European Neuropsychopharmacology最新文献

{"title":"THE ROLE OF SEX IN POLYGENIC RISK FOR SEX-BIASED BRAIN DISORDERS","authors":"Arielle Crestol ,&nbsp;Dennis van der Meer ,&nbsp;Nadine Parker ,&nbsp;Ann-Marie de Lange ,&nbsp;Espen Hagen ,&nbsp;Hannah Oppenheimer ,&nbsp;Stener Nerland ,&nbsp;Edith Breton ,&nbsp;Christian K Tamnes ,&nbsp;Ole A. Andreassen ,&nbsp;Ingrid Agartz ,&nbsp;Claudia Barth","doi":"10.1016/j.euroneuro.2025.08.552","DOIUrl":"10.1016/j.euroneuro.2025.08.552","url":null,"abstract":"<div><div>Sex differences in genetic vulnerability have been implicated in psychiatric and neurodegenerative disorders, yet their specific impact on brain health and clinical risk remains poorly understood. Leveraging data from up to 220,836 women and 187,651 men from the UK Biobank (aged 39–81), we assessed how sex and polygenic risk scores (PRSs) for major depressive disorder (PRSMDD), Alzheimer’s disease (PRSAD), schizophrenia (PRSSCZ), and Parkinson’s disease (PRSPD) relate to case-control status and brain age gap (BAG), a neuroimaging marker of brain health. We tested for sex differences in PRSs and performed regression analyses examining associations between sex, PRSs, and either case-control status or BAG. We then compared models with sex-pooled and sex-specific PRSs to explore whether sex-specific PRSs can improve predictive accuracy. While PRSSCZ was higher in women compared to men, no other sex differences were found between PRSs. Our most striking finding was a significant PRSAD-by-sex interaction, in which PRSAD conferred greater risk for AD diagnosis in women compared to men. Consistently, the women-only PRSAD model outperformed the sex-pooled model, while no differences were observed between sex-pooled and men-only models. By contrast, sex-pooled PRS models outperformed sex-specific PRS models for MDD, SCZ, and PD. No sex-by-PRS interactions were significantly associated with BAG. However, men presented with higher BAG values than women, indicative of an older brain age. Further, higher PRSMDD, higher PRSAD, and lower PRSPD were each associated with higher BAG, irrespective of sex. Finally, BAG model performance did not differ between sex-pooled and sex-specific PRS models. Our findings highlight that sex moderates AD genetic risk for diagnostic status in middle-to-late-life adults, and as such, tailoring PRSs by sex may improve risk assessment for AD. While sex-specific PRSs offered limited value for the other disorders, our findings suggest that the value of sex-specific PRSs will likely grow with increased statistical power.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 48"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204382","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":"LONGITUDINAL DATA ANALYSIS REVEALS SEX DIFFERENCES IN GENETIC RISK FACTORS UNDERLYING WORSENING DEPRESSIVE SYMPTOMS AND COGNITIVE DECLINE IN OLDER ADULTS","authors":"Jessica Dennis,&nbsp;Karanvir Singh","doi":"10.1016/j.euroneuro.2025.08.520","DOIUrl":"10.1016/j.euroneuro.2025.08.520","url":null,"abstract":"<div><div>Neuropsychiatric symptoms such as depression and apathy are among the earliest signs of dementia, are more common in females than in males, and worsen in-step with cognitive impairment. These symptoms are caused by the brain changes associated with dementia, are difficult to treat, and are not just a predictable consequence of the effects of dementia on quality of life. We sought to understand the genetic and non-genetic factors that influence depressive symptom emergence and progression across the cognitive decline spectrum. We analyzed repeated measures of cognitive and depressive symptoms spanning up to 9 years from ∼8,500 adults aged 65+ at baseline participating in the Canadian Longitudinal Study on Aging. We modeled repeated measures using hierarchical (mixed effect) models and latent class growth models, which allow for multiple possible latent growth trajectories within the study population. We found that known dementia genetic risk factors (APOE e4 allele count and a polygenic score for Alzheimer’s disease) associated with faster cognitive decline in both sexes. Using latent class growth models, we identified three different depressive symptom trajectory groups (persistent low, N=7346; persistent high, N=447; and new-onset, N=974), and we found that faster cognitive decline increased the risk of new-onset depressive symptoms