Molecular Psychiatry最新文献

{"title":"A genetic common factor underlying self-reported math ability and highest math class taken.","authors":"Alexandros Giannelis, Emily A Willoughby, Tobias Edwards, Matt McGue, James J Lee","doi":"10.1038/s41380-025-03237-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03237-0","url":null,"abstract":"<p><p>While genetic influences on general intelligence have been well documented, less is known about the genetics underlying narrower abilities (\"group factors\"). By applying structural equation modeling to results from several genome-wide association studies (GWAS), most critically of self-reported math ability (N = 564 698) and highest math class taken (N = 430 445), we identified 53 single-nucleotide polymorphisms (SNPs) associated with a latent trait, orthogonal by design with general intelligence, approximating the group factor of quantitative ability. The genes near these SNPs implicated the biological process of neuron projection development, and the genome-wide pattern of gene-set enrichment affirmed the involvement of brain development and synaptic function. We calculated a number of genetic correlations with this quantitative factor, finding negative associations with both internalizing and externalizing disorders and positive associations with STEM occupations such as computer programming. These results provide further evidence for genetic influences on traits other than general factors in human behavioral variation, point to the mechanisms mediating these genetic influences on quantitative ability and interests, and affirm the relationships of the latter traits with a number of real-world outcomes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103009","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}

{"title":"Generalizable stratification based on thalamo-somatomotor functional connectivity predicts responses to antidepressants in patients with depression.","authors":"Yuto Kashiwagi, Tomoki Tokuda, Yuji Takahara, Yukiko Masaki, Yuki Sakai, Junichiro Yoshimoto, Ayumu Yamashita, Toshinori Yoshioka, Koichi Ogawa, Go Okada, Yasumasa Okamoto, Mitsuo Kawato, Okito Yamashita","doi":"10.1038/s41380-025-03224-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03224-5","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is diagnosed based on signs and symptoms without relying on physical, biological, or cognitive tests. Patients with MDD exhibit a wide range of complex symptoms, and diverse underlying neurobiological backgrounds have been assumed. If biomarkers can stratify patients with MDD into biologically homogeneous subtypes, personalized precision medicine would be within reach. Some studies have used resting-state functional connectivity (rs-FC) to stratify and predict treatment responses for MDD subtypes. However, few studies have demonstrated the reproducibility (i.e., generalizability) of stratification biomarkers in independent validation cohorts. Lack of generalizability may be due to inherent measurement and sampling biases in functional magnetic resonance imaging (fMRI) data and overfitting to discovery cohorts. To address this problem, we previously constructed a multisite, multidisorder fMRI database from thousands of participants, proposed a hierarchical supervised-unsupervised learning strategy, and developed generalizable diagnostic biomarkers of MDD via supervised learning. Using unsupervised learning, we constructed here stratification biomarkers for patients with MDD based on subsets of the top-ranked rs-FCs in MDD diagnostic biomarkers. We utilized two multisite datasets, constructed stratification biomarkers, and identified the most stable biomarker. The identified biomarker was based on several rs-FCs between the thalamus and postcentral gyrus. MDD subtypes stratified by this biomarker showed significantly different responsiveness to treatment with a selective serotonin reuptake inhibitor. By narrowing down the feature dimensions, we avoided overfitting to the training data and successfully constructed a generalizable stratification biomarker. This biomarker might have the potential to facilitate personalized precision medicine for patients with MDD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102968","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}

