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Abstract Background Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. Methods We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. Discussion This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. Systematic review registration PROSPERO CRD42023402365.

Abstract Background Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence. Methods A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire. Results The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi2 (1) = 1.65, p = 0.199, T1: Chi2 (1) = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion. Conclusions While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers. Trial registration https://drks.de/search/de/trial/DRKS00028895

Abstract Background Non-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia. Methods We will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel–Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach. Discussion Our network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients. Systematic review registration PROSPERO-ID CRD42023410645.

Christoph U Correll,1– 4 Celso Arango,5 Andrea Fagiolini,6 Giulia Maria Giordano,7 Stefan Leucht,4,8 Gonzalo Salazar de Pablo5,9,10 1Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 2Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA; 3Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; 4German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany; 5Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain; 6Department of Molecular Medicine, School of Medicine, University of Siena, Siena, Italy; 7Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 8Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Munich, Germany; 9Child and Adolescent Mental Health Services (CAMHS) South London and Maudsley NHS Foundation Trust London, London, UK; 10Department of Child and Adolescent Psychiatry Institute of Psychiatry, Psychology & Neuroscience King’s College London, London, UKCorrespondence: Christoph U Correll, The Zucker Hillside Hospital, Department of Psychiatry, 75-59 263rd Street Glen Oaks, New York, NY, 11004, USA, Email ccorrell@northwell.eduBackground: Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery. The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizophrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine.Methods: A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13th 2023 to narratively review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion.Results: First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics.Conclusion: Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the possibility of improved short- and long-term outcomes.Keywords: schizophrenia, first-episode psychosis, acute setting, clinical care

Daniel Guinart,1– 3 Andrea Fagiolini,4 Paolo Fusar-Poli,5– 8 Giulia Maria Giordano,9 Stefan Leucht,10 Carmen Moreno,11– 13 Christoph U Correll3,14– 16 1Institut de Salut Mental, Parc de Salut Mar, Barcelona, Spain; 2Hospital Del Mar Research Institute, CIBERSAM, Barcelona, Spain; 3Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 4Department of Molecular Medicine, University of Siena School of Medicine, Siena, Italy; 5Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; 6Department of Psychosis Studies, King’s College London, London, UK; 7Outreach and Support in South-London (OASIS) Service, South London and Maudsley (Slam) NHS Foundation Trust, London, UK; 8Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany; 9Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 10Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Munich, Germany; 11Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (LISGM), Madrid, Spain; 12Centro de Investigación Biomedica en Red (CIBERSAM), ISCIII, Madrid, Spain; 13School of Medicine, Universidad Complutense, Madrid, Spain; 14Department of Psychiatry, The Zucker Hillside Hospital, New York, NY, USA; 15Department of Child and Adolescent Psychiatry, Charité Universitatsmedizin, Berlin, Germany; 16German Center for Mental Health (DZPG), Partner Site, Berlin, GermanyCorrespondence: Christoph U Correll, Department of Psychiatry, The Zucker Hillside Hospital, 75-59 263rd Street Glen Oaks, New York, NY, 11004, USA, Email ccorrell@northwell.eduIntroduction: Schizophrenia is a severe mental illness that usually begins in late adolescence or early adulthood. Current pharmacological treatments, while acceptably effective for many patients, are rarely clinically tailored or individualized. The lack of sufficient etiopathological knowledge of the disease, together with overall comparable effect sizes for efficacy between available antipsychotics and the absence of clinically actionable biomarkers, has hindered the advance of individualized medicine in the treatment of schizophrenia. Nevertheless, some degree of stratification based on clinical markers could guide treatment choices and help clinicians move toward individualized psychiatry. To this end, a panel of experts met to formally discuss the current approach to individualized treatment in schizophrenia and to define how treatment individualization could help improve clinical outcomes.Methods: A task force of seven experts iteratively developed, evaluated, and refined questionnaire items, which were then evaluated using the Delphi method. Descriptive statistics were used to summarize and rank expert responses. Expert discussion, informed by the results of a scoping review on personalizing the pharmacologic treatment of adults and adolescents with schizophrenia, ultimately generated recommendations to guide individualized pharmacologic treatment in this population.Results: There was substantial agreement among the expert group members, resulting in the following recommendations: 1) individualization of treatment requires consideration of the patient’s diagnosis, clinical presentation, comorbidities, previous treatment response, drug tolerability, adherence patterns, and social factors; 2) patient preferences should be considered in a shared decision-making approach; 3) identified barriers to personalized care that need to be overcome include the lack of actionable biomarkers and mechanistic similarities between available treatments, but digital tools should be increasingly used to enhance individualized treatment.Conclusion: Individualized care can help provide effective, tailored treatments based on an individual’s clinical characteristics, disease trajectory, family and social environment, and goals and preferences.Keywords: psychosis, psychopharmacology, treatment, personalized, psychiatry