to a greater extent in females than in males, in models adjusted for sociodemographic factors. APOE e4 carriers were more likely to experience new-onset depressive symptoms and cognitive decline compared to non-carriers, regardless of sex, but the polygenic score for Alzheimer’s disease predicted new-onset depressive symptoms and cognitive decline uniquely in females. Our results suggest that new-onset depressive symptoms and accelerated cognitive decline capture a dementia prodrome, especially in females. Moreover, our approach demonstrates the value of longitudinal data analysis in genetic studies for understanding unique patient subgroups, which can be leveraged in future GWAS efforts.</div><div><strong>Disclosure:</strong> Nothing to disclose.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 31"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204416","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":"PUTTING POLYGENIC SCORES IN CONTEXT: HOW INTERSECTIONAL FACTORS AFFECT RELATIVE AND ABSOLUTE GENETIC RISK","authors":"Mihael Cudic ,&nbsp;Justin Tubbs ,&nbsp;Tian Ge ,&nbsp;Jordan Smoller","doi":"10.1016/j.euroneuro.2025.08.546","DOIUrl":"10.1016/j.euroneuro.2025.08.546","url":null,"abstract":"<div><h3>Background</h3><div>The clinical utility of polygenic scores (PGS) is known to vary when training and test samples differ in ancestry. Recent work also suggests that variation in demographic and environmental contexts can affect PGS performance. However, little attention has been given to the ubiquitous phenomenon of intersectionality—where individuals simultaneously belong to multiple demographic and environmental contexts—and its impact on relative and absolute genetic risk.</div></div><div><h3>Methods</h3><div>We examined how lifetime odds ratios (ORs) and absolute risk (AR) for high-PGS individuals differ across intersectional contexts in the UK Biobank (UKB; n = 375,054, British-European-like ancestry), with a particular focus on major depressive disorder (MDD). Additional phenotypes studied included atrial fibrillation, coronary artery disease, type 2 diabetes, hypercholesterolemia, asthma, and obesity. PGS were computed using PRS-CS and current GWAS summary statistics. We analyzed 106 two-way intersections across sociodemographic factors (sex, age, income, smoking, alcohol intake, and deprivation). Replication was conducted in the All of Us Research Program (AoU; African-like: n = 36,552; European-like: n = 99,477).</div></div><div><h3>Results</h3><div>Odds ratios for major depression varied substantially across sociodemographic contexts, with even greater variability across intersectional combinations. In two-way intersections, the average maximal OR variation was 56% across all phenotypes. Although absolute risk differences were more moderate after adjusting for baseline prevalence within a context, intersectional effects were still observed. For example, high-PGS individuals with low income had an average 1.0 percentage-point lower AR across phenotypes when using a context-aware versus context-unaware model. For major depression specifically, the AR was 3.1 percentage points lower among those also reporting low alcohol intake in UKB (3.6 points lower in AoU European-like ancestry). Results were broadly consistent across cohorts, with the strongest replication for depression risk observed in the European-like All of Us sample.</div></div><div><h3>Conclusion</h3><div>We show that intersectional contexts can substantially shape relative genetic risk. Future clinical applications may need to consider incorporating contextual effects to enhance the precision and equity of patient-specific genetic risk assessments.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 44-45"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204426","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":"ELECTRONIC HEALTH RECORDS AND BIOBANKS IN THE ERA OF COMPUTATIONAL AND GENOMIC PSYCHIATRY","authors":"Franjo Ivankovic Chair ,&nbsp;Julia Sealock Co-chair ,&nbsp;Carol Mathews Discussant","doi":"10.1016/j.euroneuro.2025.08.486","DOIUrl":"10.1016/j.euroneuro.2025.08.486","url":null,"abstract":"&lt;div&gt;&lt;div&gt;This symposium will explore how the analysis of large-scale electronic health record (EHR) and biobank data is revolutionizing psychiatric research and driving novel discoveries impacting clinical care. Presentations highlight the utility of EHRs to study and identify sociodemographic biases in psychiatric care, leveraging the rich data across collaborative networks of EHRs to describe and validate novel subtypes of psychiatric disorders, using digital phenotyping for precision psychiatry insights, and utilizing the rich genomic data to develop resources to power the next generation of biological insights.