European Neuropsychopharmacology最新文献

{"title":"COVID-19-RELATED STRESSORS ARE ASSOCIATED WITH PSYCHIATRIC DISORDERS AND ACCELERATED EPIGENETIC IN ISLAND-BASED PUERTO RICAN POPULATION","authors":"Adriana Hernández-Garayua , Amanda Rodríguez-León , Diana Núñez , Sheila Nagamatsu , Karen G Martínez-Gonzalez , Paola Giusti-Rodriguez , Janitza Montalvo-Ortiz","doi":"10.1016/j.euroneuro.2025.08.473","DOIUrl":"10.1016/j.euroneuro.2025.08.473","url":null,"abstract":"<div><div>The COVID-19 pandemic has introduced significant stressors, exacerbating psychiatric disorder symptoms like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). These disorders and significant stressors have been linked to accelerated biological aging and epigenetic changes, particularly in at-risk populations. However, this work has been limited in Latin American populations, including Puerto Rico. Already burdened by natural disasters and economic crises, island-based Puerto Ricans are considered an at-risk population of increased susceptibility to adverse mental health outcomes. Here, we evaluate the effects of COVID-19 stressors on mental health and epigenetic aging and genome-wide DNA methylation alterations in island-based Puerto Ricans to understand the impact of these stressors on disease outcomes.</div><div>Our study cohort included 301 participants residing in Puerto Rico. We evaluated the frequency and severity of COVID-19 related stressors, examining both when it \"happened to self\" or \"happened to someone close.\" We also assessed the prevalence of symptoms of MDD and PTSD using the PHQ-9 and PCL-5 self-report measures, respectively. From the 301 participants, 237 saliva samples were collected for DNA methylation (DNAm) assessment using the Illumina EPICv2 array. Quality control and normalization were performed using ENMix. GrimAge, a composite biomarker based on smoking pack-years and seven additional DNAm surrogates, was calculated. Linear regression analyses were conducted to examine the association between the number of COVID-19 stressors and MDD/PTSD outcomes as well as GrimAge acceleration. Sex differences were explored by performing a sex-stratified analysis. Bonferroni threshold was applied for multiple testing corrections. Epigenome-wide association analysis is also conducted to examine the interplay between DNA methylation and COVID-19 stressors on psychiatric outcomes.</div><div>Among the six COVID-19 related stressors assessed, \"difficulty obtaining resources\" and \"difficulty receiving required social support\" were among the most significant. 84.4% of participants experienced COVID-related stressors, whereas 60.7% experienced 72.4% experienced stressors that \"happened to someone close\". For the combined sex analysis, we identified a significant association of the number of events with MDD symptoms with stressors that “Happened to self” (p=0.0042) and “Happened to someone close” (p=0.0078). Sex stratified analyses showed significant association with MDD symptoms in females (“Happened to Self”; p=0.022 and “Happened to someone close”; p=0.010). For PTSD symptoms, in the combined sex analysis, we obtained significance for stressors that “Happened to someone close” (p=0.016). For the GrimAge clock, we found an association between the number of stressors and accelerated epigenetic aging, even after adjusting for smoking. The epigenome-wide association analysis is ongoing.</div><div>This study high","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 10-11"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204412","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":"INVESTIGATING CROSS DISORDER GENE-ENVIRONMENT INTERACTIONS IN AUTISM AND RELATED DISORDERS: THE ROLE OF DIFFERENT TYPES OF MATERNAL INFECTIONS AND FEVER DURING PREGNANCY","authors":"Apurba Shil , Elias Speleman Arildskov , Heidi Maclean , Anders Børglum , Kelly Benke , Heather Volk , Christine Ladd-Acosta , Diana Schendel , Jakob Grove","doi":"10.1016/j.euroneuro.2025.08.469","DOIUrl":"10.1016/j.euroneuro.2025.08.469","url":null,"abstract":"<div><h3>Background</h3><div>Autism and related disorders such as Attention Deficit Hyperactivity Disorder (ADHD), Schizophrenia (SCZ), and Bipolar Disorder (BD) are heterogeneous, with both genetic and environmental factors contributing to their etiology. While some studies report associations between maternal infections during pregnancy and increased risk of these disorders, findings have been inconsistent. Research on gene-environment (GxE) interactions in this context are limited, despite their potential to inform disease risk and precision medicine. This is mainly because of the lack of large-scale datasets with comprehensive genetic and environmental information. Leveraging a nationally representative Danish cohort with integrated genetic and environmental data, we investigate GxE interactions between various types of maternal infections and fever during pregnancy period and the risk of diagnosis of Autism and related disorders such as ADHD, SCZ, and BD.