Twenty-year follow-up of promising clinical studies reported in highly circulated newspapers: a meta-epidemiological study.

OBJECTIVES: Researchers have identified cases in which newspaper stories have exaggerated the results of medical studies reported in original articles. Moreover, the exaggeration sometimes begins with journal articles. We examined what proportion of the studies quoted in newspaper stories were confirmed. METHODS: We identified newspaper stories from 2000 that mentioned the effectiveness of certain treatments or preventions based on original studies from 40 main medical journals. We searched for subsequent studies until June 2022 with the same topic and stronger research design than each original study. The results of the original studies were verified by comparison with those of subsequent studies. RESULTS: We identified 164 original articles from 1298 newspaper stories and randomly selected 100 of them. Four studies were not found to be effective in terms of the primary outcome, and 18 had no subsequent studies. Of the remaining studies, the proportion of confirmed studies was 68.6% (95% CI 58.1% to 77.5%). Among the 59 confirmed studies, 13 of 16 studies were considered to have been replicated in terms of effect size. However, the results of the remaining 43 studies were not comparable. DISCUSSION: In the dichotomous judgement of effectiveness, about two-thirds of the results were nominally confirmed by subsequent studies. However, for most confirmed results, it was impossible to determine whether the effect sizes were stable. CONCLUSIONS: Newspaper readers should be aware that some claims made by high-quality newspapers based on high-profile journal articles may be overturned by subsequent studies within the next 20 years.

Unguided Computer-Assisted Self-Help Interventions Without Human Contact in Patients With Obsessive-Compulsive Disorder: Systematic Review and Meta-analysis.

BACKGROUND: Computer-assisted treatment may reduce therapist contact and costs and promote client participation. This meta-analysis examined the efficacy and acceptability of an unguided computer-assisted therapy in patients with obsessive-compulsive disorder (OCD) compared with a waiting list or attention placebo. OBJECTIVE: This study aimed to evaluate the effectiveness and adherence of computer-assisted self-help treatment without human contact in patients with OCD using a systematic review and meta-analysis approach. METHODS: Randomized controlled trials with participants primarily diagnosed with OCD by health professionals with clinically significant OCD symptoms as measured with validated scales were included. The interventions included self-help treatment through the internet, computers, and smartphones. We excluded interventions that used human contact. We conducted a search on PubMed, Cochrane Central Register of Controlled Trials, EMBASE, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov, as well as the reference lists of the included studies. The risk of bias was evaluated using version 2 of the Cochrane risk-of-bias tool for randomized trials. We calculated the standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes. The primary outcomes were short-term improvement of OCD symptoms measured by validated scales and dropout for any reason. RESULTS: We included 11 randomized controlled trials with a total of 983 participants. The results indicated that unguided computer-assisted self-help therapy was significantly more effective than a waiting list or psychological placebo (standard mean difference -0.47, 95% CI -0.73 to -0.22). Unguided computer-assisted self-help therapy had more dropouts for any reason than waiting list or psychological placebo (risk ratio 1.98, 95% CI 1.21 to 3.23). However, the quality of evidence was very low because of the risk of bias and inconsistent results among the included studies. The subgroup analysis showed that exposure response and prevention and an intervention duration of more than 4 weeks strengthen the efficacy without worsening acceptability. Only a few studies have examined the interaction between participants and systems, and no study has used gamification. Most researchers only used text-based interventions, and no study has used a mobile device. The overall risk of bias of the included studies was high and the heterogeneity of results was moderate to considerable. CONCLUSIONS: Unguided computer-assisted self-help therapy for OCD is effective compared with waiting lists or psychological placebo. An exposure response and prevention component and intervention duration of more than 4 weeks may strengthen the efficacy without worsening the acceptability of the therapy. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) CRD42021264644; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=264644.

Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Irinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials (RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC. METHODS: This meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS: Nineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82-0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80-1.03, P = 0.15). CONCLUSION: Although the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients' condition or toxicity profiles.

Whose depression deteriorates during acute phase antidepressant treatment?

