{"title":"Comment on “A Systematic Review and Meta-Analysis of the Association Between Childhood Maltreatment and Adult Depression”","authors":"Shubham Kumar, Rachana Mehta, Ranjana Sah","doi":"10.1111/acps.13805","DOIUrl":"10.1111/acps.13805","url":null,"abstract":"","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 2","pages":"146-147"},"PeriodicalIF":5.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699193","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}
Minna Holm, Antti Tanskanen, Jari Tiihonen, Heidi Taipale
Introduction
Medication use may significantly affect work ability in bipolar disorder, but this area has been largely overlooked in research. We aimed to investigate how specific mood stabilizer and antipsychotic agents are associated with the risk of sickness absence among employed individuals with bipolar disorder.
Methods
We identified a nationwide cohort of 22,408 employed individuals with bipolar disorder, including 10,000 first-episode cases, and followed them from 2005 to 2018 through the nationwide administrative registers. The risk of sickness absence was analyzed using within-individual Cox regression where each person serves as their own control to eliminate selection bias.
Results
In the whole cohort, the monotherapies of lithium (HR = 0.75, 95% CI = 0.66–0.84), valproate (HR = 0.77, 0.70–0.85), and lamotrigine (HR = 0.87, 0.80–0.95) were associated with a lower risk of sickness absence than nonuse of mood stabilizers. In contrast, pregabalin monotherapy was associated with an increased risk of sickness absence (HR = 1.63, 1.34–1.99). Of antipsychotics, olanzapine was associated with a lower risk of sickness absence (HR = 0.75, 0.66–0.86) than antipsychotic nonuse. In the first-episode sample, lithium (HR = 0.51, 0.41–0.64), valproate (HR = 0.63, 0.52–0.75), lamotrigine (HR = 0.79, 0.68–0.91), and olanzapine (HR = 0.69, 0.54–0.87) monotherapies were associated with a lower hazard of sickness absence than nonuse.
Conclusions
Mood stabilizers including lithium, valproate, and lamotrigine, as well as olanzapine, of antipsychotics may reduce the risk of sickness absence, particularly, in first-episode patients. These findings encourage the continuous use of these medications to support occupational functioning among people with bipolar disorder.
{"title":"The Role of Antipsychotics and Mood Stabilizers in Preventing Sickness Absence Among Employed Individuals With Bipolar Disorder: A Nationwide Register-Based Study","authors":"Minna Holm, Antti Tanskanen, Jari Tiihonen, Heidi Taipale","doi":"10.1111/acps.13806","DOIUrl":"10.1111/acps.13806","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Medication use may significantly affect work ability in bipolar disorder, but this area has been largely overlooked in research. We aimed to investigate how specific mood stabilizer and antipsychotic agents are associated with the risk of sickness absence among employed individuals with bipolar disorder.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We identified a nationwide cohort of 22,408 employed individuals with bipolar disorder, including 10,000 first-episode cases, and followed them from 2005 to 2018 through the nationwide administrative registers. The risk of sickness absence was analyzed using within-individual Cox regression where each person serves as their own control to eliminate selection bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the whole cohort, the monotherapies of lithium (HR = 0.75, 95% CI = 0.66–0.84), valproate (HR = 0.77, 0.70–0.85), and lamotrigine (HR = 0.87, 0.80–0.95) were associated with a lower risk of sickness absence than nonuse of mood stabilizers. In contrast, pregabalin monotherapy was associated with an increased risk of sickness absence (HR = 1.63, 1.34–1.99). Of antipsychotics, olanzapine was associated with a lower risk of sickness absence (HR = 0.75, 0.66–0.86) than antipsychotic nonuse. In the first-episode sample, lithium (HR = 0.51, 0.41–0.64), valproate (HR = 0.63, 0.52–0.75), lamotrigine (HR = 0.79, 0.68–0.91), and olanzapine (HR = 0.69, 0.54–0.87) monotherapies were associated with a lower hazard of sickness absence than nonuse.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Mood stabilizers including lithium, valproate, and lamotrigine, as well as olanzapine, of antipsychotics may reduce the risk of sickness absence, particularly, in first-episode patients. These findings encourage the continuous use of these medications to support occupational functioning among people with bipolar disorder.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 2","pages":"104-111"},"PeriodicalIF":5.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690445","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}
Mark Shevlin, Philip Hyland, Chris R. Brewin, Marylene Cloitre, Thanos Karatzias, Enya Redican
Background
The International Trauma Questionnaire (ITQ) is the most widely used measure of ICD-11 Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD). This self-report scale has been used to estimate prevalence rates of these disorders in general populations and clinical samples, but concerns abound that prevalence estimates derived from self-report measures are too high. To address this concern, we previously introduced the concept of adding “clinical checks” to self-report measures to ensure initial responses reflected the intended clinical meaning of the scale item. Here we provide a rationale for adding clinical checks to the ITQ, describe the process of developing them, and demonstrate their effect at the symptom, cluster, and disorder levels in a general population sample.