&lt;/div&gt;&lt;div&gt;The symposium will begin with an overview of the PsycheMERGE network, an NIMH-funded collaboration across 11 institutions that leverages the resources and existing infrastructure of biobanks paired with EHRs across the country to provide a translational “sandbox” in which to evaluate the potential clinical impact of psychiatric genetic findings in a low-risk research setting. The talk will discuss how analysis of multimodal data has yielded “real-world” support for the hypothesis of an immune-metabolic subtype of depression with implications for management.&lt;/div&gt;&lt;div&gt;The following talk will focus on longitudinal modeling in the All of Us (AoU) dataset to replicate the bidirectional association between activity and mood, as measured by the Patient Health Questionnaire (PHQ-9), highlighting the potential of EHR-integrated digital phenotyping to advance precision psychiatry by informing behavior-based prevention and treatment strategies.&lt;/div&gt;&lt;div&gt;The third talk will present the two-process model of sleep regulation, a well-established model of sleep disruption in depression, and examine how this model directly translates into observable digital health behaviors that are highly associated with EHR-diagnosed depression and represent interpretable mechanistic phenotypes for further genomic and precision psychiatry approaches.&lt;/div&gt;&lt;div&gt;The final presentation will showcase a novel reference panel built from over 515,000 individuals from AoU and AnVIL data. In addition to being the largest reference panel to date, this panel prioritizes diversity, encompassing over 250,000 samples from non-European ancestries – a representation nearly twice the size of the entire TOPMed reference panel. The panel includes 101,982 of African and 90,553 individuals of admixed American ancestries. This resource will significantly improve the accuracy of genotype imputation, particularly for rare variants and underrepresented populations, empowering novel discoveries in psychiatric genetics. It will be made widely available for phasing and imputing genotype array and low-pass sequencing data through Broad Institute of MIT and Harvard.&lt;/div&gt;&lt;div&gt;By showcasing these diverse applications of EHRs, we aim to illuminate the power of computational psychiatry and genomics, when combined with rich phenotypic data, to improve diagnosis, treatment, and ultimately","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 17"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204453","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":"Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine: A one-year retrospective cohort study of 2126 patients.","authors":"Ting-Hui Liu, Jheng-Yan Wu, Po-Yu Huang, Wan-Lin Cheng, Chih-Cheng Lai","doi":"10.1016/j.euroneuro.2025.07.006","DOIUrl":"10.1016/j.euroneuro.2025.07.006","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the safety of esketamine in bipolar depression, focusing on suicide-related outcomes and manic switch across timeframe and demographic subgroups.</p><p><strong>Methods: </strong>This retrospective cohort study was conducted in May 2025 using data from the TriNetX global collaborative network. Adults with bipolar depression treated with esketamine plus a mood stabilizer were propensity score-matched 1:1 to patients who received mood stabilizers alone. The primary outcomes were suicide-related events and manic switches across 1-7, 1-30, 1-90, 1-180, and 1-365 day intervals.</p><p><strong>Results: </strong>After matching, 2126 patients (mean age, 47.0 years; 63 % female) were included. Esketamine use was associated with significantly lower risk of suicide-related outcomes at 1-7 days (hazard ratio [HR] = 0.439; 95 % CI, 0.256-0.753), 1-30 days (HR = 0.485; 95 % CI, 0.324-0.726), 1-90 days (HR = 0.641; 95 % CI, 0.456-0.901), and 1-365 days (HR = 0.754; 95 % CI, 0.577-0.985). Risk of manic switch was not increased and was significantly lower at 1-180 days (HR = 0.643; 95 % CI, 0.442-0.935) and 1-365 days (HR = 0.673; 95 % CI, 0.477-0.950). Subgroup analyses showed consistent suicide risk reduction across age, sex, and race. Female patients exhibited a significantly lower risk of manic switch at longer intervals, an effect not observed in males.