Pub Date : 2025-09-24DOI: 10.1001/jamapsychiatry.2025.2572
Hui Wang,Krisztina D László
ImportanceParental mental disorders are associated with increased risks of infant mortality and with several developmental, mental, and somatic health outcomes, yet their associations with long-term morality in offspring remain unknown.ObjectiveTo investigate the associations between parental mental disorders and the risk of mortality in offspring up to middle age.Design, Setting, and ParticipantsThis nationwide register-based cohort study used data for individuals born in Sweden from January 1973 to December 2014. Data were analyzed from October 2024 to March 2025.ExposureParental mental disorders identified from the Patient Register.Main Outcomes and MeasuresThe outcomes were offspring mortality, including deaths due to any, natural, and unnatural causes, from birth up to December 31, 2023. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for offspring mortality according to parental mental disorders. Cousin comparison analysis was performed to assess familial confounding due to genetic and shared environmental factors.ResultsAmong 3 548 788 offspring, 1 818 232 were male (51.2%; 635 213 exposed to parental mental disorders) and 1 730 556 were female (48.8%; 605 935 exposed to parental mental disorders). The mean (SD) age at index parental diagnosis was 15.8 (13.3) years. During a median (IQR) follow-up of 20.1 (11.5-32.5) years (age range at end of follow-up, 9-51 years), there were 12 725 deaths (7.93 per 10 000 person-years) among offspring exposed to parental mental disorders and 30 087 deaths (3.55 per 10 000 person-years) among unexposed offspring. Offspring exposed to parental mental disorders had increased risks of all-cause mortality (HR, 2.13; 95% CI, 2.08-2.18) and death due to natural (HR, 1.88; 95% CI, 1.83-1.95) and unnatural causes (HR, 2.45; 95% CI, 2.37-2.54). All major types of parental mental disorders were associated with increased risks of offspring mortality, with the HRs ranging from 1.58 (95% CI, 1.40-1.79) for eating disorders to 2.22 (95% CI, 1.89-2.62) for intellectual disability. The associations were strongest if both parents were diagnosed with mental disorders and did not differ significantly according to the affected parents' sex and the child's age at parental diagnosis. The observed associations remained similar in the cousin comparison analyses.Conclusions and RelevanceOffspring of parents with mental disorders had an increased risk of mortality up to the age of 51 years. The associations were observed for all major types of parental mental disorders and were strongest in case of unnatural deaths, especially when both parents were diagnosed with mental disorders. These findings emphasize the importance of providing support for families with parents with mental disorders; further studies are needed to investigate whether such support may reduce the risk of premature death in affected offspring.
{"title":"Parental Mental Disorders and Offspring Mortality up to Middle Age.","authors":"Hui Wang,Krisztina D László","doi":"10.1001/jamapsychiatry.2025.2572","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2572","url":null,"abstract":"ImportanceParental mental disorders are associated with increased risks of infant mortality and with several developmental, mental, and somatic health outcomes, yet their associations with long-term morality in offspring remain unknown.ObjectiveTo investigate the associations between parental mental disorders and the risk of mortality in offspring up to middle age.Design, Setting, and ParticipantsThis nationwide register-based cohort study used data for individuals born in Sweden from January 1973 to December 2014. Data were analyzed from October 2024 to March 2025.ExposureParental mental disorders identified from the Patient Register.Main Outcomes and MeasuresThe outcomes were offspring mortality, including deaths due to any, natural, and unnatural causes, from birth up to December 31, 2023. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for offspring mortality according to parental mental disorders. Cousin comparison analysis was performed to assess familial confounding due to genetic and shared environmental factors.ResultsAmong 3 548 788 offspring, 1 818 232 were male (51.2%; 635 213 exposed to parental mental disorders) and 1 730 556 were female (48.8%; 605 935 exposed to parental mental disorders). The mean (SD) age at index parental diagnosis was 15.8 (13.3) years. During a median (IQR) follow-up of 20.1 (11.5-32.5) years (age range at end of follow-up, 9-51 years), there were 12 725 deaths (7.93 per 10 000 person-years) among offspring exposed to parental mental disorders and 30 087 deaths (3.55 per 10 000 person-years) among unexposed offspring. Offspring exposed to parental mental disorders had increased risks of all-cause mortality (HR, 2.13; 95% CI, 2.08-2.18) and death due to natural (HR, 1.88; 95% CI, 1.83-1.95) and unnatural causes (HR, 2.45; 95% CI, 2.37-2.54). All major types of parental mental disorders were associated with increased risks of offspring mortality, with the HRs ranging from 1.58 (95% CI, 1.40-1.79) for eating disorders to 2.22 (95% CI, 1.89-2.62) for intellectual disability. The associations were strongest if both parents were diagnosed with mental disorders and did not differ significantly according to the affected parents' sex and the child's age at parental diagnosis. The observed associations remained similar in the cousin comparison analyses.Conclusions and RelevanceOffspring of parents with mental disorders had an increased risk of mortality up to the age of 51 years. The associations were observed for all major types of parental mental disorders and were strongest in case of unnatural deaths, especially when both parents were diagnosed with mental disorders. These findings emphasize the importance of providing support for families with parents with mental disorders; further studies are needed to investigate whether such support may reduce the risk of premature death in affected offspring.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127055","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}