Methods
A team of researchers and clinicians, including those who developed the ITQ, developed clinical checks for all ITQ items. These were tested using data from a non-probability quota-based representative sample of adults from the United Kingdom (N = 975).
Results
Use of clinical checks led to decreases in symptom endorsements ranging from 18.0% to 43.9%, and symptom cluster requirements from 19.1% to 35.9%. Disorder prevalence estimates without the clinical checks were 5.4% for PTSD and 9.5% for CPTSD. With the clinical checks, prevalence estimates dropped to 3.8% for PTSD (relative decrease = 29.6%) and 4.9% for CPTSD (relative decrease = 48.4%).
Conclusion
Clinical checks can be easily embedded into the ITQ and have a significant effect on prevalence estimates. We contextualize these results in relation to existing literature on population prevalence estimates derived from clinical interviews and discrepancies between clinical interviews and self-report measures.
{"title":"Testing the Use of “Clinical Checks” With the International Trauma Questionnaire to Measure PTSD and Complex PTSD","authors":"Mark Shevlin, Philip Hyland, Chris R. Brewin, Marylene Cloitre, Thanos Karatzias, Enya Redican","doi":"10.1111/acps.13799","DOIUrl":"10.1111/acps.13799","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The International Trauma Questionnaire (ITQ) is the most widely used measure of ICD-11 Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD). This self-report scale has been used to estimate prevalence rates of these disorders in general populations and clinical samples, but concerns abound that prevalence estimates derived from self-report measures are too high. To address this concern, we previously introduced the concept of adding “clinical checks” to self-report measures to ensure initial responses reflected the intended clinical meaning of the scale item. Here we provide a rationale for adding clinical checks to the ITQ, describe the process of developing them, and demonstrate their effect at the symptom, cluster, and disorder levels in a general population sample.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A team of researchers and clinicians, including those who developed the ITQ, developed clinical checks for all ITQ items. These were tested using data from a non-probability quota-based representative sample of adults from the United Kingdom (<i>N</i> = 975).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Use of clinical checks led to decreases in symptom endorsements ranging from 18.0% to 43.9%, and symptom cluster requirements from 19.1% to 35.9%. Disorder prevalence estimates without the clinical checks were 5.4% for PTSD and 9.5% for CPTSD. With the clinical checks, prevalence estimates dropped to 3.8% for PTSD (relative decrease = 29.6%) and 4.9% for CPTSD (relative decrease = 48.4%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Clinical checks can be easily embedded into the ITQ and have a significant effect on prevalence estimates. We contextualize these results in relation to existing literature on population prevalence estimates derived from clinical interviews and discrepancies between clinical interviews and self-report measures.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 1","pages":"49-59"},"PeriodicalIF":5.3,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acps.13799","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas C. Feenstra, Nathalie Denayer, Kristof Vansteelandt, Jasmien Obbels, Kaat Hebbrecht, Liese Van den Eynde, Shauni Verspecht, Esmée Verwijk, Eric van Exel, Rob M. Kok, Filip Bouckaert, Anton C. M. Vergouwen, Adriano van der Loo, Aartjan T. F. Beekman, Pascal Sienaert, Didi Rhebergen
Introduction
Cognitive side effects, such as memory loss, associated with electroconvulsive therapy (ECT) have been extensively studied. However, knowledge about (sub)acute confusional states during ECT is limited, particularly in older adults with depression. Their incidence, recurrence, and co-occurrence remain unclear. This study aimed to describe the incidence, recurrence, co-occurrence, and clinical course of various subtypes of confusional states during ECT.
Methods
Data were derived from the ‘Rivastigmine for ECT-induced Cognitive Adverse effects in Late-Life depression’ (RECALL) prospective cohort study, involving 145 older adults (≥ 55 years) with a major depressive episode receiving ECT. We assessed different subtypes of confusional states: postictal and interictal delirium (PID and IID), postictal agitation (PIA), prolonged time to reorientation (TRO), and subacute general cognitive decline (Mini Mental State Examination decline ≥ 4 points) throughout the ECT course.
Results
Over half of the older adults (55.9%) experienced at least one subtype of confusional state during their ECT course. The most prevalent subtypes were PIA (29.5%) and prolonged TRO (28.3%), while postictal (5.9%) and interictal delirium (4.2%) were less common. Recurrence rates varied, with interictal delirium (66.7%) and prolonged TRO (50.0%) showing the highest rates compared to postictal delirium (12.5%). Notably, 18.0% of older adults experienced more than one subtype of confusional state during their ECT course, and these states could emerge at any time during the ECT course.
Conclusion
This is the first study to comprehensively examine the clinical course of various subtypes of confusional states during ECT in older adults with depression Our findings reveal that confusional states are highly prevalent, heterogeneous, and may emerge at any time during the ECT course. Notably, since the instruments used were not designed to measure (subtypes of) confusional states during ECT, further research into the differentiation of (sub)acute confusional states is warranted.