{"title":"Accelerometer-measured physical activity, sedentary behavior, and incident neuropsychiatric diseases: a large prospective cohort study of 73411 participants.","authors":"Jia-Yi Wu, Yu-Zhu Li, Dan-Dan Zhang, Pei-Yang Gao, Yan Fu, Wei Zhang, Jian-Feng Feng, Ya-Ru Zhang, Wei Cheng, Jin-Tai Yu","doi":"10.1038/s41380-025-03268-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03268-7","url":null,"abstract":"<p><p>Physical activity and sedentary behavior are closely associated with neuropsychiatric diseases, while previous studies have mainly relied on self-reported data, which have been shown to be inconsistent with objectively measured metrics. Using data from 73,411 participants, objectively quantifying physical activity through energy expenditure and time allocation, we identified longitudinal associations between physical activity, sedentary behavior, and neuropsychiatric diseases using Cox proportional hazards models. Our findings indicated that moderate to vigorous physical activity energy expenditure showed the strongest protective effect on neuropsychiatric diseases (hazard ratios: 0.60-0.86, all FDR-Q < 0.001), while an increased proportion of sedentary time was identified as a risk factor for neuropsychiatric diseases (HRs: 1.05-1.54, FDR-Q < 0.05). Restricted cubic spline analyses demonstrated an L-shaped association linking physical activity and neuropsychiatric diseases and an inverted L-shaped relationship between sedentary behavior and dementia. Linear regression models further linked physical activity and sedentary behavior to cognitive function, physical function, and mental health. Key brain regions related to these behaviors included the lateral occipital cortex, cuneus, pallidum, and accumbens. Proteomics and metabolic analyses identified significant involvement of ITGAV protein and high-intensity lipoprotein. Structural equation modeling elucidated that inflammation and metabolism mediate the relationship between physical activity, sedentary behavior, and neuropsychiatric diseases. Overall, our study provides critical evidence of the link between physical activity, sedentary behavior, and neuropsychiatric diseases, shedding light on potential neurobiological mechanisms underlying these associations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102929","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}

{"title":"Genetic nurture effects in depressive and anxiety disorders and symptoms, and in related traits.","authors":"Victória Trindade Pons, Albertine J Oldehinkel, Hanna M van Loo","doi":"10.1038/s41380-025-03265-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03265-w","url":null,"abstract":"<p><p>There is an elevated risk of depression and anxiety in offspring of parents with a history of these disorders. Beyond direct transmission, parental genes may also impact offspring outcomes through the environment, in a \"genetic nurture\" pathway. The scarcity of relevant data has limited studies in this area, resulting in an incomplete understanding of the indirect impact of parental genes on the familial transmission of depression and anxiety. We investigated genetic nurture effects in 15,231-17,186 Dutch adults with at least one genotyped parent from Lifelines, a large general population cohort. We computed polygenic scores for transmitted (PGS-T) and non-transmitted (PGS-NT) parental haplotypes using genome-wide association studies for depression. Using mixed-effect regression models, we analyzed PGS-T and PGS-NT associations with offspring outcomes, ranging from narrow (depressive and anxiety disorders according to diagnostic criteria) to broader definitions (depressive and anxiety symptoms, neuroticism, and negative affect), measured at multiple assessment waves. Our results demonstrate a pattern of significant associations between PGS-T and offspring outcomes, consistent with direct genetic transmission (OR = 1.2-1.5; β = 0.09-0.20, p < 0.001). PGS-NT effects were approaching null across all outcomes, with some exceptions in specific assessment waves. The lack of robust associations for PGS-NT across outcomes suggests a minimal role of genetic nurture in depressive and anxiety disorders, symptoms, and related traits through parental genetic liability for depression. Though the possibility of indirect genetic effects through other genetic risk factors remains, our findings point to the genetic transmission of depression and anxiety primarily occurring via direct inheritance.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092217","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}

