators, attrition bias, and selective outcome reporting. All trials were impaired in at least one of the three design characteristics related to 'generalisability'; for example, they excluded participants with psychiatric comorbidity such as depression or anxiety, or included participants only with a previous positive response to methylphenidate, or similar drugs. This may limit the trials' usefulness for clinical practice, as they may overestimate the benefits and underestimate the harms. Extended-release methylphenidate versus placebo (up to 26 weeks) For the primary outcomes, we found very low-certainty evidence that methylphenidate had no effect on 'days missed at work' at 13-week follow-up (mean difference (MD) -0.15 days, 95% confidence interval (CI) -2.11 to 1.81; 1 trial, 409 participants) or serious adverse events (risk ratio (RR) 1.43, CI 95% CI 0.85 to 2.43; 14 trials, 4078 participants), whereas methylphenidate improved self-rated ADHD symptoms (small-to-moderate effect; SMD -0.37, 95% CI -0.43 to -0.30; 16 trials, 3799 participants). For secondary outcomes, we found very low-certainty evidence that methylphenidate improved self-rated quality of life (small effect; SMD -0.15, 95% CI -0.25 to -0.05; 6 trials, 1888 participants), investigator-rated ADHD symptoms (small-to-moderate effect; SMD -0.42, 95% CI -0.49 to -0.36; 18 trials, 4183 participants), ADHD symptoms rated by peers such as family members (small-to-moderate effect; SMD -0.31, 95% CI -0.48 to -0.14; 3 trials, 1005 participants), and increased the risk of experiencing any adverse event (RR 1.27, 95% CI 1.19 to 1.37; 14 trials, 4214 participants). We rated the certainty of the evidence as 'very low' for all outcomes, primarily due to high risk of bias and 'indirectness of the evidence'. One trial (419 participants) had follow-up at 52 weeks and two trials (314 participants) included active comparators, hence long-term and comparative evidence is limited., Authors' Conclusions: We found very low-certainty evidence that extended-release methylphenidate compared to placebo improved ADHD symptoms (small-to-moderate effects) measured on rating scales reported by participants, investigators, and peers such as family members. Methylphenidate had no effect on 'days missed at work' or serious adverse events, the effect on quality of life was small, and it increased the risk of several adverse effects. We rated the certainty of the evidence as 'very low' for all outcomes, due to high risk of bias, short trial durations, and limitations to the generalisability of the results. The benefits and harms of extended-release methylphenidate therefore remain uncertain., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Concern has been raised about whether HPV vaccines might cause serious neurological disorders including postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS). The European Medicines Agency (EMA) investigated the issue and declared in 2015 that there is no link between HPV vaccines and serious neurological adverse events. However, the certainty conveyed in EMA's official report is undermined by a leaked, confidential document that reveals important disagreements among the experts. Furthermore, in its assessments, EMA relied on the data the drug companies had provided to them even though it had been demonstrated that the companies had underreported possible neurological harms. Even though active comparators were used (aluminium adjuvants and other vaccines), our research group found significantly more serious neurological harms in the HPV vaccine groups than in the comparator groups in a systematic review based on clinical study reports in EMA's possession. We outline areas where we believe the basis for EMA's decision was flawed; highlight that the relationship between HPV vaccines and POTS remains uncertain; and suggest ways forward to resolve the uncertainty and debate., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fluoxetine was approved for depression in children and adolescents based on two placebo-controlled trials, X065 and HCJE, with 96 and 219 participants, respectively., Objective: To review these trials, which appear to have been misreported., Methods: Systematic review of the clinical study reports and publications. The primary outcomes were the efficacy variables in the trial protocols, suicidal events, and precursors to suicidality or violence., Results: Essential information was missing and there were unexplained numerical inconsistencies. (1) The efficacy outcomes were biased in favour of fluoxetine by differential dropouts and missing data. The efficacy on the Children's Depression Rating Scale-Revised was 4% of the baseline score, which is not clinically relevant. Patient ratings did not find fluoxetine effective. (2) Suicidal events were missing in the publications and the study reports. Precursors to suicidality or violence occurred more often on fluoxetine than on placebo. For trial HCJE, the number needed to harm was 6 for nervous system events, 7 for moderate or severe harm, and 10 for severe harm. Fluoxetine reduced height and weight over 19 weeks by 1.0 cm and 1.1 kg, respectively, and prolonged the QT interval., Conclusions: Our reanalysis of the two pivotal trials showed that fluoxetine is unsafe and ineffective.

Objectives: To determine to which degree industry partners in randomised clinical trials own the data and can constrain publication rights of academic investigators., Methods: Cohort study of trial protocols, publication agreements and other documents obtained through Freedom of Information requests, for a sample of 42 trials with industry involvement approved by ethics committees in Denmark. The main outcome measures used were: proportion of trials where data was owned by the industry partner, where the investigators right to publish were constrained and if this was mentioned in informed consent documents, and where the industry partner could review data while the trial was ongoing and stop the trial early., Results: The industry partner owned all data in 20 trials (48%) and in 16 trials (38%) it was unclear. Publication constraints were described for 30 trials (71%) and this was not communicated to trial participants in informed consent documents in any of the trials. In eight trials (19%) the industry partner could review data during the trial, for 20 trials (48%) it was unclear. The industry partner could stop the trial early without any specific reason in 23 trials (55%)., Conclusions: Publication constraints are common, and data is often owned by industry partners. This is rarely communicated to trial participants. Such constraints might contribute to problems with selective outcome reporting. Patients should be fully informed about these aspects of trial conduct., (© 2021. The Author(s).)