</p><p><strong>Conclusions: </strong>Our real-world study suggests that esketamine, when used alongside mood stabilizers, is a safe and potentially effective treatment for bipolar depression, demonstrating sustained anti-suicidal benefits without an increased risk of manic switch across both short- and long-term follow-up and across different patient subgroups.</p>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"3-12"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798546","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":"LIVING HAPPILY EVER AFTER: WHAT INFLUENCES ENDURING MENTAL HEALTH?","authors":"Christel M. Middeldorp ,&nbsp;Lianne De Vries ,&nbsp;Meike Bartels","doi":"10.1016/j.euroneuro.2025.08.485","DOIUrl":"10.1016/j.euroneuro.2025.08.485","url":null,"abstract":"<div><div>Enduring mental health (EMH) is a stable state of mental health over time. More insight into factors associated with EMH can aid prevention of mental health problems. Previous research on EMH has primarily focused on the absence of mental health problems, neglecting the equally important dimension of presence of wellbeing. In this study, EMH is defined by the absence of mental health problems and/or the presence of higher wellbeing over time.</div><div>Data on twins and their family members registered in the large Netherlands Twin Register will be examined. Individuals will be included when mental health and/or wellbeing data are available in four or more surveys, to create the EMH phenotype. For more than 17,000 individuals genotypes are also available.</div><div>Classical twin analyses will be performed to calculate the heritability of EMH. Furthermore, associations will be presented with polygenic scores (PGS) and educational attainment, self esteem, stressful life events, neuroticism, optimism, loneliness, social support, exercise and self reported health. Besides PGS for mental disorders and traits, PGS for educational attainment, wellbeing, neuroticism, loneliness, childhood maltreatment and risky behavior will be included.</div><div>First, univariate regressions will be performed. The significantly associated variables will then be included in multiple logistic regression analyses, using family as a grouping variable to account for clustering. Variables as assessed during adolescents and polygenic scores that are related to EMH can be seen as potential predictors for EMH, whereas variables assessed in the last survey in adulthood can be seen as potential outcomes of EMH.</div><div>This project follows up on a project using childhood data on enduring mental health (Alrouh et al, under revision for the Journal of the American Academy of Child and Adolescent Psychiatry). Using measures between age 3 and age 12, 37% of the sample had EMH. This was associated with parental education (OR (low) =0.77 [0.70-0.86]; OR (middle) = 0.88 [0.82-0.95]), child academic achievement (OR=1.07 [1.03,1.12]), and child wellbeing (OR=1.44 [1.35,1.54]), and was weakly associated with ADHD PGS. The heritability was estimated at 54%. These findings are now extended with findings in adults, over a longer timespan and with a more comprehensive analysis of factors that could be associated with EMH.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 16-17"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204119","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":"SLEEP MICRO-ARCHITECTURE BIOMARKERS AND GENETIC RISK FOR SCHIZOPHRENIA","authors":"Shaun Purcell ,&nbsp;Nataliia Kozhemiako ,&nbsp;Jennifer Pan ,&nbsp;The GRINS consortium","doi":"10.1016/j.euroneuro.2025.08.460","DOIUrl":"10.1016/j.euroneuro.2025.08.460","url":null,"abstract":"<div><div>Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations, are altered in individuals with schizophrenia (SCZ), with large (&gt;1 SD) effect sizes and collectively offering high predictive power in a case/control diagnostic context (AUC = 0.93). Further, NREM metrics show increased patient-to-patient variability, driven in part by accelerated age-related effects and medication regimen. Collectively, our results point to a spectrum of NREM sleep deficits among SCZ patients that can be measured objectively and at scale, with relevance to both the etiological heterogeneity of SCZ as well as potential iatrogenic effects of antipsychotic medication.