{"title":"Confusional States During Electroconvulsive Therapy for Late-Life Depression: A Prospective Cohort Study","authors":"Thomas C. Feenstra, Nathalie Denayer, Kristof Vansteelandt, Jasmien Obbels, Kaat Hebbrecht, Liese Van den Eynde, Shauni Verspecht, Esmée Verwijk, Eric van Exel, Rob M. Kok, Filip Bouckaert, Anton C. M. Vergouwen, Adriano van der Loo, Aartjan T. F. Beekman, Pascal Sienaert, Didi Rhebergen","doi":"10.1111/acps.13803","DOIUrl":"10.1111/acps.13803","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Cognitive side effects, such as memory loss, associated with electroconvulsive therapy (ECT) have been extensively studied. However, knowledge about (sub)acute confusional states during ECT is limited, particularly in older adults with depression. Their incidence, recurrence, and co-occurrence remain unclear. This study aimed to describe the incidence, recurrence, co-occurrence, and clinical course of various subtypes of confusional states during ECT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data were derived from the ‘Rivastigmine for ECT-induced Cognitive Adverse effects in Late-Life depression’ (RECALL) prospective cohort study, involving 145 older adults (≥ 55 years) with a major depressive episode receiving ECT. We assessed different subtypes of confusional states: postictal and interictal delirium (PID and IID), postictal agitation (PIA), prolonged time to reorientation (TRO), and subacute general cognitive decline (Mini Mental State Examination decline ≥ 4 points) throughout the ECT course.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Over half of the older adults (55.9%) experienced at least one subtype of confusional state during their ECT course. The most prevalent subtypes were PIA (29.5%) and prolonged TRO (28.3%), while postictal (5.9%) and interictal delirium (4.2%) were less common. Recurrence rates varied, with interictal delirium (66.7%) and prolonged TRO (50.0%) showing the highest rates compared to postictal delirium (12.5%). Notably, 18.0% of older adults experienced more than one subtype of confusional state during their ECT course, and these states could emerge at any time during the ECT course.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This is the first study to comprehensively examine the clinical course of various subtypes of confusional states during ECT in older adults with depression Our findings reveal that confusional states are highly prevalent, heterogeneous, and may emerge at any time during the ECT course. Notably, since the instruments used were not designed to measure (subtypes of) confusional states during ECT, further research into the differentiation of (sub)acute confusional states is warranted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>EudraCT 2014-003385-24</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 2","pages":"125-133"},"PeriodicalIF":5.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655692","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}
Patrick Bach, Johan Franck, Jonas Hällgren, Härje Widing, Mika Gissler, Jeanette Westman
Objectives
Despite the high prevalence of alcohol use disorder (AUD), only a minority of patients receive recommended pharmacological treatments, possibly owing to uncertainty about the real-world effectiveness of these medications. Here, we analyzed nationwide, register-based data to investigate the association between approved AUD medications (naltrexone, acamprosate, disulfiram, and nalmefene) and the risk of alcohol-related hospitalizations among individuals with AUD.
Methods
People aged 18–64 with a registered first-time diagnosis of AUD between 2009 and 2019 (N = 93,727) were identified from the Swedish National Patient Register. Cox regression models were used to analyze the association between AUD medication exposure and the risk of alcohol-related hospitalizations.
Results
Exposure to naltrexone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.73–0.87) or disulfiram (HR = 0.83, 95% CI = 0.79–0.88) as monotherapy, or a combination of naltrexone/disulfiram (HR = 0.68, 95% CI = 0.49–0.96), or disulfiram/acamprosate (HR = 0.57 95% CI = 0.44–0.74) was significantly associated with a lower risk of alcohol-related hospitalizations compared to periods without exposure to any of these medications. In contrast, no significant associations were observed for acamprosate, nalmefene, or the combination of acamprosate/naltrexone. Sensitivity analyses in individuals with severe AUD and stratified subgroup analyses by different socioeconomic groups confirmed the robustness of the results.
Conclusion
Results indicate a significant association between disulfiram and naltrexone monotherapy, as well as the combination of disulfiram with naltrexone or acamprosate, with a lower risk of alcohol-related hospitalizations among individuals with AUD. Low prescription rates suggest that AUD medications are currently underutilized. Increasing the availability of these medications for individuals with AUD could help reduce alcohol-related hospitalizations.
