Molecular Psychiatry最新文献

{"title":"Spatial concordance metrics and related risk factors of brain-peripheral barrier axes: unveiling distinct concordance patterns for mental and neurological axes.","authors":"Ziyang Cui","doi":"10.1038/s41380-026-03643-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03643-y","url":null,"abstract":"<p><p>Numerous studies have documented bidirectional interactions between the central nervous system and barrier organs (skin, gut, and lung). While genome-wide association studies have revealed shared genetic factors across brain-peripheral barrier axes, investigating these connections from an environmental perspective in large populations remains difficult. Using data from the Global Burden of Disease (GBD) 2023, I extracted annual incidence rates for 56 diseases related to brain-peripheral barrier axes and exposure rates for the 70 most detailed risk factors across 204 countries and territories. By categorizing regional incidence rates into four quartiles for each disease, I pinpointed regions with concordance of these axes and constructed a spatial atlas of disease concordance within the brain-peripheral barrier axis from a macro-epidemiologic view. Subsequently, I calculated global spatial concordance percentages for each axis, which allowed the comparatively assessment of concordance patterns across different axes, specific diseases, and their variations over time, across the lifespan, and by gender. Finally, I applied machine learning models and Shapley additive explanations to identify risk factors related to the spatial concordance of each axis. From 1990 to 2023, the overall trend for most brain-peripheral barrier axis pairs remained stable. Spatial concordance patterns showed dynamic fluctuations across the lifespan, followed by a convergence toward stability in older age. Several risk factors are related to most brain-peripheral barrier axes. Notably, the mental and neurological axes exhibited distinct concordance patterns. Compared with neurological axes, concordance within mental axes showed a broader and more dispersed geographic distribution, with greater variation across sexes and over time. Furthermore, concordance percentages of mental and neurological axes exhibited opposing age-related trends, contrasting disease spectra for peripheral conditions, and inverse relationships with alcohol and sodium consumption. Those divergences suggest distinct mechanisms underlying the brain-peripheral barrier axes in mental and neurological diseases. Related risk factors offer population-based hypotheses for further investigation in individual-level studies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856875","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":"Cocaine facilitates Ca²⁺ fluctuations in prefrontal cortex astrocytes via norepinephrine transmission in awake mice.","authors":"Suhua Sun, Xi Wu, Min Gao, Jie Li, Liyuan Sun, Lun Wang, Guoqing Chen, Qinglong Wang, Yingfei Xiong, Yang Lu, Bo Zhou, Bing Liu, Quanfeng Zhang, Changhe Wang, Feipeng Zhu, Zhuan Zhou","doi":"10.1038/s41380-026-03582-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03582-8","url":null,"abstract":"<p><p>Astrocytic Ca²⁺ activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca²⁺ imaging in awake mice, we show that a physiologically relevant level of cocaine induces synchronized and hyperactive Ca²⁺ signals in frontal cortical astrocytes. Mechanistically, this process occurs primarily through the volume release of norepinephrine from locus coeruleus innervation, followed by the activation of Gq-coupled α1 adrenergic receptors in the prefrontal cortex and the subsequent IP₃R2-dependent store Ca²⁺ release, thus causing hyperactive Ca²⁺ fluctuations in astrocytes. Importantly, interrupting the hyperactive astrocytic Ca²⁺ signals either by blocking store Ca²⁺ release or by conditionally knocking out the astrocytic α1AR rescued FrA neuronal activity and aggravated cocaine-induced locomotor sensitization. These findings revealed that, in addition to neurons, astrocytes can be super-activated by cocaine through the crosstalk between norepinephrine nerves and glia, providing a new perspective for the understanding and clinical treatment of cocaine addiction.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856868","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":"Physiological Age and Homeostatic Dysregulation Following Child Maltreatment in Youth.","authors":"Qiaofeng Ye, Abner T Apsley, Laura Etzel, Waylon J Hastings, Christopher R Chiaro, Hannah M C Schreier, Eric D Claus, Alan A Cohen, Zachary Fisher, Christine M Heim, Jennie G Noll, Chad E Shenk, Idan Shalev","doi":"10.1038/s41380-026-03642-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03642-z","url":null,"abstract":"<p><p>Child maltreatment has been associated with biological hallmarks of aging, including telomere shortening and epigenetic instability; however, its influence on physiological age and homeostatic dysregulation in early life remains unclear. The current study examined pediatric versions of physiological age and homeostatic dysregulation in children aged 8-13 with and without exposure to maltreatment. Maltreatment exposure was determined based on investigational records within 12 months prior to enrollment. Physiological measures were trained and validated utilizing external datasets - the National Health and Nutrition Examination Survey III and IV, respectively. Physiological age was computed using the Klemera-Doubal Method to indicate physiological developmental status. Homeostatic dysregulation level was computed as the Mahalanobis distance from an external reference group. 