ImportanceSoft drink consumption is linked to negative physical and mental health outcomes, but its association with major depressive disorder (MDD) and the underlying mechanisms remains unclear.ObjectiveTo examine the association between soft drink consumption and MDD diagnosis and severity and whether this association is mediated by changes in the gut microbiota, particularly Eggerthella and Hungatella abundance.Design, Setting, and ParticipantsThis multicenter cohort study was conducted in Germany using cross-sectional data from the Marburg-Münster Affective Cohort. Patients with MDD and healthy controls (aged 18-65 years) recruited from the general population and primary care between September 2014 and September 2018 were analyzed. Data analyses were conducted between May and December 2024.Main Outcomes and MeasuresPrimary analyses included multivariable regression and analysis of variance (ANOVA) models examining the association between soft drink consumption and MDD diagnosis and symptom severity, controlling for site and education, and Eggerthella and Hungatella abundance, controlling for site, education, and library size. Mediation analyses tested whether microbiota abundance mediated the soft drink-MDD link.ResultsA total of 405 patients with MDD (275 female patients [67.9%]; mean [SD] age, 36.37 [13.33] years) and 527 healthy controls (345 female controls [65.5%]; mean [SD] age, 35.33 [13.13] years) were included. Soft drink consumption predicted MDD diagnosis (odds ratio [OR], 1.081; 95% CI, 1.008-1.159; P = .03) and symptom severity (P < .001; partial η2 [ηp2], 0.012; 95% CI, 0.004-0.035), with stronger effects in women (diagnosis: OR, 1.167; 95% CI, 1.054-1.292; P = .003; severity: P < .001; ηp2, 0.036; 95% CI, 0.011-0.062). In women, consumption was linked to increased Eggerthella (P = .007; ηp2, 0.017; 95% CI, 0.0002-0.068), but not Hungatella abundance. Mediation analyses confirmed that Eggerthella significantly mediated the soft drink-MDD association (diagnosis: P = .011; severity: P = .005), explaining 3.82% and 5.00% of the effect, respectively.Conclusions and RelevanceIn this cohort study, it was found that soft drink consumption may contribute to MDD through gut microbiota alterations, notably involving Eggerthella. Public health strategies to reduce soft drink intake may help mitigate depression risk, especially among vulnerable populations; in addition, interventions for depression targeting the microbiome composition appear promising.
{"title":"Soft Drink Consumption and Depression Mediated by Gut Microbiome Alterations.","authors":"Sharmili Edwin Thanarajah,Adèle H Ribeiro,Jaehyun Lee,Nils R Winter,Frederike Stein,Rachel N Lippert,Ruth Hanssen,Carmen Schiweck,Leon Fehse,Mirjam Bloemendaal,Mareike Aichholzer,Aicha Bouzouina,Carmen Uckermark,Marius Welzel,Jonathan Repple,Silke Matura,Susanne Meinert,Corinna Bang,Andre Franke,Ramona Leenings,Maximilian Konowski,Jan Ernsting,Lukas Fisch,Carlotta Barkhau,Florian Thomas-Odenthal,Paula Usemann,Lea Teutenberg,Benjamin Straube,Nina Alexander,Hamidreza Jamalabadi,Igor Nenadic,Andreas Lügering,Robert Nitsch,Sarah Kittel-Schneider,John F Cryan,Andreas Reif,Tilo Kircher,Dominik Heider,Udo Dannlowski,Tim Hahn","doi":"10.1001/jamapsychiatry.2025.2579","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2579","url":null,"abstract":"ImportanceSoft drink consumption is linked to negative physical and mental health outcomes, but its association with major depressive disorder (MDD) and the underlying mechanisms remains unclear.ObjectiveTo examine the association between soft drink consumption and MDD diagnosis and severity and whether this association is mediated by changes in the gut microbiota, particularly Eggerthella and Hungatella abundance.Design, Setting, and ParticipantsThis multicenter cohort study was conducted in Germany using cross-sectional data from the Marburg-Münster Affective Cohort. Patients with MDD and healthy controls (aged 18-65 years) recruited from the general population and primary care between September 2014 and September 2018 were analyzed. Data analyses were conducted between May and December 2024.Main Outcomes and MeasuresPrimary analyses included multivariable regression and analysis of variance (ANOVA) models examining the association between soft drink consumption and MDD diagnosis and symptom severity, controlling for site and education, and Eggerthella and Hungatella abundance, controlling for site, education, and library size. Mediation analyses tested whether microbiota abundance mediated the soft drink-MDD link.ResultsA total of 405 patients with MDD (275 female patients [67.9%]; mean [SD] age, 36.37 [13.33] years) and 527 healthy controls (345 female controls [65.5%]; mean [SD] age, 35.33 [13.13] years) were included. Soft drink consumption predicted MDD diagnosis (odds ratio [OR], 1.081; 95% CI, 1.008-1.159; P = .03) and symptom severity (P < .001; partial η2 [ηp2], 0.012; 95% CI, 0.004-0.035), with stronger effects in women (diagnosis: OR, 1.167; 95% CI, 1.054-1.292; P = .003; severity: P < .001; ηp2, 0.036; 95% CI, 0.011-0.062). In women, consumption was linked to increased Eggerthella (P = .007; ηp2, 0.017; 95% CI, 0.0002-0.068), but not Hungatella abundance. Mediation analyses confirmed that Eggerthella significantly mediated the soft drink-MDD association (diagnosis: P = .011; severity: P = .005), explaining 3.82% and 5.00% of the effect, respectively.Conclusions and RelevanceIn this cohort study, it was found that soft drink consumption may contribute to MDD through gut microbiota alterations, notably involving Eggerthella. Public health strategies to reduce soft drink intake may help mitigate depression risk, especially among vulnerable populations; in addition, interventions for depression targeting the microbiome composition appear promising.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"73 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127053","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 : 2025-09-17DOI: 10.1001/jamapsychiatry.2025.2221