BACKGROUND: Few studies have investigated the proportion of patients with depression who experience worsening of depression symptoms during adequate antidepressant treatment. The current study aimed to investigate the proportion and predictors of worsening depression during antidepressant treatment in a multi-center randomized trial involving patients with major depression. METHODS: We defined the deterioration of depression using depression symptom severity evaluated by total Patient Health Questionnaire (PHQ-9) score increases from week 0 to week 9 during acute phase antidepressant treatment. Patients' baseline demographic and clinical data, change in PHQ-9 scores from week 0 to week 3, and side effects at week 3 were evaluated as potential predictors of subsequent deterioration of depression. RESULTS: Of 1,647 patients, 99 (6.0%) exhibited deterioration of depression, and this proportion was smaller when reliable change index criteria were applied. Logistic regression analysis revealed that the following factors were significantly associated with deterioration of depression: younger age at onset of first episode of major depressive disorder, current older age, and greater increase in PHQ-9 scores between week 0 and week 3. LIMITATIONS: The time of the primary endpoint might not have been sufficiently long. The present study did not include a placebo arm, and potentially relevant predictors might not have been comprehensively investigated. CONCLUSIONS: A small proportion of patients may experience deterioration of depression during acute phase antidepressant treatment. Age at onset at first depressive episode, current age, and early negative response to antidepressants may be useful predictors of subsequent worsening of depression.

Primary Endpoints in Current Phase II/III Trials for Alzheimer Disease: A Systematic Survey of Trials Registered at ClinicalTrials.gov.

This study examined the primary and secondary endpoints used by recent phase II/III randomized controlled trials (RCTs) of drugs for the Alzheimer disease. We searched the Clinical Trials.gov database to identify all RCTs registered from January 1, 2011 until August 19, 2018. We identified 122 RCTs and examined primary and secondary endpoints most commonly used. The median number of primary endpoints was 1 (range: 1 to 48) and the median number of secondary endpoints was 4 (range: 1 to 19). Cognitive function was used as a primary endpoint by 59% of the RCTs identified. Although few trials included a primary outcome set that fulfilled the US Food and Drug Administration (FDA) or European Committee for Medicinal Products for Human Use (CHMP) requirements, these were met by a combination of the primary and secondary outcomes of more than half of the trials.

Antidepressants plus benzodiazepines for adults with major depression.