Background Music therapy is a commonly used intervention added to usual care for psychiatric disorders. Aims We review the evidence for music therapy and assess its efficacy as an adjunct therapy across psychiatric disorders. Method A systematic literature search was conducted in four scientific databases to identify relevant meta-analyses. Articles were assessed with the AMSTAR-2 tool. The results of the high-quality articles were recalculated with the data from the primary studies. We decided to add the results of the lower-rated articles, using a narrative approach. We pooled the primary studies and calculated standardised mean differences (SMD) for the transdiagnostic outcomes of depression, anxiety and quality of life. We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool to assess the level of evidence. Results Meta-analyses were available for autism, dementia, depression, insomnia, schizophrenia and substance use disorders. We identified 40 relevant articles. One article per domain was identified as high quality. Music therapy added to treatment as usual showed therapeutic value in each disorder. The transdiagnostic results showed a positive effect of music therapy on depression (SMD = 0.57, 95% CI 0.36–0.78), anxiety (SMD = 0.47, 95% CI 0.27–0.66) and quality of life (SMD = 0.47, 95% CI 0.24–0.71). However, these effects were not maintained at follow-up, and all results were based on low or very low evidence. Conclusions Music therapy shows promising potential as an adjunctive treatment for psychiatric disorders, but methodological weaknesses and variability limit the evidence. More high-quality, well-powered studies are needed to reliably confirm its effect size.

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Introduction Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs. Protocol First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions. Discussion This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients’ genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions.

Abstract 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.

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Abstract. Infection and chronic post-traumatic osteomyelitis of the tibia after open fracture are complex problems that cause significant morbidity and threaten the viability of a limb. Therefore, it is of utmost importance for the orthopaedic surgeon to understand both patient and treatment factors that modify the risk of developing these disastrous complications. Infection risk is largely based on severity of open injury in addition to inherent patient factors. Orthopaedic surgeons can work to mitigate this risk with prompt antibiotic administration, thorough and complete debridement, expedient fracture stabilization, and early wound closure. In the case osteomyelitis does occur, the surgeon should use a systematic multidisciplinary approach for eradication.

Aim To describe the pattern of the prevalence of mental health problems during the first year of the COVID-19 pandemic and examine the impact of containment measures on these trends.Methods We identified articles published until 30 August 2021 that reported the prevalence of mental health problems in the general population at two or more time points. A crowd of 114 reviewers extracted data on prevalence, study and participant characteristics. We collected information on the number of days since the first SARS-CoV-2 infection in the study country, the stringency of containment measures and the number of cases and deaths. We synthesised changes in prevalence during the pandemic using a random-effects model. We used dose-response meta-analysis to evaluate the trajectory of the changes in mental health problems.Results We included 41 studies for 7 mental health conditions. The average odds of symptoms increased during the pandemic (mean OR ranging from 1.23 to 2.08). Heterogeneity was very large and could not be explained by differences in participants or study characteristics. Average odds of psychological distress, depression and anxiety increased during the first 2 months of the pandemic, with increased stringency of the measures, reported infections and deaths. The confidence in the evidence was low to very low.Conclusions We observed an initial increase in the average risk of psychological distress, depression-related and anxiety-related problems during the first 2 months of the pandemic. However, large heterogeneity suggests that different populations had different responses to the challenges imposed by the pandemic.

Background and objective Various ways exist to display the effectiveness of medical treatment options. This study examined various psychiatric, medical and allied professionals’ understanding and perceived usefulness of eight effect size indices for presenting both dichotomous and continuous outcome data.Methods We surveyed 1316 participants from 13 countries using an online questionnaire. We presented hypothetical treatment effects of interventions versus placebo concerning chronic pain using eight different effect size measures. For each index, the participants had to judge the magnitude of the shown effect, to indicate how certain they felt about their own answer and how useful they found the given effect size index.Findings Overall, 762 (57.9%) participants fully completed the questionnaire. In terms of understanding, the best results emerged when both the control event rate (CER) and the experimental event rate (EER) were presented. The difference in minimal importance difference units (MID unit) was understood worst. Respondents also found CER and EER to be the most useful presentation approach while they rated MID unit as the least useful. Confidence in the risk ratio ranked high, even though it was rather poorly understood.Conclusions and clinical implications For dichotomous outcomes, presenting the effects in terms of the CER and EER could lead to the most correct interpretation. Relative measures including the risk ratio must be supplemented with absolute measures such as the CER and EER. Effects on continuous outcomes were better understood through standardised mean differences than mean differences. These can also be supplemented by dichotomised CER and EER.