Background: Healthcare professionals are exposed to advertisements for prescription drugs in medical journals. Such advertisements may increase prescriptions of new drugs at the expense of older treatments even when they have no added benefits, are more harmful, and are more expensive. The publication of medical advertisements therefore raises ethical questions related to editorial integrity., Methods: We conducted a descriptive cross-sectional study of all medical advertisements published in the Journal of the Danish Medical Association in 2015. Drugs advertised 6 times or more were compared with older comparators: (1) comparative evidence of added benefit; (2) Defined Daily Dose cost; (3) regulatory safety announcements; and (4) completed and ongoing post-marketing studies 3 years after advertising., Results: We found 158 medical advertisements for 35 prescription drugs published in 24 issues during 2015, with a median of 7 advertisements per issue (range 0 to 11). Four drug groups and 5 single drugs were advertised 6 times or more, for a total of 10 indications, and we made 14 comparisons with older treatments. We found: (1) 'no added benefit' in 4 (29%) of 14 comparisons, 'uncertain benefits' in 7 (50%), and 'no evidence' in 3 (21%) comparisons. In no comparison did we find evidence of 'substantial added benefit' for the new drug; (2) advertised drugs were 2 to 196 times (median 6) more expensive per Defined Daily Dose; (3) 11 safety announcements for five advertised drugs were issued compared to one announcement for one comparator drug; (4) 20 post-marketing studies (7 completed, 13 ongoing) were requested for the advertised drugs versus 10 studies (4 completed, 6 ongoing) for the comparator drugs, and 7 studies (2 completed, 5 ongoing) assessed both an advertised and a comparator drug at 3 year follow-up., Conclusions and Relevance: In this cross-sectional study of medical advertisements published in the Journal of the Danish Medical Association during 2015, the most advertised drugs did not have documented substantial added benefits over older treatments, whereas they were substantially more expensive. From January 2021, the Journal of the Danish Medical Association no longer publishes medical advertisements.

Aims: The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) produce guidelines for the design of pivotal psychiatric drug trials used in new drug applications. It is unknown who are involved in the guideline development and what specific trial design recommendations they give., Methods: Cross-sectional study of EMA Clinical Efficacy and Safety Guidelines and FDA Guidance Documents. Study outcomes: (1) guideline committee members and declared conflicts of interest; (2) guideline development and organisation of commenting phases; (3) categorisation of stakeholders who comment on draft and final guidelines according to conflicts of interest ('industry', 'not-industry but with industry-related conflicts', 'independent', 'unclear'); and (4) trial design recommendations (trial duration, psychiatric comorbidity, 'enriched design', efficacy outcomes, comparator choice). Protocol registration https://doi.org/10.1101/2020.01.22.20018499 (27 January 2020)., Results: We included 13 EMA and five FDA guidelines covering 15 psychiatric indications. Eleven months after submission, the EMA had not processed our request regarding committee member disclosures. FDA offices draft the Guidance Documents, but the Agency is not in possession of employee conflicts of interest declarations because FDA employees generally may not hold financial interests (although some employees may hold interests up to $15,000). The EMA and FDA guideline development phases are similar; drafts and final versions are publicly announced and everybody can submit comments. Seventy stakeholders commented on ten guidelines: 38 (54%) 'industry', 18 (26%) 'not-industry but with industry-related conflicts', six (9%) 'independent' and eight (11%) 'unclear'. They submitted 1014 comments: 640 (68%) 'industry', 243 (26%) 'not-industry but with industry-related conflicts', 44 (5%) 'independent' and 20 (2%) 'unclear' (67 could not be assigned to a specific stakeholder). The recommended designs were generally for trials of short duration; with restricted trial populations; allowing previous exposure to the drug; and often recommending rating scale efficacy outcomes. EMA mainly recommended three arm designs (both placebo and active comparators), whereas FDA mainly recommended placebo-controlled designs. There were also other important differences and FDA's recommendations regarding the exclusion of psychiatric comorbidity seemed less restrictive., Conclusions: The EMA and FDA clinical research guidelines for psychiatric pivotal trials recommend designs that tend to have limited generalisability. Independent and non-conflicted stakeholders are underrepresented in the guideline development. It seems warranted with more active involvement of scientists and independent organisations without conflicts of interest in the guideline development process.

Background: Selective reporting of trial results is common., Objective: To study selective reporting in clinical study reports, company trial registers and publications of quality of life in placebo-controlled trials of antidepressants., Methods: We compared clinical study reports of four antidepressants (fluoxetine, duloxetine, paroxetine and sertraline) obtained from two European drug regulators, data from online company registers, and publications received or retrieved from Eli Lilly and GlaxoSmithKline. Pfizer was also contacted but did not provide any publications., Results: We included 15 trials (19,015 pages) and 4717 patients. Six trials had used SF-36, seven EQ-5D and two both instruments. Nine of the 15 CSRs (60%) displayed selective reporting. In the companies' online registers, there was selective reporting for all 15 trials (100%). We received 20 publications from Eli Lilly and retrieved six from the GlaxoSmithKline register. There was selective reporting in 24 of the 26 publications (92%). Despite extensive selective reporting, we found only small differences between placebo and active drugs., Conclusions: Access to the full raw data from clinical trials and to case report forms for all patients are needed to evaluate the effect of antidepressants on quality of life. Regulatory agencies should refuse to approve drugs or new indications based on incomplete reporting.