BACKGROUND: Anxiety frequently coexists with depression and adding benzodiazepines to antidepressant treatment is common practice to treat people with major depression. However, more evidence is needed to determine whether this combined treatment is more effective and not any more harmful than antidepressants alone. It has been suggested that benzodiazepines may lose their efficacy with long-term administration and their chronic use carries risks of dependence.This is the 2019 updated version of a Cochrane Review first published in 2001, and previously updated in 2005. This update follows a new protocol to conform with the most recent Cochrane methodology guidelines, with the inclusion of 'Summary of findings' tables and GRADE evaluations for quality of evidence. OBJECTIVES: To assess the effects of combining antidepressants with benzodiazepines compared with antidepressants alone for major depression in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Group's Controlled Trials Register (CCMDCTR), the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PsycINFO to May 2019. We searched the World Health Organization (WHO) trials portal and ClinicalTrials.gov to identify any additional unpublished or ongoing studies. SELECTION CRITERIA: All randomised controlled trials that compared combined antidepressant plus benzodiazepine treatment with antidepressants alone for adults with major depression. We excluded studies administering psychosocial therapies targeted at depression and anxiety disorders concurrently. Antidepressants had to be prescribed, on average, at or above the minimum effective dose as presented by Hansen 2009 or according to the North American or European regulations. The combination therapy had to last at least four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. We entered data into Review Manager 5. We used intention-to-treat data. We combined continuous outcome variables of depressive and anxiety severity using standardised mean differences (SMD) with 95% confidence intervals (CIs). For dichotomous efficacy outcomes, we calculated the risk ratio (RR) with 95% CI. Regarding the primary outcome of acceptability, only overall dropout rates were available for all studies. MAIN RESULTS: We identified 10 studies published between 1978 to 2002 involving 731 participants. Six studies used tricyclic antidepressants (TCAs), two studies used selective serotonin reuptake inhibitors (SSRIs), one study used another heterocyclic antidepressant and one study used TCA or heterocyclic antidepressant.Combined therapy of benzodiazepines plus antidepressants was more effective than antidepressants alone for depressive severity in the early phase (four weeks) (SMD -0.25, 95% CI -0.46 to -0.03; 10 studies, 598 participants; moderate-quality evidence), but there was no difference between treatments in the acute phase (five to 12 weeks) (SMD -0.18, 95% CI -0.40 to 0.03; 7 studies, 347 participants; low-quality evidence) or in the continuous phase (more than 12 weeks) (SMD -0.21, 95% CI -0.76 to 0.35; 1 study, 50 participants; low-quality evidence). For acceptability of treatment, there was no difference in the dropouts due to any reason between combined therapy and antidepressants alone (RR 0.76, 95% CI 0.54 to 1.07; 10 studies, 731 participants; moderate-quality evidence).For response in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.34, 95% CI 1.13 to 1.58; 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.12, 95% CI 0.93 to 1.35; 7 studies, 383 participants) or in the continuous phase (RR 0.97, 95% CI 0.73 to 1.29; 1 study, 52 participants). For remission in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.39, 95% CI 1.03 to 1.90, 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.27, 95% CI 0.99 to 1.63; 7 studies, 383 participants) or in the continuous phase (RR 1.31, 95% CI 0.80 to 2.16; 1 study, 52 participants). There was no evidence of a difference between combined therapy and antidepressants alone for anxiety severity in the early phase (SMD -0.76, 95% CI -1.67 to 0.14; 3 studies, 129 participants) or in the acute phase (SMD -0.48, 95% CI -1.06 to 0.10; 3 studies, 129 participants). No studies measured severity of insomnia. In terms of adverse effects, the dropout rates due to adverse events were lower for combined therapy than for antidepressants alone (RR 0.54, 95% CI 0.32 to 0.90; 10 studies, 731 participants; moderate-quality evidence). However, participants in the combined therapy group reported at least one adverse effect more often than participants who received antidepressants alone (RR 1.12, 95% CI 1.01 to 1.23; 7 studies, 510 participants; moderate-quality evidence).Most domains of risk of bias in the majority of the included studies were unclear. Random sequence generation, allocation concealment, blinding and selective outcome reporting were problematic due to insufficient details reported in most of the included studies and lack of availability of the study protocols. The greatest limitation in the quality of evidence was issues with attrition. AUTHORS' CONCLUSIONS: Combined antidepressant plus benzodiazepine therapy was more effective than antidepressants alone in improving depression severity, response in depression and remission in depression in the early phase. However, these effects were not maintained in the acute or the continuous phase. Combined therapy resulted in fewer dropouts due to adverse events than antidepressants alone, but combined therapy was associated with a greater proportion of participants reporting at least one adverse effect.The moderate quality evidence of benefits of adding a benzodiazepine to an antidepressant in the early phase must be balanced judiciously against possible harms and consideration given to other alternative treatment strategies when antidepressant monotherapy may be considered inadequate. We need long-term, pragmatic randomised controlled trials to compare combination therapy against the monotherapy of antidepressant in major depression.

Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial.

BACKGROUND: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. METHODS: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. RESULTS: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. CONCLUSIONS: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. METHODS: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. FINDINGS: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. INTERPRETATION: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. FUNDING: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Maternal exposure to benzodiazepine and risk of preterm birth and low birth weight: A case-control study using a claims database in Japan.

PURPOSE: To examine (1) if the use of benzodiazepines and antidepressants during pregnancy may increase the risk of preterm birth and/or low birth weight (LBW), and, if yes, (2) which types of benzodiazepines or antidepressants have stronger influences. METHODS: A case-control study was performed using a large claims database in Japan. Cases were mothers who had given birth to preterm and/or LBW infants between 2005 and 2014 (737 with preterm births and 1615 with LBW). Controls were mothers who had neither experienced preterm birth nor given birth to an LBW infant. RESULTS: Overall, 42 058 births were included. The maternal use of benzodiazepines was significantly associated with an increased risk of preterm birth (adjusted odds ratio [OR], 2.03; 95% confidence interval [CI], 1.11-3.69, P < .05), while the maternal use of benzodiazepines was not significantly associated with LBW (adjusted OR, 1.55; 0.96-2.50). The use of antidepressants was not significantly associated with both preterm deliveries (adjusted OR, 0.57; 0.08-4.16) and LBW (adjusted OR, 0.56; 0.14-2.29). CONCLUSIONS: Benzodiazepine use was associated with increased risk of preterm birth but not with LBW. Antidepressant use was not associated with both preterm deliveries and LBW.