目的：尽管酒精使用障碍（AUD）的患病率很高，但只有少数患者接受推荐的药物治疗，可能是由于这些药物在现实世界中的有效性不确定。在这里，我们分析了全国范围内基于登记的数据，以调查批准的AUD药物（纳曲酮、阿坎普罗酸、双硫仑和纳美芬）与AUD患者酒精相关住院风险之间的关系。方法：从瑞典国家患者登记册中确定2009年至2019年首次诊断为AUD的18-64岁患者（N = 93,727）。使用Cox回归模型分析AUD药物暴露与酒精相关住院风险之间的关系。结果：纳曲酮暴露(危险比[HR] = 0.80；95%可信区间[CI] = 0.73-0.87)或双硫仑（HR = 0.83, 95% CI = 0.79-0.88）作为单一疗法，或纳曲酮/双硫仑（HR = 0.68, 95% CI = 0.49-0.96）或双硫仑/阿坎普罗酸（HR = 0.57, 95% CI = 0.44-0.74）与未使用任何这些药物的时期相比，酒精相关住院的风险较低显著相关。相比之下，阿坎普罗酸、纳美芬或阿坎普罗酸/纳曲酮联合用药未观察到显著相关性。严重AUD患者的敏感性分析和不同社会经济群体的分层亚组分析证实了结果的稳健性。结论：研究结果表明，双硫仑与纳曲酮单药治疗，以及双硫仑与纳曲酮或阿坎普罗酸联合用药，与AUD患者酒精相关住院的风险较低。低处方率表明AUD药物目前未得到充分利用。增加这些药物对AUD患者的可用性有助于减少与酒精相关的住院治疗。
{"title":"Pharmacological Treatments in Alcohol Use Disorder and Risk of Alcohol-Related Hospitalizations: A Register Study","authors":"Patrick Bach, Johan Franck, Jonas Hällgren, Härje Widing, Mika Gissler, Jeanette Westman","doi":"10.1111/acps.13802","DOIUrl":"10.1111/acps.13802","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite the high prevalence of alcohol use disorder (AUD), only a minority of patients receive recommended pharmacological treatments, possibly owing to uncertainty about the real-world effectiveness of these medications. Here, we analyzed nationwide, register-based data to investigate the association between approved AUD medications (naltrexone, acamprosate, disulfiram, and nalmefene) and the risk of alcohol-related hospitalizations among individuals with AUD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>People aged 18–64 with a registered first-time diagnosis of AUD between 2009 and 2019 (<i>N</i> = 93,727) were identified from the Swedish National Patient Register. Cox regression models were used to analyze the association between AUD medication exposure and the risk of alcohol-related hospitalizations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Exposure to naltrexone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.73<b>–</b>0.87) or disulfiram (HR = 0.83, 95% CI = 0.79<b>–</b>0.88) as monotherapy, or a combination of naltrexone/disulfiram (HR = 0.68, 95% CI = 0.49<b>–</b>0.96), or disulfiram/acamprosate (HR = 0.57 95% CI = 0.44<b>–</b>0.74) was significantly associated with a lower risk of alcohol-related hospitalizations compared to periods without exposure to any of these medications. In contrast, no significant associations were observed for acamprosate, nalmefene, or the combination of acamprosate/naltrexone. Sensitivity analyses in individuals with severe AUD and stratified subgroup analyses by different socioeconomic groups confirmed the robustness of the results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Results indicate a significant association between disulfiram and naltrexone monotherapy, as well as the combination of disulfiram with naltrexone or acamprosate, with a lower risk of alcohol-related hospitalizations among individuals with AUD. Low prescription rates suggest that AUD medications are currently underutilized. Increasing the availability of these medications for individuals with AUD could help reduce alcohol-related hospitalizations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 2","pages":"94-103"},"PeriodicalIF":5.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acps.13802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Merete Osler, Thomas Wolff Rosenqvist, Maarten Pieter Bjørn-Rozing, Anders Jorgensen, Martin Balslev Jorgensen, Terese Sara Høj Jørgensen, Frederikke Hørdam Gronemann
Background
Mental disorders are associated with excess risk of death from unnatural and natural causes, but few studies have differentiated causes of death among patients with major depression. We examined cumulative and relative risks of all-cause and cause-specific mortality in individuals with major depression up to 50 years after diagnosis according to sex, age, and time since depression diagnosis.
Methods
In this nationwide matched-cohort study, we included individuals diagnosed with major depression in Danish National Patient registries from 1970 through 2021 and a 1:5 matched sample of the general population (reference population). Individuals were followed for their underlying cause of death in the Danish Cause of Death Registry up to 2022, and we estimated cumulative risk and hazard ratios for all-cause and 10 specific causes of death.
Results
The study included 330,577 adults diagnosed with major depression in Denmark (median age at first diagnosis, 45 years; 63.4%women) and 1,652,885 members of the matched reference population (median age, 45 years; 63.4%women). During the study period, 116,628 (35.2%) individuals with depression and 389,135 (23.5%) matches from the reference population died. Individuals with depression had considerably higher mortality risk at all time periods and ages compared to the reference population, and the increased risk was most pronounced in the first year after diagnosis. The lifetime risk of suicide was 11.2% in individuals with depression compared with 1% in the reference population, and before age 65 years, suicide was the leading cause of death in patients with depression. When compared with the reference population, individuals with depression also exhibited a higher risk of various specific natural causes of death before the age of 85 years.
Conclusions
The risk of death from suicide and medical disorders is elevated in individuals with depression, especially the first year after diagnosis. Because a large number of deaths can be attributed to depression shortly after onset, clinicians should be aware of this risk.