{"title":"Polygenic Risk and Exposure Severity Predict Trajectories of PTSD: A Prospective Cohort Study.","authors":"Frank D Mann, Monika A Waszczuk, Sean A P Clouston, Evelyn J Bromet, Brian P Marx, Andrey A Shabalin, Anna R Docherty, Pei-Fen Kuan, Melissa A Carr, Xiaohua Yang, Benjamin J Luft, Roman Kotov","doi":"10.1038/s41380-025-03235-2","DOIUrl":"10.1038/s41380-025-03235-2","url":null,"abstract":"<p><p>Posttraumatic stress disorder (PTSD) is persistent over time, thus identifying risk factors for chronic PTSD is crucial for clinical research. Trauma exposure severity and polygenic liability are two established predictors of PTSD onset and severity, but their contributions to the long-term course of PTSD remain largely unknown. In this prospective longitudinal cohort study, we tested whether severity of trauma exposure and polygenic risk for symptoms of PTSD independently predict long-term trajectories of PTSD symptoms. Data included 49,402 observations, spanning July 2002 to December 2022, from n = 5687 World Trade Center responders who had predominately European ancestry (baseline mean age = 37.74, SD = 8.19, range = 16-75; 92.89% male). First, the best-fitting model of 20-year PTSD trajectories was determined. Next, a polygenic risk score and a sum score of traumatic exposures were included as predictors of individual differences in intercepts (initial levels) and slopes (rates of change), adjusting for demographic covariates. The polygenic risk score significantly predicted rates of change in PTSD symptoms, independent of the intercept, such that higher polygenic risk was associated with more rapid increases in the years after trauma and a steeper arch-shaped trajectory. Exposure severity predicted initial levels and rates of change in symptoms, with more pronounced effects on initial levels. These findings indicate that polygenic liability and exposure severity predict the long-term prognosis of PTSD and have the potential to inform future clinical studies in trauma-exposed populations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092266","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}

{"title":"hiPSC-derived cortical neurons from ADHD individuals reveal dysregulated glutamatergic development.","authors":"Rhiannon Victoria McNeill, Zora Schickardt, Franziska Radtke, Robert Blum, Sarah Kittel-Schneider","doi":"10.1038/s41380-025-03213-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03213-8","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterised by inattention, hyperactivity, and impulsivity, significantly impacting life quality and mortality. It is among the most heritable neuropsychiatric disorders, yet its aetiology remains unclear, hindering the development of novel medications. Previously, research has primarily focused on the dopaminergic and noradrenergic systems using animal models. However, there is growing evidence for a role of the glutamatergic system in ADHD pathomechanisms, and a translational failure between pre-clinical animal models and human clinical trials. We therefore established and characterised a functional cortical neuronal model using human induced pluripotent stem cells (hiPSCs) to investigate glutamatergic development in healthy controls and adult ADHD patients. hiPSCs from healthy controls and ADHD patients showed no difference in their capacity to form cortical neurons (CNs). However, CNs from ADHD patients showed an altered developmental pattern, characterised by changes in extracellular glutamate and decreased transcription of NEUN, PSD95 and EEAT2. Moreover, a significant ~50% reduction in vGLUT2 transcription was observed at multiple time points, suggesting a robust cellular disease endophenotype which might be suitable for future drug screening. Lastly, calcium imaging analysis revealed decreased synaptic signalling strength and frequency, indicating a hypoactive phenotype. In summary, we were able to establish a functional hiPSC-derived cortical neuronal model to investigate ADHD pathomechanisms, which revealed impaired glutamatergic development in ADHD individuals. Our results suggest that the glutamatergic system should also be a target for future drug development.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092304","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}

