Pub Date : 2025-10-01DOI: 10.1001/jamapsychiatry.2025.2525
Iris E Sommer,Franciska de Beer,Shiral Gangadin,Lieuwe de Haan,Wim Veling,Nico van Beveren,Nynke Boonstra,Bram-Sieben Rosema,Jim van Os,Martijn Kikkert,Sanne Koops,Jort Noorman,Frederick Thielen,Ben Wijnen,Marieke Begemann,
ImportanceDose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings.ObjectiveTo compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP.Design, Setting, and ParticipantsThe Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included.InterventionsDRD within 12 months after remission compared with 12 months maintenance treatment.Main Outcomes and MeasuresThe primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects.ResultsA total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = -3.31; 95% CI, -6.34 to -0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (P for trend = .06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group.Conclusions and RelevanceThis randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks.Trial registrationEudraCT number: 2017-002406-12.
{"title":"Early Dose Reduction or Discontinuation vs Maintenance Antipsychotics After First Psychotic Episode Remission: A Randomized Clinical Trial.","authors":"Iris E Sommer,Franciska de Beer,Shiral Gangadin,Lieuwe de Haan,Wim Veling,Nico van Beveren,Nynke Boonstra,Bram-Sieben Rosema,Jim van Os,Martijn Kikkert,Sanne Koops,Jort Noorman,Frederick Thielen,Ben Wijnen,Marieke Begemann, ","doi":"10.1001/jamapsychiatry.2025.2525","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2525","url":null,"abstract":"ImportanceDose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings.ObjectiveTo compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP.Design, Setting, and ParticipantsThe Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included.InterventionsDRD within 12 months after remission compared with 12 months maintenance treatment.Main Outcomes and MeasuresThe primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects.ResultsA total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = -3.31; 95% CI, -6.34 to -0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (P for trend = .06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group.Conclusions and RelevanceThis randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks.Trial registrationEudraCT number: 2017-002406-12.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"7 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194535","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 : 2025-10-01DOI: 10.1001/jamapsychiatry.2025.2700
David Eddie,Marina Nguyen,Katherine Zeng,Sara Mei,Noah Emery
ImportancePreliminary studies suggest heart rate variability biofeedback (HRVB) may reduce craving and negative affect in individuals with substance use disorder (SUD), but few studies have evaluated whether this translates into improved substance use outcomes, and no prior studies have examined second-generation wearable HRVB technology in this context.ObjectiveTo evaluate the effects of second-generation HRVB on negative affect, positive affect, craving, and alcohol and other drug (AOD) use in adults with SUD.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial included 8 weeks of outpatient treatment. Recruitment was conducted virtually across the US from February 2023 to June 2024. Treatment-seeking adults with SUD were randomized to receive HRVB + treatment as usual (TAU) or TAU only.InterventionEight weeks of HRVB.Main Outcomes and MeasuresThe primary outcomes were negative affect, positive affect, craving, and substance use, assessed with ecological momentary assessment.ResultsOf 260 individuals assessed for eligibility, 120 were randomized to receive HRVB + TAU or TAU only. Among study participants (69 female participants of 115 [60.0%]; mean [SD] age, 46.18 [11.59] years), HRVB was associated with significant reductions in negative affect (b, -0.01; z, -3.21; P = .001) and craving (b, -0.01; z, -4.60; P < .001) over 8 weeks. In contrast, the control group experienced increases in both negative affect and craving. No differences were observed for positive affect. HRVB was also associated with a significantly lower proportion of AOD use days (odds ratio [OR], 0.36; 95% credible interval [CrI], 0.25-0.54), representing a 64% reduction in AOD use compared to controls. Treatment condition moderated the within-person relationship between craving and later AOD use (OR, 0.84; 95% CrI, 0.73-0.97), such that those receiving HRVB were less likely to use AOD following craving (b, -0.18; 95% CrI, -0.32 to -0.03).Conclusions and RelevanceIn this randomized clinical trial, findings suggest second-generation HRVB can reduce negative affect, craving, and substance use among individuals in early recovery from SUD. HRVB appears to confer benefit in part by disrupting the association between craving and subsequent AOD use; these results support HRVB as a potentially efficacious treatment for SUD and warrant further investigation in phase 3 trials.Trial RegistrationClinicalTrials.gov Identifier: NCT05454657.