</div><div>In this presentation, we consider how human genetics may help to unpick the causal pathways between sleep neurophysiology biomarkers and SCZ. Specifically, following a brief review of our previous work identifying and replicating NREM biomarkers associated with SCZ disease status, we will report 1) an application of polygenic risk score (PRS) analysis to the GRINS sample, aiming to test whether genetic risk for disease is partially mediated by these NREM metrics, 2) a simulation study to quantify the prospects for using PRS-based analyses to study disease-biomarker relationships, 3) parallel work in mice characterizing the effects of mutations in SCZ-associated genes on analogous NREM EEG metrics, and 4) a broader review of some of the challenges faced by current genetic approaches to study the role of sleep in psychiatric disease.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 3-4"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204134","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":"NEW DIRECTIONS FOR PGC-ANX GENOMICS RESEARCH: PANIC DISORDER, EPIGENETICS, BRAIN STRUCTURE, AND GENE-ENVIRONMENT MODERATION","authors":"John Hettema Chair ,&nbsp;Nora Strom Co-chair ,&nbsp;Jordan Smoller Discussant","doi":"10.1016/j.euroneuro.2025.08.461","DOIUrl":"10.1016/j.euroneuro.2025.08.461","url":null,"abstract":"<div><div>Until recently, research in the genetics of anxiety disorders has suffered from the lack of powerful datasets and significant genetic association findings. Without that valid genetic basis, the application of genetics to fuel anxiety research has been limited compared to other psychiatric disorders. The recently published PGC-ANX meta-analysis has provided a major advancement in anxiety genetics. This symposium will cover a variety of follow-up anxiety genomic research directions. Nora Strom from Humboldt-Universität will present preliminary results from a large GWAS of panic disorder. Dr. Shaunna Clark from Texas A&amp;M University will review the results of the largest meta-analysis of epigenome-wide association studies of anxiety disorders. Dr Mary Mufford from University of Cape Town will discuss the genetic connections between anxiety susceptibility and brain structure. Dr. Brad Verhulst from Texas A&amp;M University will examine genome-wide moderation for anxiety and depression as a function of adverse life events. Dr. Jordan Smoller from Harvard University will serve as the Discussant.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 4"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204139","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":"DISSECTING THE GENETICS OF PANIC DISORDER, AGORAPHOBIA, AND PANIC ATTACKS: THE FIRST DISORDER-SPECIFIC LARGE-SCALE GENOME-WIDE ASSOCIATION STUDY FROM PGC-ANXIETY","authors":"Nora Strom ,&nbsp;Brittany Mitchell ,&nbsp;John Hettema ,&nbsp;Manuel Mattheisen ,&nbsp;Iiris Hovatta ,&nbsp;Angelika Erhardt","doi":"10.1016/j.euroneuro.2025.08.462","DOIUrl":"10.1016/j.euroneuro.2025.08.462","url":null,"abstract":"<div><div>Panic disorder (PD) is a disabling anxiety disorder with a moderate heritability estimated at 30–40%. It often co-occurs with agoraphobia, which is characterized by anxiety in situations perceived as unsafe or difficult to escape, frequently leading to panic attacks. Despite its public health impact, progress in identifying robust genetic risk loci for PD has lagged behind that of other psychiatric conditions. To address this, we will conduct the first large-scale genome-wide association study (GWAS) meta-analysis of PD (with or without agoraphobia) within the Psychiatric Genomics Consortium Anxiety Disorders Working Group (PGC-ANX), leveraging international collaboration to maximize discovery power.</div><div>We will aggregate phenotypic and genetic data from over 100K individuals with lifetime PD across multiple international cohorts and consortia. Standardized quality control and imputation protocols will be applied across datasets in accordance with our standard operation procedure. All individual GWASs will consecutively be meta-analyzed. Beyond primary GWAS, secondary analyses will include functional annotation of associated loci, gene-set enrichment, and genetic correlation analyses to explore shared genetic architecture with related psychiatric and somatic phenotypes.