We assessed the records for 30 consecutive patients who had appealed decisions about forced medication with antipsychotics to the Psychiatric Appeals Board in Denmark. In all 21 cases where there was information about the effects of previous drugs, the psychiatrists stated that antipsychotics had had a good effect whereas none of the patients shared this view. The harm caused by earlier or currently used antipsychotics did not seem to have played any role in the psychiatrists' decision-making. The legal requirements for using force to protect the patients' health were never met and less intrusive treatments than antipsychotics, eg, benzodiazepines or psychotherapy, were never mentioned as options. The power imbalance was extreme, the patients felt misunderstood and ignored, their legal protection was a sham, and the harm done was immense. The violation of patient rights is a global problem. We suggest that forced medication be abandoned.

Objective: To study whether three widely differing drug classes, benzodiazepines and similar agents, stimulants and lithium, showed similar patterns of long-term usage., Method: I constructed usage curves over a ten-year period, from 2007 to 2017, based on data from Statistics Denmark., Results: In 2007, a total of 478,097 patients deemed a prescription for a benzodiazepine or similar agent, 13,225 for lithium and 8,800 for a stimulant, corresponding to 8.8%, 0.24% and 0.16%, respectively, of the Danish population of 5,427,459 people. Only 6,2102, 5,339 and 983 of these were first-time users (13.0%, 40.4% and 11.2%, respectively). The percentage of current users who redeemed a prescription for the same or a similar drug in each of the following years fell most quickly for benzodiazepines and similar agents and most slowly for lithium, and after ten years, it was 18%, 40% and 29%, respectively.For first-time users, the drop in usage was much quicker. The percentage of first-time users who redeemed a prescription for the same or a similar drug in each of the following years fell to 12%, 59% and 49%, respectively, already after only two years., Conclusions: We should focus on helping patients withdraw slowly and safely from the drugs they are on instead of telling them that they need to stay on them., Competing Interests: Competing interests: None., (© 2020 Giovanni Fioriti Editore s.r.l.)

Competing Interests: Competing interests: PCG is a co-founder of the Cochrane Collaboration and a strong supporter of its basic principles. PCG strongly opposes Cochrane’s current direction of travel.

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: https://doi.org/10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: https://doi.org/10.1136/bmj.k3694.

Objective: To assess the benefits and harms of the human papillomavirus (HPV) vaccines., Data Sources: Clinical study reports obtained from the European Medicines Agency and GlaxoSmithKline from 2014 to 2017., Eligibility Criteria: Randomised trials that compared an HPV vaccine with a placebo or active comparator in healthy participants of all ages., Appraisal and Synthesis: Two researchers extracted data and judged risk of bias with the Cochrane tool (version 2011). Risk ratio (RR) estimates were pooled using random-effects meta-analysis., Outcomes: Clinically relevant outcomes in intention to treat populations-including HPV-related cancer precursors irrespective of involved HPV types, treatment procedures and serious and general harms., Results: Twenty-four of 50 eligible clinical study reports were obtained with 58,412 pages of 22 trials and 2 follow-up studies including 95,670 participants: 79,102 females and 16,568 males age 8-72; 393,194 person-years; and 49 months mean weighted follow-up. We judged all 24 studies to be at high risk of bias. Serious harms were incompletely reported for 72% of participants (68,610/95,670). Nearly all control participants received active comparators (48,289/48,595, 99%). No clinical study report included complete case report forms. At 4 years follow-up, the HPV vaccines reduced HPV-related carcinoma in situ (367 in the HPV vaccine group vs. 490 in the comparator group, RR 0.73 [95% confidence interval, CI, 0.53 to 1.00], number needed to vaccinate [NNV] 387, P = 0.05, I 2  = 67%) and HPV-related treatment procedures (1018 vs. 1416, RR 0.71 [95% CI 0.63 to 0.80], NNV 75, P < 0.00001, I 2  = 45%). The HPV vaccines increased serious nervous system disorders (exploratory analysis: 72 vs. 46, RR 1.49 [1.02 to 2.16], number needed to harm [NNH] 1325, P = 0.040, I 2  = 0%) and general harms (13,248 vs. 12,394, RR 1.07 [95% CI 1.03 to 1.11], NNH 51, P = 0.0002, I 2  = 77%) but did not significantly increase fatal harms (45 vs. 38, RR 1.19 [95% CI 0.65 to 2.19], P = 0.58, I 2  = 30%) or serious harms (1404 vs. 1357, RR 1.01 [95% CI 0.94 to 1.08], P = 0.79, I 2  = 0%)., Conclusion: At 4 years follow-up, the HPV vaccines decreased HPV-related cancer precursors and treatment procedures but increased serious nervous system disorders (exploratory analysis) and general harms. As the included trials were primarily designed to assess benefits and were not adequately designed to assess harms, the extent to which the HPV vaccines' benefits outweigh their harms is unclear. Limited access to clinical study reports and trial data with case report forms prevented a thorough assessment., Systematic Review Registration: CRD42017056093. Our systematic review protocol was registered on PROSPERO in January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093&#95;PROTOCOL&#95;20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093&#95;PROTOCOL&#95;20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews in January 2018: https://doi.org/10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published in September 2018: https://doi.org/10.1136/bmj.k3694.