{"title":"Heart Rate Variability Biofeedback for Substance Use Disorder: A Randomized Clinical Trial.","authors":"David Eddie,Marina Nguyen,Katherine Zeng,Sara Mei,Noah Emery","doi":"10.1001/jamapsychiatry.2025.2700","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2700","url":null,"abstract":"ImportancePreliminary studies suggest heart rate variability biofeedback (HRVB) may reduce craving and negative affect in individuals with substance use disorder (SUD), but few studies have evaluated whether this translates into improved substance use outcomes, and no prior studies have examined second-generation wearable HRVB technology in this context.ObjectiveTo evaluate the effects of second-generation HRVB on negative affect, positive affect, craving, and alcohol and other drug (AOD) use in adults with SUD.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial included 8 weeks of outpatient treatment. Recruitment was conducted virtually across the US from February 2023 to June 2024. Treatment-seeking adults with SUD were randomized to receive HRVB + treatment as usual (TAU) or TAU only.InterventionEight weeks of HRVB.Main Outcomes and MeasuresThe primary outcomes were negative affect, positive affect, craving, and substance use, assessed with ecological momentary assessment.ResultsOf 260 individuals assessed for eligibility, 120 were randomized to receive HRVB + TAU or TAU only. Among study participants (69 female participants of 115 [60.0%]; mean [SD] age, 46.18 [11.59] years), HRVB was associated with significant reductions in negative affect (b, -0.01; z, -3.21; P = .001) and craving (b, -0.01; z, -4.60; P < .001) over 8 weeks. In contrast, the control group experienced increases in both negative affect and craving. No differences were observed for positive affect. HRVB was also associated with a significantly lower proportion of AOD use days (odds ratio [OR], 0.36; 95% credible interval [CrI], 0.25-0.54), representing a 64% reduction in AOD use compared to controls. Treatment condition moderated the within-person relationship between craving and later AOD use (OR, 0.84; 95% CrI, 0.73-0.97), such that those receiving HRVB were less likely to use AOD following craving (b, -0.18; 95% CrI, -0.32 to -0.03).Conclusions and RelevanceIn this randomized clinical trial, findings suggest second-generation HRVB can reduce negative affect, craving, and substance use among individuals in early recovery from SUD. HRVB appears to confer benefit in part by disrupting the association between craving and subsequent AOD use; these results support HRVB as a potentially efficacious treatment for SUD and warrant further investigation in phase 3 trials.Trial RegistrationClinicalTrials.gov Identifier: NCT05454657.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"69 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194534","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}
ImportanceTransdiagnostic clinical staging models for mental disorders are receiving increased attention. However, their underlying assumptions are underresearched; for example, it is not clear whether the observed progression across stages occurs independently of preexisting risk factors.ObjectivesTo test the likelihood of progression from stage 0 (familial risk) in childhood to stage 1a (mild symptoms) in adolescence and subsequently to stage 1b (clinically significant symptoms) in young adulthood, accounting for confounders, and to explore potential mediators.Design, Setting, and ParticipantsThis prospective cohort study included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC included pregnant women and their offspring residing in Avon, United Kingdom, between 1991 and 1992, with a proportion of offspring followed up into young adulthood. Eligible participants provided data on stage determinants and potential confounders from birth until age 24 years. Data were collected from 1991 to 2015 and analyzed from January 2002 to June 2025.ExposuresExposures were clinical stages 0 and 1a in separate tests of association with stages 1a and 1b, respectively. Criteria for stage 0 were the presence of schizophrenia or severe depression in a first-degree relative. Criteria for stage 1a were the presence of 1 to 2 symptoms of depression, anxiety, or psychosis at ages 12 to 13 years.Main Outcomes and MeasuresOutcomes were stage 1a in adolescence and stage 1b in young adulthood. Criteria for stage 1b were at least moderate symptoms of depression, anxiety, or psychosis, with associated functional impact at ages 18 to 24 years. Confounders were sex assigned at birth, obstetric risk, parental social class, ethnicity, family adversity, temperament, early life events, and neurocognition, measured in childhood.ResultsAmong those with complete data at all 3 time points (1375 participants; weighted, 7342), 796 participants (57.9%; weighted, 51.5%) were female and 579 (42.1%; weighted, 48.5%) were male. After adjusting for potential confounders, there was an association between stage 0 in childhood and stage 1a in adolescence (3860 participants; weighted, 7388 participants; odds ratio [OR], 1.65, 95% CI, 1.30-2.11) and between stage 1a in adolescence and stage 1b in young adulthood (1661 participants; weighted, 7466 participants; OR, 2.07; 95% CI, 1.07-4.01). Level of neuroticism in adolescence mediated 18% of the association between stage 1a in adolescence and stage 1b in young adulthood.Conclusions and RelevanceIn this cohort study, young people with mental health problems meeting criteria for early clinical stages were at heightened risk of developing subsequent stages, independent of early life risk factors. This study supports the assumption of progression underlying clinical staging models for mental disorders.