{"title":"All-Cause and Cause-Specific Mortality Among Individuals With Major Depression: A Nationwide Danish Matched-Cohort Study","authors":"Merete Osler, Thomas Wolff Rosenqvist, Maarten Pieter Bjørn-Rozing, Anders Jorgensen, Martin Balslev Jorgensen, Terese Sara Høj Jørgensen, Frederikke Hørdam Gronemann","doi":"10.1111/acps.13800","DOIUrl":"10.1111/acps.13800","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mental disorders are associated with excess risk of death from unnatural and natural causes, but few studies have differentiated causes of death among patients with major depression. We examined cumulative and relative risks of all-cause and cause-specific mortality in individuals with major depression up to 50 years after diagnosis according to sex, age, and time since depression diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this nationwide matched-cohort study, we included individuals diagnosed with major depression in Danish National Patient registries from 1970 through 2021 and a 1:5 matched sample of the general population (reference population). Individuals were followed for their underlying cause of death in the Danish Cause of Death Registry up to 2022, and we estimated cumulative risk and hazard ratios for all-cause and 10 specific causes of death.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 330,577 adults diagnosed with major depression in Denmark (median age at first diagnosis, 45 years; 63.4%women) and 1,652,885 members of the matched reference population (median age, 45 years; 63.4%women). During the study period, 116,628 (35.2%) individuals with depression and 389,135 (23.5%) matches from the reference population died. Individuals with depression had considerably higher mortality risk at all time periods and ages compared to the reference population, and the increased risk was most pronounced in the first year after diagnosis. The lifetime risk of suicide was 11.2% in individuals with depression compared with 1% in the reference population, and before age 65 years, suicide was the leading cause of death in patients with depression. When compared with the reference population, individuals with depression also exhibited a higher risk of various specific natural causes of death before the age of 85 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The risk of death from suicide and medical disorders is elevated in individuals with depression, especially the first year after diagnosis. Because a large number of deaths can be attributed to depression shortly after onset, clinicians should be aware of this risk.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 1","pages":"60-68"},"PeriodicalIF":5.3,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acps.13800","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Robert Løvsletten Smith, Ole A. Andreassen, John M. Kane, Georgios Schoretsanitis, Espen Molden
Aims
Both inflammation and smoking are known to affect clozapine metabolism. However, the impact of inflammation on clozapine metabolism in relation to smoking status is unclear. Therefore, we investigated correlations between C-reactive protein (CRP) and clozapine levels in smokers and non-smokers separately.
Methods
Patients were included retrospectively from a therapeutic drug monitoring (TDM) service in Oslo, Norway, during January 2005–April 2022. Inclusion criteria were known smoking status and CRP measurements no longer than 7 days before or after clozapine TDM. Exclusion criteria were confirmed blood sampling for TDM outside 10–30 h after the last clozapine intake. Information about clozapine dosing was retrieved from the requisition forms.
Results
In 126 patients fulfilling the criteria (47% smokers), dose-adjusted serum concentration (CD) of clozapine correlated significantly with CRP in non-smokers (R = 0.492; p < 001) but not in smokers (R = 0.191; p = 0.166). When subgrouping non-smoking patients into low CRP (< 5 mg/L; reference [51% of the population]), mid CRP (5–50 [37%]) and high CRP (> 50 [12%]), clozapine CD gradually increased in mid- (+48%, p = 0.004) and high-CRP groups (+204%, p < 0.001) compared with the low-CRP group. No significant differences in clozapine CD were found between CRP groups among smokers (p > 0.15).
Conclusions
We report a significant correlation between CD of clozapine and CRP levels in non-smoking patients only. In these patients, clozapine CD is more than 3-fold higher at CRP > 50 versus CRP < 5. This suggests that non-smokers are most susceptible to clozapine side effects during inflammation or infection and represent patients where TDM analyses are especially important for guiding clozapine dosing.
{"title":"Correlation Between Clozapine and CRP Levels in Relation to Smoking Status","authors":"Robert Løvsletten Smith, Ole A. Andreassen, John M. Kane, Georgios Schoretsanitis, Espen Molden","doi":"10.1111/acps.13801","DOIUrl":"10.1111/acps.13801","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Both inflammation and smoking are known to affect clozapine metabolism. However, the impact of inflammation on clozapine metabolism in relation to smoking status is unclear. Therefore, we investigated correlations between C-reactive protein (CRP) and clozapine levels in smokers and non-smokers separately.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients were included retrospectively from a therapeutic drug monitoring (TDM) service in Oslo, Norway, during January 2005–April 2022. Inclusion criteria were known smoking status and CRP measurements no longer than 7 days before or after clozapine TDM. Exclusion criteria were confirmed blood sampling for TDM outside 10–30 h after the last clozapine intake. Information about clozapine dosing was retrieved from the requisition forms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 126 patients fulfilling the criteria (47% smokers), dose-adjusted serum concentration (CD) of clozapine correlated significantly with CRP in non-smokers (<i>R</i> = 0.492; <i>p</i> < 001) but not in smokers (<i>R</i> = 0.191; <i>p</i> = 0.166). When subgrouping non-smoking patients into low CRP (< 5 mg/L; reference [51% of the population]), mid CRP (5–50 [37%]) and high CRP (> 50 [12%]), clozapine CD gradually increased in mid- (+48%, <i>p</i> = 0.004) and high-CRP groups (+204%, <i>p</i> < 0.001) compared with the low-CRP group. No significant differences in clozapine CD were found between CRP groups among smokers (<i>p</i> > 0.15).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We report a significant correlation between CD of clozapine and CRP levels in non-smoking patients only. In these patients, clozapine CD is more than 3-fold higher at CRP > 50 versus CRP < 5. This suggests that non-smokers are most susceptible to clozapine side effects during inflammation or infection and represent patients where TDM analyses are especially important for guiding clozapine dosing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"152 1","pages":"69-76"},"PeriodicalIF":5.3,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639361","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}
Bee Leng Per, Susan Loeser, Suzanne Edwards, Wen Siew Lee, Lisa R. Wilton, Scott Richard Clark
Background
Metformin shows potential in combating clozapine-induced weight gain (CIWG). However, current evidence for its use remains limited. Through an audit we determined the prevalence of metformin use among clozapine-treated patients and its impact on weight and waist circumference (WC).