Background: Many people use the Internet for obtaining information about their medications., Objective: To investigate whether information about antidepressants on popular websites reflects the scientific evidence and enables people to make informed choices., Methods: Cross-sectional study using a checklist with 14 predefined criteria of 39 websites from 10 countries., Results: All 39 websites mentioned the benefits of antidepressants. Twenty-nine (74%) websites attributed depression to a "chemical imbalance" or claimed they could fix an imbalance. Sexual dysfunction was mentioned as a harmful effect on 23 (59%) websites while five (13%) mentioned emotional numbing. Twenty-five (64%) stated that antidepressants may cause increased suicidal ideation, but 23 (92%) of them contained incorrect information, and only two (5%) websites noted that the suicide risk is increased in people of all ages. Twenty-eight websites (72%) warned patients about withdrawal effects but only one stated that antidepressants can be addictive., Conclusions: None of the websites met our predefined criteria. The information was generally inaccurate and unhelpful and has potential to lead to inappropriate use and overuse of antidepressants and reduce the likelihood that people will seek better options for depression like psychotherapy.

Background: The widespread use of psychiatric drugs does not appear to be evidence-based but seems to be driven mainly by commercial pressures. I studied whether two widely differing drug classes, antipsychotics and antidepressants, showed similar patterns in long-term usage., Methods: I constructed usage curves over a ten-year period, from 2006 to 2016, based on data from Statistics Denmark., Results: In 2006, a total of 110,235 patients deemed a prescription for an antipsychotic and 395,018 for an antidepressant, corresponding to 2.0% and 7.3% of the Danish population. Only 21,846 vs. 79,030 of these were first-time users (19.8% vs. 20.0%). The percentage of current users who redeemed a prescription for the same or a similar drug in each of the following years was remarkably similar for the two classes of drugs, and after ten years, it was 35% vs. 33%.Using the requirement that the patients identified in 2006 needed to redeem the prescription only once during the next ten years, 42% vs. 43% were taking a drug in 2016. This suggests that most patients identified at any given point in time as drug users continue taking such drugs for many years, with little or no interruption in drug intake.For first-time users, the drop in usage was much quicker. The percentage of first-time users who redeemed a prescription for the same or a similar drug in each of the following years fell to about one-third (29% vs. 36%) already after two years.Using 2011 as the starting year yielded similar results., Conclusions: If we accept the evidence-based premises that antipsychotics and antidepressants do not have clinically relevant effects and that the patients dislike them, the data suggest massive overuse of the drugs, to a remarkably similar degree. We need to focus on helping patients withdraw slowly and safely from the drugs they are on instead of telling them that they need to stay on them.

Background: Antidepressants are much used and have been tested for many conditions., Objective: To investigate the type of diagnoses in placebo-controlled trials apart from depression and anxiety., Methods: This was a systematic review., Results: We downloaded 5471 records from PubMed and excluded 3017 that contained depression or anxiety. After exclusion of non-eligible studies, meta-analyses and reviews, and records that were unclear, 1273 records remained. We counted 214 unique diagnoses, of which the most common were abuse of drugs or substances (227 records), pain or neuropathy (170), obesity (125), other eating disorders (45), obsessive compulsive disorder (66), sexual dysfunction (41), gastrointestinal disorders (40), menopausal symptoms/hot flashes (36), premenstrual dysphoric disorder (27), urinary incontinence (21), post-traumatic stress disorder (38), schizophrenia (31), dementia or cognition problems (25), insomnia (19), ADHD (17), autism spectrum disorders (14), and stroke or traumatic brain injury (15)., Conclusions: Trials of antidepressants may be driven mainly by commercial interests, focusing on prevalent diseases and everyday problems. No one can live a full life without experiencing several of the problems for which these drugs were tested. Antidepressants, sometimes called happy pills, could be seen as the modern version of Aldous Huxley's soma pill intended to keep everyone happy in the "Brave New World".

On September 13, 2018, one of the founders of the Cochrane Collaboration was expelled from the organisation, by a narrow vote of 6 to 5. Many see this as a moral collapse in what was once a magnificent grassroots organisation, guided by ethical principles and helping people make better decisions about healthcare interventions. I am that excommunicated person. I review here the essential issues leading to my expulsion, which occurred primarily because, in my capacity as a board member, I had challenged the CEO's virtually total control over the board, his mismanagement of Cochrane, and the direction in which he was taking the organisation. My criticism of psychiatric drugs and the highly prestigious Cochrane review of HPV vaccines also played a role. Freedom of Information requests revealed that the CEO went well beyond his brief to demand my removal from the Nordic Cochrane Centre, resulting in my sacking. Cochrane has become too close to industry and has introduced scientific censorship, which is detrimental for a scientific organisation. The board has announced a "zero tolerance" policy for repeated, serious bad behaviour. It would be beneficial if its CEO and board members applied this principle to themselves. I also discuss a recent paper by Trisha Greenhalgh et al that purported to have analysed the current Cochrane crisis in a disinterested fashion, which it did not. Instead of discussing the undeniable facts and the horrific abuses of power, TG consistently used positive terms about Cochrane and negative ones about me and my supporters.

