Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased?:Exploratory meta- and subgroup analysis

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.</p

Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis.

Cognitive-behaviour therapy (CBT) for panic disorder may consist of different combinations of several therapeutic components such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure and/or in vivo exposure. It is therefore important both theoretically and clinically to examine whether specific components of CBT or their combinations are superior to others in the treatment of panic disorder. Component network meta-analysis (NMA) is an extension of standard NMA that can be used to disentangle the treatment effects of different components included in composite interventions. We searched MEDLINE, EMBASE, PsycINFO and Cochrane Central, with supplementary searches of reference lists and clinical trial registries, for all randomized controlled trials comparing different CBT-based psychological therapies for panic disorder with each other or with control interventions. We applied component NMA to disentangle the treatment effects of different components included in these interventions. After reviewing 2526 references, we included 72 studies with 4064 participants. Interoceptive exposure and face-to-face setting were associated with better treatment efficacy and acceptability. Muscle relaxation and virtual-reality exposure were associated with significantly lower efficacy. Components such as breathing retraining and in vivo exposure appeared to improve treatment acceptability while having small effects on efficacy. The comparison of the most v. the least efficacious combination, both of which may be provided as 'evidence-based CBT,' yielded an odds ratio for the remission of 7.69 (95% credible interval: 1.75 to 33.33). Effective CBT packages for panic disorder would include face-to-face and interoceptive exposure components, while excluding muscle relaxation and virtual-reality exposure

Psychological characteristics of Japanese patients with chronic pain assessed by the Rorschach test

<p>Abstract</p> <p>Background</p> <p>The increasing number of patients with chronic pain in Japan has become a major issue in terms of the patient's quality of life, medical costs, and related social problems. Pain is a multi-dimensional experience with physiological, affective, cognitive, behavioral and social components, and recommended to be managed via a combination of bio-psycho-social aspects. However, a biomedical approach is still the dominant method of pain treatment in Japan. The current study aimed to evaluate comprehensive psychological functions and processes in Japanese chronic pain patients.</p> <p>Methods</p> <p>The Rorschach Comprehensive System was administered to 49 in-patients with non-malignant chronic pain. Major variables and frequencies from the test were then compared to normative data from non-patient Japanese adults by way of the t-test and chi-square test.</p> <p>Results</p> <p>Patients exhibited high levels of emotional distress with a sense of helplessness with regard to situational stress, confusion, and ambivalent feelings. These emotions were managed by the patients in an inappropriate manner. Cognitive functions resulted in moderate dysfunction in all stages. Information processing tended to focus upon minute features in an inflexible manner. Mediational dysfunction was likely to occur with unstable affective conditions. Ideation was marked by pessimistic and less effective thinking. Since patients exhibited negative self-perception, their interpersonal relationship skills tended to be ineffective. Originally, our patients displayed average psychological resources for control, stress tolerance, and social skills for interpersonal relationships. However, patient coping styles were either situation- or emotion-dependent, and patients were more likely to exhibit emotional instability influenced by external stimuli, resulting in increased vulnerability to pain.</p> <p>Conclusions</p> <p>Data gathered from the Rorschach test suggested psychological approaches to support chronic pain patients that are likely to be highly beneficial, and we thus recommend their incorporation into the course of current pain treatments.</p

Mood Stabilizers and Antipsychotics for Acute Mania: Systematic Review and Meta-Analysis of Augmentation Therapy vs Monotherapy From the Perspective of Time to the Onset of Treatment Effects

Background: Existing meta-analytic evidence on bipolar mania treatment has revealed that augmentation therapy (AUG) with antipsychotics and mood stabilizers is more effective than monotherapy. However, the speed of the onset of treatment effects and subsequent changes in risk/benefit are unclear. Methods: We searched the Cochrane CENTRAL, MEDLINE, and EMBASE databases until January 2021. Our primary outcomes were response and tolerability. We set 3 time points: 1, 3, and 6 weeks after randomization. Results: Seventeen studies compared AUG therapy and MS monotherapy (comparison 1), and 8 studies compared AUG therapy and antipsychotics monotherapy (comparison 2). In comparison 1, AUG therapy resulted in significantly more responses than monotherapy, with an odds ratio of 1.45 (95% confidence interval [CI]: 1.17 to 1.80) at 3 weeks and 1.59 (95% CI: 1.28 to 1.99) at 6 weeks. Significant improvement was observed in the first week with a standardized mean difference of −0.25 (95% CI: −0.38 to −0.12). In comparison 2, AUG therapy was significantly more effective than monotherapy, with an odds ratio of 1.73 (95% CI: 1.25 to 2.40) at 3 weeks and 1.74 (95% CI: 1.11 to 2.73) at 6 weeks. Significant improvement was observed in the first week with an standardized mean difference of −0.23 (95% CI: −0.39 to −0.07). Regarding tolerability, there was no significant difference between AUG therapy and monotherapy at 3 and 6 weeks in both comparisons. Conclusions: Early AUG therapy should be considered, as it has shown efficacy from weeks 1 to 6, although attention to side effects is necessary for acute mania treatment

