Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00273-1
Melissa P DelBello, Jeffrey A Welge, Christina C Klein, Thomas J Blom, Victor Fornari, Claudine Higdon, Michael T Sorter, Brian Kurtz, Cindy Starr, Andrew Smith, Bin Huang, Chen Chen, Avani C Modi, Nancy Crimmins, Christoph U Correll
<h3>Background</h3>Second-generation antipsychotics are widely used to treat patients with bipolar spectrum disorders and effectively manage mood symptoms but can often cause substantial weight gain and other metabolic alterations that elevate long-term risks of cardiovascular disease and premature mortality. Metformin has been shown to be safe and efficacious for ameliorating weight gain but has not been evaluated in typical clinical settings or for more than 6 months in this population and is not widely used as standard of care. Therefore, we conducted a pragmatic clinical trial to assess the effect of metformin treatment in young people treated with second-generation antipsychotics who had a bipolar spectrum disorder along with overweight or obesity.<h3>Methods</h3>In this multi-site, open-label, pragmatic parallel group study, we enrolled overweight or obese youth aged 8–19 years, previously or currently diagnosed with a bipolar spectrum disorder, and treated with or starting a second-generation antipsychotic. Participants were recruited and followed at 64 clinical sites (community-based mental health centres or academic health centres) in the USA. Sites were eligible for participation if they projected an enrolment rate of at least three patients per month and a minimum total number of 90 patients. Participants were randomly assigned (1:1) to the healthy eating and physical activity (LIFE) or the metformin plus LIFE (MET plus LIFE) interventions, within eight strata defined by baseline BMI percentile (overweight [85th to <95th] <em>vs</em> obese [≥95th]); second-generation antipsychotic-naive (starting <em>vs</em> continuing a second-generation antipsychotic at baseline); and sex assigned at birth, and using block randomisation (blocks of six). The co-primary outcomes were change in age-normalised and sex-normalised BMI Z-score at 6 months and 24 months in the intention-to-treat population. People with lived experience with bipolar disorders were involved in the design, conduct, and reporting of this trial. The Patient-Centered Outcomes Research Institute identification was PCS-1406-19276 and the study was registered at ClinicalTrials.gov, NCT02515773, and is completed.<h3>Findings</h3>Between Nov 5, 2015, and Feb 10, 2022, 1633 individuals provided consent for study inclusion, 68 were excluded (26 withdrew before baseline assessments and 42 did not pass screening assessments), and 1565 were randomly assigned (777 assigned to the MET plus LIFE group and 788 assigned to the LIFE group). Data were available from 1252 participants at month 6 (565 in the MET plus LIFE group and 687 in the LIFE group), and 1299 participants at month 24 (579 in the MET plus LIFE group and 720 in the LIFE group). 829 (53%) participants were male and 736 (47%) were female. The mean age of participants was 13·9 years (SD 2·9). 1023 (65%) were White or Caucasian and 290 (19%) were Black or African American. After 6 months and 24 months, assignment to the MET plus L
{"title":"Metformin for overweight and obese children and adolescents with bipolar spectrum and related mood disorders treated with second-generation antipsychotics: a randomised, pragmatic trial","authors":"Melissa P DelBello, Jeffrey A Welge, Christina C Klein, Thomas J Blom, Victor Fornari, Claudine Higdon, Michael T Sorter, Brian Kurtz, Cindy Starr, Andrew Smith, Bin Huang, Chen Chen, Avani C Modi, Nancy Crimmins, Christoph U Correll","doi":"10.1016/s2215-0366(25)00273-1","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00273-1","url":null,"abstract":"<h3>Background</h3>Second-generation antipsychotics are widely used to treat patients with bipolar spectrum disorders and effectively manage mood symptoms but can often cause substantial weight gain and other metabolic alterations that elevate long-term risks of cardiovascular disease and premature mortality. Metformin has been shown to be safe and efficacious for ameliorating weight gain but has not been evaluated in typical clinical settings or for more than 6 months in this population and is not widely used as standard of care. Therefore, we conducted a pragmatic clinical trial to assess the effect of metformin treatment in young people treated with second-generation antipsychotics who had a bipolar spectrum disorder along with overweight or obesity.