</div></div><div><h3>Methods</h3><div>We used the iPSYCH case-cohort genotyped and Danish health registry data of unrelated individuals with European ancestry born in 1981-2008, including individuals with autism (n=20,067), ADHD (n=23,593), SCZ (n=6218), and BD (n=3094). LDpred2 was used to generate polygenic risk scores (PGSs) for these disorders utilizing appropriate GWAS summary statistics available in public repository. Different types of prenatal infection and fever exposures, as well as autism and related disorders were measured based on ICD-8/ICD-10 codes. Generalized linear models (GLMs) were used to estimate the main and interaction effects of trimester-specific prenatal infections/fever on the diagnosis of autism and related disorders, adjusting for genotype batch, birth year, sex, maternal education, maternal age, and the first five PCs.</div></div><div><h3>Results</h3><div>For autism, we identified significant main effects of bacterial (β = 0.247, p < 0.05), viral (β = 0.190, p < 0.05), genital (β = 0.786, p < 0.05) and any infections (β = 0.271, p < 0.05) and fever (β = 0.366, p < 0.05). Autism-PGS interaction with bacterial infection prenatal exposure was significant in the second trimester (β = 0.185, p < 0.05). Similarly, significant interaction between Autism-PGS and maternal fever during the third trimester was observed (β = 0.198, p < 0.05). In contrast for ADHD, none of the interaction effects were significant, however, the main effects of bacterial (β = 0.371, p < 0.05), viral (β = 0.280, p < 0.05), genital (β = 0.678, p < 0.05) and any infections (β = 0.373, p < 0.05) and fever (β = 0.179, p < 0.05) were mostly stronger except for genital infection. Interestingly, SCZ-PGS exhibited significant negative interactions with bacterial infections in trimesters 1 (β = -0.431, p < 0.05) and 2 (β = -0.404, p < 0.05), and with any infections in all the trimesters (e.g., T1: β = -0.372, p < 0.05). BD-PGS showed strongest negative intera","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 8"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204422","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":"PSYCHEMERGE: ADVANCING PRECISION PSYCHIATRY AT SCALE","authors":"Lea Davis","doi":"10.1016/j.euroneuro.2025.08.487","DOIUrl":"10.1016/j.euroneuro.2025.08.487","url":null,"abstract":"<div><div>The success of precision psychiatry depends on implementation of translational paradigms in clinical settings. Thus, a major challenge is determining which translational strategies are robust to the imprecision in healthcare delivery systems, in which time with each patient is limited, family histories are often unknown, and complex comorbidities are the rule rather than the exception. This challenging clinical environment can be reconstructed using the EHR. Moreover, the large-scale collection of genetic material paired with the EHR provides a translational “sandbox” in which to evaluate the potential clinical impact of psychiatric genetic findings in a low-risk research setting. The PsycheMERGE network is a NIMH-funded collaboration across 11 institutions that leverages biobank-linked research EHRs across the country to achieve this goal. Current focus of the network includes the development of AI-assisted phenotyping approaches to characterize individual diagnoses for subsequent genetic investigation, as well as development of clinical risk prediction models with additional genomic features. I will share, on behalf of the PsycheMERGE network, recent updates on these efforts and describe the framework that PsycheMERGE is building to facilitate this work at scale. Lastly, working on psychiatric phenotypes in the EHR often includes extending investigations beyond psychiatric diagnoses to include physical symptoms, comorbid chronic diseases, medication histories, and quantitative laboratory measurements. Moreover, because the delivery of care is woven into the data itself, EHR-based research also creates a window into the practice of medicine. This transdiagnostic perspective facilitates precision psychiatry research while gaining a deeper understanding of the mind-body relationship. During this talk, I will also 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.