216 females and 245 males with a mean age of 11.4 years (SD 1.5) were included (76.6% White, 13.2% Black, and 13.0% Hispanic, 76.6% with maltreatment). Exposure to maltreatment was not associated with changes in physiological age but was associated with greater homeostatic dysregulation. Further analyses by maltreatment type and sex revealed that physical abuse was associated with greater homeostatic dysregulation, while sexual abuse was associated with delayed physiological development, specifically in males. Exposure to multiple types of maltreatment was associated with greater homeostatic dysregulation among males, but not among females. This study revealed that recent exposure to certain types of maltreatment may impair physiological development or regulation in children, with sex-specific patterns suggesting greater effects in males. Findings further indicate that physiological development composites in youth are sensitive to the impact of child maltreatment and can be incorporated in future work to evaluate the long-term sequelae of adverse exposures in pediatric populations. As the impact of maltreatment was only nominally significant after correction for multiple testing, validation work in other samples is needed.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840464","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":"Stable depression subtypes identified using functional connectome normative deviation models and their response to rTMS.","authors":"Chengfeng Chen, Liyuan Lin, Yuan Liu, Shiying Wang, Jiang Wang, Yufeng Zang, Jijun Wang, Wen Qin, Bin Zhang","doi":"10.1038/s41380-026-03634-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03634-z","url":null,"abstract":"<p><p>The heterogeneity of depression complicates treatment. Identifying stable biological subtypes could advance precision-targeted interventions. This study aims to identify stable depression subtypes using functional connectome normative deviation models and to assess their response to repetitive transcranial magnetic stimulation (rTMS). We analyzed 1204 patients spanning different states of depression, together with 1636 healthy controls. Functional connectome normative models were derived from healthy controls to generate individual deviation maps for patients with depression, which were clustered using k-means to identify biologically informed subtypes. Subtype-specific responses to dorsolateral prefrontal cortex rTMS were evaluated, and putative neurobiological mechanisms underlying differential rTMS responsiveness were investigated. Two reproducible subtypes emerged across various clinical and methodological conditions: subtype-1 exhibited hyperconnectivity in somatomotor and ventral attention networks and hypoconnectivity in frontoparietal and default mode networks, whereas subtype-2 showed the opposite pattern. Only subtype-2 showed significant improvement in anhedonia following rTMS treatment (SHAPS: z =- 2.92, P = 0.001, FDR), which was significantly greater than that of subtype-1 (SHAPS, subtype-1 vs. subtype-2 efficacy: z = -2.43, P = 0.046, FDR). Patients whose connectome deviation patterns more closely resembled subtype-2 had better anhedonia improvement (r = 0.48, P = 0.012), while those closer to subtype-1 had less improvement (r = -0.46, P = 0.016). Only the pattern of deviation changes in subtype-2 was positively correlated with the anhedonia-related functional connectivity network mapping (r = 0.43, P < 0.001). These preliminary findings highlight potential avenues for subtype-targeted interventions in depression and warrant validation in larger randomized controlled trials.