European Neuropsychopharmacology最新文献

{"title":"Toward rigorous control conditions in trials of digital therapeutics","authors":"Nathan T.M. Huneke , Blanca Bolea-Alamañac","doi":"10.1016/j.euroneuro.2025.09.013","DOIUrl":"10.1016/j.euroneuro.2025.09.013","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"101 ","pages":"Pages 1-2"},"PeriodicalIF":6.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to the letter regarding “Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine”","authors":"Ting-Hui Liu , Jheng-Yan Wu , Po-Yu Huang , Wan-Lin Cheng , Chih-Cheng Lai","doi":"10.1016/j.euroneuro.2025.10.001","DOIUrl":"10.1016/j.euroneuro.2025.10.001","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"101 ","pages":"Page 5"},"PeriodicalIF":6.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidepressant use in pregnancy and neonatal outcomes: reassuring findings from an asian cohort","authors":"Qing Ren , Mingyi Gu , Xin Wang","doi":"10.1016/j.euroneuro.2025.10.003","DOIUrl":"10.1016/j.euroneuro.2025.10.003","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"101 ","pages":"Page 6"},"PeriodicalIF":6.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is psychosis an obstetric condition? Revisiting the role of early-life environmentally stressful events","authors":"Inmaculada Baeza , Clemente García-Rizo","doi":"10.1016/j.euroneuro.2025.10.002","DOIUrl":"10.1016/j.euroneuro.2025.10.002","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"101 ","pages":"Pages 3-4"},"PeriodicalIF":6.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural connectomic signatures of childhood maltreatment across affective and psychotic disorders","authors":"Linda M. Bonnekoh ,&nbsp;Marius Gruber ,&nbsp;Cathrine Thams ,&nbsp;Kira Flinkenflügel ,&nbsp;Susanne Meinert ,&nbsp;Janik Goltermann ,&nbsp;Dominik Grotegerd ,&nbsp;Julia Hubbert ,&nbsp;Judith Krieger ,&nbsp;Christoph Jurischka ,&nbsp;Ruth H. Fellmeth ,&nbsp;Nils R. Winter ,&nbsp;Tim Hahn ,&nbsp;Elisabeth J. Leehr ,&nbsp;Nils Opel ,&nbsp;Marc Pawlitzki ,&nbsp;Paula Rehm ,&nbsp;Nina v. Werthern ,&nbsp;Sharmili Edwin Thanarajah ,&nbsp;Stefanie Fischer ,&nbsp;Jonathan Repple","doi":"10.1016/j.euroneuro.2025.09.009","DOIUrl":"10.1016/j.euroneuro.2025.09.009","url":null,"abstract":"<div><div>Exposure to childhood maltreatment (CM) is a crucial risk factor for affective disorders and schizophrenia, which are linked to structural brain network alterations. We hypothesized a significant association between CM and brain structural connectivity in a transdiagnostic sample. Participants included patients with major depressive disorder (<em>n</em> = 827), bipolar disorder (<em>n</em> = 134), schizophrenia spectrum disorders (<em>n</em> = 118), and healthy controls (<em>n</em> = 932) aged 18–65 from the Marburg-Muenster Affective Disorders Cohort Study. Structural brain networks were reconstructed from structural and diffusion-weighted MRI. CM was assessed using the Childhood Trauma Questionnaire (CTQ) based on established cut-offs. Analyses of covariance investigated the main effect of CM and the interaction of diagnosis and CM on global network metrics. In addition, network-based statistic (NBS) analyses were performed to identify the underlying subnetworks. History of CM was positively associated with the number of connections (p_FDR=0.01; CM: 95 %-CI=[533.9; 540.6], No CM: 95 %-CI=[529.1; 535.0]), normalized (p_FDR=0.02; CM: 95 %-CI=[0.860; 0.863], No CM: 95 %-CI=[0.857; 0.860]) and non-normalized network efficiency (p_FDR=0.01; CM: 95 %-CI=[0.405; 0.407], No CM: 95 %-CI=[0.403; 0.405]) and negatively associated with normalized network clustering (p_FDR=0.045; CM: 95 %-CI=[4.976; 5.065], No CM: 95 %-CI=[5.100; 5.150]). There were no significant interaction effects of CM and diagnosis. NBS analyses revealed a large network of edges, in which individuals with CM exhibited higher structural connectivity compared to those without, which persisted after correcting for diagnosis. These findings indicate a connectome signature of CM, marked by hyperconnectivity, across major mental disorders and in healthy individuals, suggesting that CM affects connectome architecture independent of present psychiatric diagnoses.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"100 ","pages":"Pages 42-52"},"PeriodicalIF":6.