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 17-18"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204454","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":"THE GENETIC OVERLAP BETWEEN SLEEP AND PSYCHIATRIC DISORDERS: FROM MOLECULAR MECHANISMS TO CLINICAL IMPLICATIONS","authors":"Hanna Ollila Chair ,&nbsp;Shaun Purcell Co-chair ,&nbsp;Kathleen Merikangas Discussant","doi":"10.1016/j.euroneuro.2025.08.456","DOIUrl":"10.1016/j.euroneuro.2025.08.456","url":null,"abstract":"<div><div>Sleep is a cornerstone of human health. Sufficient, uninterrupted sleep is fundamental to brain development, emotional regulation, and overall health. Disruptions in sleep, whether in quantity, quality, or timing, are strongly associated with a range of psychiatric conditions, including depression, addiction, bipolar disorder, and schizophrenia. This relationship is bidirectional: psychiatric illnesses typically impair sleep, and persistent sleep disturbances can worsen psychiatric symptoms and even precipitate their onset. Growing evidence from genetic and omics studies supports the notion that sleep traits and psychiatric disorders share overlapping biological mechanisms, offering a compelling framework for understanding their co-occurrence and guiding more targeted therapeutic strategies.</div><div>Emerging genomic research is beginning to uncover the pleiotropic genetic architecture that links sleep regulation to neuropsychiatric phenotypes. Large-scale genome-wide association studies (GWAS), polygenic risk score, and integrated multi-omic analyses have revealed that genetic mechanisms influencing sleep duration, chronotype, and insomnia overlap with neurodevelopmental and neuropsychiatric pathways. These findings suggest that the same genetic risk factors may influence both sleep patterns, motor activity and psychiatric vulnerability, offering opportunities for early risk prediction and intervention. Effective treatment of sleep problems in individuals with neuropsychiatric disorders may improve quality of life and reduce the severity of core psychiatric symptoms.</div><div>Ultimately, this work moves us toward a precision medicine approach: one in which an individual’s genetic risk for both sleep and psychiatric traits can inform early intervention, personalized treatment, and improved outcomes across the lifespan. Understanding the genetic interplay between sleep and psychiatric conditions is not only crucial for unraveling disease mechanisms but also holds transformative potential for clinical practice.</div><div>Our symposium highlights research that connects molecular genetics, systems biology, and clinical psychiatry to uncover the shared causes of sleep and psychiatric disorders. The presentations will include the use of diverse data sources from large-scale genome-wide association studies, studies on familial aggregation and coaggregation, longitudinal epidemiological cohorts, and functional genomics. Studies will include the full range of sleep phenotypes including patterns and disorders, objective assessments of sleep and 24 hour patterns of motor activity both in individuals and families, We focus on results from studies that elucidate genetic pathways and environmental factors that shape both sleep and circadian rhythms in psychiatric traits.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 2"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204135","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":"WELLBEING AS A CATALYST: GENE–ENVIRONMENT CORRELATION AND THE CONSTRUCTIVE ROLE OF WELLBEING","authors":"Meike Bartels,&nbsp;Anne Geijsen,&nbsp;Lianne De Vries","doi":"10.1016/j.euroneuro.2025.08.480","DOIUrl":"10.1016/j.euroneuro.2025.08.480","url":null,"abstract":"<div><div>Psychiatric genetics has often positioned wellbeing as an outcome of favorable genetic or environmental conditions. In contrast, this contribution presents two studies suggesting that wellbeing itself may serve as a starting point—a genetically influenced trait that actively shapes environments over time, consistent with active and evocative gene–environment correlation (rGE).</div><div>Drawing on longitudinal data from the Netherlands Twin Register (NTR), the first study followed an adolescent cohort (N=14518) into adulthood, revealing that higher teenage wellbeing predicts more favorable psychosocial outcomes years later. Between-family analyses showed positive associations between teenage wellbeing and wellbeing, flourishing, consciousness, self-rated health and sleep quality in early adulthood, and inverse associations with early adulthood neuroticism and smoking habits. The associations with wellbeing, flourishing, self-rated health, sleep quality, and neuroticism were also observed when including a sibling fixed effect. Results emphasize the catalyzing effect of teenage wellbeing in shaping later life trajectories</div><div>The second study (N=1086) employed Ecological Momentary Assessment to examine how momentary wellbeing affects subsequent social experience in daily life. Results showed that individuals with higher momentary wellbeing experienced less social mismatch in their next interactions—suggesting that positive affective states may guide individuals toward more aligned, affirming social environments. These findings support a dynamic, micro-level model of wellbeing where short-term affective states influence social behavior and perception in ways that reinforce wellbeing over time.