Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials

Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method

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

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

Background: SUN(^_^)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. Results: We 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. Conclusion: This 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 registration: ClinicalTrials.gov: NCT01109693(registered on 21 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. Both pharmacological and non-pharmacological treatments are available, however, because of lack of resources, antidepressants are used more frequently. Prescription of these agents should be informed by the best available evidence. Consequently, we aimed to update and expand our previous work to compare and rank antidepressants for major depressive disorder in adults. Methods We searched Cochrane CENTRAL, CINAHL, EMBASE, LiLACS, MEDLINE, PSYCINFO, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to January 8th 2016, for the acute treatment of major depressive disorder diagnosed according to standard operationalised criteria. We included placebo-controlled and head-to-head trials of 21 antidepressants in adults. We assessed the certainty of evidence using GRADE. Primary outcomes were efficacy (response rate) and acceptability (discontinuations due to any cause). Secondary outcomes included symptom severity, remission rate and discontinuations due to adverse events. We estimated summary odds ratios (OR) and standardised mean differences (with 95% credibility intervals - 95% CrIs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO (CRD42012002291). Findings We included 522 trials with 116,477 participants. The certainty of evidence was moderate to very low. In terms of efficacy, all antidepressants were more effective than placebo, with OR ranging between 2·13 (95% CrI 1·89 to 2·41) for amitriptyline and 1·38 (95% CrI 1·16 to 1·63) for reboxetine. For acceptability, agomelatine and fluoxetine were associated with fewer dropouts than placebo (OR 0·84, 95% CrI 0·72 to 0·97 and 0·88, 95% CrI 0·80 to 0·96, respectively), while clomipramine was worse than placebo (OR 1.31, 95% CrI 1·01 to 1·68). When all trials were considered, differences in OR between antidepressants ranged from 1·15 (95% CrI 1·04 to 1·27) to 1·55 (95% CrI 1·27 to 1·91) for efficacy and from 0.64 (95% CrI 0·48 to 0·86) to 0.85 (95% CrI 0·75 to 0·96) for acceptability, with wide confidence intervals on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, sertraline, venlafaxine and vortioxetine were more effective than other antidepressants (OR range: 1.12 [95% CrI 1·00 to 1·32] to 1.96 [95% CrI 1·09 to 3·57]), while fluoxetine, reboxetine and trazodone were the least efficacious drugs (OR range: 0.51 [95% CrI 0·72 to 0·97] to 0.89 [95% CrI 0·72 to 0·97]). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were the best drugs (OR range: 0.42 [95% CrI 0·72 to 0·97] to 0.81 [95% CrI 0·72 to 0·97]), while amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine had the highest dropout rates (OR range: 1.23 [95% CrI 1·00 to 1·32] to 2.37 [95% CrI 1·00 to 1·32]). 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, while there was more variability in efficacy and rate of drop out 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.</p

ベンゾジアゼピン処方の継続と中止：大規模レセプトデータを用いたコホート研究

京都大学0048新制・課程博士博士(医学)甲第19890号医博第4139号新制||医||1016(附属図書館)32967京都大学大学院医学研究科医学専攻(主査)教授 川上 浩司, 教授 福原 俊一, 教授 村井 俊哉学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Which is more generalizable, powerful and interpretable in meta-analyses, mean difference or standardized mean difference?

Background: To examine empirically whether the mean difference (MD) or the standardised mean difference (SMD) is more generalizable and statistically powerful in meta-analyses of continuous outcomes when the same unit is used. Methods: From all the Cochrane Database (March 2013), we identified systematic reviews that combined 3 or more randomised controlled trials (RCT) using the same continuous outcome. Generalizability was assessed using the I-squared (I2) and the percentage agreement. The percentage agreement was calculated by comparing the MD or SMD of each RCT with the corresponding MD or SMD from the meta-analysis of all the other RCTs. The statistical power was estimated using Z-scores. Meta-analyses were conducted using both random-effects and fixed-effect models. Results: 1068 meta-analyses were included. The I2 index was significantly smaller for the SMD than for the MD (P < 0.0001, sign test). For continuous outcomes, the current Cochrane reviews pooled some extremely heterogeneous results. When all these or less heterogeneous subsets of the reviews were examined, the SMD always showed a greater percentage agreement than the MD. When the I2 index was less than 30%, the percentage agreement was 55.3% for MD and 59.8% for SMD in the random-effects model and 53.0% and 59.8%, respectively, in the fixed effect model (both P < 0.0001, sign test). Although the Z-scores were larger for MD than for SMD, there were no differences in the percentage of statistical significance between MD and SMD in either model. Inclusions: The SMD was more generalizable than the MD. The MD had a greater statistical power than the SMD but did not result in material differences

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