Optimal duration of antibiotic treatment for community-acquired pneumonia in adults: a systematic review and duration-effect meta-analysis.

OBJECTIVES To find the optimal treatment duration with antibiotics for community-acquired pneumonia (CAP) in adults. DESIGN Systematic review and duration-effect meta-analysis. DATA SOURCES MEDLINE, Embase and CENTRAL through 25 August 2021. ELIGIBILITY CRITERIA All randomised controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. Both outpatients and inpatients were included but not those admitted to intensive care units. We imposed no date, language or publication status restriction. DATA EXTRACTION AND SYNTHESIS Data extraction by two independent reviewers. We conducted a random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the prespecified non-inferiority margin of 10% examined against 10 days . The primary outcome was clinical improvement on day 15 (range 7-45 days). SECONDARY OUTCOMES all-cause mortality, serious adverse events and clinical improvement on day 30 (15-60 days). RESULTS We included nine trials (2399 patients with a mean (SD) age of 61.2 (22.1); 39% women). The duration-effect curve was monotonic with longer duration leading to a lower probability of improvement, and shorter treatment duration (3-9 days) was likely to be non-inferior to 10-day treatment. Harmful outcome curves indicated no association. The weighted average percentage of the primary outcome in the 10-day treatment arms was 68%. Using that average, the absolute clinical improvement rates of the following durations were: 3-day treatment 75% (95% CI: 68% to 81%), 5-day treatment 72% (95% CI: 66% to 78%) and 7-day treatment 69% (95% CI: 61% to 76%). CONCLUSIONS Shorter treatment duration (3-5 days) probably offers the optimal balance between efficacy and treatment burden for treating CAP in adults if they achieved clinical stability. However, the small number of included studies and the overall moderate-to-high risk of bias may compromise the certainty of the results. Further research on the shorter duration range is required. PROSPERO REGISTRATION NUMBER CRD 42021273357

Development and validation of a meta-learner for combining statistical and machine learning prediction models in individuals with depression.

BACKGROUND The debate of whether machine learning models offer advantages over standard statistical methods when making predictions is ongoing. We discuss the use of a meta-learner model combining both approaches as an alternative. METHODS To illustrate the development of a meta-learner, we used a dataset of 187,757 people with depression. Using 31 variables, we aimed to predict two outcomes measured 60 days after initiation of antidepressant treatment: severity of depressive symptoms (continuous) and all-cause dropouts (binary). We fitted a ridge regression and a multi-layer perceptron (MLP) deep neural network as two separate prediction models ("base-learners"). We then developed two "meta-learners", combining predictions from the two base-learners. To compare the performance across the different methods, we calculated mean absolute error (MAE, for continuous outcome) and the area under the receiver operating characteristic curve (AUC, for binary outcome) using bootstrapping. RESULTS Compared to the best performing base-learner (MLP base-learner, MAE at 4.63, AUC at 0.59), the best performing meta-learner showed a 2.49% decrease in MAE at 4.52 for the continuous outcome and a 6.47% increase in AUC at 0.60 for the binary outcome. CONCLUSIONS A meta-learner approach may effectively combine multiple prediction models. Choosing between statistical and machine learning models may not be necessary in practice

Acute interventions for aggression and agitation in psychosis: study protocol for a systematic review and network meta-analysis

Introduction: Individuals with psychosis may access emergency services due to aggression and agitation. When the de-escalation technique fails to achieve tranquillisation, several pharmacological options are available. However, evidence on which intervention to prefer in terms of efficacy and tolerability to achieve resolution of the acute episode (ie, rapid tranquillisation) of aggression and agitation is currently fragmentary.Methods and analysis: We will include all randomised controlled trials comparing drugs or drug combinations or placebo for aggression or agitation episodes in adult individuals with psychosis. We will include individuals with psychosis (eg, schizophrenia and related disorders, bipolar disorder with psychotic symptoms, psychotic depression) but not substance or medication-induced psychosis or psychosis due to another medical condition. Our primary outcomes are the change in aggression or agitation scores within few hours since the administration of the intervention (efficacy outcome) and the proportion of participants who dropped out due to adverse effects (tolerability outcome). We will retrieve relevant studies from the register of studies of the Cochrane Schizophrenia Group. Also, we will run additional searches on CENTRAL, Embase and PubMed to retrieve potentially eligible studies focusing on other psychiatric diagnoses than those in the schizophrenia spectrum. We will conduct a random-effects network meta-analysis (NMA) for primary and secondary outcomes. In case of rare events of dichotomous outcomes, a common-effect Mantel-Haenszel NMA will be used instead. We will use the surface under the cumulative ranking curve and the mean ranks to rank all available treatments. Local and global methods of evaluation of inconsistency will be employed. Quality of evidence contributing to network estimates of the main outcomes will also be assessed with Confidence in Network Meta-Analysis.Ethics and dissemination: This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.PROSPERO registration number CRD42019137945