Kenneth N Fish,Robert A Sweet,Matthew L MacDonald,David A Lewis
ImportanceSchizophrenia (SZ) is characterized by deficits in visual-spatial working memory, a function dependent on a distributed cortical network that includes nodes in the primary visual (V1), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. The connections across these regions involve excitatory synapses on the dendritic spines of pyramidal neurons in layer 3 (L3).ObjectiveTo assess whether SZ is associated with regional differences in the magnitude or nature of L3 spine alterations.Design, Setting, and ParticipantsThis case-control study examined brain tissue from 20 individuals with SZ and 20 matched unaffected comparison (UC) individuals, obtained by the Allegheny County Office of the Medical Examiner (Pittsburgh, Pennsylvania). Dendritic spines were labeled using fluorescent phalloidin (for F-actin) and immunolabeling for spinophilin and imaged by confocal microscopy.ExposureSchizophrenia.Main Outcomes and MeasuresPrimary outcomes were between-group differences in L3 dendritic spine density and size across V1, PPC, and DLPFC. Secondary outcomes included spine fluorescence intensities of phalloidin and spinophilin.ResultsForty individuals were studied (20 UC: 14 [70%] male and 6 [30%] female; mean [SD] age, 47.7 [9.6] years; 20 SZ: 14 [70%] male and 6 [30%] female; mean [SD] age, 45.6 [9.5] years). Dendritic spine density reductions in individuals with SZ varied by spine size across regions, with lower densities of small spines in V1 (-18%; 95% CI, -31% to -5%; P = .009), medium spines in PPC (-16%; 95% CI, -28% to -4%; P = .01) and DLPFC (-13%; 95% CI, -21% to -4%; P = .009), and large spines in PPC (-38%; 95% CI, -58% to -17%; P < .001) and DLPFC (-30%; 95% CI, -50% to -11%; P = .004). Phalloidin fluorescence was lower in small (-9.5%; 95% CI, -17% to -1%; P = .04) and medium (-9.8%; 95% CI, -18% to -1%; P = .04) V1 spines and higher in large DLPFC spines (9.5%; 95% CI, 0.4% to 19%; P = .049). Spinophilin fluorescence was lower across all spine sizes and regions (a range from -13%; 95% CI, -24% to -2%, to -34%; 95% CI, -46% to -21%; P values ranging .02 to <.001).Conclusions and RelevanceL3 dendritic spine density differs by diagnosis and cortical region in SZ. Because dendritic spine size is associated with synaptic stability (large/medium spines) and plasticity (small spines), regional differences in the sizes of affected spines in SZ may reflect differing functional impairments in the primary sensory and association regions of the cortical visual-spatial working memory network.
{"title":"Regional Specificity of Cortical Layer 3 Dendritic Spine Deficits in Schizophrenia.","authors":"Kenneth N Fish,Robert A Sweet,Matthew L MacDonald,David A Lewis","doi":"10.1001/jamapsychiatry.2025.2221","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2221","url":null,"abstract":"ImportanceSchizophrenia (SZ) is characterized by deficits in visual-spatial working memory, a function dependent on a distributed cortical network that includes nodes in the primary visual (V1), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. The connections across these regions involve excitatory synapses on the dendritic spines of pyramidal neurons in layer 3 (L3).ObjectiveTo assess whether SZ is associated with regional differences in the magnitude or nature of L3 spine alterations.Design, Setting, and ParticipantsThis case-control study examined brain tissue from 20 individuals with SZ and 20 matched unaffected comparison (UC) individuals, obtained by the Allegheny County Office of the Medical Examiner (Pittsburgh, Pennsylvania). Dendritic spines were labeled using fluorescent phalloidin (for F-actin) and immunolabeling for spinophilin and imaged by confocal microscopy.ExposureSchizophrenia.Main Outcomes and MeasuresPrimary outcomes were between-group differences in L3 dendritic spine density and size across V1, PPC, and DLPFC. Secondary outcomes included spine fluorescence intensities of phalloidin and spinophilin.ResultsForty individuals were studied (20 UC: 14 [70%] male and 6 [30%] female; mean [SD] age, 47.7 [9.6] years; 20 SZ: 14 [70%] male and 6 [30%] female; mean [SD] age, 45.6 [9.5] years). Dendritic spine density reductions in individuals with SZ varied by spine size across regions, with lower densities of small spines in V1 (-18%; 95% CI, -31% to -5%; P = .009), medium spines in PPC (-16%; 95% CI, -28% to -4%; P = .01) and DLPFC (-13%; 95% CI, -21% to -4%; P = .009), and large spines in PPC (-38%; 95% CI, -58% to -17%; P < .001) and DLPFC (-30%; 95% CI, -50% to -11%; P = .004). Phalloidin fluorescence was lower in small (-9.5%; 95% CI, -17% to -1%; P = .04) and medium (-9.8%; 95% CI, -18% to -1%; P = .04) V1 spines and higher in large DLPFC spines (9.5%; 95% CI, 0.4% to 19%; P = .049). Spinophilin fluorescence was lower across all spine sizes and regions (a range from -13%; 95% CI, -24% to -2%, to -34%; 95% CI, -46% to -21%; P values ranging .02 to <.001).Conclusions and RelevanceL3 dendritic spine density differs by diagnosis and cortical region in SZ. Because dendritic spine size is associated with synaptic stability (large/medium spines) and plasticity (small spines), regional differences in the sizes of affected spines in SZ may reflect differing functional impairments in the primary sensory and association regions of the cortical visual-spatial working memory network.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"35 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071735","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 : 2025-09-17DOI: 10.1001/jamapsychiatry.2025.2508
Katie Witkiewitz,Raymond F Anton,Stephanie S O'Malley,Deborah S Hasin,Bernard L Silverman,Arnie Aldridge,Karl Mann,
