Most recommended medical interventions reach P<0.005 for their primary outcomes in meta-analyses.

This is a pre-copyedited, author-produced version of an article accepted for publication in International Journal of Epidemiology, following peer review. The version of record: Despina Koletsi, Marco Solmi, Nikolaos Pandis, Padhraig S Fleming, Christoph U Correll, John P A Ioannidis, Most recommended medical interventions reach P<0.005 for their primary outcomes in meta-analyses, International Journal of Epidemiology, dyz241, https://doi.org/10.1093/ije/dyz241 is available online at: https://doi.org/10.1093/ije/dyz241.BACKGROUND: It has been proposed that the threshold of statistical significance should shift from P-value < 0.05 to P-value < 0.005, but there is concern that this move may dismiss effective, useful interventions. We aimed to assess how often medical interventions are recommended although their evidence in meta-analyses of randomized trials lies between P-value = 0.05 and P-value = 0.005. METHODS: We included Cochrane systematic reviews (SRs) published from 1 January 2013 to 30 June 2014 that had at least one meta-analysis with GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment and at least one primary outcome having favourable results for efficacy at P-value < 0.05. Only comparisons of randomized trials between active versus no treatment/placebo were included. We then assessed the respective UpToDate recommendations for clinical practice from 22 May 2018 to 5 October 2018 and recorded how many treatments were recommended and what were the P-values in their meta-analysis evidence. The primary analysis was based on the first-listed outcomes. RESULTS: Of 608 screened SRs with GRADE assessment, 113 SRs were eligible, including 143 comparisons of which 128 comparisons had first-listed primary outcomes with UpToDate coverage. Altogether, 60% (58/97) of interventions with P-values < 0.005 for their evidence were recommended versus 32% (10/31) of those with P-value 0.005-0.05. Therefore, most (58/68, 85.2%) of the recommended interventions had P-values < 0.005 for the first-listed primary outcome. Of the 10 exceptions, 4 had other primary outcomes with P-values < 0.005 and another 4 had additional extensive evidence for similar indications that would allow extrapolation for practice recommendations. CONCLUSIONS: Few interventions are recommended without their evidence from meta-analyses of randomized trials reaching P-value < 0.005

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

Staging Bipolar Disorder.

The purpose of this study was to analyze the evidence supporting a staging model for bipolar disorder. The authors conducted an extensive Medline and Pubmed search of the published literature using a variety of search terms (staging, bipolar disorder, early intervention) to find relevant articles, which were reviewed in detail. Only recently specific proposals have been made to apply clinical staging to bipolar disorder. The staging model in bipolar disorder suggests a progression from prodromal (at-risk) to more severe and refractory presentations (Stage IV). A staging model implies a longitudinal appraisal of different aspects: clinical variables, such as number of episodes and subsyndromal symptoms, functional and cognitive impairment, comorbidity, biomarkers, and neuroanatomical changes. Staging models are based on the fact that response to treatment is generally better when it is introduced early in the course of the illness. It assumes that earlier stages have better prognosis and require simpler therapeutic regimens. Staging may assist in bipolar disorder treatment planning and prognosis, and emphasize the importance of early intervention. Further research is required in this exciting and novel area

Finding the Right Setting for the Right Treatment During the Acute Treatment of Individuals with Schizophrenia: A Narrative Review and Clinical Practice Guideline

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 [email protected]: 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 car

Monitoring and prevalence rates of metabolic syndrome in military veterans with serious mental illness

Background: Cardiovascular disease is the leading cause of mortality among patients with serious mental illness (SMI) and the prevalence of metabolic syndrome-a constellation of cardiovascular risk factors-is significantly higher in these patients than in the general population. Metabolic monitoring among patients using second generation antipsychotics (SGAs)-a risk factor for metabolic syndrome-has been shown to be inadequate despite the release of several guidelines. However, patients with SMI have several factors independent of medication use that predispose them to a higher prevalence of metabolic syndrome. Our study therefore examines monitoring and prevalence of metabolic syndrome in patients with SMI, including those not using SGAs. Methods and Findings: We retrospectively identified all patients treated at a Veterans Affairs Medical Center with diagnoses of schizophrenia, schizoaffective disorder or bipolar disorder during 2005-2006 and obtained demographic and clinical data. Incomplete monitoring of metabolic syndrome was defined as being unable to determine the status of at least one of the syndrome components. Of the 1,401 patients included (bipolar disorder: 822; schizophrenia: 222; and schizoaffective disorder: 357), 21.4% were incompletely monitored. Only 54.8% of patients who were not prescribed SGAs and did not have previous diagnoses of hypertension or hypercholesterolemia were monitored for all metabolic syndrome components compared to 92.4% of patients who had all three of these characteristics. Among patients monitored for metabolic syndrome completely, age-adjusted prevalence of the syndrome was 48.4%, with no significant difference between the three psychiatric groups. Conclusions: Only one half of patients with SMI not using SGAs or previously diagnosed with hypertension and hypercholesterolemia were completely monitored for metabolic syndrome components compared to greater than 90% of those with these characteristics. With the high prevalence of metabolic syndrome seen in this population, there appears to be a need to intensify efforts to reduce this monitoring gap

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents

Background: Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives: The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods: Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results: In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th–75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0–180.5 µg/L]) than in non-responders (58.0 µg/L [14.9–105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions: Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100–400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account

Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event

addresses: Peninsula College of Medicine and Dentistry, St Luke's Campus, University of Exeter, Exeter, UK. [email protected]: PMCID: PMC3528446types: Journal Article; Research Support, Non-U.S. Gov't© 2012 Warren et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Adverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention