Pub Date : 2025-12-24DOI: 10.1016/j.euroneuro.2025.11.008
Ana Catalán , Paolo Fusar-Poli
{"title":"From first-episode psychosis to the future: Insights and challenges","authors":"Ana Catalán , Paolo Fusar-Poli","doi":"10.1016/j.euroneuro.2025.11.008","DOIUrl":"10.1016/j.euroneuro.2025.11.008","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"103 ","pages":"Article 112731"},"PeriodicalIF":6.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.euroneuro.2025.112747
Jose de Leon
{"title":"Prescribing clozapine to 10% of patients with schizophrenia may save 320,000 lives and cost 2400 deaths from agranulocytosis","authors":"Jose de Leon","doi":"10.1016/j.euroneuro.2025.112747","DOIUrl":"10.1016/j.euroneuro.2025.112747","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"104 ","pages":"Article 112747"},"PeriodicalIF":6.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.euroneuro.2025.112745
Christoph U Correll , Brahim K Bookhart , Carmela Benson , Zhiwen Liu , Zhongyun Zhao , Wenze Tang
Antipsychotic nonadherence is related to adverse outcomes in schizophrenia, including relapse and hospitalization; however, its impact on mortality remains unclear. This study evaluated associations between antipsychotic adherence levels and all-cause mortality using longitudinal claims data from the Optum Clinformatics® Data Mart Database. Eligible adults had ≥2 outpatient claims on separate dates or ≥1 inpatient claim with a schizophrenia diagnosis during the 12 months prior to/at index (i.e., antipsychotic initiation/reinitiation date) and no antipsychotic prescriptions or bipolar disorder diagnoses within 12 months pre-index. Medication adherence levels were defined by cumulative proportion of days covered (PDC): high adherence (≥0.8), low/moderate adherence (≥0.2 to <0.8), and nonadherence (<0.2). Adherence and all-cause mortality were evaluated during follow-up. A marginal structural model adjusting for baseline and time-varying confounding factors was used to estimate hazard ratios (HRs) and 95% CIs for mortality at different adherence levels. Of 6417 included adults (age=55.3 ± 20.5 years; males=54.0%; White=51.0%), the majority (81.7%) were prescribed second-generation oral antipsychotics at index. Within 6 months of antipsychotic initiation, mean cumulative PDC was 0.59±0.33. During a median follow-up of 17.3 months (interquartile range: 6.2–36.7), compared with high-adherent patients, all-cause mortality hazard was significantly greater in nonadherent (HR=1.80 [95%CI: 1.43–2.27]) and low/moderate-adherent (HR=1.53 [95% CI: 1.25–1.89]) patients. Five-year estimated survival rates were 67%, 71%, and 80% for nonadherent, low/moderate-adherent, and high-adherent patients, respectively. In this study, suboptimal antipsychotic adherence was associated with elevated mortality risk in patients with schizophrenia. Improved adherence may enhance survival and should be reinforced early in the disease course.
{"title":"Association of antipsychotic nonadherence with all-cause mortality in adults with schizophrenia newly treated or reinitiating antipsychotic medication: A retrospective healthcare claims study","authors":"Christoph U Correll , Brahim K Bookhart , Carmela Benson , Zhiwen Liu , Zhongyun Zhao , Wenze Tang","doi":"10.1016/j.euroneuro.2025.112745","DOIUrl":"10.1016/j.euroneuro.2025.112745","url":null,"abstract":"<div><div>Antipsychotic nonadherence is related to adverse outcomes in schizophrenia, including relapse and hospitalization; however, its impact on mortality remains unclear. This study evaluated associations between antipsychotic adherence levels and all-cause mortality using longitudinal claims data from the Optum Clinformatics® Data Mart Database. Eligible adults had ≥2 outpatient claims on separate dates or ≥1 inpatient claim with a schizophrenia diagnosis during the 12 months prior to/at index (i.e., antipsychotic initiation/reinitiation date) and no antipsychotic prescriptions or bipolar disorder diagnoses within 12 months pre-index. Medication adherence levels were defined by cumulative proportion of days covered (PDC): high adherence (≥0.8), low/moderate adherence (≥0.2 to <0.8), and nonadherence (<0.2). Adherence and all-cause mortality were evaluated during follow-up. A marginal structural model adjusting for baseline and time-varying confounding factors was used to estimate hazard ratios (HRs) and 95% CIs for mortality at different adherence levels. Of 6417 included adults (age=55.3 ± 20.5 years; males=54.0%; White=51.0%), the majority (81.7%) were prescribed second-generation oral antipsychotics at index. Within 6 months of antipsychotic initiation, mean cumulative PDC was 0.59±0.33. During a median follow-up of 17.3 months (interquartile range: 6.2–36.7), compared with high-adherent patients, all-cause mortality hazard was significantly greater in nonadherent (HR=1.80 [95%CI: 1.43–2.27]) and low/moderate-adherent (HR=1.53 [95% CI: 1.25–1.89]) patients. Five-year estimated survival rates were 67%, 71%, and 80% for nonadherent, low/moderate-adherent, and high-adherent patients, respectively. In this study, suboptimal antipsychotic adherence was associated with elevated mortality risk in patients with schizophrenia. Improved adherence may enhance survival and should be reinforced early in the disease course.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"104 ","pages":"Article 112745"},"PeriodicalIF":6.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.euroneuro.2025.11.017
Carlo Colosimo , Rakesh Jain , Krzysztof Duma , Anna Kurzeja , Celso Arango
Tardive dyskinesia (TD) is a medication-induced movement disorder associated with long-term use of dopamine receptor–blocking agents, most frequently antipsychotics. Its clinical presentation comprises involuntary hyperkinetic movements of the face, trunk, and extremities that can severely impair patients’ quality of life. Despite advances in antipsychotic treatment options, TD remains prevalent, with estimates suggesting that in Europe, approximately 22 % of patients treated with antipsychotics (regardless of drug subclass) have TD. Prevalence rates are affected by several factors, including antipsychotic subclass, with higher rates associated with older (first- versus second-generation) antipsychotics. Currently, there is no formal consensus for the optimal diagnosis and management of patients with TD in Europe, meaning that TD may be overlooked, misdiagnosed, and/or undertreated. There is also little knowledge about unmet needs within Europe, due to critical gaps in European research on TD. This narrative review advocates for the establishment of evidence-based standards of care tailored to the needs of European clinicians. It also underscores the necessity for further research to elucidate the impact of TD on patient outcomes and to develop effective management strategies to address the complexities of TD within the European health care landscape.
{"title":"A European perspective on tardive dyskinesia","authors":"Carlo Colosimo , Rakesh Jain , Krzysztof Duma , Anna Kurzeja , Celso Arango","doi":"10.1016/j.euroneuro.2025.11.017","DOIUrl":"10.1016/j.euroneuro.2025.11.017","url":null,"abstract":"<div><div>Tardive dyskinesia (TD) is a medication-induced movement disorder associated with long-term use of dopamine receptor–blocking agents, most frequently antipsychotics. Its clinical presentation comprises involuntary hyperkinetic movements of the face, trunk, and extremities that can severely impair patients’ quality of life. Despite advances in antipsychotic treatment options, TD remains prevalent, with estimates suggesting that in Europe, approximately 22 % of patients treated with antipsychotics (regardless of drug subclass) have TD. Prevalence rates are affected by several factors, including antipsychotic subclass, with higher rates associated with older (first- versus second-generation) antipsychotics. Currently, there is no formal consensus for the optimal diagnosis and management of patients with TD in Europe, meaning that TD may be overlooked, misdiagnosed, and/or undertreated. There is also little knowledge about unmet needs within Europe, due to critical gaps in European research on TD. This narrative review advocates for the establishment of evidence-based standards of care tailored to the needs of European clinicians. It also underscores the necessity for further research to elucidate the impact of TD on patient outcomes and to develop effective management strategies to address the complexities of TD within the European health care landscape.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"104 ","pages":"Article 112740"},"PeriodicalIF":6.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.euroneuro.2025.11.012
Kyle Valentino , Bianca Shen , Bethany Waisman , Gia Han Le , Hana Ballum , William Cheung , Roger S. McIntyre
The high prevalence, persistence and clinical burden of cognitive impairment on health outcomes in persons with schizophrenia and bipolar disorder invites the need for innovative, mechanistically informed pharmacotherapeutic interventions. Evidence implicates dysregulation of muscarinic signalling as a mediator of cognitive dysfunction, identifying it as a potential therapeutic target. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to May 1, 2025. Study screening and selection was performed by three reviewers (K.V., B.S., and B.W.). Included studies reported on the effects of xanomeline and/or xanomeline trospium on cognitive function. A total of 24 studies were included in this review. Preclinical and clinical studies consistently demonstrate that xanomeline trospium is well tolerated in both short and long-term evaluations. Furthermore, xanomeline trospium has been associated with cognitive improvements in both animal models and clinical populations (e.g., Alzheimer’s disease (AD), schizophrenia), including improvements in verbal learning, delayed memory, and reaction time. Xanomeline trospium, an FDA approved muscarinic M1/M4 partial agonist with demonstrated safety, tolerability, and efficacy, represents a novel pharmacological intervention for the treatment of schizophrenia. The convergence of preclinical and clinical findings supports the hypothesis that xanomeline trospium exerts direct pro cognitive effects in persons with schizophrenia, bipolar disorder, and potentially other neuropsychiatric conditions (e.g., AD). Limitations of the current study include limited indications investigated and the absence of a comprehensive analysis of xanomeline’s overall neurobiologic effects.
精神分裂症和双相情感障碍患者中认知障碍的高流行率、持续性和临床负担对健康结果的影响促使人们需要创新的、机械知情的药物治疗干预措施。证据暗示毒蕈碱信号失调是认知功能障碍的中介，将其确定为潜在的治疗靶点。根据PRISMA指南，使用以下电子数据库进行系统检索：PubMed、Medline、Cochrane Library、PsycInfo、Embase、Scopus和Web of Science。数据库从开始到2025年5月1日进行了搜索。研究筛选和选择由三位审稿人（k.v.、b.s.和B.W.）进行。纳入的研究报告了xanomeline和/或xanomeline trospium对认知功能的影响。本综述共纳入24项研究。临床前和临床研究一致表明，xanomeline trospium在短期和长期评估中都具有良好的耐受性。此外，xanomeline trospium与动物模型和临床人群（例如阿尔茨海默病（AD）、精神分裂症）的认知改善有关，包括改善言语学习、延迟记忆和反应时间。Xanomeline trospium是FDA批准的毒蕈碱M1/M4部分激动剂，具有安全性、耐受性和有效性，代表了一种治疗精神分裂症的新型药物干预。临床前和临床研究结果的融合支持了xanomeline trospium对精神分裂症、双相情感障碍和潜在的其他神经精神疾病（如AD）患者有直接的认知促进作用的假设。目前研究的局限性包括调查的适应症有限和缺乏对xanomeline整体神经生物学效应的全面分析。
{"title":"Efficacy of xanomeline and xanomeline trospium in the treatment of cognitive impairment: A systematic review of preclinical and clinical trials","authors":"Kyle Valentino , Bianca Shen , Bethany Waisman , Gia Han Le , Hana Ballum , William Cheung , Roger S. McIntyre","doi":"10.1016/j.euroneuro.2025.11.012","DOIUrl":"10.1016/j.euroneuro.2025.11.012","url":null,"abstract":"<div><div>The high prevalence, persistence and clinical burden of cognitive impairment on health outcomes in persons with schizophrenia and bipolar disorder invites the need for innovative, mechanistically informed pharmacotherapeutic interventions. Evidence implicates dysregulation of muscarinic signalling as a mediator of cognitive dysfunction, identifying it as a potential therapeutic target. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to May 1, 2025. Study screening and selection was performed by three reviewers (K.V., B.S., and B.W.). Included studies reported on the effects of xanomeline and/or xanomeline trospium on cognitive function. A total of 24 studies were included in this review. Preclinical and clinical studies consistently demonstrate that xanomeline trospium is well tolerated in both short and long-term evaluations. Furthermore, xanomeline trospium has been associated with cognitive improvements in both animal models and clinical populations (e.g., Alzheimer’s disease (AD), schizophrenia), including improvements in verbal learning, delayed memory, and reaction time. Xanomeline trospium, an FDA approved muscarinic M1/M4 partial agonist with demonstrated safety, tolerability, and efficacy, represents a novel pharmacological intervention for the treatment of schizophrenia. The convergence of preclinical and clinical findings supports the hypothesis that xanomeline trospium exerts direct pro cognitive effects in persons with schizophrenia, bipolar disorder, and potentially other neuropsychiatric conditions (e.g., AD). Limitations of the current study include limited indications investigated and the absence of a comprehensive analysis of xanomeline’s overall neurobiologic effects.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"103 ","pages":"Article 112735"},"PeriodicalIF":6.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.euroneuro.2025.112741
Agorastos Agorastos , Trevor Thompson , Marco Solmi , Samuele Cortese , Andrés Estradé , Joaquim Radua , Elena Dragioti , Davy Vancampfort , Lau Caspar Thygesen , Harald Aschauer , Monika Schlögelhofer , Elena Aschauer , Andres Schneeberger , Christian G. Huber , Gregor Hasler , Philippe Conus , Kim Q. Do Cuénod , Roland von Känel , Gonzalo Arrondo , Paolo Fusar-Poli , Christoph U Correll
Few multinational studies have assessed risk factors and coping strategies associated with the impact of the COVID-19 pandemic on children’s mental health over time. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is the largest transcontinental, multi-wave, cross-sectional survey collecting multi-nation data on well-being and psychopathology during the pandemic. We analyzed country-specific, general-population-based, representative COH-FIT data of 6067 children aged 6–13 years from 12 countries across repeated cross-sectional waves over a period of >2 years (Apr/2020–May/2022), addressing through current and retrospective assessment pre- to intra-pandemic changes in well-being (WHO-5) and general psychopathology scores (Pc) (0–100) in relation to COVID-related deaths, stringency index, eight a priori risk factors, and 16 coping strategies in different responders at each wave. From pre- to intra-pandemic, WHO-5 scores decreased (−4.59, 95 %CI=−6.18 to −2.99, p < 0.001), while PC-scores increased (+6.68, 95 %CI=4.48–8.88, p < 0.001) significantly, following distinct time patterns but both returning to near pre-pandemic levels. Changes in both scores varied by country. WHO-5 scores correlated strongly with PC and subdomain scores. Both score changes were significantly but minimally associated to COVID-19 deaths/stringency index. The proportion of children screening positive for depression increased from 3.9 % to 8.3 % (χ²=145.70, p < 0.001) and for major depression from 0.6 % to 2.2 % (χ²=68.64, p < 0.001) intrapandemic. WHO-5 and PC-score changes were significantly associated with female gender, school closure, and pre-existing physical and mental conditions, with cumulative effects. The five most frequently endorsed coping strategies were family contact (85.2 %), friends (67.3 %), outdoor play (54.0 %), pet interaction (51.5 %), and internet use (50.9 %). Identified risk groups and coping strategies can inform targeted interventions and global public health policy.