<h3>Methods</h3>In this multi-site, open-label, pragmatic parallel group study, we enrolled overweight or obese youth aged 8–19 years, previously or currently diagnosed with a bipolar spectrum disorder, and treated with or starting a second-generation antipsychotic. Participants were recruited and followed at 64 clinical sites (community-based mental health centres or academic health centres) in the USA. Sites were eligible for participation if they projected an enrolment rate of at least three patients per month and a minimum total number of 90 patients. Participants were randomly assigned (1:1) to the healthy eating and physical activity (LIFE) or the metformin plus LIFE (MET plus LIFE) interventions, within eight strata defined by baseline BMI percentile (overweight [85th to <95th] <em>vs</em> obese [≥95th]); second-generation antipsychotic-naive (starting <em>vs</em> continuing a second-generation antipsychotic at baseline); and sex assigned at birth, and using block randomisation (blocks of six). The co-primary outcomes were change in age-normalised and sex-normalised BMI Z-score at 6 months and 24 months in the intention-to-treat population. People with lived experience with bipolar disorders were involved in the design, conduct, and reporting of this trial. The Patient-Centered Outcomes Research Institute identification was PCS-1406-19276 and the study was registered at ClinicalTrials.gov, NCT02515773, and is completed.<h3>Findings</h3>Between Nov 5, 2015, and Feb 10, 2022, 1633 individuals provided consent for study inclusion, 68 were excluded (26 withdrew before baseline assessments and 42 did not pass screening assessments), and 1565 were randomly assigned (777 assigned to the MET plus LIFE group and 788 assigned to the LIFE group). Data were available from 1252 participants at month 6 (565 in the MET plus LIFE group and 687 in the LIFE group), and 1299 participants at month 24 (579 in the MET plus LIFE group and 720 in the LIFE group). 829 (53%) participants were male and 736 (47%) were female. The mean age of participants was 13·9 years (SD 2·9). 1023 (65%) were White or Caucasian and 290 (19%) were Black or African American. After 6 months and 24 months, assignment to the MET plus L","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"110 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00309-8
Aoife Carolan, Caroline Hynes-Ryan, Donal O'Shea, Dolores Keating, Brian O’Donoghue
Melissa DelBello and colleagues1 should be commended on their clinical trial evaluating the effectiveness of metformin in mitigating weight gain in young people with bipolar disorder and related mood disorders taking second-generation antipsychotics. This clinical trial has many merits, including being sufficiently powered, and focusing on children and adolescents who are often neglected in clinical trials but are more prone to metabolic side effects. Furthermore, the trial had a long follow-up period of 2 years and examined the efficacy of an agent that is long off patent. We wish to expand upon the points raised by DelBello and colleagues regarding the preventative use of metformin; the role of glucagon-like peptide-1 (GLP-1) receptor agonists; and how the findings of this clinical trial could be implemented in routine clinical practice.
{"title":"Metformin: translating the evidence for prevention of weight gain","authors":"Aoife Carolan, Caroline Hynes-Ryan, Donal O'Shea, Dolores Keating, Brian O’Donoghue","doi":"10.1016/s2215-0366(25)00309-8","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00309-8","url":null,"abstract":"Melissa DelBello and colleagues<span><span><sup>1</sup></span></span> should be commended on their clinical trial evaluating the effectiveness of metformin in mitigating weight gain in young people with bipolar disorder and related mood disorders taking second-generation antipsychotics. This clinical trial has many merits, including being sufficiently powered, and focusing on children and adolescents who are often neglected in clinical trials but are more prone to metabolic side effects. Furthermore, the trial had a long follow-up period of 2 years and examined the efficacy of an agent that is long off patent. We wish to expand upon the points raised by DelBello and colleagues regarding the preventative use of metformin; the role of glucagon-like peptide-1 (GLP-1) receptor agonists; and how the findings of this clinical trial could be implemented in routine clinical practice.","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00329-3
Deanna M Barch
In this issue of the Lancet Psychiatry, Richard S E Keefe and colleagues1 report on the findings from a set of three phase 3 randomised, placebo-controlled, double-blind clinical trials of a drug called iclepertin for the treatment of cognitive impairment associated with schizophrenia (CIAS). Iclepertin is a selective GlyT1 inhibitor that was designed to try to improve NMDA receptor hypofunction in schizophrenia, one mechanism hypothesised to contribute to CIAS.
在这一期的《柳叶刀精神病学》上，Richard S . E . Keefe和他的同事们报道了一种名为iclepertin的药物治疗与精神分裂症相关的认知障碍（CIAS）的3期随机、安慰剂对照、双盲临床试验的结果。Iclepertin是一种选择性GlyT1抑制剂，旨在改善精神分裂症患者的NMDA受体功能低下，这是一种可能导致CIAS的机制。
{"title":"Enhancing cognitive function in schizophrenia: we must make better choices","authors":"Deanna M Barch","doi":"10.1016/s2215-0366(25)00329-3","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00329-3","url":null,"abstract":"In this issue of the <em>Lancet Psychiatry</em>, Richard S E Keefe and colleagues<span><span><sup>1</sup></span></span> report on the findings from a set of three phase 3 randomised, placebo-controlled, double-blind clinical trials of a drug called iclepertin for the treatment of cognitive impairment associated with schizophrenia (CIAS). Iclepertin is a selective GlyT1 inhibitor that was designed to try to improve NMDA receptor hypofunction in schizophrenia, one mechanism hypothesised to contribute to CIAS.","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"159 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00276-7
Rowalt Alibudbud
In their third report, entitled Implementing lifestyle interventions in mental health care, the Lancet Psychiatry Physical Health Commission discussed the fact that people with mental illness face higher rates of physical health issues, which contribute to a 13–15-year reduction in life expectancy.1 Although lifestyle interventions can improve physical and mental health, they are not consistently included in mental health services.1 Tailoring these interventions to socioeconomic conditions is crucial, particularly in low-income and middle-income countries (LMICs), where mental health systems are often underdeveloped and underfunded.1, 2
{"title":"Lifestyle interventions in mental health care in the Philippines","authors":"Rowalt Alibudbud","doi":"10.1016/s2215-0366(25)00276-7","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00276-7","url":null,"abstract":"In their third report, entitled <em>Implementing lifestyle interventions in mental health care</em>, the <em>Lancet Psychiatry</em> Physical Health Commission discussed the fact that people with mental illness face higher rates of physical health issues, which contribute to a 13–15-year reduction in life expectancy.<span><span><sup>1</sup></span></span> Although lifestyle interventions can improve physical and mental health, they are not consistently included in mental health services.<span><span><sup>1</sup></span></span> Tailoring these interventions to socioeconomic conditions is crucial, particularly in low-income and middle-income countries (LMICs), where mental health systems are often underdeveloped and underfunded.<span><span>1</span></span>, <span><span>2</span></span>","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"141 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00296-2
Richard S E Keefe, Philip D Harvey, Christoph U Correll, Peter Falkai, Naoki Hashimoto, Hans Klein, John H Krystal, Stephen Marder, Alice Medalia, Tomiki Sumiyoshi, Gang Wang, Hongyan Zhang, Zuzana Blahova, Ingrid Bichard-Sall, Brett A English, Eric Fu, Fredrik Gruenenfelder, Martina Groeschl, Karen Kimura, Wenbo Tang, Corey Fowler
Background
There are no pharmacotherapies available for cognitive impairment associated with schizophrenia (CIAS). The CONNEX programme investigated the efficacy and safety of iclepertin, a glycine transporter-1 (GlyT1) inhibitor, for the treatment of CIAS.
Methods
CONNEX-1, CONNEX-2, and CONNEX-3 were phase 3, randomised, double-blind, placebo-controlled trials conducted across 338 specialist psychiatric centres in 41 countries. Adults aged 18–50 years with schizophrenia were randomised 1:1 using interactive response technology to oral 10 mg iclepertin or placebo once daily for 26 weeks in combination with standard-of-care antipsychotic therapy. Patients, investigators, and trial personnel were masked to treatment assignment. The primary endpoint was change from baseline at week 26 in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) overall composite T-score. Efficacy analyses included randomly allocated patients, excluding those allocated in error or who discontinued from the trial before receiving treatment. Safety and tolerability assessments included adverse event monitoring in patients who received one or more doses of trial medication. These trials were registered with ClinicalTrials.gov (NCT04846868, NCT04846881, NCT04860830) and are complete. Individuals with lived experience informed the trial designs and selection of outcome measures; they were not involved in the writing process.
Findings
Between Sept 8, 2021, and April 24, 2024, 1835 patients were recruited and received at least one dose of trial medication (918 for iclepertin and 917 for placebo); 1602 patients completed treatment. 1207 (66%) of 1836 patients were male and 629 (34%) patients were female. Most patients were either White (903 [49%]) or Asian (558 [30%]), and the majority were not of Hispanic or Latino ethnicity (1238 [67%]). The mean age was 34·7 years (SD 8·8). At week 26, there was no significant difference between treatment groups in the primary endpoint. The adjusted mean difference for iclepertin versus placebo for MCCB overall composite T-score was 0·127 [95% CI −0·396 to 0·650]; p=0·63). On-treatment adverse events were reported in 604 (66%) of 918 and 633 (69%) of 917 patients in the iclepertin and placebo groups, respectively. One patient receiving placebo died during the treatment period; the death was deemed unrelated to the trial treatment.
Interpretation
Iclepertin was not associated with significant improvements in cognition in adults with schizophrenia, but it was well tolerated by patients. Findings from CONNEX provide insights into the challenges associated with studying new pharmacotherapies for CIAS.
{"title":"Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials","authors":"Richard S E Keefe, Philip D Harvey, Christoph U Correll, Peter Falkai, Naoki Hashimoto, Hans Klein, John H Krystal, Stephen Marder, Alice Medalia, Tomiki Sumiyoshi, Gang Wang, Hongyan Zhang, Zuzana Blahova, Ingrid Bichard-Sall, Brett A English, Eric Fu, Fredrik Gruenenfelder, Martina Groeschl, Karen Kimura, Wenbo Tang, Corey Fowler","doi":"10.1016/s2215-0366(25)00296-2","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00296-2","url":null,"abstract":"<h3>Background</h3>There are no pharmacotherapies available for cognitive impairment associated with schizophrenia (CIAS). The CONNEX programme investigated the efficacy and safety of iclepertin, a glycine transporter-1 (GlyT1) inhibitor, for the treatment of CIAS.<h3>Methods</h3>CONNEX-1, CONNEX-2, and CONNEX-3 were phase 3, randomised, double-blind, placebo-controlled trials conducted across 338 specialist psychiatric centres in 41 countries. Adults aged 18–50 years with schizophrenia were randomised 1:1 using interactive response technology to oral 10 mg iclepertin or placebo once daily for 26 weeks in combination with standard-of-care antipsychotic therapy. Patients, investigators, and trial personnel were masked to treatment assignment. The primary endpoint was change from baseline at week 26 in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) overall composite T-score. Efficacy analyses included randomly allocated patients, excluding those allocated in error or who discontinued from the trial before receiving treatment. Safety and tolerability assessments included adverse event monitoring in patients who received one or more doses of trial medication. These trials were registered with ClinicalTrials.gov (NCT04846868, NCT04846881, NCT04860830) and are complete. Individuals with lived experience informed the trial designs and selection of outcome measures; they were not involved in the writing process.<h3>Findings</h3>Between Sept 8, 2021, and April 24, 2024, 1835 patients were recruited and received at least one dose of trial medication (918 for iclepertin and 917 for placebo); 1602 patients completed treatment. 1207 (66%) of 1836 patients were male and 629 (34%) patients were female. Most patients were either White (903 [49%]) or Asian (558 [30%]), and the majority were not of Hispanic or Latino ethnicity (1238 [67%]). The mean age was 34·7 years (SD 8·8). At week 26, there was no significant difference between treatment groups in the primary endpoint. The adjusted mean difference for iclepertin versus placebo for MCCB overall composite T-score was 0·127 [95% CI −0·396 to 0·650]; p=0·63). On-treatment adverse events were reported in 604 (66%) of 918 and 633 (69%) of 917 patients in the iclepertin and placebo groups, respectively. One patient receiving placebo died during the treatment period; the death was deemed unrelated to the trial treatment.<h3>Interpretation</h3>Iclepertin was not associated with significant improvements in cognition in adults with schizophrenia, but it was well tolerated by patients. Findings from CONNEX provide insights into the challenges associated with studying new pharmacotherapies for CIAS.<h3>Funding</h3>Boehringer Ingelheim.","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"138 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/s2215-0366(25)00337-2
The 2025 UN High-Level Meeting on the Prevention and Control of Noncommunicable Diseases and the Promotion of Mental Health marked an important turning point for mental health. Never before had the UN General Assembly put forth a political declaration with mental health as a central component. Although the declaration did not reach formal consensus endorsement, the message from the high-level meeting was clear: mental health is a global concern that requires a coordinated global response.
{"title":"The importance of partnerships","authors":"","doi":"10.1016/s2215-0366(25)00337-2","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00337-2","url":null,"abstract":"The 2025 UN High-Level Meeting on the Prevention and Control of Noncommunicable Diseases and the Promotion of Mental Health marked an important turning point for mental health. Never before had the UN General Assembly put forth <span><span>a political declaration</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> with mental health as a central component. Although the declaration did not reach formal consensus endorsement, the message from the high-level meeting was clear: mental health is a global concern that requires a coordinated global response.","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"1 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/s2215-0366(25)00299-8
Jamileh Shadid, Alize J Ferrari, Bo Bach, Martin Sellbom, Carla Sharp, Joost Hutsebaut, Delfine d'Huart, Damian F Santomauro, Andrew Chanen
<h3>Background</h3>Personality disorder is a persistent and pervasive mental disorder, defined as an enduring pattern of inner experience and behaviour that deviates markedly from the expectations of an individual's culture, but it remains under-recognised in global mental health estimates. To our knowledge, no comprehensive synthesis has quantified the global prevalence, mortality, or diagnostic stability of personality disorder using population-representative data. We aimed to address these gaps to support future burden of disease modelling.<h3>Methods</h3>We conducted a systematic review and meta-regression of population-based surveys following PRISMA and GATHER guidelines. Eligible studies were cross-sectional or longitudinal studies published in peer-reviewed journals that reported prevalence or mortality associated with any personality disorder using DSM or ICD diagnostic criteria on representative samples. Personality disorder encompassed paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive, and other specified and unspecified personality disorders. Studies using self-report instruments and non-representative samples (eg, clinical, incarcerated, or university populations) were excluded. Studies were identified through systematic searches in PubMed, Embase, and PsycINFO from Jan 1, 1980, to Feb 13, 2024. Studies were reviewed (by JS and a research assistant), and eligible data were extracted by JS. All data were non-identifiable and pre-aggregated from existing sources. Study quality was assessed using Joanna Briggs Institute critical appraisal tools. Due to data availability, we did two separate meta-regression analyses to estimate the prevalence and standardised mortality ratios associated with personality disorder, and a descriptive analysis to examine diagnostic stability. Between-study heterogeneity was assessed using the <em>I</em><sup>2</sup> statistic. Meta-regression models assessed the effect of study-level covariates. Members of our authorship team have lived personal experience with mental disorders, but we did not consult individuals diagnosed with personality disorder for this work. The study is registered with PROSPERO, CRD42021269169.<h3>Findings</h3>We identified 60 studies across 28 countries. Prevalence analyses included 139 373 individuals, and mortality analyses included 392 420 individuals with a personality disorder. Between-study heterogeneity was high for prevalence (<em>I</em><sup>2</sup>=98·8%) and mortality (<em>I</em><sup>2</sup>=99·4%). Study quality assessment indicated that 59 studies were of high quality, with only one study of moderate quality. Pooled prevalence of any personality disorder ranged from 4·1% (95% uncertainty interval [UI] 2·8–6·0) in low-income and middle-income countries to 5·2% (3·7–7·3) in high-income countries for mid-age 43 years. Prevalence was found to be higher among male individuals (compared with female individu
{"title":"The global epidemiology of personality disorder: a systematic review and meta-regression","authors":"Jamileh Shadid, Alize J Ferrari, Bo Bach, Martin Sellbom, Carla Sharp, Joost Hutsebaut, Delfine d'Huart, Damian F Santomauro, Andrew Chanen","doi":"10.1016/s2215-0366(25)00299-8","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00299-8","url":null,"abstract":"<h3>Background</h3>Personality disorder is a persistent and pervasive mental disorder, defined as an enduring pattern of inner experience and behaviour that deviates markedly from the expectations of an individual's culture, but it remains under-recognised in global mental health estimates. To our knowledge, no comprehensive synthesis has quantified the global prevalence, mortality, or diagnostic stability of personality disorder using population-representative data. We aimed to address these gaps to support future burden of disease modelling.