Kiyomi Shinohara

Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta‐analysis

Various control conditions have been employed in psychotherapy trials, but there is growing suspicion that they may lead to different effect size estimates. The present study aims to examine the differences among control conditions including waiting list (WL), no treatment (NT) and psychological placebo (PP).

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 Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at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.

Protocol registration and selective outcome reporting in recent psychiatry trials: new antidepressants and cognitive behavioural therapies

The selective reporting of favorable outcomes has a serious influence on our evidence base. However, this problem has not yet been systematically investigated in the field of psychiatry. Our study aimed to evaluate registration and outcome reporting in randomized controlled trials (RCTs) of standard treatments for depression: cognitive behavioural therapy (CBT) or new‐generation antidepressants (ADs).

Prescription patterns following first-line new generation antidepressants for depression in Japan: A naturalistic cohort study based on a large claims database

BACKGROUND Several studies have described real-world prescription patterns of first-line antidepressants for depression but little is known about their fate in terms of duration, intensity and changes. METHODS An inception cohort of new onset non-psychotic depression initiating antidepressant treatment with a new generation antidpressive agent was identified in a large health insurance claims database in Japan between 2009 and 2010. The duration and intensity of first-line antidepressants, the timing and kind of second-line antidepressants and the total duration of antidepressant treatment were examined. RESULTS We identified 1592 patients. The starting dose and the maximum dose attained with the first-line agent appeared to be largely in line with the guideline recommendations although the latter tended toward the minimum of the recommended range. The continuity of the first-line antidepressant was far below the guideline recommendations, with 28% never returning after the initial prescription and 55% dropping out within 3 months. Of all the first-line antidepressants, 14% were subsequently augmented by another psychotropic agent while 17% were switched to another antidepressant after a median of 3 or 2 months, respectively. The choice of the second-line agents varied extremely widely. The total duration of antidepressant therapy was as short as a median of 4 months, with 68% stopping treatment by 6 months. LIMITATIONS The diagnosis of non-psychotic unipolar depression in the claims database analyses remains approximate. CONCLUSIONS The current guidelines are grossly out of touch with the clinical realities. On the one hand, guidelines need to reflect the real-world practices; on the other hand clinicians should limit their treatment options and allow evidence-based comparative effectiveness research among them so that patients shall no longer be given less effective and more effective treatments without being able to distinguish among them.

Antidepressants might work for people with major depression: where do we go from here?

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Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan

BackgroundSUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.ResultsWe implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.ConclusionThis paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.Trial registrationClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).

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.

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)

Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial

Objectives To investigate whether overstatements in abstract conclusions influence primary care physicians’ evaluations when they read reports of randomised controlled trials (RCTs) Design RCT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis. Participants Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into ‘without overstatement’ (n=307) and ‘with overstatement’ (n=315) groups. Interventions We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention. Outcome measures The primary outcome was the participants’ evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion. Results There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI −0.28 to 0.42, p=0.69). Participants in the ‘without’ group considered the study conclusion to be more valid than those in the ‘with’ group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001). Conclusion The overstatements in abstract conclusions did not significantly influence the primary care physicians’ evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported. Trial registration number UMIN000025317; Pre-results.

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).