An umbrella review of adverse effects associated with antipsychotic medications: the need for complementary study designs

Antipsychotic medications are widely prescribed in psychotic illnesses and other mental disorders. Effectiveness is well-established, particularly for reducing symptoms such as delusions and hallucinations, but can be impacted by tolerability. Adverse effects are wide-ranging, and vary between antipsychotics, which is clinically important. This umbrella review aimed to comprehensively summarise the extent and quality of evidence for adverse effects associated with antipsychotic use in people with mental disorders. We included 32 meta-analyses of randomised trials and observational studies. The overall robustness of reported associations was considered in terms of review quality, heterogeneity, excess significance bias, and prediction intervals. Using this approach, endocrine and metabolic, movement-related, and sedation and sleep problems were the clinical domains with strongest evidence. The overall quality of included meta-analyses was low, and individual adverse effects were not typically examined in meta-analyses of both randomised trials and observational study designs. Future reviews should focus on adhering to methodological guidelines, consider the complementary strengths of different study designs, and integrate clinically relevant information on absolute rates and severity of adverse effects

Community interventions for anxiety and depression in adults and young people: A systematic review

Background: Growing evidence suggests that community-based interventions may be effective for anxiety and depression. This study aimed to describe studies of community interventions delivered to adults and/or young people, either in person or online, evaluated in randomised controlled trials and provide an indication as to their effectiveness, acceptability, quality of data and where possible, mechanisms of action. We included interventions delivered at and/or by museums, art galleries, libraries, gardens, music groups/choirs and sports clubs. Method: We developed and followed a preregistered protocol: PROSPERO CRD42020204471. Randomised controlled trials in adults and young people were identified in an extensive search with no date/time, language, document type and publication status limitations. Studies were selected according to predetermined eligibility criteria and data independently extracted and then assessed using Risk of Bias 1. The studies were deemed too heterogeneous for meta-analysis and were therefore reported using a narrative synthesis. Results: Our analysis included 31 studies, with 2898 participants. Community interventions most studied in randomised controlled trials were community music (12 studies, 1432 participants), community exercise (14 studies, 955 participants) and community gardens/gardening (6 studies, 335 participants). The majority of studies were from high-income countries – many were in specific populations (such as those with physical health problems) and were generally of low quality. Dropout rates across the included studies were low (1 participant on average per 100 participants). The inadequate description of interventions limited identification of potential mechanisms of action. Discussion: The uncertainty of the evidence allows only a weak recommendation in support of community interventions for anxiety and depression. The results suggest community engagement is a promising area for wide-reaching interventions to be implemented and evaluated, but more high-quality trials are needed, especially in young people and under-represented communities

Different control conditions can produce different effect estimates in psychotherapy trials for depression

OBJECTIVES: Control conditions' influence on effect estimates of active psychotherapeutic interventions for depression has not been fully elucidated. We used network meta-analysis to estimate the differences between control conditions. STUDY DESIGN AND SETTING: We have conducted a comprehensive literature search of randomized trials of psychotherapies for adults with depression up to January 1, 2019 in four major databases (PubMed, PsycINFO, Embase, and Cochrane). The network meta-analysis included broadly conceived cognitive behavior therapies in comparison with the following control conditions: Waiting List (WL), No Treatment (NT), Pill Placebo (PillPlacebo), Psychological Placebo (PsycholPlacebo). RESULTS: 123 studies with 12,596 participants were included. The I-squared was 55.9% (95% CI: 45.9%; to 64.0%) (moderate heterogeneity). The design-by-treatment global test of inconsistency was not significant (P = 0.44). Different control conditions led to different estimates of efficacy for the same intervention. WL appears to be the weakest control (odds ratio of response against NT = 1.93 (1.30 to 2.86), PsycholPlacebo = 2.03 (1.21 to 3.39), and PillPlacebo = 2.66 (1.45 to 4.89), respectively). CONCLUSIONS: Different control conditions produce different effect estimates in psychotherapy randomized controlled trials for depression. WL was the weakest, followed by NT, PsycholPlacebo, and PillPlacebo in this order. When conducting meta-analyses of psychotherapy trials, different control conditions should not be lumped into a single group