{"title":"Progression of Transdiagnostic Stages From Childhood to Young Adulthood.","authors":"Aswin Ratheesh,Yufan Chen,Dylan Hammond,Zoe Aitken,Jai Shah,Frank Iorfino,Jan Scott,Ian Hickie,Chris Davey,Andrew Chanen,Michael Berk,Patrick McGorry,Steven Marwaha,Andrew Thompson,Barnaby Nelson","doi":"10.1001/jamapsychiatry.2025.2648","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.2648","url":null,"abstract":"ImportanceTransdiagnostic clinical staging models for mental disorders are receiving increased attention. However, their underlying assumptions are underresearched; for example, it is not clear whether the observed progression across stages occurs independently of preexisting risk factors.ObjectivesTo test the likelihood of progression from stage 0 (familial risk) in childhood to stage 1a (mild symptoms) in adolescence and subsequently to stage 1b (clinically significant symptoms) in young adulthood, accounting for confounders, and to explore potential mediators.Design, Setting, and ParticipantsThis prospective cohort study included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC included pregnant women and their offspring residing in Avon, United Kingdom, between 1991 and 1992, with a proportion of offspring followed up into young adulthood. Eligible participants provided data on stage determinants and potential confounders from birth until age 24 years. Data were collected from 1991 to 2015 and analyzed from January 2002 to June 2025.ExposuresExposures were clinical stages 0 and 1a in separate tests of association with stages 1a and 1b, respectively. Criteria for stage 0 were the presence of schizophrenia or severe depression in a first-degree relative. Criteria for stage 1a were the presence of 1 to 2 symptoms of depression, anxiety, or psychosis at ages 12 to 13 years.Main Outcomes and MeasuresOutcomes were stage 1a in adolescence and stage 1b in young adulthood. Criteria for stage 1b were at least moderate symptoms of depression, anxiety, or psychosis, with associated functional impact at ages 18 to 24 years. Confounders were sex assigned at birth, obstetric risk, parental social class, ethnicity, family adversity, temperament, early life events, and neurocognition, measured in childhood.ResultsAmong those with complete data at all 3 time points (1375 participants; weighted, 7342), 796 participants (57.9%; weighted, 51.5%) were female and 579 (42.1%; weighted, 48.5%) were male. After adjusting for potential confounders, there was an association between stage 0 in childhood and stage 1a in adolescence (3860 participants; weighted, 7388 participants; odds ratio [OR], 1.65, 95% CI, 1.30-2.11) and between stage 1a in adolescence and stage 1b in young adulthood (1661 participants; weighted, 7466 participants; OR, 2.07; 95% CI, 1.07-4.01). Level of neuroticism in adolescence mediated 18% of the association between stage 1a in adolescence and stage 1b in young adulthood.Conclusions and RelevanceIn this cohort study, young people with mental health problems meeting criteria for early clinical stages were at heightened risk of developing subsequent stages, independent of early life risk factors. This study supports the assumption of progression underlying clinical staging models for mental disorders.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127093","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 : 2025-09-24DOI: 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}
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