Methods
This retrospective cohort study examined electronic medical records of community-based clozapine patients under the care of metropolitan community mental health teams within the Central Adelaide Local Health Network (CALHN) from January 2014 to June 2023. We included patients treated with clozapine both with and without metformin, above 18 years of age, with complete physical monitoring data at baseline, 6, and 12 months.
Results
There were 357 patients, who met study criteria. Metformin was prescribed to 23% of patients, of whom 78% had diabetes. At baseline, WC was > 101 cm in 71% of males and > 87 cm in 86% of females, placing them at increased risk of weight-related comorbidities, including cardiovascular disease, cancer, and death. After 1 year, males and females in the highest risk group for WC-related comorbidities increased to 76.3% and 95.4%, respectively. Co-prescription of metformin with clozapine was associated with unadjusted mean weight loss (−1.67 kg) and decrease in WC (−1.00 cm). Patients not using metformin gained weight (0.68 kg) and WC (2.49 cm). Using a linear mixed-effects models adjusting for repeated measurements, age, sex, and type 2 diabetes, over 12 months, patients treated with metformin were 3.08 kg lighter than those not taking metformin (95% confidence interval [CI]: 0.54–5.62, p = 0.018). Similar models suggested patients treated with metformin showed an average 2.83 cm decrease in WC compared with those not taking metformin (CI: 0.26–5.40, p = 0.03). There was no significant interaction between difference from baseline in weight or WC and metformin dose (p > 0.05).
Discussion/Conclusion
The prevalence of metformin use for CIWG appears low in this cohort, where over 84% of patients were overweight or obese. Metformin use was associated with a significantly lower incidence of weight and WC gain over 12 months. Pharmacists are crucial for educating clinicians and patients about the benefits of metformin for reducing CIWG.
背景：二甲双胍显示出对抗氯氮平引起的体重增加（CIWG）的潜力。然而，目前使用它的证据仍然有限。通过审计，我们确定了二甲双胍在氯氮平治疗患者中的使用情况及其对体重和腰围（WC）的影响。方法：本回顾性队列研究检查了2014年1月至2023年6月阿德莱德中央地方卫生网络（CALHN）内大都市社区精神卫生团队护理的社区氯氮平患者的电子病历。我们纳入了接受氯氮平联合或不联合二甲双胍治疗的患者，年龄大于18岁，在基线、6个月和12个月有完整的身体监测数据。结果：357例患者符合研究标准。23%的患者开了二甲双胍，其中78%患有糖尿病。基线时，71%的男性腰围为1010cm， 86%的女性腰围为87cm，这使他们患体重相关合并症的风险增加，包括心血管疾病、癌症和死亡。1年后，wc相关合并症最高风险组的男性和女性分别增加到76.3%和95.4%。二甲双胍与氯氮平合用与未经调整的平均体重减轻（-1.67 kg）和腰围减少（-1.00 cm）相关。未使用二甲双胍的患者体重增加（0.68 kg），腰围增加（2.49 cm）。使用线性混合效应模型调整重复测量、年龄、性别和2型糖尿病，在12个月内，接受二甲双胍治疗的患者比未服用二甲双胍的患者轻3.08 kg（95%置信区间[CI]: 0.54-5.62, p = 0.018）。类似模型显示，与未服用二甲双胍的患者相比，接受二甲双胍治疗的患者WC平均下降2.83 cm （CI: 0.26-5.40, p = 0.03）。与基线相比，体重和腰围的差异与二甲双胍剂量之间没有显著的相互作用（p < 0.05）。讨论/结论：在这个队列中，使用二甲双胍治疗CIWG的患病率似乎很低，超过84%的患者超重或肥胖。二甲双胍的使用与12个月内体重和体重增加的发生率显著降低相关。药剂师在教育临床医生和患者二甲双胍对减少CIWG的益处方面至关重要。
{"title":"The Impact of Metformin on Weight and Waist Circumference in Patients Treated With Clozapine: A One-Year Retrospective Cohort Study","authors":"Bee Leng Per, Susan Loeser, Suzanne Edwards, Wen Siew Lee, Lisa R. Wilton, Scott Richard Clark","doi":"10.1111/acps.13796","DOIUrl":"10.1111/acps.13796","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metformin shows potential in combating clozapine-induced weight gain (CIWG). However, current evidence for its use remains limited. Through an audit we determined the prevalence of metformin use among clozapine-treated patients and its impact on weight and waist circumference (WC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective cohort study examined electronic medical records of community-based clozapine patients under the care of metropolitan community mental health teams within the Central Adelaide Local Health Network (CALHN) from January 2014 to June 2023. We included patients treated with clozapine both with and without