{"title":"Mental health, coping and related risk factors during the first 2 years of the COVID-19 pandemic in children: Nationally representative, multi-wave, cross-sectional results from 12 countries from the global COH-FIT study","authors":"Agorastos Agorastos , Trevor Thompson , Marco Solmi , Samuele Cortese , Andrés Estradé , Joaquim Radua , Elena Dragioti , Davy Vancampfort , Lau Caspar Thygesen , Harald Aschauer , Monika Schlögelhofer , Elena Aschauer , Andres Schneeberger , Christian G. Huber , Gregor Hasler , Philippe Conus , Kim Q. Do Cuénod , Roland von Känel , Gonzalo Arrondo , Paolo Fusar-Poli , Christoph U Correll","doi":"10.1016/j.euroneuro.2025.112741","DOIUrl":"10.1016/j.euroneuro.2025.112741","url":null,"abstract":"<div><div>Few multinational studies have assessed risk factors and coping strategies associated with the impact of the COVID-19 pandemic on children’s mental health over time. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is the largest transcontinental, multi-wave, cross-sectional survey collecting multi-nation data on well-being and psychopathology during the pandemic. We analyzed country-specific, general-population-based, representative COH-FIT data of 6067 children aged 6–13 years from 12 countries across repeated cross-sectional waves over a period of >2 years (Apr/2020–May/2022), addressing through current and retrospective assessment pre- to intra-pandemic changes in well-being (WHO-5) and general psychopathology scores (P<sub>c</sub>) (0–100) in relation to COVID-related deaths, stringency index, eight a priori risk factors, and 16 coping strategies in different responders at each wave. From pre- to intra-pandemic, WHO-5 scores decreased (−4.59, 95 %CI=−6.18 to −2.99, <em>p</em> < 0.001), while PC-scores increased (+6.68, 95 %CI=4.48–8.88, <em>p</em> < 0.001) significantly, following distinct time patterns but both returning to near pre-pandemic levels. Changes in both scores varied by country. WHO-5 scores correlated strongly with P<sub>C</sub> and subdomain scores. Both score changes were significantly but minimally associated to COVID-19 deaths/stringency index. The proportion of children screening positive for depression increased from 3.9 % to 8.3 % (χ²=145.70, <em>p</em> < 0.001) and for major depression from 0.6 % to 2.2 % (χ²=68.64, <em>p</em> < 0.001) intrapandemic. WHO-5 and P<sub>C</sub>-score changes were significantly associated with female gender, school closure, and pre-existing physical and mental conditions, with cumulative effects. The five most frequently endorsed coping strategies were family contact (85.2 %), friends (67.3 %), outdoor play (54.0 %), pet interaction (51.5 %), and internet use (50.9 %). Identified risk groups and coping strategies can inform targeted interventions and global public health policy.</div><div><strong>Trial Registration:</strong> ClinicalTrials.gov; Identifier: NCT04383470</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"104 ","pages":"Article 112741"},"PeriodicalIF":6.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145766092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.euroneuro.2025.112742
Joe Kwun-Nam Chan , Ryan Cheuk-Yin Li , Oleguer Plana-Ripoll , Natalie C. Momen , Christoph U. Correll , Marco Solmi , Corine Sau-Man Wong , Kam-Ming Ku , Vanessa Ramesh Mahboobani , Albert Kar-Kin Chung , Simon Sai-Yu Lui , Pak-Chung Sham , Wing-Chung Chang
Mental-disorders (MDs) are associated with premature mortality. Previous studies had limitations including confounding by physical-morbidities and lack of cause-specific mortality evaluation. We aimed to quantify mortality risk and life-expectancy gap across MDs in an Asian population. This retrospective population-based study investigated people with MDs (ascertained by ICD10-codes) in 2006–2021, utilizing comprehensive health-record-database of public-healthcare services in Hong-Kong. Individuals without MDs attending primary-care-clinics during study period served as comparisons. We estimated relative all-cause and cause-specific mortality risk using Cox-proportional hazards-regression models, and calculated excess life-years-lost (LYLs). Effect modification (sex, age, Charlson-comorbidity-index, socioeconomic-status (SES)) on relative risks was evaluated with subgroup-analyses. This analysis included 332,298 people with and 902,927 people without MDs. Any MD was associated with increased all-cause mortality (hazard-ratio (HR): 2.04 [95%Confidence-interval (CI)=2.02–2.07]) and excess LYLs (13.81 years [95%CI=13.60–13.98]). Eating-disorders exhibited the highest all-cause mortality (HR=9.43 [95%CI=6.83–13.02]), followed by developmental-disorders (HR=5.55 [95%CI=4.45–6.92]), personality-disorders (HR=4.50 [95%CI=4.06–4.98]) and substance-use disorders (HR=3.83 [95%CI=3.70–3.96]), with pronounced excess LYLs (14.18–17.41 years). Psychiatric-multimorbidity further increased excess mortality. Suicide was associated with the highest mortality risk (HR=8.69 [95%CI=7.97–9.45]). Natural causes accounted for most deaths (85%; HR range=1.50–2.76), while external causes explained 5% of all deaths (suicide: HR=8.69 [95%CI=7.97–9.45]). Men, younger age and lower SES were associated with increased all-cause and natural-cause mortality, while women and higher SES were linked to elevated external-cause mortality. This study highlighted transdiagnostic nature of premature mortality associated with MDs. Implementation of comprehensive multilevel interventions is warranted to narrow this mortality gap.