{"title":"A low frequency damaging SORCS2 variant identified in a family with ADHD compromises receptor stability and quenches activity.","authors":"Mathias Kaas, Sarah Broholt Dinesen, Ole Ahlgreen, Peder Madsen, Simon Mølgaard, Anders Dalby, Camilla Gustafsen, Ditte Olsen, Jinjie Duan, Joachim Vilstrup, Jonas Lende, Sanne Nordestgaard, Tetyana Zayats, Per Morten Knappskog, Stefan Johansson, Gesche Neckelmann, Barbara Franke, Søren Thirup, Anders Børglum, Andreas Reif, Christian Vægter, Ditte Demontis, Jan Haavik, Simon Glerup, Sune Skeldal","doi":"10.1038/s41380-025-03242-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03242-3","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting 5% of children and 2.5% of adults worldwide. ADHD is considered a polygenic disorder caused by a combination of both common and rare risk variants, each with low individual effect size. The Vps10p domain receptor SorCS2 is involved in neuronal development and synaptic plasticity by modulating brain-derived neurotrophic factor (BDNF) signaling. We here describe the identification and characterization of a heterozygous damaging variant in the SORCS2 gene found in two members of a family with persistent ADHD. The SORCS2 variant results in an arginine to tryptophan substitution in the 10CC region of the extracellular Vps10p domain, leading to aberrant posttranslational receptor processing, subcellular localization and ligand binding. Furthermore, the variant abrogates BDNF signaling in a dominant negative manner. Biochemical analysis of additional rare missense variants from ADHD cohorts suggested that SorCS2 structural stability and function is susceptible to such variation in the Vps10p domain. Our findings provide insights into how low frequency damaging variants in SORCS2 may contribute to the risk of ADHD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086503","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}

{"title":"Impact of acute anorexia nervosa and of short-/long-term recovery after refeeding on the hormonal profiles of activin A, GDF-15 and follistatins.","authors":"Stefan Ehrlich, Louisa Licht, Theresa Kolb, Carlotta Hoffmann, Evelina Stender, Friederike I Tam, David Poitz, Veit Roessner, Stefan R Bornstein, Nikolaos Perakakis","doi":"10.1038/s41380-025-03245-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03245-0","url":null,"abstract":"<p><p>Anorexia Nervosa (AN) is a severe eating disorder characterized by endocrine and metabolic abnormalities. In this study, we evaluated how the concentrations of proteins recently linked with energy homeostasis might be altered in acute AN (acAN), whether their levels are associated with reproductive hormones and whether they are restored after weight recovery. Our results show that activin A, follistatin, LH and estradiol concentrations are decreased while growth/differentiation factor-15 (GDF-15) concentrations are increased in 79 females with acAN before weight restoration (acAN_T1) compared to 79 healthy control females not receiving oral contraception (HC_OCP^-). The concentrations of all hormones were partially or completely restored after weight restoration by short-term refeeding (acAN_T2) and in 35 females after long-term ( >6 months) recovery from AN not receiving OCPs (recAN_OCP^-). Low activin A and high GDF-15 concentrations, as in acAN_T1, were also observed in 45 healthy control females under OCP (HC_OCP⁺) compared to HC_OCP^-. Follistatin levels were ~3-fold higher in HC_OCP⁺ and recAN_OCP⁺ (45 female recAN under OCP) compared to HC_OCP^- or recAN_OCP^- respectively. LH, FSH and estradiol concentrations were positively associated with activin A and negatively with GDF-15 and follistatin. In conclusion, we report profound alterations in GDF-15, activin A and follistatin concentrations in acAN, which are associated with the concentrations of reproductive hormones and they are regulated by OCP and weight recovery by refeeding. Our findings support the evaluation of strategies targeting these hormones (e.g. GDF-15 inhibition) in AN to potentially increase body weight and thereby facilitate the resumption of reproductive function.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086507","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}