metformin, above 18 years of age, with complete physical monitoring data at baseline, 6, and 12 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were 357 patients, who met study criteria. Metformin was prescribed to 23% of patients, of whom 78% had diabetes. At baseline, WC was > 101 cm in 71% of males and > 87 cm in 86% of females, placing them at increased risk of weight-related comorbidities, including cardiovascular disease, cancer, and death. After 1 year, males and females in the highest risk group for WC-related comorbidities increased to 76.3% and 95.4%, respectively. Co-prescription of metformin with clozapine was associated with unadjusted mean weight loss (−1.67 kg) and decrease in WC (−1.00 cm). Patients not using metformin gained weight (0.68 kg) and WC (2.49 cm). Using a linear mixed-effects models adjusting for repeated measurements, age, sex, and type 2 diabetes, over 12 months, patients treated with metformin were 3.08 kg lighter than those not taking metformin (95% confidence interval [CI]: 0.54–5.62, <i>p</i> = 0.018). Similar models suggested patients treated with metformin showed an average 2.83 cm decrease in WC compared with those not taking metformin (CI: 0.26–5.40, <i>p</i> = 0.03). There was no significant interaction between difference from baseline in weight or WC and metformin dose (<i>p</i> > 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion/Conclusion</h3>\u0000 \u0000 <p>The prevalence of metformin use for CIWG appears low in this cohort, where over 84% of patients were overweight or obese. Metformin use was associated with a significantly lower incidence of weight and WC gain over 12 months. Pharmacists are crucial for educating clinicians and patients about the benefits of metformin for reducing CIWG.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"151 6","pages":"719-730"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acps.13796","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mirko Manchia, Alessandro Miola, Leonardo Tondo, Ross J. Baldessarini
Objectives
Recurrent [hypo]mania without major depressive episodes (“unipolar mania” [UPM]) is an uncommon form of major affective disorder related to bipolar disorder (BD). We characterized UPM patients and estimated the prevalence of their characteristics based on prolonged times-at-risk.
Methods
Using standard bivariate and multivariate statistics, we compared the characteristics of 63 consecutive UPM patients to 1210 other BD patients over prolonged, close, prospective follow-up at expert mood disorder centers.
Results
UPM was uncommon (4.95% of 1273 BD cases during 18.2 years at risk) with a 2.5-fold excess of men and 93.4% considered type I BD. UPM cases had earlier initial clinical interventions than other BD patients, more psychotic features with first episodes, and fewer UPM patients were married but did not have fewer children and were more unemployed. UPM cases experienced more morbidity (episodes and hospitalizations/year and %-time ill) than other BD patients and made more follow-up clinic visits/year. They were less likely to be suicidal and had less general medical comorbidity but did not differ in substance abuse. They had lower ratings of depressive symptoms, used mood stabilizers more, and as expected, received antidepressants 27 times less than other BD patients. Observed rates of UPM declined with longer observation times.
Conclusions
UPM was uncommon (4.95% of BD cases; 0.31% with hypomania only). Compared to ordinary BD, UPM had significantly greater morbidity and unemployment but a lower risk of suicidal behavior or general medical disorders associated with bipolar depression. This unusual disorder needs greater recognition, clarification of its nosological status, and efforts to optimize its treatment.