ImportanceAlcohol use disorder (AUD) is a highly prevalent and costly psychiatric disorder. Abstinence has been considered the optimal outcome of treatment for AUD. Yet, most individuals with AUD do not seek treatment because they do not have a goal of abstinence. The Food and Drug Administration (FDA) has recently qualified reductions in drinking, defined by at least a 2-level reduction in the World Health Organization risk drinking levels (WHO RDLs), as a primary end point for alcohol pharmacotherapy trials. The approval of drinking reductions as an end point for alcohol clinical trials aligns with an accumulating literature on drinking reductions in the alcohol field. This article provides a narrative review of 34 articles that have examined WHO RDLs as a surrogate marker of how people with AUD feel and function.ObservationsResults from epidemiological studies, community samples, and clinical trials indicate that drinking reductions are associated with improvements in how patients feel and function, including reduced risk of substance use disorder and medical and psychiatric diseases and reductions in alcohol-related consequences, craving, and health care costs. Drinking reductions are also associated with improvements in functioning and quality of life. Drinking reductions are also achieved by most clinical trial participants, and effect sizes for the WHO RDL reductions for active medications vs placebo are similar to or better than alternative end points.Conclusions and RelevanceThe FDA acceptance of reduction in WHO RDLs as a primary end point for alcohol clinical trials may increase opportunities for AUD medications development, encourage patients to seek treatments that target drinking reductions, and engage clinicians in prescribing medications shown to be effective in supporting drinking reductions. The WHO RDLs may be particularly useful for targeted drinking reductions in clinical practice. Qualification of the WHO RDL end point facilitates a paradigm shift toward a harm reduction approach in AUD treatment.
{"title":"Reductions in World Health Organization Risk Drinking Levels as a Primary Efficacy End Point for Alcohol Clinical Trials: A Review.","authors":"Katie Witkiewitz,Raymond F Anton,Stephanie S O'Malley,Deborah S Hasin,Bernard L Silverman,Arnie Aldridge,Karl Mann, ","doi":"10.1001/jamapsychiatry.2025.2508","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2508","url":null,"abstract":"ImportanceAlcohol use disorder (AUD) is a highly prevalent and costly psychiatric disorder. Abstinence has been considered the optimal outcome of treatment for AUD. Yet, most individuals with AUD do not seek treatment because they do not have a goal of abstinence. The Food and Drug Administration (FDA) has recently qualified reductions in drinking, defined by at least a 2-level reduction in the World Health Organization risk drinking levels (WHO RDLs), as a primary end point for alcohol pharmacotherapy trials. The approval of drinking reductions as an end point for alcohol clinical trials aligns with an accumulating literature on drinking reductions in the alcohol field. This article provides a narrative review of 34 articles that have examined WHO RDLs as a surrogate marker of how people with AUD feel and function.ObservationsResults from epidemiological studies, community samples, and clinical trials indicate that drinking reductions are associated with improvements in how patients feel and function, including reduced risk of substance use disorder and medical and psychiatric diseases and reductions in alcohol-related consequences, craving, and health care costs. Drinking reductions are also associated with improvements in functioning and quality of life. Drinking reductions are also achieved by most clinical trial participants, and effect sizes for the WHO RDL reductions for active medications vs placebo are similar to or better than alternative end points.Conclusions and RelevanceThe FDA acceptance of reduction in WHO RDLs as a primary end point for alcohol clinical trials may increase opportunities for AUD medications development, encourage patients to seek treatments that target drinking reductions, and engage clinicians in prescribing medications shown to be effective in supporting drinking reductions. The WHO RDLs may be particularly useful for targeted drinking reductions in clinical practice. Qualification of the WHO RDL end point facilitates a paradigm shift toward a harm reduction approach in AUD treatment.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071736","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 : 2025-09-17DOI: 10.1001/jamapsychiatry.2025.2515
Raymond F Anton,Stephanie S O'Malley,Karl Mann,Bernard L Silverman
{"title":"New Reduced Drinking Goals in Alcohol Pharmacotherapy Trials-A Novel Public-Private Effort and FDA Approval Process.","authors":"Raymond F Anton,Stephanie S O'Malley,Karl Mann,Bernard L Silverman","doi":"10.1001/jamapsychiatry.2025.2515","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2515","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071737","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 : 2025-09-17DOI: 10.1001/jamapsychiatry.2025.2518
Nili Solomonov,Daniel Kerchner,Oded Bein,Courtney E Lee,Jihui L Diaz,Adam Ciarleglio,Soohyun Kim,Jo Anne Sirey,Faith M Gunning,Patrick J Raue,Samprit Banerjee,Patricia A Areán,George S Alexopoulos