{"title":"Associations of polygenic risk scores for major depression and depression severity: an investigation of 105 623 individuals with 16 years follow-up.","authors":"Marit Haram, Andreas Jangmo, Piotr Jaholkowski, Joëlle Pasman, Joeri Meijsen, John R Shorter, Elizabeth C Corfield, Oleksandr Frei, Ted Reichborn-Kjennerud, Alfonso Buil, Yi Lu, Thomas Werge, Patrick Sullivan, Ole A Andreassen, Martin Tesli","doi":"10.1038/s41380-025-03243-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03243-2","url":null,"abstract":"<p><p>Genetic risk could be informative for identifying individuals at risk of depression with severe outcomes. With the novel approach of combined health care registries and self-report measures related to depression, the authors aimed to identify the impact of polygenic risk scores (PRS) for major depression on self report measures and a diagnosis of depression across diagnostic thresholds. The study sample comprised participants from the Norwegian Mother, Father and Child Cohort Study with linked information of depression diagnoses during 2006-2022 from health registries. Linear and logistic models were used to estimate the associations between PRS for major depression and self-reported measures related to depression (Symptom Checklist- 5, Satisfaction With Life Scale, Rosenberg Self-Esteem Scale), and a diagnosis of depression. Analyses were performed in groups stratified by level of depression severity defined by registrations in primary and specialist health care. Among the 105 623 individuals included in the study, mean (SD) age was 33.9 (5.3) and 58.5% were female. The associations between PRS for major depression and Rosenberg Self-Esteem Scale were more prominent in individuals with a history of inpatient status compared to outpatient status (β = 0.095, cluster robust 95% CI 0.029-0.162; P = 0.005) and status of primary care (β = 0.098, cluster robust 95% CI 0.035-0.160; P = 0.002). PRS for major depression were associated with a diagnosis of depression in all groups of depression severity, with highest effect sizes for more severe types (history of inpatient status: OR = 1.85, cluster robust 95% CI 1.75-1.94; P < 0.01). The results provide new knowledge of how PRS for major depression vary with depression severity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081169","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}

{"title":"Dietary caffeine to assess CYP1A2 activity, tailor clozapine doses, and predict treatment response: genetic, epigenetic and clinical analyses.","authors":"Nermine Laaboub, Frederik Vandenberghe, Nicolas Ansermot, Marianna Piras, Setareh Ranjbar, Dusan Petrovic, Giorgio Pistis, Sophie Vandenberghe-Dürr, Marie-Pierre F Strippoli, Pedro Marques-Vidal, Belen Ponte, Menno Pruijm, Bruno Vogt, Franziska Gamma, Armin von Gunten, Kerstin Jessica Plessen, Philippe Conus, Séverine Crettol, Peter Vollenweider, Martin Preisig, Murielle Bochud, Chin B Eap","doi":"10.1038/s41380-025-03256-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03256-x","url":null,"abstract":"<p><p>Caffeine metabolic ratios (CMR) following monitored caffeine intake are the gold standard to probe cytochrome P450 (CYP) 1A2 activity, which metabolizes antipsychotics like clozapine and olanzapine. Given caffeine's ubiquity, we tested whether random CMR from dietary caffeine were associated with (1) clinical, genetic, and epigenetic factors linked to CYP1A2 activity; (2) plasma concentrations of clozapine and olanzapine; and (3) psychotropic treatment response. First, we analyzed two population-based studies (CoLaus|PsyCoLaus, N = 4898; SKIPOGH, N = 2054) to investigate random CMR associations with clinical, genome-wide, and epigenome-wide factors associated with CYP1A2 activity. Second, in psychiatric cohorts, we tested CMR associations with dose-normalized plasma concentrations (C/D) of clozapine (N = 164) and olanzapine (N = 222) and with psychotropic treatment response, including hospital admission risk (N = 1019) and prolonged stays (N = 1349). CMR were positively associated with age, CYP1A2 inducers including smoking, and negatively with female sex. CMR were negatively associated with clozapine C/D, explaining up to 14.9% of the variance; over six-fold the variance explained by genetic factors. A one-unit increase in CMR was associated with a 26% increased likelihood of hospital admission (p = 0.002) and reduced short-stay chance by 11% (p < 10^-3). Random CMR provides a useful method to probe CYP1A2 activity, contributing, alongside other variables, to personalizing clozapine doses and identifying psychiatric patients at risk of hospital admission and lengthy stays. Incorporating routine measurement of random CMR before introduction of clozapine could be considered to allow early assessment of CYP1A2 activity, a key determinant of personalized clozapine dose titration.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081236","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}