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A REPEATED MEASURES GWAS IN RELATIVES: DETECTING AGE-VARYING GENETIC EFFECTS ON MATERNAL DEPRESSION IN MOBA","authors":"Christopher Rayner ,&nbsp;Tom McAdams ,&nbsp;Alexandra Havdahl ,&nbsp;Eivind Ystrom ,&nbsp;Ziada Ayorech","doi":"10.1016/j.euroneuro.2025.08.483","DOIUrl":"10.1016/j.euroneuro.2025.08.483","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Genome-wide association studies (GWAS) of depression typically rely on case-control analyses, using lifetime history (LTH) of a diagnosis as the primary outcome. Longitudinal cohorts provide opportunities to understand how genetic effects on depression vary across time and contexts. We aimed to harness repeated measures in a single sample to minimise phenotypic heterogeneity and improve statistical power to detect genetic effects on depression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We used data from mothers who participated in the Norwegian Mother, Father and Child study (MoBa). We restructured the Hopkins Symptoms Checklist Depression (SCL-D) scores for 76,044 mothers by age, producing an accelerated longitudinal design with 418,159 depression observations across the lifecourse (age range: 16, 60 years old). We used continuous-time item response theory models to minimise measurement error, and Empirical Bayes Estimates with Simultaneous Correction (SCEBE) to conduct repeated measures GWAS (GWASRM). We estimated genetic effects on depression symptoms at age 30, and the linear change in age (variant by age interaction), which were combined to compute age-specific effects at ages 20 to 50 (GWASt=20..50). For comparison, we performed a GWAS of LTH depression assessed in the same sample (GWASLTH). Summary statistics from GWASRM and GWASLTH were compared using heritability and genetic correlations. We also performed 10-fold-leave-one-out GWASRM and GWASLTH, leaving 10 test datasets for polygenic index (PGI) analyses. The efficacy and robustness of SCEBE was further assessed via comparison with linear mixed effects models applied to a subset of the data. The impact of selective attrition on GWASRM is also currently under investigation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;SCEBE is an efficient and robust method for estimating genetic variant main effects and variant-by-age interactions, with perfect overlap with effects estimated using a linear mixed model. Following GWASRM, there was one independently significant (p &lt; 5e-8) locus associated with depression symptoms at age 30 and an additional locus at age 40. The SNP-based heritability (h2SNP) of GWASt ranged from 0.01 to 0.05. Following GWASLTH there was one independently significant locus associated with lifetime history of depression, and the h2SNP estimate was 0.15. The age-specific PGI (PGIt) was associated with higher SCL-D symptoms (β=4.21, 95% CI: 6.27, 2.14; p=6.68e-5). The PGILTH was also associated with SCL-D symptoms (β=3.73, 95% CI: 2.78, 4.68).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Discussion&lt;/h3&gt;&lt;div&gt;Despite the anticipated gains in statistical power from a repeated measures approach in a homogenous sample, we did not detect substantial improvement in genome-wide signal for depression. These results might be due to etiological heterogeneity associated with depression and unobserved confounding. For example, medication status was not available across these time-points and wa","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 15-16"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MULTIVARIATE GENOME-WIDE ASSOCIATION STUDY OF PTSD, ALCOHOL USE AND ALCOHOL USE DISORDERS","authors":"","doi":"10.1016/j.euroneuro.2025.08.497","DOIUrl":"10.1016/j.euroneuro.2025.08.497","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 21"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GENETIC UNDERPINNINGS OF TREATMENT-RESISTANT DEPRESSION: INSIGHTS FROM THE PSYCHSTRATA CONSORTIUM","authors":"Julia Kraft ,&nbsp;Chiara Fabbri ,&nbsp;Eleni Friligkou ,&nbsp;Brittany Mitchell ,&nbsp;Kristi Krebs ,&nbsp;Joanna Biernacka ,&nbsp;Julia Sealock ,&nbsp;Mikael Landén ,&nbsp;Danyang Li ,&nbsp;deCODE Genetics Team ,&nbsp;FinnGen consortium ,&nbsp;Juan De La Hoz ,&nbsp;FinnGen consortium ,&nbsp;Yingzhe Zhang ,&nbsp;Elise Koch ,&nbsp;Bernhard T. Baune ,&nbsp;Stephan Ripke","doi":"10.1016/j.euroneuro.2025.08.535","DOIUrl":"10.1016/j.euroneuro.2025.08.535","url":null,"abstract":"<div><div>Depressive Symptoms in Major Depressive Disorder (MDD) are primarily treated with antidepressant medication. However, a substantial proportion of patients do not achieve a meaningful symptom improvement, even after multiple medication trials, posing a major clinical and public health challenge. Investigating the genetic underpinnings of treatment-resistant depression (TRD) may potentially reveal biological components that contribute to poor treatment outcomes.