ImportanceMost older adults with depression lack access to efficacious psychotherapies due to a critical clinician shortage. Even when treated, response rates are limited to approximately 50%. A treatment decision rule (TDR) may maximize treatment efficacy and resources by assigning patients to their optimal intervention. This is the first study to propose a TDR for late-life depression designed for community settings.ObjectiveTo develop a scalable TDR for assignment to a psychotherapy or usual care intervention for late-life depression that can be delivered easily in community settings.Design, Setting, and ParticipantsIn this prognostic study, adults 60 years or older with major depression participated in randomized controlled trials comparing psychotherapy with usual care. Participants were recruited from outpatient and community settings of Weill Cornell Medicine and the University of California San Francisco between 2002 and 2011. Data were analyzed from May 2023 to May 2025.InterventionsParticipants received either psychotherapy (problem-solving therapy, psychotherapy for late-life depression and medical burden) or usual care (supportive therapy, treatment as usual, or case management).Main Outcomes and MeasuresThe primary outcome was mean reduction in depression severity (measured by the Hamilton Depression Rating Scale [HAM-D]). A generated effect modifier TDR was applied to identify the optimal intervention for each patient based on baseline characteristics (demographics, depression severity, social support, cognition, and disability). The TDR maximized depression severity reduction and the proportion of patients treated with the usual care intervention.ResultsIn 427 older adults with late-life depression (mean [SD] age, 72.7 [8.7] years; 70% female), the predicted HAM-D score reduction with TDR-based intervention was a mean of 49.1% (95% CI, 47.4%-51.0%). The TDR improved expected depression severity reduction by 34% compared with usual care (HAM-D reduction, 36.6% [95% CI, 34.5%-38.7%]) and the TDR was somewhat superior to assigning all patients to receive psychotherapy (HAM-D reduction, 46.7% [95% CI, 44.2%-48.8%]). Older adults with higher depression severity, stronger social support, and lower cognitive functioning should receive psychotherapy; those with lower depression severity, higher cognitive functioning, and low social support would benefit from usual care.Conclusions and RelevanceIn this study of older adults with depression, pending prospective testing, the automatic TDR may be used in community settings to inform treatment assignment. The TDR has the potential to increase precision, cost-effectiveness, and response rates among older adults with depression.Trial RegistrationClinicalTrials.gov Identifiers: NCT00601055, NCT00151372, NCT00052091, NCT00540865.
{"title":"Precision Assignment to Psychosocial Interventions for Late-Life Depression: An Automated Treatment Decision Rule.","authors":"Nili Solomonov,Daniel Kerchner,Oded Bein,Courtney E Lee,Jihui L Diaz,Adam Ciarleglio,Soohyun Kim,Jo Anne Sirey,Faith M Gunning,Patrick J Raue,Samprit Banerjee,Patricia A Areán,George S Alexopoulos","doi":"10.1001/jamapsychiatry.2025.2518","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2518","url":null,"abstract":"ImportanceMost older adults with depression lack access to efficacious psychotherapies due to a critical clinician shortage. Even when treated, response rates are limited to approximately 50%. A treatment decision rule (TDR) may maximize treatment efficacy and resources by assigning patients to their optimal intervention. This is the first study to propose a TDR for late-life depression designed for community settings.ObjectiveTo develop a scalable TDR for assignment to a psychotherapy or usual care intervention for late-life depression that can be delivered easily in community settings.Design, Setting, and ParticipantsIn this prognostic study, adults 60 years or older with major depression participated in randomized controlled trials comparing psychotherapy with usual care. Participants were recruited from outpatient and community settings of Weill Cornell Medicine and the University of California San Francisco between 2002 and 2011. Data were analyzed from May 2023 to May 2025.InterventionsParticipants received either psychotherapy (problem-solving therapy, psychotherapy for late-life depression and medical burden) or usual care (supportive therapy, treatment as usual, or case management).Main Outcomes and MeasuresThe primary outcome was mean reduction in depression severity (measured by the Hamilton Depression Rating Scale [HAM-D]). A generated effect modifier TDR was applied to identify the optimal intervention for each patient based on baseline characteristics (demographics, depression severity, social support, cognition, and disability). The TDR maximized depression severity reduction and the proportion of patients treated with the usual care intervention.ResultsIn 427 older adults with late-life depression (mean [SD] age, 72.7 [8.7] years; 70% female), the predicted HAM-D score reduction with TDR-based intervention was a mean of 49.1% (95% CI, 47.4%-51.0%). The TDR improved expected depression severity reduction by 34% compared with usual care (HAM-D reduction, 36.6% [95% CI, 34.5%-38.7%]) and the TDR was somewhat superior to assigning all patients to receive psychotherapy (HAM-D reduction, 46.7% [95% CI, 44.2%-48.8%]). Older adults with higher depression severity, stronger social support, and lower cognitive functioning should receive psychotherapy; those with lower depression severity, higher cognitive functioning, and low social support would benefit from usual care.Conclusions and RelevanceIn this study of older adults with depression, pending prospective testing, the automatic TDR may be used in community settings to inform treatment assignment. The TDR has the potential to increase precision, cost-effectiveness, and response rates among older adults with depression.Trial RegistrationClinicalTrials.gov Identifiers: NCT00601055, NCT00151372, NCT00052091, NCT00540865.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"47 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071742","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 : 2025-09-10DOI: 10.1001/jamapsychiatry.2025.2319
Karyn E Richardson,Chao Suo,Lucy Albertella,Suzan Maleki,James Coxon,Josh Hendrikse,Sam Hughes,Joseph Pitt,Edouard Kayayan,Catherine Brown,Liam Nguyen,Nadia Solowij,Dan I Lubman,Rebecca Segrave,Murat Yücel