{"title":"Unipolar Mania: Prevalence and Patient Characteristics","authors":"Mirko Manchia, Alessandro Miola, Leonardo Tondo, Ross J. Baldessarini","doi":"10.1111/acps.13798","DOIUrl":"10.1111/acps.13798","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Recurrent [hypo]mania without major depressive episodes (“unipolar mania” [UPM]) is an uncommon form of major affective disorder related to bipolar disorder (BD). We characterized UPM patients and estimated the prevalence of their characteristics based on prolonged times-at-risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using standard bivariate and multivariate statistics, we compared the characteristics of 63 consecutive UPM patients to 1210 other BD patients over prolonged, close, prospective follow-up at expert mood disorder centers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>UPM was uncommon (4.95% of 1273 BD cases during 18.2 years at risk) with a 2.5-fold excess of men and 93.4% considered type I BD. UPM cases had earlier initial clinical interventions than other BD patients, more psychotic features with first episodes, and fewer UPM patients were married but did not have fewer children and were more unemployed. UPM cases experienced more morbidity (episodes and hospitalizations/year and %-time ill) than other BD patients and made more follow-up clinic visits/year. They were less likely to be suicidal and had less general medical comorbidity but did not differ in substance abuse. They had lower ratings of depressive symptoms, used mood stabilizers more, and as expected, received antidepressants 27 times less than other BD patients. Observed rates of UPM declined with longer observation times.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>UPM was uncommon (4.95% of BD cases; 0.31% with hypomania only). Compared to ordinary BD, UPM had significantly greater morbidity and unemployment but a lower risk of suicidal behavior or general medical disorders associated with bipolar depression. This unusual disorder needs greater recognition, clarification of its nosological status, and efforts to optimize its treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"151 6","pages":"680-688"},"PeriodicalIF":5.3,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584048","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}
Gestational exposure to valproate has been associated with a wide range of adverse pregnancy outcomes, including major congenital malformations in offspring. However, to date, no meta-analysis has comprehensively examined the risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children gestationally exposed to valproate.
Methods
We searched MEDLINE, Embase, and Scopus from inception until 15 May 2024 for relevant English-language articles. Primary outcomes of interest were the risk of ASD and ADHD, two independent primary outcomes, in children exposed to valproate anytime during pregnancy relative to unexposed children. Secondary outcomes were trimester-wise analyses of risk. We used a random effects model to pool the overall and trimester-wise hazard ratios (HRs) and obtained 95% confidence intervals (CIs), separately for the risks of ASD and ADHD. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist.
Results
Eight cohort studies (pooled N = 6,033,300) met our search criteria. Anytime gestational exposure to valproate was associated with a large increase in the risk of ASD (adjusted HR [aHR], 3.10; 95% confidence interval [CI], 2.24–4.28; N = 1,841,198) and a modest increase in the risk of ADHD (aHR, 1.62; 95% CI, 1.30–2.01; N = 24,295). The findings in sensitivity analyses for both outcomes were generally consistent with those of the main analyses. Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1 g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32; 95% CI, 3.12–12.80, N = 1,719,825). Likewise, in monotherapy (aHR, 4.21; 95% CI, 2.97–5.95; N = 1,745,253) and discordant sibling pair (aHR, 6.42; 95% CI, 2.02–20.42; N = 1133) analyses, the risk of ASD was substantially elevated.
Conclusion
Gestational exposure to valproate was associated with an increased risk of ASD and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day. These findings add to the literature that strongly discourages the use of valproate by women of childbearing age, especially during pregnancy.
{"title":"Gestational Exposure to Valproate and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring: Systematic Review and Meta-Analysis","authors":"Chittaranjan Andrade, Natarajan Varadharajan, Sharmi Bascarane, Akshayee Kale, Jilisha Gnanadhas, Vikas Menon","doi":"10.1111/acps.13797","DOIUrl":"10.1111/acps.13797","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Gestational exposure to valproate has been associated with a wide range of adverse pregnancy outcomes, including major congenital malformations in offspring. However, to date, no meta-analysis has comprehensively examined the risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children gestationally exposed to valproate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched MEDLINE, Embase, and Scopus from inception until 15 May 2024 for relevant English-language articles. Primary outcomes of interest were the risk of ASD and ADHD, two independent primary outcomes, in children exposed to valproate anytime during pregnancy relative to unexposed children. Secondary outcomes were trimester-wise analyses of risk. We used a random effects model to pool the overall and trimester-wise hazard ratios (HRs) and obtained 95% confidence intervals (CIs), separately for the risks of ASD and ADHD. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eight cohort studies (pooled <i>N</i> = 6,033,300) met our search criteria. Anytime gestational exposure to valproate was associated with a large increase in the risk of ASD (adjusted HR [aHR], 3.10; 95% confidence interval [CI], 2.24–4.28; <i>N</i> = 1,841,198) and a modest increase in the risk of ADHD (aHR, 1.62; 95% CI, 1.30–2.01; <i>N</i> = 24,295). The findings in sensitivity analyses for both outcomes were generally consistent with those of the main analyses. Notably, anytime gestational exposure to high-dose valproate (> 1.0 to 1.1 g/day) was associated with a substantially elevated risk of ASD (aHR, 6.32; 95% CI, 3.12–12.80, <i>N</i> = 1,719,825). Likewise, in monotherapy (aHR, 4.21; 95% CI, 2.97–5.95; <i>N</i> = 1,745,253) and discordant sibling pair (aHR, 6.42; 95% CI, 2.02–20.42; <i>N</i> = 1133) analyses, the risk of ASD was substantially elevated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Gestational exposure to valproate was associated with an increased risk of ASD and ADHD; the risks for ASD were greater at doses ≥ 1000 mg/day. These findings add to the literature that strongly discourages the use of valproate by women of childbearing age, especially during pregnancy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":108,"journal":{"name":"Acta Psychiatrica Scandinavica","volume":"151 6","pages":"668-679"},"PeriodicalIF":5.3,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584047","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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