Objective: We investigated if the law and the patients' rights are being respected in Denmark when patients appeal forced medication orders., Method: We assessed 30 consecutive cases described on the webpage of the Psychiatric Appeals Board., Results: No clear and convincing evidence was presented in any case that the proposed treatment was in the patient's best interests. Furthermore, according to Danish law, forced medication should be with drugs with the fewest possible adverse effects, but this condition was violated in 29 of the 30 cases (97%).In seven cases (23%), where the board disagreed with an earlier decision made by the Psychiatric Patients' Complaints Board and resolved that the conditions for forced treatment with an antipsychotic had not been met, the issues were formal and minor, and the Appeals Board argued, also in these cases, that force was justified because the patient was insane and that the prospect of cure or a significant and decisive improvement in the condition would otherwise be significantly impaired. This view lacks support in reliable science.The board seems mainly to have a cosmetic function, rubber stamping what the psychiatrists want. It focused on uncontroversial issues it could easily check and not on what is important for patients., Conclusions: Patients' rights and the law were not being respected. We suggest forced medication be abandoned, in accordance with the United Nations Convention on the Rights of Persons with Disabilities., Competing Interests: Competing interests: No author or any immediate family member has current financial relationships with commercial organizations that might present the appearance of a potential conflict of interest with the material presented., (© 2019 Giovanni Fioriti Editore s.r.l.)

Background: Screening for malignant melanoma has the potential to reduce morbidity and mortality from the disease through earlier detection, as prognosis is closely associated with the thickness of the lesion at the time of diagnosis. However, there are also potential harms from screening people without skin lesion concerns, such as overdiagnosis of lesions that would never have caused symptoms if they had remained undetected. Overdiagnosis results in harm through unnecessary treatment and the psychosocial consequences of being labelled with a cancer diagnosis. For any type of screening, the benefits must outweigh the harms. Screening for malignant melanoma is currently practised in many countries, and the incidence of the disease is rising sharply, while mortality remains largely unchanged., Objectives: To assess the effects on morbidity and mortality of screening for malignant melanoma in the general population., Search Methods: We searched the following databases up to May 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registries, checked the reference lists of included and other relevant studies for further references to randomised controlled trials (RCTs), used citation tracking (Web of Science) for key articles, and asked trialists about additional studies and study reports., Selection Criteria: RCTs, including cluster-randomised trials, of screening for malignant melanoma compared with no screening, regardless of screening modality or setting, in any type of population and in any age group where people were not suspected of having malignant melanoma. We excluded studies in people with a genetic disposition for malignant melanoma (e.g. familial atypical mole and melanoma syndrome) and studies performed exclusively in people with previous melanomas., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. The primary outcomes of this review were total mortality, overdiagnosis of malignant melanoma, and quality of life/psychosocial consequences., Main Results: We included two studies with 64,391 participants. The first study was a randomised trial of an intervention developed to increase the rate of performance of thorough skin self-examination. The intervention group received instructional materials, including cues and aids, a 14-minute instruction video, and a brief counselling session, and at three weeks a brief follow-up telephone call from a health educator, aimed at increasing performance of thorough skin self-examination. The control group received a diet intervention with similar follow-up. The trial included 1356 people, who were recruited from 11 primary care practices in the US between 2000 and 2001. Participant mean age was 53.2 years and 41.7% were men. This study did not report on any of our primary outcomes or the following secondary outcomes: mortality specific to malignant melanoma, false-positive rates (skin biopsies/excisions with benign outcome), or false-negative rates (malignant melanomas diagnosed between screening rounds and up to one year after the last round). All participants were asked to complete follow-up telephone interviews at 2, 6, and 12 months after randomisation.The second study was a pilot study for a cluster-RCT of population-based screening for malignant melanoma in Australia. This pilot trial included 63,035 adults aged over 30 years. The three-year programme involved community education, an education and support component for medical practitioners, and the provision of free skin screening services. The mean age of people attending the skin screening clinics (which were held by primary care physicians in workplaces, community venues, and local hospitals, and included day and evening sessions) was 46.5 years, and 51.5% were men. The study included whole communities, targeting participants over 30 years of age, but information on age and gender of the whole study population was not reported. Study duration was three years (1998 to 2001), and outcomes were measured at the screening clinics during these three years. There was no further follow-up for any outcomes. The control group received no programme. The ensuing, planned cluster randomised trial in 560,000 adults was never carried out due to lack of funding. At the time of this review, there are no published or unpublished data on our prespecified outcomes available, and no results for mortality outcomes from the pilot study are to be expected.The risk of bias in these studies was high for performance bias (blinding study personnel and participants) and high or unclear for detection bias (blinding of outcome assessment). Risk of bias in the other domains was either unclear or low. We were unable to assess the certainty of the evidence for our primary outcomes as planned due to lack of data., Authors' Conclusions: Adult general population screening for malignant melanoma is not supported or refuted by current evidence from RCTs. It therefore does not fulfil accepted criteria for implementation of population screening programmes. This review did not investigate the effects of screening people with a history of malignant melanoma or in people with a genetic disposition for malignant melanoma (e.g. familial atypical mole and melanoma syndrome). To determine the benefits and harms of screening for malignant melanoma, a rigorously conducted randomised trial is needed, which assesses overall mortality, overdiagnosis, psychosocial consequences, and resource use.