</div><div>Through the PsychSTRATA consortium, we aim to investigate the biological basis of treatment resistance across major psychiatric disorders, including MDD, bipolar disorder, and schizophrenia. In this study, we focus specifically on the genetic basis of TRD within MDD by performing a genome-wide associations study comparing individuals with and without TRD. In collaboration with many international sites and the antidepressant working group of the PGC, we collated and harmonized data from clinical studies, large-scale biobanks, and population-based cohorts, using electronic healthcare records (EHR), structured clinical interviews, and self-report questionnaires to define TRD.</div><div>Analyses are currently ongoing and leverage data from ∼265,000 individuals with MDD, of whom ∼39,500 were classified as TRD and ∼225,500 as non-TRD. Planned analyses include a GWAS meta-analysis, SNP-based heritability estimation, polygenic risk scoring, and comparisons across definitions to characterize the genetic architecture of TRD and validate genetic findings.</div><div>Our results will lead to an improved understanding of the pharmacogenetic mechanisms underlying TRD and help to identify both disorder-specific and shared genetic contributions with bipolar disorder and schizophrenia. Ultimately, this may inform the development of targeted or novel pharmacological strategies for individuals with treatment resistance.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 39"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POLYGENIC AGGREGATION OF EQTL EFFECTS REVEALS CELL-TYPE AND TRAIT-SPECIFIC LONG-RANGE REGULATORY PATTERNS","authors":"Toni Boltz,&nbsp;Ajay Nadig,&nbsp;Steve McCarroll,&nbsp;Wei Zhou,&nbsp;Elise Robinson","doi":"10.1016/j.euroneuro.2025.08.527","DOIUrl":"10.1016/j.euroneuro.2025.08.527","url":null,"abstract":"<div><div>Gene regulation varies across genomic regions and cellular contexts, shaped by both linear distance and 3D genome architecture. Recent work on chromosomes 22q and 16p revealed that common polygenic risk for neuropsychiatric disorders - particularly schizophrenia (SCZ), autism, ADHD, and low IQ - is associated with widespread decreases in gene expression across these chromosome arms in neuronal cell types. These findings motivated our development of a scalable method to investigate the extent to which long-range regulatory patterns exist genome-wide, and whether these patterns are specific to neuropsychiatric disease or neuronal cellular contexts.</div><div>To systematically assess how regulatory effects vary with SNP-gene distance, we developed a polygenic risk score (PRS)-inspired framework that aggregates eQTL effect sizes weighted by GWAS effect sizes across different trait and cell-type contexts.</div><div>Our initial analysis successfully replicated the previous 22q findings across four neuronal cell types: glutamatergic and GABAergic neurons, astrocytes, and oligodendrocytes. We observed that SCZ-weighted eQTL effects were consistently negative across distances up to 16 Mb, particularly in glutamatergic neurons and astrocytes, where height-weighted eQTL effects were null. Oligodendrocytes exhibited null effects in both trait contexts. These results confirmed the existence of trait- and cell-type-specific signatures of long-range gene regulation. We subsequently expanded the analysis genomewide, identifying many regions of the genome in which long range eQTL effects could not be identified in any trait context (e.g. chr4: 118Mb - 151Mb), and a small number of regions of the genome in which common variant risk for SCZ, but not somatic traits, was similarly downregulating genes across large genomic territories (e.g. chr1: 1Mb - 33Mb).