Examining the effectiveness of web-based interventions to enhance resilience in health care professionals: Systematic review

Background: Internationally, the impact of continued exposure to workplace environmental and psychological stressors on health care professionals’ mental health is associated with increased depression, substance misuse, sleep disorders, and posttraumatic stress. This can lead to staff burnout, poor quality health care, and reduced patient safety outcomes. Strategies to improve the psychological health and well-being of health care staff have been highlighted as a critical priority worldwide. The concept of resilience for health care professionals as a tool for negotiating workplace adversity has gained increasing prominence. Objective: This systematic review aims to examine the effectiveness of web-based interventions to enhance resilience in health care professionals. Methods: We searched the PubMed, CINAHL, PsycINFO, and Ovid SP databases for relevant records published after 1990 until July 2021. We included studies that focused on internet-delivered interventions aiming at enhancing resilience. Study quality was assessed with the Risk of Bias 2 tool for randomized controlled trial designs and Joanna Briggs Institute critical appraisal tool for other study designs. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42021253190). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Results: A total of 8 studies, conducted between 2014 and 2020 and involving 1573 health care workers, were included in the review. In total, 4 randomized controlled trial designs and 4 pre- and postdesign studies were conducted across a range of international settings and health care disciplines. All of these studies aimed to evaluate the impact of web-based interventions on resilience or related symptoms in health care professionals involved in patient-facing care. Interventions included various web-based formats and therapeutic approaches over variable time frames. One randomized controlled trial directly measured resilience, whereas the remaining 3 used proxy measures to measure psychological concepts linked to resilience. Three pretest and posttest studies directly measured resilience, whereas the fourth study used a proxy resilience measure. Owing to the heterogeneity of outcome measures and intervention designs, meta-analysis was not possible, and qualitative data synthesis was undertaken. All studies found that resilience or proxy resilience levels were enhanced in health care workers following the implementation of web-based interventions. The overall risk of bias of all 8 studies was low. Conclusions: The findings indicate that web-based interventions designed to enhance resilience may be effective in clinical practice settings and have the potential to provide support to frontline staff experiencing prolonged workplace stress across a range of health care professional groups. However, the heterogeneity of included studies means that findings should be interpreted with caution; more web-based interventions need rigorous testing to further develop the evidence base

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Evidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study. [Protocol]

INTRODUCTION Depressive disorders are the most common, burdensome and costly mental disorders. Their treatments have developed through the past decades and we now have more than a dozen new generation antidepressants, while a series of guidelines have been published to provide recommendations over the years. However, there still may exist important gaps in this evidence synthesis and implementation process. Systematic reviews may not have been conducted in the most unbiased, informative and timely manners; guidelines may not have reflected the most up-to-date evidence; clinicians may not have changed their clinical decision-makings in accordance with the relevant evidence. The aim of this study is to examine the gaps between the ideally synthesised evidence, guideline recommendations and real-world clinical practices in the prescription of new generation antidepressants for major depression through the past three decades. METHODS AND ANALYSIS We will conduct cumulative network meta-analyses (cNMAs) based on the comprehensive systematic review which has identified published and unpublished head-to-head randomised controlled trials comparing the following antidepressants in the acute phase treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The primary outcomes will be the proportions of patients who responded (efficacy) and who withdrew from treatment for any reasons (acceptability). We will conduct a random effects cNMA to synthesise evidence and obtain a comprehensive ranking of all new generation antidepressants based on their surface under the cumulative ranking curves. We will identify series of international clinical practice guidelines for the treatment of major depression of adults and summarise their recommendations. We will estimate real-world prescription patterns of antidepressants in the nationally representative samples in USA in the Medical Expenditure Panel Survey. We will compare and evaluate the gaps between the rankings according to cNMAs conducted at 5-year intervals between 1990 and 2015, recommendations in guidelines published in the ensuing 5 years and actual practices thereafter. ETHICS AND DISSEMINATION This review does not require ethical approval. We will disseminate our findings through publications in peer-reviewed journals and presentations at conferences. TRIAL REGISTRATION NUMBER UMIN000031898

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING UK National Institute for Health Research Oxford Health Biomedical Research Centre