Background: General health checks are common elements of health care in some countries. They aim to detect disease and risk factors for disease with the purpose of reducing morbidity and mortality. Most of the commonly used individual screening tests offered in general health checks have been incompletely studied. Also, screening leads to increased use of diagnostic and therapeutic interventions, which can be harmful as well as beneficial. It is therefore important to assess whether general health checks do more good than harm. This is the first update of the review published in 2012., Objectives: To quantify the benefits and harms of general health checks., Search Methods: We searched CENTRAL, MEDLINE, Embase, two other databases and two trials registers on 31 January 2018. Two review authors independently screened titles and abstracts, assessed papers for eligibility and read reference lists. One review author used citation tracking (Web of Knowledge) and asked trial authors about additional studies., Selection Criteria: We included randomised trials comparing health checks with no health checks in adults unselected for disease or risk factors. We did not include geriatric trials. We defined health checks as screening for more than one disease or risk factor in more than one organ system., Data Collection and Analysis: Two review authors independently extracted data and assessed the risk of bias in the trials. We contacted trial authors for additional outcomes or trial details when necessary. When possible, we analysed the results with a random-effects model meta-analysis; otherwise, we did a narrative synthesis., Main Results: We included 17 trials, 15 of which reported outcome data (251,891 participants). Risk of bias was generally low for our primary outcomes. Health checks have little or no effect on total mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.97 to 1.03; 11 trials; 233,298 participants and 21,535 deaths; high-certainty evidence, I 2 = 0%), or cancer mortality (RR 1.01, 95% CI 0.92 to 1.12; 8 trials; 139,290 participants and 3663 deaths; high-certainty evidence, I 2 = 33%), and probably have little or no effect on cardiovascular mortality (RR 1.05, 95% CI 0.94 to 1.16; 9 trials; 170,227 participants and 6237 deaths; moderate-certainty evidence; I 2 = 65%). Health checks have little or no effect on fatal and non-fatal ischaemic heart disease (RR 0.98, 95% CI 0.94 to 1.03; 4 trials; 164,881 persons, 10,325 events; high-certainty evidence; I 2 = 11%), and probably have little or no effect on fatal and non-fatal stroke (RR 1.05 95% CI 0.95 to 1.17; 3 trials; 107,421 persons, 4543 events; moderate-certainty evidence, I 2 = 53%)., Authors' Conclusions: General health checks are unlikely to be beneficial.

Objective: To study the drop-out rates in trials of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs)., Methods: This study is a systematic review and meta-analysis of trials. The main outcome measure: Overall drop-out rate. Secondary outcomes were drop-outs due to adverse events and lack of effect. We obtained clinical study reports (CSRs) of five antidepressant drugs from the European Medicines Agency and the UK's Medicines and Healthcare products Regulatory Agency. The eligibility criteria for selecting studies: double-blind randomised, placebo-controlled trials for any indication., Data Extraction and Analysis: The primary outcome was extracted by two researchers independently and meta-analysed using the Mantel-Haenszel method (fixed effect model). The secondary outcomes were extracted by one researcher and checked by another. Sensitivity analyses were performed using Peto's odds ratio and beta binomial methods, due to presence of null events, and by excluding unreliable trials., Results: We included 71 CSRs (67,319 pages) with information on 73 trials (11,057 patients on SSRI or SNRI drugs, and 7,369 on placebo). There were minor discrepancies within the CSRs when a modified intention to treat principle was used and patients lost to follow up early in the trial were not accounted for. Significantly more patients dropped out on active drug than on placebo, risk ratio 1.08 (95% CI 1.03 to 1.13), with no difference between adults and children/ adolescents, RR = 1.08 (1.03 to 1.13) and 1.07 (0.95 to 1.21), respectively. When three trials with a prior single-blind phase on active drug were removed, the difference was a risk ratio of 1.12 (1.07 to 1.18), whereas the result was the same after removal of three trials with fraudulent data or other issues with data validity, risk ratio 1.08 (1.03 to 1.13). There were more drop-outs due to adverse events on active drug than on placebo, risk ratio 2.63 (2.33 to 2.96). There were fewer drop-outs due to lack of effect, risk ratio 0.47 (0.43 to 0.53). However, this result is biased; when more people drop out due to adverse effects, fewer can drop out because of lack of effect., Conclusions: By using CSRs, we were able to demonstrate for the first time that more patients dropped out on active drug than on placebo. As it can be argued that the drop-out rate reflects the patients' overall assessment of the balance between benefits and harms, our review adds to the growing concern that SSRIs and SNRIs might not have the desired effect. Our review also highlights the importance of using CSRs for undertaking reviews of drugs.