</div><div>Together, these studies provide converging evidence that wellbeing is not merely a psychological endpoint, but a heritable, environment-shaping force. By tracing the bidirectional links between positive affect and environmental context, they contribute to a growing body of research redefining wellbeing as both a trait and a developmental catalyst. This has significant implications for psychiatric genetics, as it expands the translational scope from treatment and risk reduction toward the promotion of flourishing as a core principle of mental health science.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 14"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204209","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":"ASSOCIATION OF PTSD SYMPTOM TRAJECTORIES WITH ACCELERATED PACE OF EPIGENETIC AGING IN U.S. MILITARY VETERANS","authors":"Sheila Nagamatsu ,&nbsp;Robert H. Pietrzak ,&nbsp;Ian C. Fischer ,&nbsp;Joel Gelernter ,&nbsp;Janitza Montalvo-Ortiz","doi":"10.1016/j.euroneuro.2025.08.498","DOIUrl":"10.1016/j.euroneuro.2025.08.498","url":null,"abstract":"<div><h3>Background</h3><div>Mental disorders such as posttraumatic stress disorder (PTSD) are prevalent among U.S. military veterans. PTSD is often a chronic and disabling condition characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and heightened arousal and reactivity. It is associated with poor mental and physical health outcomes, as well as accelerated biological (i.e., epigenetic) aging, the latter of which may serve as a mechanism linking PTSD to adverse health effects and premature mortality. While numerous studies have demonstrated cross-sectional associations between PTSD and accelerated epigenetic aging, the longitudinal impact of PTSD symptom trajectories on the pace of epigenetic aging remains poorly understood.</div></div><div><h3>Methods</h3><div>We conducted a 10-year prospective study of 156 European American male U.S. military veterans and assessed PTSD symptoms at five time points over the study period. Saliva samples were collected at baseline and again at the 10-year follow-up for DNA methylation (DNAm) analysis. Epigenetic aging was estimated using the DNA Methylation Age Calculation for DNAm GrimAge2. PTSD symptom trajectories were identified using the “Traj” R package. The pace of epigenetic aging (PACE) was calculated as the difference in accelerated GrimAge2 between 2011 and 2021 (AccelGrimAge2021 - AccelGrimAge2011). Multivariable linear regression followed by a stepwise regression analyses were conducted to assess the relationship between PTSD symptom trajectories and PACE, adjusting for buccal cells CD4+ T cells, and monocytes. Additional cell types were removed to avoid multicollinearity.</div></div><div><h3>Results</h3><div>Three distinct PTSD symptom trajectories emerged: stable/no change from baseline (N=48), increasing symptoms over time (N=36), and decreasing symptoms (N=10). A significant positive association was observed between the increasing PTSD symptom trajectory and GrimAge2 PACE (estimate=1.67,p=0.007), indicating that veterans with worsening PTSD symptoms over the 10-year period exhibited a more accelerated pace of biological aging relative to the stable condition. No significant association was identified for decreasing symptoms.</div></div><div><h3>Conclusion</h3><div>Increases in PTSD symptoms over a 10-year period are associated with an accelerated pace of epigenetic aging in U.S. military veterans. These results underscore the biological toll of chronic stress and highlight the importance of early and sustained interventions for PTSD. Further research is needed to elucidate causal mechanisms and evaluate whether evidence-based treatments for PTSD mitigate accelerated epigenetic aging.