ImportanceCannabis is the most commonly used illicit drug, with 10% to 30% of regular users developing cannabis use disorder (CUD), a condition linked to altered hippocampal integrity. Evidence suggests high-intensity interval training (HIIT) enhances hippocampal structure and function, with this form of physical exercise potentially mitigating CUD-related cognitive and mental health impairments.ObjectiveTo determine the impact of a 12-week HIIT intervention on hippocampal integrity (ie, structure, connectivity, biochemistry) compared with 12 weeks of strength and resistance (SR) training in CUD.Design, Setting, and ParticipantsThis randomized, single-blind, comparator-controlled clinical trial (Brain Exercise and Addiction Trial [BEAT]) assessed the efficacy of a 12-week exercise intervention for improving hippocampal integrity. Participants were adults with moderate to severe CUD and were not required to cease cannabis consumption. In-person assessments and interventions were conducted at Monash University's BrainPark facility (Melbourne, Australia). The trial was conducted from 2018 to 2022 and the data analysis from September 2022 to February 2023.InterventionHIIT (3 times a week, high lactate condition) for 12 weeks, compared with 12 weeks of SR (3 times a week, low lactate, active control condition) to 12 weeks. Exercise interventions were supervised by exercise physiologists and tailored to target specific (lactate) and personalized physiological mechanisms.Main Outcomes and MeasuresThe primary outcome was hippocampal integrity as indicated by a composite of 3 magnetic resonance imaging (MRI) measures: anatomical volume, fractional anisotropy, and N-acetylaspartate. Secondary outcomes included cognitive and mental health measures. Outcomes were assessed at baseline and at the end of the intervention. Adverse events were tracked throughout participation.ResultsFifty-nine participants with moderate to severe CUD were randomized 1:1 to receive HIIT or SR. The mean (SD) age was 27.0 (6.3) years (range, 20-53 years); 47 participants (80%) were male and 12 (20%) female. Overall, 47 participants (80%) completed the 12-week intervention, attending a mean of 29 of 36 exercise sessions (80%). Hippocampal integrity did not increase after 12 weeks of HIIT (estimated marginal means [SE], -0.14 [0.43] at baseline; 0.10 [0.45] after intervention) or SR (0.38 [0.37] at baseline; -0.16 [0.37] after intervention).Conclusions and RelevanceThis trial found that a 12-week HIIT intervention did not improve hippocampal integrity or associated cognitive or mental health impairments while people continued to consume cannabis. However, results indicated that people with CUD can engage in regular physical exercise programs and highlighted exercise as a potential strategy to reduce cannabis craving.Trial RegistrationClinicalTrials.gov Identifier: NCT04902092.
{"title":"High-Intensity Exercise and Hippocampal Integrity in Adults With Cannabis Use Disorder: A Randomized Clinical Trial.","authors":"Karyn E Richardson,Chao Suo,Lucy Albertella,Suzan Maleki,James Coxon,Josh Hendrikse,Sam Hughes,Joseph Pitt,Edouard Kayayan,Catherine Brown,Liam Nguyen,Nadia Solowij,Dan I Lubman,Rebecca Segrave,Murat Yücel","doi":"10.1001/jamapsychiatry.2025.2319","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2319","url":null,"abstract":"ImportanceCannabis is the most commonly used illicit drug, with 10% to 30% of regular users developing cannabis use disorder (CUD), a condition linked to altered hippocampal integrity. Evidence suggests high-intensity interval training (HIIT) enhances hippocampal structure and function, with this form of physical exercise potentially mitigating CUD-related cognitive and mental health impairments.ObjectiveTo determine the impact of a 12-week HIIT intervention on hippocampal integrity (ie, structure, connectivity, biochemistry) compared with 12 weeks of strength and resistance (SR) training in CUD.Design, Setting, and ParticipantsThis randomized, single-blind, comparator-controlled clinical trial (Brain Exercise and Addiction Trial [BEAT]) assessed the efficacy of a 12-week exercise intervention for improving hippocampal integrity. Participants were adults with moderate to severe CUD and were not required to cease cannabis consumption. In-person assessments and interventions were conducted at Monash University's BrainPark facility (Melbourne, Australia). The trial was conducted from 2018 to 2022 and the data analysis from September 2022 to February 2023.InterventionHIIT (3 times a week, high lactate condition) for 12 weeks, compared with 12 weeks of SR (3 times a week, low lactate, active control condition) to 12 weeks. Exercise interventions were supervised by exercise physiologists and tailored to target specific (lactate) and personalized physiological mechanisms.Main Outcomes and MeasuresThe primary outcome was hippocampal integrity as indicated by a composite of 3 magnetic resonance imaging (MRI) measures: anatomical volume, fractional anisotropy, and N-acetylaspartate. Secondary outcomes included cognitive and mental health measures. Outcomes were assessed at baseline and at the end of the intervention. Adverse events were tracked throughout participation.ResultsFifty-nine participants with moderate to severe CUD were randomized 1:1 to receive HIIT or SR. The mean (SD) age was 27.0 (6.3) years (range, 20-53 years); 47 participants (80%) were male and 12 (20%) female. Overall, 47 participants (80%) completed the 12-week intervention, attending a mean of 29 of 36 exercise sessions (80%). Hippocampal integrity did not increase after 12 weeks of HIIT (estimated marginal means [SE], -0.14 [0.43] at baseline; 0.10 [0.45] after intervention) or SR (0.38 [0.37] at baseline; -0.16 [0.37] after intervention).Conclusions and RelevanceThis trial found that a 12-week HIIT intervention did not improve hippocampal integrity or associated cognitive or mental health impairments while people continued to consume cannabis. However, results indicated that people with CUD can engage in regular physical exercise programs and highlighted exercise as a potential strategy to reduce cannabis craving.Trial RegistrationClinicalTrials.gov Identifier: NCT04902092.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"308 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025550","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 : 2025-09-10DOI: 10.1001/jamapsychiatry.2025.2416