Objective: To assess if lithium treatment in patients with mood disorders, for instance depression, bipolar disorders, and schizoaffective disorders, has an effect on total mortality and suicide., Design: Systematic review and meta-analysis., Main Outcome Measure: Total mortality. Secondary outcome was suicide., Data Sources: PubMed and ClinicalTrials.gov. Eligible trials were randomized double-blind trials comparing lithium with placebo in patients with mood disorders who were not already on lithium before randomization in order to avoid withdrawal effects in the placebo group., Data Extraction and Analysis: Two researchers extracted data independently. Data were analysed with Review Manager 5.3 (Peto odds ratio)., Results: We found 45 eligible studies. Only four studies reported any suicides or other deaths in the lithium or placebo group. There was a significant reduction in total mortality (two versus nine), odds ratio 0.28 (95% confidence interval 0.08 to 0.93). There was no statistically significant reduction in suicides, (none versus three), odds ratio 0.13 (0.01 to 1.27)., Conclusion: According to our study, lithium reduces total mortality in mood disorders but not suicide. Because of small numbers and unreliable data, the findings should be interpreted with caution.

Competing Interests: Competing interests: LJ and PCG have no conflicts of interest to declare. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011–2013, TJ acted as an expert witness in a litigation case related to the antiviral oseltamivir, in two litigation cases on potential vaccine related damage and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997–1999), GSK (2001–2002), Sanofi-Synthelabo (2003), and IMS Health (2013) and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. TJ was a member of three advisory boards for Boerhinger Ingelheim. TJ was holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the coordinator of the Cochrane Vaccines Field. TJ was a co-signatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms of HPV vaccines and consequent complaints to the European Ombudsman. TJ is co-holder of a John and Laura Arnold Foundation grant for development of a RIAT support centre (2017-2020) and Jean Monnet Network Grant, 2017-2020 for The Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018-2022).

Objective To describe the redactions in contemporary protocols for industry-sponsored randomised drug trials with patient relevant outcomes and to evaluate whether there was a legitimate rationale for the redactions. Design Cohort study. Under the Freedom of Information Act, we requested access to trial protocols approved by a research ethics committee in Denmark from October 2012 to March 2013. We received 17 consecutive protocols, which had been redacted before we got them, and nine protocols without redactions. In five additional cases, the companies refused to let the committees give us access, and in three other cases, documents were missing. Participants Not applicable. Setting Not applicable. Main outcome measure Amount and nature of redactions in 22 predefined key protocol variables. Results The redactions were most widespread in those sections of the protocol where there is empirical evidence of substantial problems with the trustworthiness of published drug trials: data analysis, handling of missing data, detection and analysis of adverse events, definition of the outcomes, interim analyses and premature termination of the study, sponsor's access to incoming data while the study is running, ownership to the data and investigators' publication rights. The parts of the text that were redacted differed widely, both between companies and within the same company. Conclusions We could not identify any legitimate rationale for the redactions. The current mistrust in industry-sponsored drug trials can only change if the industry offers unconditional access to its trial protocols and other relevant documents and data.

Background: Unabridged access to drug industry and regulatory trial registers and data reduces reporting bias in systematic reviews and may provide a complete index of a drug's clinical study programme. Currently, there is no public index of the human papillomavirus (HPV) vaccine industry study programmes or a public index of non-industry funded studies., Methods: By cross-verification via study programme enquiries to the HPV vaccine manufacturers and regulators and searches of trial registers and journal publication databases, we indexed clinical HPV vaccine studies as a basis to address reporting bias in a systematic review of clinical study reports., Results: We indexed 206 clinical studies: 145 industry and 61 non-industry funded studies. One of the four HPV vaccine manufacturers (GlaxoSmithKline) provided information on its study programme. Most studies were cross-verified from two or more sources (160/206, 78%) and listed on regulatory or industry trial registers or journal publication databases (195/206, 95%)-in particular, on ClinicalTrials.gov (176/195, 90%). However, study results were only posted for about half of the completed studies on ClinicalTrials.gov (71/147, 48%). Two thirds of the industry studies had a study programme ID, manufacturer specific ID, and national clinical trial (NCT) ID (91/145, 63%). Journal publications were available in journal publication databases (the Cochrane Collaboration's Central Register of Controlled Trials, Google Scholar and PubMed) for two thirds of the completed studies (92/149, 62%)., Conclusion: We believe we came close to indexing complete HPV vaccine study programmes, but only one of the four manufacturers provided information for our index and a fifth of the index could not be cross-verified. However, we indexed larger study programmes than those listed by major regulators (i.e., the EMA and FDA that based their HPV vaccine approvals on only half of the available trials). To reduce reporting bias in systematic reviews, we advocate the registration and publication of all studies and data in the public domain.