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840488","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":"ASD mutations in the ciliary gene CEP41 impact development of projection neurons and interneurons in a human cortical organoid model.","authors":"Kerstin Hasenpusch-Theil, Alexandra Lesayova, Zrinko Kozić, Mariana Beltran, Grace Wilson, Neil C Henderson, Owen Dando, Thomas Theil","doi":"10.1038/s41380-026-03615-2","DOIUrl":"https://doi.org/10.1038/s41380-026-03615-2","url":null,"abstract":"<p><p>Primary cilia control cell-cell signalling and their dysfunction has been implicated in Autism Spectrum Disorders (ASD) but their roles in the ASD aetiology remain largely unexplored. Here, we analysed the impact of ASD mutations in CEP41 using human cortical organoids. CEP41 encodes a centrosomal protein located at the basal body and the ciliary axoneme and is mutated in ASD individuals and in Joubert syndrome, a ciliopathy with high incidence of ASD. To gain insights into CEP41's role in ASD aetiology, we characterised human cortical organoids carrying the CEP41 R242H point mutations found in ASD individuals. This mutation did not interfere with CEP41's ciliary localisation but cilia were shorter and had lower levels of tubulin polyglutamylation, which is indicative of altered cilia stability and signalling. Moreover, scRNAseq analyses revealed that the expression of several transcription factors with critical roles in interneuron development was altered in mutant interneurons and their progenitors. The CEP41 mutation also caused an augmented formation of upper layer cortical neurons. Taken together, these findings indicate that CEP41 controls excitatory and inhibitory neuron differentiation, alterations in which might lead to an excitation/inhibition imbalance that is widely recognized as a convergent mechanism underlying neurodevelopmental disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840505","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":"Heterogeneous functional state dynamics and its structural substrates in male individuals with autism spectrum disorder.","authors":"Tianhang Liu, Xi Chen, Xiangyu Zheng, Haoda Ren, Yapei Xie, Zhao Fu, Yilu Zhao, Li Yang, Yong He, Xuhong Liao","doi":"10.1038/s41380-026-03627-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03627-y","url":null,"abstract":"<p><p>Neuroimaging studies have revealed altered functional connectome dynamics in autism spectrum disorder (ASD) and linked these alterations to clinical symptoms. However, most studies have emphasized population-level contrasts, leaving interindividual variability in connectome dynamics and its structural underpinnings poorly understood. To address this gap, we analyzed resting-state functional and structural MRI data from 939 male participants (440 with ASD, 499 typically developing controls) across 18 sites in the Autism Brain Imaging Data Exchange (ABIDE). Whole-brain functional state dynamics was characterized using five leading activity modes and their expressions via eigen-microstate analysis. Age-related trajectories of mode expressions were constructed for typically developing controls using normative modeling, enabling quantification of individual-level deviations in functional dynamics. Compared with controls, ASD individuals showed greater interindividual variability in functional deviation profiles. Unsupervised clustering of these profiles identified two robust ASD subtypes with distinct mode-specific dysfunctions. One subtype primarily involved the visual, default-mode, frontoparietal, and dorsal attention networks, whereas the other subtype primarily involved the somatomotor, visual, frontoparietal, and ventral attention networks. These subtypes were clinically dissociable, differing in restricted and repetitive behaviors and social impairments, and exhibited mode-specific brain-symptom associations. Furthermore, the subtypes exhibited distinct cortical thickness alterations, and individual subtype membership was predicted with high accuracy (83%) using a random forest classifier based on cortical thickness. The main findings were replicated in an independent cohort outside ABIDE. This study delineates two reproducible and clinically dissociable ASD subtypes and links functional connectome dynamics to structural substrates, offering novel insights into the neurobiological basis behind ASD heterogeneity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817885","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":"The role of microRNAs in executive functions: a comprehensive review and bioinformatics analysis of human and animal studies.","authors":"Alba Navarro-Flores, Dennis M Krüger, Lalit Kaurani, Andre Fischer, Thomas G Schulze, Urs Heilbronner","doi":"10.1038/s41380-026-03623-2","DOIUrl":"https://doi.org/10.1038/s41380-026-03623-2","url":null,"abstract":"<p><p>Executive functions (EFs) are meta-cognitive abilities that orchestrate goal-directed behavior (i.e., set-shifting, working memory, and inhibitory control). Despite their strong genetic composition, the development of EFs is shaped by environmental exposures - as maternal distress, perinatal hypoxia, household dysfunction, neglection - which have varying degrees of impact depending on the duration or severity of the exposure, sensitive neurodevelopmental periods, and individual resiliency. Furthermore, they are negatively affected by aging and psychiatric, neurologic, and inflammatory diseases. MicroRNA dysregulation interferes with normal brain development and function and has been associated with various neuropsychiatric disorders; however, its effects on EFs remain unclear. Therefore, in this review we focus on the evidence