<h3>Methods</h3>We conducted a systematic review and meta-regression of population-based surveys following PRISMA and GATHER guidelines. Eligible studies were cross-sectional or longitudinal studies published in peer-reviewed journals that reported prevalence or mortality associated with any personality disorder using DSM or ICD diagnostic criteria on representative samples. Personality disorder encompassed paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive, and other specified and unspecified personality disorders. Studies using self-report instruments and non-representative samples (eg, clinical, incarcerated, or university populations) were excluded. Studies were identified through systematic searches in PubMed, Embase, and PsycINFO from Jan 1, 1980, to Feb 13, 2024. Studies were reviewed (by JS and a research assistant), and eligible data were extracted by JS. All data were non-identifiable and pre-aggregated from existing sources. Study quality was assessed using Joanna Briggs Institute critical appraisal tools. Due to data availability, we did two separate meta-regression analyses to estimate the prevalence and standardised mortality ratios associated with personality disorder, and a descriptive analysis to examine diagnostic stability. Between-study heterogeneity was assessed using the <em>I</em><sup>2</sup> statistic. Meta-regression models assessed the effect of study-level covariates. Members of our authorship team have lived personal experience with mental disorders, but we did not consult individuals diagnosed with personality disorder for this work. The study is registered with PROSPERO, CRD42021269169.<h3>Findings</h3>We identified 60 studies across 28 countries. Prevalence analyses included 139 373 individuals, and mortality analyses included 392 420 individuals with a personality disorder. Between-study heterogeneity was high for prevalence (<em>I</em><sup>2</sup>=98·8%) and mortality (<em>I</em><sup>2</sup>=99·4%). Study quality assessment indicated that 59 studies were of high quality, with only one study of moderate quality. Pooled prevalence of any personality disorder ranged from 4·1% (95% uncertainty interval [UI] 2·8–6·0) in low-income and middle-income countries to 5·2% (3·7–7·3) in high-income countries for mid-age 43 years. Prevalence was found to be higher among male individuals (compared with female individu","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-02DOI: 10.1016/s2215-0366(25)00297-4
Jurjen J Luykx, Mark Colgan, Eduard Vieta, Aleksi Hamina, Peter F J Schulte, Christoph U Correll, Ellenor Mittendorfer-Rutz, Dan Siskind, Johannes Lieslehto, Antti Tanskanen, Jari Tiihonen, Heidi Taipale
<h3>Background</h3>Pharmacotherapy with clozapine is listed as an optional treatment for several psychiatric disorders in guidelines across the globe. Nonetheless, its transdiagnostic effectiveness across most psychiatric disorders remains uncertain due to scant evidence. We therefore aimed to assess the effectiveness and safety of clozapine across multiple psychiatric disorders.<h3>Methods</h3>This cohort study used nationwide register-based data from Finland and Sweden in individuals aged 16 years or older diagnosed with schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, psychotic depression, major depressive disorder, and borderline personality disorder (BPD). The effectiveness of clozapine was compared with other oral antipsychotics as a group, and for bipolar disorder additionally against mood stabilisers. The primary outcome was all-cause psychiatric hospitalisation. Secondary outcomes were all-cause hospitalisation or mortality as a composite outcome, all-cause discontinuation (for which clozapine use was compared with olanzapine use), and disorder-specific hospitalisations (eg, hospitalisation due to psychosis for schizophrenia-spectrum disorders and hospitalisation due to mood episodes for affective disorders). A within-individual design was used, where each patient served as their own control, minimising selection bias. Data were analysed separately in each country and combined using meta-analytical methods. People with lived experience were not involved in the research and writing process.