Gang Wang,Mario Aguado,Matthew A Spear,Larry Alphs,Crystal Chen,Holly Huang,Xiao-Xiong Lu,Julie Doostzadeh,Shaohui Wu,Shikai Wang,Ashok Patel,Charles B Nemeroff,Zhiqiang Wang,Anning Li,Wen Luo
ImportanceThis study represents a first successful use of a genetic biomarker to select potential responders in a prospective study in psychiatry. Liafensine, a triple reuptake inhibitor, may become a new precision medicine for treatment-resistant depression (TRD), a major unmet medical need.ObjectiveTo determine whether ANK3-positive patients with TRD benefit from a 1-mg and/or 2-mg daily oral dose of liafensine, compared with placebo, in a clinical trial.Design, Setting, and ParticipantsA novel pharmacogenomic biomarker, ANK3, was discovered as a predictor of liafensine's efficacy retrospectively. In this biomarker-guided, randomized, double-blind, placebo-controlled, phase 2b clinical trial conducted at 58 sites from July 2022 through March 2024, 1967 patients were assessed for eligibility and 189 ANK3-positive patients with TRD were randomized. Key exclusion criteria included specified disorders, concomitant medications, or organ dysfunction. Investigators, patients, raters, and sponsors were blinded to ANK3 status and treatment. Data analysis was performed from March 26 to April 23, 2024.InterventionsPatients were randomized 1:1:1 to once-daily oral liafensine, 1 mg; once-daily oral liafensine, 2 mg; or oral placebo once daily.Main Outcomes and MeasuresThe primary outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to day 42.ResultsOf the 189 ANK3-positive patients with TRD who were randomized, 188 received study drug (mean [SD] age, 43.2 [14.8] years; 119 [63.3%] female), and 186 had at least 1 dose of study drug and 1 postrandomization efficacy evaluation. The mean (SE) MADRS score change in these patients was -15.4 (0.9) for liafensine (including both 1- and 2-mg doses) vs -11.0 (1.3) for placebo (mean treatment difference, -4.4; 95% CI, -7.6 to -1.3; P = .006). Statistically significant improvements were also seen in all secondary end points. Adverse events were tolerable, with low rates of meaningful events. Adverse events leading to discontinuation of treatment occurred in 5 patients (4.0%) receiving liafensine and 9 (14.1%) receiving placebo.Conclusions and RelevanceLiafensine was efficacious and well tolerated in ANK3-positive patients with TRD, with clinically meaningful and statistically significant improvements over placebo suggesting ANK3 as a predictive genetic biomarker for liafensine. This represents a first successful prospective genetic biomarker-guided trial in psychiatry.Trial RegistrationClinicalTrials.gov Identifier: NCT05113771.
{"title":"ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial.","authors":"Gang Wang,Mario Aguado,Matthew A Spear,Larry Alphs,Crystal Chen,Holly Huang,Xiao-Xiong Lu,Julie Doostzadeh,Shaohui Wu,Shikai Wang,Ashok Patel,Charles B Nemeroff,Zhiqiang Wang,Anning Li,Wen Luo","doi":"10.1001/jamapsychiatry.2025.2416","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2416","url":null,"abstract":"ImportanceThis study represents a first successful use of a genetic biomarker to select potential responders in a prospective study in psychiatry. Liafensine, a triple reuptake inhibitor, may become a new precision medicine for treatment-resistant depression (TRD), a major unmet medical need.ObjectiveTo determine whether ANK3-positive patients with TRD benefit from a 1-mg and/or 2-mg daily oral dose of liafensine, compared with placebo, in a clinical trial.Design, Setting, and ParticipantsA novel pharmacogenomic biomarker, ANK3, was discovered as a predictor of liafensine's efficacy retrospectively. In this biomarker-guided, randomized, double-blind, placebo-controlled, phase 2b clinical trial conducted at 58 sites from July 2022 through March 2024, 1967 patients were assessed for eligibility and 189 ANK3-positive patients with TRD were randomized. Key exclusion criteria included specified disorders, concomitant medications, or organ dysfunction. Investigators, patients, raters, and sponsors were blinded to ANK3 status and treatment. Data analysis was performed from March 26 to April 23, 2024.InterventionsPatients were randomized 1:1:1 to once-daily oral liafensine, 1 mg; once-daily oral liafensine, 2 mg; or oral placebo once daily.Main Outcomes and MeasuresThe primary outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to day 42.ResultsOf the 189 ANK3-positive patients with TRD who were randomized, 188 received study drug (mean [SD] age, 43.2 [14.8] years; 119 [63.3%] female), and 186 had at least 1 dose of study drug and 1 postrandomization efficacy evaluation. The mean (SE) MADRS score change in these patients was -15.4 (0.9) for liafensine (including both 1- and 2-mg doses) vs -11.0 (1.3) for placebo (mean treatment difference, -4.4; 95% CI, -7.6 to -1.3; P = .006). Statistically significant improvements were also seen in all secondary end points. Adverse events were tolerable, with low rates of meaningful events. Adverse events leading to discontinuation of treatment occurred in 5 patients (4.0%) receiving liafensine and 9 (14.1%) receiving placebo.Conclusions and RelevanceLiafensine was efficacious and well tolerated in ANK3-positive patients with TRD, with clinically meaningful and statistically significant improvements over placebo suggesting ANK3 as a predictive genetic biomarker for liafensine. This represents a first successful prospective genetic biomarker-guided trial in psychiatry.Trial RegistrationClinicalTrials.gov Identifier: NCT05113771.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025547","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 : 2025-09-10DOI: 10.1001/jamapsychiatry.2025.2429