Is placebo response in antidepressant trials rising or not? A reanalysis of datasets to conclude this long-lasting controversy.

It had long been believed that placebo response rates in antidepressant trials have been increasing and that they were responsible for rising numbers of so-called failed antidepressant trials. Two recent systematic reviews examined this issue and reached completely opposite findings. Furukawa and colleagues in a paper published in 2016 found that the placebo response rates are stable since 1991 and the apparent increase up to 2000 was confounded by changes in trial design features. By contrast, Khan and colleagues more recently concluded that placebo response rates had grown steadily in the past 30 years. The two reviews differed in the datasets they used, definitions of placebo response and statistical analyses. In this perspective article, we examined if such differences were responsible for the two reviews' contrasting conclusions. Our reanalyses confirmed our previous results. We found that in any dataset and for any placebo response definition, there was no increase in placebo response over the years when the analysis was adjusted for the confounders related to study design features or when it was limited to studies published after 1990s. We conclude that placebo response in antidepressant trials has remained stable for the past 25 years, during which time the large majority of the studies have come to share similar design features.

Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis.

(Reprinted with permission from Lancet 2018; 391:1357-66).

Efficacy of antidepressants over placebo is similar in two-armed versus three-armed or more-armed randomized placebo-controlled trials.

Previous studies have reported that effect sizes of antidepressants were larger in two-armed than in three-armed or more-armed (multiarmed) randomized trials, where the probability of being allocated to placebo is lower. However, these studies have not taken into account the publication bias, differences among antidepressants, or covariance in multiarmed studies, or examined sponsorship bias. We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multiarmed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multivariate meta-analysis. A random-effects model was used throughout. Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multiarmed trials was 1.09 (95% confidence interval: 0.96-1.24). The ROR did not materially change between types of antidepressants, publication year, or sponsorship. The differences between two-armed versus multiarmed studies were much smaller than were suggested in previous studies and were not significant.

Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: A meta-epidemiological investigation.

OBJECTIVE: Abstracts of scientific reports are sometimes criticized for exaggerating significant results when compared to the corresponding full texts. Such abstracts can mislead the readers. We aimed to conduct a systematic review of overstatements in abstract conclusions in psychiatry trials. METHODS: We searched for randomized controlled trials published in 2014 that explicitly claimed effectiveness of any intervention for mental disorders in their abstract conclusion, using the Cochrane Register of Controlled Trials. Claims of effectiveness in abstract conclusion were categorized into three types: superiority (stating superiority of intervention to control), limited superiority (intervention has limited superiority), and equal efficactiveness (claiming equal effectiveness of intervention with standard treatment control), and full text results into three types: significant (all primary outcomes were statistically significant in favor of the intervention), mixed (primary outcomes included both significant and non-significant results), or all results non-significant. By comparing these classifications, we assessed whether each abstract was overstated. Our primary outcome was the proportion of overstated abstract conclusions. RESULTS: We identified and included 60 relevant trials. 20 out of 60 studies (33.3%) showed overstatements. Nine reports reported only significant results although none of their primary outcomes were significant. Large sample size (>300) and publication in high impact factor (IF>10) journals were associated with low occurrence of overstatements. CONCLUSIONS: We found that one in three psychiatry studies claiming effectiveness in their abstract conclusion, either superior to control or equal to standard treatment, for any mental disorders were overstated in comparison with the full text results. Readers of the psychiatry literature are advised to scrutinize the full text results regardless of the claims in the abstract. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000018668).

Choto-san versus placebo for patients with dementia: systematic review and meta-analysis.