{"title":"All-cause and cause-specific mortality in people with mental disorders: a population-based study on risk evaluation, effect modifiers and excess life-years lost in Hong Kong","authors":"Joe Kwun-Nam Chan , Ryan Cheuk-Yin Li , Oleguer Plana-Ripoll , Natalie C. Momen , Christoph U. Correll , Marco Solmi , Corine Sau-Man Wong , Kam-Ming Ku , Vanessa Ramesh Mahboobani , Albert Kar-Kin Chung , Simon Sai-Yu Lui , Pak-Chung Sham , Wing-Chung Chang","doi":"10.1016/j.euroneuro.2025.112742","DOIUrl":"10.1016/j.euroneuro.2025.112742","url":null,"abstract":"<div><div>Mental-disorders (MDs) are associated with premature mortality. Previous studies had limitations including confounding by physical-morbidities and lack of cause-specific mortality evaluation. We aimed to quantify mortality risk and life-expectancy gap across MDs in an Asian population. This retrospective population-based study investigated people with MDs (ascertained by ICD10-codes) in 2006–2021, utilizing comprehensive health-record-database of public-healthcare services in Hong-Kong. Individuals without MDs attending primary-care-clinics during study period served as comparisons. We estimated relative all-cause and cause-specific mortality risk using Cox-proportional hazards-regression models, and calculated excess life-years-lost (LYLs). Effect modification (sex, age, Charlson-comorbidity-index, socioeconomic-status (SES)) on relative risks was evaluated with subgroup-analyses. This analysis included 332,298 people with and 902,927 people without MDs. Any MD was associated with increased all-cause mortality (hazard-ratio (HR): 2.04 [95%Confidence-interval (CI)=2.02–2.07]) and excess LYLs (13.81 years [95%CI=13.60–13.98]). Eating-disorders exhibited the highest all-cause mortality (HR=9.43 [95%CI=6.83–13.02]), followed by developmental-disorders (HR=5.55 [95%CI=4.45–6.92]), personality-disorders (HR=4.50 [95%CI=4.06–4.98]) and substance-use disorders (HR=3.83 [95%CI=3.70–3.96]), with pronounced excess LYLs (14.18–17.41 years). Psychiatric-multimorbidity further increased excess mortality. Suicide was associated with the highest mortality risk (HR=8.69 [95%CI=7.97–9.45]). Natural causes accounted for most deaths (85%; HR range=1.50–2.76), while external causes explained 5% of all deaths (suicide: HR=8.69 [95%CI=7.97–9.45]). Men, younger age and lower SES were associated with increased all-cause and natural-cause mortality, while women and higher SES were linked to elevated external-cause mortality. This study highlighted transdiagnostic nature of premature mortality associated with MDs. Implementation of comprehensive multilevel interventions is warranted to narrow this mortality gap.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"104 ","pages":"Article 112742"},"PeriodicalIF":6.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.euroneuro.2025.11.009
Isabel Werle , Francisco S. Guimarães , Rafael G. dos Santos , Jaime E.C. Hallak , Leandro J. Bertoglio
Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic N,N-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder.