</div><div>Ongoing work will incorporate additional brain and non-brain cell types, and integrate chromatin contact data to connect spatial genome organization with the observed regulatory patterns. These analyses will provide additional insight into how transcriptome-wide gene dysregulation creates risk for SCZ and other neuropsychiatric disorders, and the assign biological consequence to polygenic influences on psychiatric disease. More broadly, this PRS-style eQTL aggregation framework offers a scalable approach for identifying how genetic risk influences gene regulation across distance, cellular identity, and disease relevance.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 34"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RARE CODING VARIANTS IN 195,257 INDIVIDUALS REVEAL 29 NOVEL BIPOLAR DISORDER GENES AND STRUCTURAL MISSENSE HOTSPOTS IN PROTEIN SPACE","authors":"Calwing Liao,&nbsp;The Bipolar Exome Consortium (BipEx),&nbsp;Benjamin Neale","doi":"10.1016/j.euroneuro.2025.08.543","DOIUrl":"10.1016/j.euroneuro.2025.08.543","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Bipolar disorder (BD) is a complex psychiatric disorder characterized by recurrent mood disturbances with significant variations in disease severity and treatment response. Despite its substantial impact on individuals, the genetic factors contributing to BD remain incompletely understood. Here, we present an updated effort from the Bipolar Exome (BipEx) consortium. We increased the effective sample size by 5-fold relative to BipEx 1.0 across diverse populations to investigate the role of protein-truncating variants (PTVs), copy number variants (CNVs), and damaging missense variants in the pathogenesis of BD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Our study cohort comprised 195,257 individuals, including 45,479 cases and 149,778 controls from ancestrally diverse populations. Whole exome sequencing was performed to capture protein-coding regions, followed by robust variant calling and stringent quality control. We analyzed ultra-rare variants with a minor allele count &lt; 5, focusing on PTVs and damaging missense variants. CNVs were identified using GATK-gCNV, focusing on rare exonic deletions and duplications spanning more than three exons. To characterize structural convergence of missense variation, we mapped variant positions to protein 3D structures using AlphaFold and identified significant clustering in spatial neighborhoods across the proteome.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results/Discussion&lt;/h3&gt;&lt;div&gt;We identified 29 FDR-significant genes, including AKAP11, SHANK1, ATP2B2, KDM5B, and DOP1A, associated with increased burden of PTVs and damaging missense variants. These genes cluster into early and late neurodevelopmental expression patterns and recapitulate clinically relevant pathways, including those associated with clozapine response. Using regional missense constraint metrics, we observed damaging missense variants in BD cases—but not controls—within a highly constrained region of ATP2B2. We also identified significant 3D missense clustering in ATP2A2 and G3BP2, implicating structurally focused hotspots as contributing to BD risk. CNV analysis revealed BPNT2 as the strongest deletion-associated gene (OR: 9.04, P = 2.67 × 10⁻⁹), a known lithium target, and BIRC6 as the most significant duplication hit (OR: 5.04, P = 2.49 × 10⁻¹⁴). We also found evidence for a potential reciprocal CNV locus at 15q11.2, where the duplication increases BD risk while the deletion is depleted in cases.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;By leveraging data from nearly 200,000 individuals, BipEx 2.0 provides a comprehensive view of rare genetic variation in BD, emphasizing contributions from PTVs, CNVs, and damaging missense variants. The identification of missense-convergent 3D protein hotspots, including in ATP2A2 and G3BP2, highlights the value of integrating structural biology into psychiatric gene discovery. These results illuminate convergent biological mechanisms across variant classes and point to new directions for mechanistic i","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 43"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}