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 21-22"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204248","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":"HARNESSING THE POWER OF ELECTRONIC HEALTH RECORDS TO STUDY THE GENETICS OF TREATMENT RESPONSE: ANTIDEPRESSANT SWITCHING IN UK BIOBANK","authors":"","doi":"10.1016/j.euroneuro.2025.08.503","DOIUrl":"10.1016/j.euroneuro.2025.08.503","url":null,"abstract":"","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Pages 23-24"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204254","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":"HETEROGENEITY OF MAJOR DEPRESSIVE DISORDER INVESTIGATED THROUGH SUSTAINED FILL OF SPECIFIC ANTIDEPRESSANT SCRIPTS","authors":"Alicia Walker ,&nbsp;Brittany Mitchell ,&nbsp;Tian Lin ,&nbsp;Jacob Crouse ,&nbsp;Nick Martin ,&nbsp;Maxime Taquet ,&nbsp;Sarah E. Medland ,&nbsp;Ian Hickie ,&nbsp;Naomi Wray","doi":"10.1016/j.euroneuro.2025.08.504","DOIUrl":"10.1016/j.euroneuro.2025.08.504","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Pharmacological treatment of Major Depressive Disorder (MDD) remains largely empirical with only 27% of patients remitting on first-line medications. These differential responses to antidepressants likely reflect underlying biological heterogeneity in MDD. Here, we investigated MDD heterogeneity through mutually-exclusive groups based on sustained fill of specific antidepressant scripts.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Using the Australian Genetics of Depression Study (AGDS, 2017-2018) linked to pharmaceutical records (Jul 2013-Dec 2018), we identified mutually exclusive MDD subgroups based on sustained use of a single antidepressant (≥360 cumulative days over 4.5 years) among the 10 most commonly dispensed antidepressants. Among 9,844 participants with self-reported MDD, inferred European ancestry, genotyping, and antidepressant records, we identified 6,106 (62%) with sustained single-antidepressant use without comorbid self-reported bipolar disorder (BIP), 220 (2.2%) with comorbid BIP and ≥4 lithium dispenses (BIP+L group), and 846 (14%) with comorbid BIP but &lt; 4 lithium dispenses (BIP-L group). The reference category for medication class comparisons was the Selective Serotonin Reuptake Inhibitors (SSRIs, N=3,573) group, and for within-class comparisons, it was the SSRI-sertraline (N=1,117) group, as the most common sustained treatments in the AGDS. As a sensitivity analysis, the sustained use threshold was increased to ≥600 cumulative days. To understand innate biological heterogeneity predating depression onset, we investigated associations with 18 polygenic scores (PGS) and reported results passing Bonferroni correction.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The high self-reported treatment response rates among participants after 360+ days of antidepressant use (&gt;90%) support our dispense threshold as a reasonable proxy for treatment acceptability. Compared to the SSRI group, the tetracyclic antidepressant (TeCA-mirtazapine) group (N=177) had higher self-reported suicidal ideation (OR=1.8, 95% CI=1.3-2.6, p=8.7e-4), while the tricyclic antidepressant (TCA-amitriptyline) group (N=151) showed higher rates of physical comorbidities, specifically chronic pain (OR=4.2, CI=2.9-5.9, p=5.3e-15). Reassuringly, the BIP±L groups were strongly associated with BIP PGS (BIP+L: β=0.280 AGDS standard deviation units, SE=0.069, p=5.6e-5; BIP-L: β=0.323, SE=0.038, p=3.5e-17). Under the more stringent sustained use threshold (≥600 days), the duloxetine group (a serotonin norepinephrine reuptake inhibitor, SNRI; N=500) had higher mean body mass index (BMI) PGS (β=0.18, SE= 0.057, p=1.60e-2) and higher self-reported BMI (β=1.35, SE=0.038, p=3.50e-4) compared to the SSRI-sertraline group. After adjustment for BMI PGS, the higher mean self-reported BMI in the duloxetine group was completely eliminated (β=-0.37, SE=0.85, p=0.66), indicating a potential genetic-cardiometabolic influence on SNRI-duloxetine acceptability.&lt;/div&gt;&lt;/","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 24"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204255","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":"NAVIGATING THE GENETICS OF DEPRESSION: ACADEMIC INTEGRITY, CULTURE, AND LEADERSHIP","authors":"Cathryn Lewis","doi":"10.1016/j.euroneuro.2025.08.538","DOIUrl":"10.1016/j.euroneuro.2025.08.538","url":null,"abstract":"<div><div>The genetics of depression and treatment response represents a frontier in precision medicine balancing the critical need for improved patient care with the challenges of disorder heterogeneity, polygenicity, and the impact of societal factors. Progress relies not only on scientific innovation, but also on the research environment that enables it. Through collaborative genetic studies, we have made substantial progress in dissecting the biological underpinnings of depression, yet we are still far from being able to reliably predict diagnosis, prognosis or treatment response.</div><div>In this plenary lecture, I will give a broad overview of our current knowledge of the genetics of depression, highlighting the work of the PGC major depressive disorder (MDD) working group. MDD is one of the most prevalent psychiatric conditions, making it a strategic starting point for developing more personalised approaches. Advances in this area have the potential to inform precision psychiatry more broadly and improve care for many people.