{"title":"Ayahuasca modulation of traumatic-like fear memories requires infralimbic cortex BDNF-dependent mechanisms in rats","authors":"Isabel Werle , Francisco S. Guimarães , Rafael G. dos Santos , Jaime E.C. Hallak , Leandro J. Bertoglio","doi":"10.1016/j.euroneuro.2025.11.009","DOIUrl":"10.1016/j.euroneuro.2025.11.009","url":null,"abstract":"<div><div>Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic <em>N,N</em>-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"103 ","pages":"Article 112732"},"PeriodicalIF":6.7,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.euroneuro.2025.11.010
Chieh-Hsin Lin , Hsien-Yuan Lane
Oxidative stress is implicated in schizophrenia. Glutathione (GSH), a crucial endogenous antioxidant, is usually reduced in individuals with schizophrenia. GSH and its precursor, N-acetyl cysteine, have demonstrated potential as adjunctive treatment for schizophrenia; however, their effectiveness appears inconsistent, possibly because of their limited ability to penetrate the blood-brain barrier (BBB). Administration of sodium benzoate, capable of crossing BBB, enhanced GSH capacity and antipsychotic-like activity in animals. Further, adjunctive benzoate therapy improved clinical and functional outcomes in patients with schizophrenia, including clozapine-resistant schizophrenia (CRS). Whether sodium benzoate can also boost GSH to exert its therapeutic efficacy for schizophrenia deserves elucidation. This secondary analysis used data from a double-blind trial, in which 60 patients with CRS were randomized to receive addon treatment of sodium benzoate (n = 40) or placebo (n = 20) for 6 weeks. Clinical and functional assessments were conducted bi-weekly. Plasma levels of GSH were assayed at baseline and endpoint. As a result, six-week treatment of sodium benzoate was linked to increased GSH levels than placebo. Among the 40 benzoate receivers, the changes in GSH levels were correlated with the improvements in positive symptoms, negative symptoms, quality of life, and global function. In comparison, among placebo recipients, GSH changes were not associated with any changes in clinical or functional variables. The findings suggest that benzoate treatment may be related with elevation in GSH levels in CRS patients and improvement in functional outcomes as well as positive and negative symptoms. Longer-term studies in other populations are necessary in the future.
{"title":"Sodium benzoate treatment linked to increased glutathione levels and improved positive and negative symptoms, global function, and quality of life in patients with clozapine-resistant schizophrenia: secondary analysis of a randomized clinical trial","authors":"Chieh-Hsin Lin , Hsien-Yuan Lane","doi":"10.1016/j.euroneuro.2025.11.010","DOIUrl":"10.1016/j.euroneuro.2025.11.010","url":null,"abstract":"<div><div>Oxidative stress is implicated in schizophrenia. Glutathione (GSH), a crucial endogenous antioxidant, is usually reduced in individuals with schizophrenia. GSH and its precursor, N-acetyl cysteine, have demonstrated potential as adjunctive treatment for schizophrenia; however, their effectiveness appears inconsistent, possibly because of their limited ability to penetrate the blood-brain barrier (BBB). Administration of sodium benzoate, capable of crossing BBB, enhanced GSH capacity and antipsychotic-like activity in animals. Further, adjunctive benzoate therapy improved clinical and functional outcomes in patients with schizophrenia, including clozapine-resistant schizophrenia (CRS). Whether sodium benzoate can also boost GSH to exert its therapeutic efficacy for schizophrenia deserves elucidation. This secondary analysis used data from a double-blind trial, in which 60 patients with CRS were randomized to receive addon treatment of sodium benzoate (n = 40) or placebo (n = 20) for 6 weeks. Clinical and functional assessments were conducted bi-weekly. Plasma levels of GSH were assayed at baseline and endpoint. As a result, six-week treatment of sodium benzoate was linked to increased GSH levels than placebo. Among the 40 benzoate receivers, the changes in GSH levels were correlated with the improvements in positive symptoms, negative symptoms, quality of life, and global function. In comparison, among placebo recipients, GSH changes were not associated with any changes in clinical or functional variables. The findings suggest that benzoate treatment may be related with elevation in GSH levels in CRS patients and improvement in functional outcomes as well as positive and negative symptoms. Longer-term studies in other populations are necessary in the future.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"103 ","pages":"Article 112733"},"PeriodicalIF":6.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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