<h3>Findings</h3>The study population included 505 474 individuals, of whom 283 809 (56·1%) were women and 221 665 (43·9%) were men, with a mean age of 41·6 years (SD 4·4). Data on ethnicity were unavailable. Altogether, clozapine was used by 19 910 individuals. Parsed by disorder, clozapine was used by 12·2–18·7% (n=5258 in Sweden, 10 115 in Finland) of people with schizophrenia, 8·8–20·7% (n=1131, n=1591) with schizoaffective disorder, 1·8% (n=341; data only available in Sweden) with delusional disorder, 0·5% (n=118, n=331) with major depressive disorder, 0·5–0·6% (n=490, n=371) with bipolar disorder, 0·3–0·6% (n=39, n=111) with psychotic depression, and 0·3% (n=36; data only available in Sweden) with BPD. Clozapine use was associated with reduced psychiatric hospitalisation risks versus other oral antipsychotics in all disorders, except for BPD. The greatest reductions were observed in schizophrenia (meta-analysis of adjusted hazard ratios [maHR] 0·70 [95% CI 0·67–0·72]) and schizoaffective disorder (maHR 0·71 [0·67–0·74]), followed by delusional disorder (adjusted hazard ratio 0·73 [0·60–0·89]), major depressive disorder (maHR 0·74 [0·66–0·84]), psychotic depression (maHR 0·76 [0·61–0·96]), and bipolar disorder (maHR 0·77 [0·69–0·87]). Moreover, we found no evidence of increased all-cause hospitalisation or mortality risks associated with clozapine use for all disorders examined. Furthermore, for all disorders studied
{"title":"Transdiagnostic effectiveness and safety of clozapine in individuals with psychotic, affective, and personality disorders: nationwide and meta-analytic comparisons with other antipsychotics","authors":"Jurjen J Luykx, Mark Colgan, Eduard Vieta, Aleksi Hamina, Peter F J Schulte, Christoph U Correll, Ellenor Mittendorfer-Rutz, Dan Siskind, Johannes Lieslehto, Antti Tanskanen, Jari Tiihonen, Heidi Taipale","doi":"10.1016/s2215-0366(25)00297-4","DOIUrl":"https://doi.org/10.1016/s2215-0366(25)00297-4","url":null,"abstract":"<h3>Background</h3>Pharmacotherapy with clozapine is listed as an optional treatment for several psychiatric disorders in guidelines across the globe. Nonetheless, its transdiagnostic effectiveness across most psychiatric disorders remains uncertain due to scant evidence. We therefore aimed to assess the effectiveness and safety of clozapine across multiple psychiatric disorders.<h3>Methods</h3>This cohort study used nationwide register-based data from Finland and Sweden in individuals aged 16 years or older diagnosed with schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, psychotic depression, major depressive disorder, and borderline personality disorder (BPD). The effectiveness of clozapine was compared with other oral antipsychotics as a group, and for bipolar disorder additionally against mood stabilisers. The primary outcome was all-cause psychiatric hospitalisation. Secondary outcomes were all-cause hospitalisation or mortality as a composite outcome, all-cause discontinuation (for which clozapine use was compared with olanzapine use), and disorder-specific hospitalisations (eg, hospitalisation due to psychosis for schizophrenia-spectrum disorders and hospitalisation due to mood episodes for affective disorders). A within-individual design was used, where each patient served as their own control, minimising selection bias. Data were analysed separately in each country and combined using meta-analytical methods. People with lived experience were not involved in the research and writing process.<h3>Findings</h3>The study population included 505 474 individuals, of whom 283 809 (56·1%) were women and 221 665 (43·9%) were men, with a mean age of 41·6 years (SD 4·4). Data on ethnicity were unavailable. Altogether, clozapine was used by 19 910 individuals. Parsed by disorder, clozapine was used by 12·2–18·7% (n=5258 in Sweden, 10 115 in Finland) of people with schizophrenia, 8·8–20·7% (n=1131, n=1591) with schizoaffective disorder, 1·8% (n=341; data only available in Sweden) with delusional disorder, 0·5% (n=118, n=331) with major depressive disorder, 0·5–0·6% (n=490, n=371) with bipolar disorder, 0·3–0·6% (n=39, n=111) with psychotic depression, and 0·3% (n=36; data only available in Sweden) with BPD. Clozapine use was associated with reduced psychiatric hospitalisation risks versus other oral antipsychotics in all disorders, except for BPD. The greatest reductions were observed in schizophrenia (meta-analysis of adjusted hazard ratios [maHR] 0·70 [95% CI 0·67–0·72]) and schizoaffective disorder (maHR 0·71 [0·67–0·74]), followed by delusional disorder (adjusted hazard ratio 0·73 [0·60–0·89]), major depressive disorder (maHR 0·74 [0·66–0·84]), psychotic depression (maHR 0·76 [0·61–0·96]), and bipolar disorder (maHR 0·77 [0·69–0·87]). Moreover, we found no evidence of increased all-cause hospitalisation or mortality risks associated with clozapine use for all disorders examined. Furthermore, for all disorders studied ","PeriodicalId":48784,"journal":{"name":"Lancet Psychiatry","volume":"156 1","pages":""},"PeriodicalIF":64.3,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145428156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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