Abstract Negative symptoms of schizophrenia are linked with poor functioning and quality of life. Therefore, appropriate measurement tools to assess negative symptoms are needed. The NIMH-MATRICS Consensus defined five domains for negative symptoms. We used the COSMIN guidelines for systematic reviews to evaluate the quality of psychometric data of negative symptom scales as Clinician-Rated Outcome Measure (ClinROM). COSMIN assesses risk of bias, so called updated criteria of measurement properties, a modified GRADE approach and a final judgement on the rating scale. In the lecture the process will be described using the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms (CAINS) as examples. Disclosure of Interest None Declared

Background Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions TAAR1 agonists may be less efficacious than dopamine D2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration PROSPERO-ID:CRD42023451628.

Abstract Background The relative treatment effects estimated from network meta-analysis can be employed to rank treatments from the most preferable to the least preferable option. These treatment hierarchies are typically based on ranking metrics calculated from a single outcome. Some approaches have been proposed in the literature to account for multiple outcomes and individual preferences, such as the coverage area inside a spie chart, that, however, does not account for a trade-off between efficacy and safety outcomes. We present the net-benefit standardised area within a spie chart, $$SAWIS$$ SAWIS to explore the changes in treatment performance with different trade-offs between benefits and harms, according to a particular set of preferences. Methods We combine the standardised areas within spie charts for efficacy and safety/acceptability outcomes with a value λ specifying the trade-off between benefits and harms. We derive absolute probabilities and convert outcomes on a scale between 0 and 1 for inclusion in the spie chart. Results We illustrate how the treatments in three published network meta-analyses perform as the trade-off λ varies. The decrease of the $$SAWIS$$ SAWIS quantity appears more pronounced for some drugs, e.g. haloperidol. Changes in treatment performance seem more frequent when SUCRA is employed as outcome measures in the spie charts. Conclusions $$SAWIS$$ SAWIS should not be interpreted as a ranking metric but it is a simple approach that could help identify which treatment is preferable when multiple outcomes are of interest and trading-off between benefits and harms is important.

Abstract Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Abstract. The immune system plays an integral role in the regulation of cellular processes responsible for fracture healing. Local and systemic influences on fracture healing correlate in many ways with fracture-related outcomes, including soft tissue healing quality and fracture union rates. Impaired soft tissue healing, restricted perfusion of a fracture site, and infection also in turn affect the immune response to fracture injury. Modern techniques used to investigate the relationship between immune system function and fracture healing include precision medicine, using vast quantities of data to interpret broad patterns of inflammatory response. Early data from the PRECISE trial have demonstrated distinct patterns of inflammatory response in polytrauma patients, which thereby directly and indirectly regulate the fracture healing response. The clearly demonstrated linkage between immune function and fracture healing suggests that modulation of immune function has significant potential as a therapeutic target that can be used to enhance fracture healing.

BackgroundIn recent years, a growing body of evidence has demonstrated the efficacy of non-pharmacological interventions for schizophrenia spectrum disorders (SSD) including positive symptoms such as auditory hallucinations (AH). However, clinical trials predominantly examine general treatment effects for positive symptoms. Therefore, previous research is lacking in comprehensive and clear evidence about psychological and psychosocial approaches that are primarily tailored to treat AH. To overcome this knowledge gap in the current literature, we will conduct a systematic review and meta-analysis to assess the efficacy of clearly targeted psychological and psychosocial interventions for AH in persons with SSD.Methods and analysisThis study protocol has been developed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We will include all randomized controlled trials analyzing the efficacy of targeted psychological and psychosocial interventions especially aimed at treating AH in SSD. We will include studies on adult patients with SSD experiencing AH. The primary outcome will be the change on a published rating scale measuring AH. Secondary outcomes will be delusions, overall symptoms, negative symptoms, depression, social functioning, quality of life, and acceptability (drop-out). We will search relevant databases and the reference lists of included literature. The study selection process will be conducted by two independent reviewers. We will conduct a random-effect meta-analysis to consider heterogeneity across studies. Analyses will be carried out by software packages in R. The risk of bias in each study will be evaluated using the Cochrane Risk of Bias tool. Assessment of heterogeneity and sensitivity analysis will be conducted.DiscussionThe proposed study will augment the existing evidence by providing an overview of effective treatment approaches and their overall efficacy at treating AH in SSD. These findings will complement existing evidence that may impact future treatment implementations in clinical practice by addressing effective strategies to treat AH and therefore improve outcomes for the addressed population.Ethics and disseminationNo ethical issues are foreseen. We will publish the results from this study in peer-reviewed journals and at relevant scientific conferences.Trial registrationPROSPERO registration number: CRD42023475704.

Abstract Background A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer’s disease. Hence, we aimed to shorten the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure. Methods Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer’s disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups. Results Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34). Conclusions IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.