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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. [ABSTRACT FROM AUTHOR]

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". [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth. OBJECTIVE: To assess whether ADHD drugs impair reproduction in mammals. METHODS: Systematic review of reproduction in studies of animals treated with ADHD drugs. DATA SOURCES: PubMed, Biosis and EMBASE. RESULTS:We included 17 studies. The studies were generally of poor quality or poorly reported. Two studies reported the use of one of three advised randomisation methods. Fifteen studies used placebo which suggested blinding. On clonidine, the ability to produce offspring was reduced for male rats, which approached two females each. In one study, 10 treated rats produced no offspring while all four controls did. In another study, 10 treated rats impregnated nine females while 10 controls impregnated 16. On methylphenidate, vaginal opening was delayed in two studies (in one, the mean difference was 4.0 days, 95% CI 2.5 to 5.6, and number of estrous cycles was halved; in the other, the minimum delay was 6 days), while in two other studies no difference occurred. Generally, the impairments improved after a drug-free period and were less pronounced when treatment started later in life. CONCLUSION: ADHD drugs impair the reproduction in animals. [ABSTRACT FROM AUTHOR]

Background: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials.Methods and Findings: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs.Conclusions: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles. [ABSTRACT FROM AUTHOR]

The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims To explore the rationale for claiming that benzodiazepines cause dependence while selective serotonin re-uptake inhibitors (SSRIs) do not. Methods We analysed the definitions of dependence and withdrawal reactions as they had appeared over time in the Diagnostic Statistical Manual of Mental Diseases (DSM) and the International Classification of Diseases (ICD). We also compared the discontinuation symptoms described for the two drug groups in a systematic review. Results The definition of substance dependence has changed over time in both the DSM and ICD. In the most recent classifications several criteria, including behavioural, physiological and cognitive manifestations, must be fulfilled. This change was published with the revision of the DSM-III revision in 1987 (DSM-IIIR), after the recognition of benzodiazepine dependence and just before the SSRIs were marketed in 1987-88. We found that discontinuation symptoms were described with similar terms for benzodiazepines and SSRIs and were very similar for 37 of 42 identified symptoms described as withdrawal reactions. Conclusions Withdrawal reactions to selective serotonin re-uptake inhibitors appear to be similar to those for benzodiazepines; referring to these reactions as part of a dependence syndrome in the case of benzodiazepines, but not selective serotonin re-uptake inhibitors, does not seem rational. [ABSTRACT FROM AUTHOR]

Abstract: Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document—intended to enhance the use, understanding, and dissemination of the CONSORT statement—has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www.consort-statement.org) should be helpful resources to improve reporting of randomised trials. [Copyright &y& Elsevier]

Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement--a reporting guideline published in 1999--there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (www .prisma-statement.org) should be helpful resources to improve reporting of systematic reviews and meta-analyses. [ABSTRACT FROM AUTHOR]

Background: Assessing the risk of bias in individual studies in a systematic review can be done using individual components or by summarizing the study quality in an overall score. Methods: We examined the instructions to authors of the 50 Cochrane Review Groups that focus on clinical interventions for recommendations on methodological quality assessment of studies. Results: Forty-one of the review groups (82%) recommended quality assessment using components and nine using a scale. All groups recommending components recommended to assess concealment of allocation, compared to only two of the groups recommending scales (P < 0.0001). Thirty-five groups (70%) recommended assessment of sequence generation and 21 groups (42%) recommended assessment of intention-to-treat analysis. Only 28 groups (56%) had specific recommendations for using the quality assessment of studies analytically in reviews, with sensitivity analysis, quality as an inclusion threshold and subgroup analysis being the most commonly recommended methods. The scales recommended had problems in the individual items and some of the groups recommending components recommended items not related to bias in their quality assessment. Conclusion: We found that recommendations by some groups were not based on empirical evidence and many groups had no recommendations on how to use the quality assessment in reviews. We suggest that all Cochrane Review Groups refer to the Cochrane Handbook for Systematic Reviews of Interventions, which is evidence-based, in their instructions to authors and that their own guidelines are kept to a minimum and describe only how methodological topics that are specific to their fields should be handled. [ABSTRACT FROM AUTHOR]

Conclusions: Cochrane reviews have previously been shown to be of higher quality and less biased on average than other systematic reviews, but improvement is always possible. The Cochrane Collaboration has taken steps to improve editorial processes and the quality of its reviews. Meanwhile, the Cochrane Library remains a key source of evidence about the effects of healthcare interventions. Its users should interpret reviews cautiously, particularly those with conclusions favouring experimental interventions and those with many typographical errors. [ABSTRACT FROM AUTHOR]

Aim: To study the analgesic effect of acupuncture and placebo acupuncture and to explore whether the type of the placebo acupuncture is associated with the estimated effect of acupuncture. Data sources: Cochrane Library, Medline, Embase, Biological Abstracts, and PsycLIT. Study selection: Three armed randomised clinical trials (including both a placebo or sham acupuncture group and a group receiving no acupuncture) Data extraction: Standardised mean differences from each trial were used to estimate the effect of acupuncture and placebo acupuncture. The different types of placebo acupuncture were ranked from 1 to 5 according to assessment of the possibility of a physiological effect, and this ranking was meta-regressed with the effect of acupuncture. Main results: Thirteen trials (3,025 patients) involving a variety of pain conditions were eligible. The allocation of patients was adequately concealed in eight trials. The clinicians managing the acupuncture and placebo acupuncture treatments were not blinded in any of the trials. One clearly outlying trial (70 patients) was excluded. A small difference was found between acupuncture and placebo acupuncture: standardised mean difference −0.17 (95 % confidence interval −0.26 to −0.08), corresponding to 4 mm (2 mm to 6 mm) on a 100 mm visual analogue scale. No statistically significant heterogeneity was present (P = 0.10, I2 = 36 %). A moderate difference was found between placebo acupuncture and no acupuncture: standardised mean difference −0.42 (−0.60 to −0.23). However, considerable heterogeneity (P < 0.001, I2 = 66 %) was also found, as large trials reported both small and large effects of placebo. No association was detected between the type of placebo acupuncture and the effect of acupuncture (P = 0.60). Conclusion: A small analgesic effect of acupuncture was found, which seems to lack clinical relevance and cannot be clearly distinguished from bias. Whether needling at acupuncture points, or at any site, reduces pain independently of the psychological impact of the treatment ritual is unclear. [Copyright &y& Elsevier]

The article reports a study which examined benefits and harms of general health checks in terms of outcomes relevant to patients. The study revealed that general health checks did not reduce morbidity or mortality, neither overall nor for cardiovascular or cancer causes, although they increased the number of new diagnoses. In the absence of benefits, the increased number of diagnoses with health checks suggests overdiagnosis and overtreatment.

The article focuses on a study related to the usage of composite outcomes in clinical trials. The study found that the application of composite outcomes along with its definition, reporting and interpretation in clinical trials should be avoided as it creates confusion. It informs that 40 clinical trials were included during the study. A chart depicting the definition and reporting of composite outcomes in 40 trials is also presented.

Abstract: Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document—intended to enhance the use, understanding, and dissemination of the CONSORT statement—has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www.consort-statement.org) should be helpful resources to improve reporting of randomised trials. [Copyright &y& Elsevier]