Objectives: The aim of the study was to identify the validity of effect estimates for serious rare adverse events in clinical study reports of antidepressants trials, across different meta-analysis methods., Study Design and Setting: Four serious rare adverse events (all-cause mortality, suicidality, aggressive behavior, and akathisia) were meta-analyzed using different methods. The Yusuf-Peto odds ratio ignores studies with no events and was compared with the alternative approaches of generalized linear mixed models (GLMMs), conditional logistic regression, a Bayesian approach using Markov Chain Monte Carlo (MCMC), and a beta-binomial regression model., Results: The estimates for the four outcomes did not change substantially across the different methods; the Yusuf-Peto method underestimated the treatment harm and overestimated its precision, especially when the estimated odds ratio deviated greatly from 1. For example, the odds ratio for suicidality for children and adolescents was 2.39 (95% confidence interval = 1.32-4.33), using the Yusuf-Peto method but increased to 2.64 (1.33-5.26) using conditional logistic regression, to 2.69 (1.19-6.09) using beta-binomial, to 2.73 (1.37-5.42) using the GLMM, and finally to 2.87 (1.42-5.98) using the MCMC approach., Conclusion: The method used for meta-analysis of rare events data influences the estimates obtained, and the exclusion of double-zero event studies can give misleading results. To ensure reduction of bias and erroneous inferences, sensitivity analyses should be performed using different methods instead of the Yusuf-Peto approach, in particular the beta-binomial method, which was shown to be superior through a simulation study., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective To study whether cognitive behavioural therapy decreases suicide attempts in people with previous suicide attempts. Design Systematic review and meta-analysis. Setting Randomised trials that compare cognitive behavioural therapy with treatment as usual. Participants Patients who had engaged in any type of suicide attempt in the six months prior to trial entry resulting in presentation to clinical services. Main outcome measure Suicide attempt. Results We included ten trials, eight from Cochrane reviews and two from our updated searches (1241 patients, 219 of whom had at least one new suicide attempt). Cognitive behavioural therapy compared to treatment as usual reduced the risk of a new suicide attempt; risk ratio 0.47; 95% confidence interval 0.30-0.73; p = 0.0009; I 2  = 57%. Only seven suicides were reported (3 versus 4). One trial had an unusually large effect; if this trial is excluded, the risk ratio becomes 0.61 (0.46-0.80) and the heterogeneity in the results disappears (I 2  = 0%). Conclusions Cognitive behavioural therapy reduces not only repeated self-harm but also repeated suicide attempts. It should be the preferred treatment for all patients with depression.

A Cochrane systematic review on immediate-release methylphenidate for adults with attention deficit hyperactivity disorder (ADHD) was withdrawn from the Cochrane Library on 26 May 2016 after substantial criticism of its methods and flawed conclusions. Retraction of scientific papers on this basis is unusual but can be necessary. We provide a summary of the criticism that led to the withdrawal. We detail the methodological flaws of the withdrawn Cochrane systematic review and general issues of bias and shortcomings of the included ADHD trials: cross-over designs compared with parallel-group designs, exclusion of participants with psychiatric comorbidity, absence of 'functional outcomes' and use of clinical outcomes with limited relevance, short trial duration and small trial populations, broken blinding caused by easily recognisable side effects, combining outcome assessments by trial investigators and participants, outcome reporting bias, poor evaluation of cardiovascular and psychiatric harms and conflicts of interest of trialists and systematic reviewers. The withdrawal of the Cochrane systematic review signals recognition of previous unreliable clinical ADHD research. We conclude that clinical trials of immediate-release methylphenidate in adults with ADHD are of very low quality. We urgently need well-conducted long-term trials free of bias to assess the benefits and harms of central stimulant treatment in adult ADHD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Effective breast cancer screening should detect early-stage cancer and prevent advanced disease., Objective: To assess the association between screening and the size of detected tumors and to estimate overdiagnosis (detection of tumors that would not become clinically relevant)., Design: Cohort study., Setting: Denmark from 1980 to 2010., Participants: Women aged 35 to 84 years., Intervention: Screening programs offering biennial mammography for women aged 50 to 69 years beginning in different regions at different times., Measurements: Trends in the incidence of advanced (>20 mm) and nonadvanced (≤20 mm) breast cancer tumors in screened and nonscreened women were measured. Two approaches were used to estimate the amount of overdiagnosis: comparing the incidence of advanced and nonadvanced tumors among women aged 50 to 84 years in screening and nonscreening areas; and comparing the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in screening and nonscreening areas., Results: Screening was not associated with lower incidence of advanced tumors. The incidence of nonadvanced tumors increased in the screening versus prescreening periods (incidence rate ratio, 1.49 [95% CI, 1.43 to 1.54]). The first estimation approach found that 271 invasive breast cancer tumors and 179 ductal carcinoma in situ (DCIS) lesions were overdiagnosed in 2010 (overdiagnosis rate of 24.4% [including DCIS] and 14.7% [excluding DCIS]). The second approach, which accounted for regional differences in women younger than the screening age, found that 711 invasive tumors and 180 cases of DCIS were overdiagnosed in 2010 (overdiagnosis rate of 48.3% [including DCIS] and 38.6% [excluding DCIS])., Limitation: Regional differences complicate interpretation., Conclusion: Breast cancer screening was not associated with a reduction in the incidence of advanced cancer. It is likely that 1 in every 3 invasive tumors and cases of DCIS diagnosed in women offered screening represent overdiagnosis (incidence increase of 48.3%)., Primary Funding Source: None.

Background: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence., Methods: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation])., Results: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted., Interpretation: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits., (© 2017 Canadian Medical Association or its licensors.)