Dimitry S Davydow,Morgan Brasfield,Christopher B Morrow,Adam M Staffaroni,Gregory M Pontone,Breton M Asken
ImportanceBehavioral variant frontotemporal dementia (bvFTD), the most common subtype of FTD, is a leading form of early-onset dementia worldwide. Accurate and timely diagnosis of bvFTD is frequently delayed due to symptoms overlapping with common psychiatric disorders, and interest has increased in identifying biomarkers that may aid in differentiating bvFTD from psychiatric disorders.ObjectiveTo summarize and critically review studies examining whether neurofilament light chain (NfL) in cerebrospinal fluid (CSF) or blood is a viable aid in the differential diagnosis of bvFTD vs psychiatric disorders.Evidence ReviewA systematic review was conducted, searching PubMed, Embase, Web of Science, PsycINFO, and the Cochrane Collaborative according to Preferred Reporting Items for a Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies (PRISMA-DTA) guidelines. Eligible articles included cohorts of patients with bvFTD and psychiatric disorders ascertained using validated methods and conducted analyses to evaluate NfL from CSF and/or blood in distinguishing bvFTD from psychiatric disorders. Study quality was assessed using the Quality Assessment Of Diagnostic Accuracy Studies-2 tool.FindingsA total of 3828 titles and abstracts and 434 full-text articles were reviewed, yielding 12 articles meeting eligibility criteria. The studies included 694 unique patients with bvFTD and 1594 unique patients with a range of psychiatric disorders. Four studies measured NfL levels in CSF, 6 in blood, and 2 in both. Levels of NfL in CSF and blood were significantly higher among patients with bvFTD than patients with psychiatric disorders. In receiving operator characteristic curve analyses, the area under the curve (AUC) for NfL in CSF for bvFTD vs psychiatric disorders ranged from 0.86 to 0.95 (sensitivities: 63%-96%, specificities: 81%-100%). The AUCs for NfL in blood ranged from 0.79 to 0.98 (sensitivities: 65%-100%, specificities: 69%-96%).Conclusions and RelevanceThe findings in this systematic review indicate that NfL may help supplement clinical diagnostic evaluations in differentiating bvFTD from psychiatric disorder diagnoses. Considering the limitations of the existing literature, future studies should prospectively recruit patients with neuropsychiatric symptoms, quantify symptom severity, obtain NfL levels in real-time using clinically available assays, consider the potential impact of patient age on diagnostic accuracy, establish clinically relevant cutoffs, and correlate NfL with autopsy-confirmed brain pathology.
{"title":"Neurofilament Light Chain and Differentiation of Behavioral Variant Frontotemporal Dementia From Psychiatric Disorders: A Systematic Review.","authors":"Dimitry S Davydow,Morgan Brasfield,Christopher B Morrow,Adam M Staffaroni,Gregory M Pontone,Breton M Asken","doi":"10.1001/jamapsychiatry.2025.2429","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2429","url":null,"abstract":"ImportanceBehavioral variant frontotemporal dementia (bvFTD), the most common subtype of FTD, is a leading form of early-onset dementia worldwide. Accurate and timely diagnosis of bvFTD is frequently delayed due to symptoms overlapping with common psychiatric disorders, and interest has increased in identifying biomarkers that may aid in differentiating bvFTD from psychiatric disorders.ObjectiveTo summarize and critically review studies examining whether neurofilament light chain (NfL) in cerebrospinal fluid (CSF) or blood is a viable aid in the differential diagnosis of bvFTD vs psychiatric disorders.Evidence ReviewA systematic review was conducted, searching PubMed, Embase, Web of Science, PsycINFO, and the Cochrane Collaborative according to Preferred Reporting Items for a Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies (PRISMA-DTA) guidelines. Eligible articles included cohorts of patients with bvFTD and psychiatric disorders ascertained using validated methods and conducted analyses to evaluate NfL from CSF and/or blood in distinguishing bvFTD from psychiatric disorders. Study quality was assessed using the Quality Assessment Of Diagnostic Accuracy Studies-2 tool.FindingsA total of 3828 titles and abstracts and 434 full-text articles were reviewed, yielding 12 articles meeting eligibility criteria. The studies included 694 unique patients with bvFTD and 1594 unique patients with a range of psychiatric disorders. Four studies measured NfL levels in CSF, 6 in blood, and 2 in both. Levels of NfL in CSF and blood were significantly higher among patients with bvFTD than patients with psychiatric disorders. In receiving operator characteristic curve analyses, the area under the curve (AUC) for NfL in CSF for bvFTD vs psychiatric disorders ranged from 0.86 to 0.95 (sensitivities: 63%-96%, specificities: 81%-100%). The AUCs for NfL in blood ranged from 0.79 to 0.98 (sensitivities: 65%-100%, specificities: 69%-96%).Conclusions and RelevanceThe findings in this systematic review indicate that NfL may help supplement clinical diagnostic evaluations in differentiating bvFTD from psychiatric disorder diagnoses. Considering the limitations of the existing literature, future studies should prospectively recruit patients with neuropsychiatric symptoms, quantify symptom severity, obtain NfL levels in real-time using clinically available assays, consider the potential impact of patient age on diagnostic accuracy, establish clinically relevant cutoffs, and correlate NfL with autopsy-confirmed brain pathology.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"35 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025549","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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