</div><div>Precision psychiatry is founded on the principle of delivering the ‘right treatment, to the right person, at the right time’ but this is challenging. Although antidepressants are among the most widely prescribed medications, response rates are low with only one third of patients responding effectively to the first antidepressant prescribed. With few actionable predictors of who will respond to which drug, prescribing remains a frustrating trial-and-error process for both clinicians and patients, impacting quality of life and delaying time to remission. I will describe our Wellcome-funded AMBER project, which seeks to identify the causal mechanisms underpinning antidepressant treatment outcomes, with the aim of developing personalised prescribing strategies.</div><div>Projects like AMBER rely not only on innovation, data and methodological rigour, but also on the environment in which research takes place. Sustainable scientific progress depends on a research culture that promotes integrity, collaboration, and the development of early career researchers. Good science thrives in environments where researchers are trusted and valued, and where career progression and professional development are interwoven with research achievements. Academic leadership plays a central role in creating these conditions, championing collaboration, mentorship, and responsible approaches to scientific investigation.</div><div>This plenary lecture will explore the intersection of genetic research on depression with the essential values that underpin trustworthy and impactful scientific research. I will highlight how a commitment to scientific integrity and effective leadership can drive innovation, shaping a future where genetic discoveries meaningfully improve mental health care while reinforcing trust in academic institutions.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 40"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204280","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":"MAPPING CELL TYPE-SPECIFIC EPIGENETIC REGULATION IN DORSOLATERAL PREFRONTAL CORTEX (DLPFC) TO UNCOVER MOLECULAR MECHANISMS IN PSYCHIATRIC DISORDERS","authors":"Jennie Pouget","doi":"10.1016/j.euroneuro.2025.08.507","DOIUrl":"10.1016/j.euroneuro.2025.08.507","url":null,"abstract":"<div><div>Psychiatric disorders have a strong genetic basis, with GWAS implicating hundreds of loci. Most of these GWAS variants are non-coding, and likely influence disease by altering gene expression in specific neuronal and glial cell types. Existing bulk tissue studies obscure cell type-specific gene regulation, making disease mechanisms difficult to parse. Leveraging advances in multimodal single-cell technologies, we developed robust cell type-specific maps of epigenetic regulation in DLPFC. Our enhancer-gene maps can be leveraged to understand epigenetic regulation in the brain, and uncover molecular mechanisms underlying GWAS loci.</div><div>We analyzed &gt;170,000 cells from postmortem DLPFC tissue from neurotypical individuals spanning developmental timepoints from fetus to adulthood. All cells had paired multiomic measurements of enhancer activity (sn-ATACseq) and gene expression (sn-RNAseq) using the 10x Genomics Multiome protocol. We used SCENT, a novel non-parametric bootstrapping enhancer-gene mapping method, to link ATAC peaks (putative enhancers) with gene expression (target genes) in six major brain cell types: inhibitory neurons, excitatory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs).</div><div>Among &gt;1.2M possible enhancer-gene pairs, we identified &gt;14k putative enhancer-gene links (FDR &lt; 0.10). Our enhancer-gene maps uncovered putative cell type-specific mechanisms underlying known psychiatric disorder GWAS loci, often resolving a single high-confidence variant. To validate our findings, we are evaluating whether these putative causal variants prioritized by SCENT influence chromatin accessibility in an allele-specific manner using matched genotype and sn-ATACseq data. These analyses could provide orthogonal support that SCENT peaks capture biologically meaningful regulatory variation. Overall, our multiomic single-cell resolution approach demonstrates potential to improve fine-mapping of GWAS loci by pinpointing what genes are dysregulated in psychiatric disorders, and in which specific cell types.</div></div>","PeriodicalId":12049,"journal":{"name":"European Neuropsychopharmacology","volume":"99 ","pages":"Page 25"},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204368","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}