HTR1A polymorphisms and clinical efficacy of antipsychotic drug treatment in schizophrenia: A meta-analysis

Background: This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Methods: Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. Results: The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. However, C allele carriers of the rs6295 polymorphism showed a significantly greater negative symptoms improvement than G allele carriers (P = .04, standardized mean difference = -0.14, 95%CI = 0.01 to 0.28). Conclusions: The results of our present analysis indicate that the HTR1A rs6295 polymorphism may impact negative symptoms improvement but not on either overall symptoms or positive symptoms improvement. However, this metaanalysis was based on a small number of studies and patients, and the effect size on negative symptoms was small. Given this limitation, the results should be confirmed by further investigations

Minimal important changes in standard deviation units are highly variable and no universally applicable value can be determined

[Objectives] This study aims to describe the distribution of anchor-based minimal important change (MIC) estimates in standard deviation (SD) units and examine if the robustness of such estimates depends on the specific SD used or on the methodological credibility of the anchor-based estimates. [Design and Setting] We included all anchor-based MIC estimates from studies published in MEDLINE and relevant literature databases upto October 2018. Each MIC was converted to SD units using baseline, endpoint, and change from baseline SDs. We performed a descriptive analysis of MICs in SD units and checked how the distribution would change if MICs with low methodological credibility were excluded from the analysis. [Results] We included 1, 009 MIC estimates from 182 studies. The medians and interquartile ranges of MICs in SD units were 0.43 (0.25 to 0.69), 0.42 (0.22 to 0.70), and 0.51 (0.28 to 0.78) for baseline, endpoint, and change SD units, respectively. Some MICs were extremely large or small. The distribution did not change significantly after excluding MICs estimated by less credible methods. [Conclusions] The size of the universally applicable MIC in SD units could not be determined. Anchor-based MICs in SD units were widely distributed, with more than half in the range of 0.2 to 0.8

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)

Antidepressants, benzodiazepines and azapirones for panic disorder in adults:a network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare individual active drugs (antidepressants, benzodiazepines and azapirones) and placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank treatments for panic disorder (antidepressants, benzodiazepines, azapirones and placebo) according to their effectiveness and acceptability

Prognostic factors and effect modifiers for personalisation of internet-based cognitive behavioural therapy among university students with subthreshold depression: A secondary analysis of a factorial trial

BACKGROUND: Internet-cognitive behavioural therapy (iCBT) for depression can include multiple components. This study explored depressive symptom improvement prognostic factors (PFs) and effect modifiers (EMs) for five common iCBT components including behavioural activation, cognitive restructuring, problem solving, self-monitoring, and assertion training. METHODS: We used data from a factorial trial of iCBT for subthreshold depression among Japanese university students (N = 1093). The primary outcome was the change in PHQ-9 scores at 8 weeks from baseline. Interactions between each component and various baseline characteristics were estimated using a mixed-effects model for repeated measures. We calculated multiplicity-adjusted p-values at 5 % false discovery rate using the Benjamini-Hochberg procedure. RESULTS: After multiplicity adjustment, the baseline PHQ-9 total score emerged as a PF and exercise habits as an EM for self-monitoring (adjusted p-values <0.05). The higher the PHQ-9 total score at baseline (range: 5-14), the greater the decrease after 8 weeks. For each 5-point increase at baseline, the change from baseline to 8 weeks was bigger by 2.8 points. The more frequent the exercise habits (range: 0-2 points), the less effective the self-monitoring component. The difference in PHQ-9 change scores between presence or absence of self-monitoring was smaller by 0.94 points when the participant exercised one level more frequently. Additionally, the study suggested seven out of 36 PFs and 14 out of 160 EMs examined were candidates for future research. LIMITATIONS: Generalizability is limited to university students with subthreshold depression. CONCLUSIONS: These results provide some helpful information for the future development of individualized iCBT algorithms for depression