</div><div>Since panic attacks are also common in other psychiatric disorders - such as anxious depression, OCD, PTSD, and schizophrenia - we will conduct an extended cross-disorder analysis to investigate whether panic attacks represent a transdiagnostic phenotype with distinct genetic features. Additionally, we will examine the genetic relationship between PD and dimensional anxiety phenotypes. Given that genetic liability can aggregate within families, we will include anamnestic information on familial anxiety to test whether individuals with a positive family history show increased genetic risk. Finally, we will explore whether genetic liability is enriched in individuals with an early age of onset.</div><div>Preliminary results from Data Freeze 1 will be presented. This meta-analysis aims to significantly advance our understanding of the biological basis of panic disorder and related anxiety dimensions. The findings will highlight the importance of large-scale, collaborative efforts in psychiatric genetics and inform future work toward precision psychiatry in anxiety disorders.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 4"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204141","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":"PHARMACOPOLYGENIC PREDICTORS FOR ANTIDEPRESSANT RESPONSE: CURRENT STATUS, FUTURE DIRECTIONS","authors":"Cathryn Lewis","doi":"10.1016/j.euroneuro.2025.08.502","DOIUrl":"10.1016/j.euroneuro.2025.08.502","url":null,"abstract":"<div><div>Antidepressants are one of the most widely prescribed medications worldwide, but only one-third of people respond to the first drug prescribed, and there are few predictors of who will respond to which antidepressant. This trial-and-error strategy of finding an effective drug is harmful to patients and families and imposes a burden to health services and the economy.</div><div>Pharmacogenetics offers a promising route to personalised prescribing. This symposium introduction will summarise current progress, describe studies underway, and outline the potential for genetic testing for antidepressant prescribing.</div><div>Most antidepressants are metabolised by CYP2C19, CYP2D6 and CYP2C9, but genetic variation in these genes accounts for only a small proportion of response to antidepressants, suggesting broader genetic contributions. The largest genome-wide association study for antidepressant response, conducted by the Psychiatric Genomics Consortium, assessed remission and percentage change in depressive symptoms in 5,000 patients from clinical trials and research studies. The study reported a SNP-based heritability of 13%, with modest polygenic prediction between studies. Notably, antidepressant response was only weakly associated with polygenic scores for depression, indicating a largely distinct genetic architecture between susceptibility to depression and treatment response. New results from a targeted GWAS of selective serotonin reuptake inhibitors (SSRIs) will be reported, providing response predictors by drug class.</div><div>As the polygenic basis of antidepressant response becomes clearer, the primary barrier to expanding our understanding of the genetic predictors becomes sample size. Few studies collect the longitudinal information necessary to robustly evaluate response to treatment, and although clinical trials are the gold standard for rigorous assessment of drug response, their scale is limited.</div><div>Harnessing real world data from electronic health records, or assessing self-reported response from patients, will allow us to define proxy phenotypes of antidepressant response, and perform sufficiently powerful genetic studies. In this talk, I will assess the potential of these novel sources of treatment response phenotypes, which we are investigating in the AMBER project. I will outline a plan for expanding genetic studies of antidepressant response to build pharmacopolygenic predictors that might be powerful enough to test and implement clinically, with the potential of personalised prescribing for depression.</div><div><strong>Disclosure:</strong> Myriad Genetics, Advisory Board</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 23"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204253","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}