BACKGROUND: Choto-san is a traditional medicine used for hypertension and headaches in Japan and China. Some studies have shown its effectiveness in the treatment of dementia. The present review aimed to assess the effectiveness and acceptability of Choto-san in the treatment of adults with cognitive impairment. METHODS: We included randomized controlled trials comparing Choto-san with placebo for patients with dementia or mild cognitive impairment. RESULTS: Three randomized controlled trials evaluating 219 participants were included. Two were studies on vascular dementia, and the other was on Alzheimer's dementia. There was no difference between Choto-san and placebo in terms of short-term dichotomous judgement of improvement, but Choto-san was more effective than placebo in terms of short-term improvement of cognitive function as measured by continuous outcomes. Also, dropouts judged it to be acceptable. However, the results were imprecise and/or heterogeneous. The number of participants included in the analysis was small (n = 199 in the primary analysis) and sometimes inconsistent, as indicated by the large I 2 (72% in the primary analysis). CONCLUSION: Low-quality evidence was suggestive of Choto-san's efficacy for vascular dementia, but the present results may be overestimated. Studies with a larger sample size and conducted over longer periods should be performed. Regardless, Choto-san can be one of the choices for the treatment of vascular dementia as it is well tolerated.

Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies.

BACKGROUND: Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics. METHODS: In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression. FINDINGS: We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk [RR] 1·00, 95% CI 0·97-1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01-1·05 for 1 more week in trial length; 1·32, 1·11-1·57 for multicentre vs single-centre trials). INTERPRETATION: Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view. FUNDING: Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.

Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis.

INTRODUCTION: Many antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct and indirect comparisons; however, these reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. METHODS AND ANALYSIS: We will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework. ETHICS AND DISSEMINATION: This review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42012002291.

Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: a study protocol for a meta-epidemiological investigation.

INTRODUCTION: Abstracts are the major and often the most important source of information for readers of the medical literature. However, there is mounting criticism that abstracts often exaggerate the positive findings and emphasise the beneficial effects of intervention beyond the actual findings mentioned in the corresponding full texts. In order to examine the magnitude of this problem, we will introduce a systematic approach to detect overstated abstracts and to quantify the extent of their prevalence in published randomised controlled trials (RCTs) in the field of psychiatry. METHODS AND ANALYSIS: We will source RCTs published in 2014 from the Cochrane Register of Controlled Trials (CENTRAL) that claim effectiveness of any intervention for mental disorders. The abstract conclusions will be categorised into three types: superior (only stating significant superiority of intervention to control), limited (suggesting that intervention has limited superiority to control) and equal (claiming equal effectiveness of intervention as control). The full texts will also be classified as one of the following based on the primary outcome results: significant (all primary outcomes were statistically significant in favour of the intervention), mixed (primary outcomes included both significant and non-significant results) or all non-significant results. By comparing the abstract conclusion classification and that of the corresponding full text, we will assess whether each study exhibited overstatements in its abstract conclusion. ETHICS AND DISSEMINATION: This trial requires no ethical approval. We will publish our findings in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000018668; Pre-results.

Continuation and discontinuation of benzodiazepine prescriptions: A cohort study based on a large claims database in Japan.

Although benzodiazepines (BZDs) are often prescribed to treat a wide range of psychiatric and neurological conditions, they are also associated with various harms and risks including dependence. However the frequency of its continued use in the real world has not been well studied, especially at longer follow-ups. The aim of this study was to clarify the frequency of long-term BZD use among new BZD users over longer follow-ups and to identify its predictors. We conducted a cohort study to examine how frequently new BZD users became chronic users, based on a large claims database in Japan from January 2005 to June 2014. We used Cox proportional hazards models to identify potential predictors. A total 84,412 patients with new BZD prescriptions were included in our cohort. Among them, 35.8% continued to use BZD for three months, 15.2% for one year and 4.9% for eight years without ever attaining three months of no BZD prescription. The confirmed predictors for long-term BZD use were older age, psychiatrist-prescriber, regular use, high dose of BZD, and concomitant prescription of psychotropic drugs. When we consider BZD use, we have to keep in mind these figures and avoid these predictors as much as possible.