regarding microRNA changes and their effects on EFs. We performed a systematic search from inception until October 2023 of four databases of human and animal studies. The results are presented narratively. Moreover, we conducted a bioinformatics analysis using experimental mRNA targets of the candidate microRNAs, as well as assessed the risk of bias of the included studies. We found 46 studies (23 in humans, 22 in animals, and one in both). The studies evaluated mild cognitive impairment, psychiatric disorders, and healthy aging. Gene mutations in MIR137 were associated with decreased EF performance, whereas MIR885 gene methylation was associated with increased executive functioning. Mutations in the genes of enzymes relevant for microRNA biosynthesis also impacted EFs. In the revised literature, the microRNAs that were consistently reported as dysregulated in two or more samples in relation to variations in EFs were miR-148a-3p for humans; miR-155, miR-30e, and miR-384-5p for rodents; and miR-132, miR-146a-5p, miR-148-3p, miR-181a-5p, miR-190b, miR-31, miR-501-3p, and miR-9-5p for both humans and rodents. The suggested regulatory pathways behind EFs included changes in neurogenesis, neurodevelopment, and synaptic plasticity/signaling. Changes in the various steps of microRNA biogenesis - such as mutations in the genes coding for microRNAs, reduced availability of relevant processing enzymes, or dysregulation of microRNA expression - are potentially associated with changes in EFs. Future research is required to better understand these associations in relation to developmental stage, diagnosis, disease severity, and the degree of the microRNA dysregulation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817867","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":"Polysubstance use disorders among US adults.","authors":"Beth Han, Nora D Volkow, Christopher M Jones, Deborah Dowell, Grant Baldwin, Emily B Einstein, Geetha A Subramaniam, Yngvild Olsen, Carlos Blanco, Wilson M Compton","doi":"10.1038/s41380-026-03618-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03618-z","url":null,"abstract":"<p><p>Polysubstance use disorders ( ≥ 2 substance use disorders (SUDs)) are associated with high morbidity and mortality. We analyzed data from 92,233 adult participants in the 2022-2023 US National Surveys on Drug Use and Health to estimate past-year prevalence of polysubstance use disorders and to examine their associations with age of substance use initiation. Multivariable logistic regression and Poisson regression were applied. Age- and sex-adjusted past-year prevalence of 2 SUDs was 19.2-44.9% (95% CIs=11.1-62.3%) among adults with any SUD. Age- and sex-adjusted past-year prevalence of ≥3 SUDs ranged from 16.4% (95% CI = 14.3-18.6%) among adults with cannabis use disorder, to 32.4-44.7% (95% CIs=29.1-51.3%) among those with opioid use disorder or prescription stimulant or tranquilizer/sedative use disorder, and up to 48.2-72.0% (95% CIs=39.4-81.7%) among those with methamphetamine, cocaine, or hallucinogen use disorder. Overall, compared to adults who initiated substance use before age 18, the number of SUDs was 73-83% lower for those who initiated at age ≥21 (range of incidence density ratios (IDRs)=0.17-0.27, 95% CIs=0.12-0.31). Specifically, compared with corresponding adult counterparts who initiated before age 18, the number of moderate-severe SUDs was 32% lower among those initiating alcohol at ages 21-29 (IDR = 0.68, 95% CI = 0.57-0.83), 21% lower among those initiating cannabis at ages 21-29 (IDR = 0.79, 95% CI = 0.69-0.90), and 45-62% lower (IDRs=0.38-0.55, 95% CIs=0.31-0.76) among adults who never initiated alcohol, cannabis, or nicotine use. The elevated prevalence of polysubstance use disorders associated with early initiation of substance use underscores the critical need for evidence-based strategies to prevent alcohol, cannabis, and nicotine consumption before age 21.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776986","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":"Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.","authors":"Samantha Corrà, Valeria Balmaceda, Carlo Viscomi","doi":"10.1038/s41380-026-03570-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03570-y","url":null,"abstract":"<p><p>Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy with its broad and customizable tissue tropism achieved through natural and engineered serotypes offers a highly effective platform for delivering therapeutic genes to affected tissues. However, the intricate genetics and biology of mitochondria present unique challenges for the development of AAV-based therapies. While gene replacement therapy remains a viable strategy for correcting nuclear gene defects, mutations in mtDNA require specialized approaches, such as mitochondrially targeted, RNA-free base editors and nucleases capable of precise editing within the mitochondrial genome. As an alternative, allotopic expression, which involves expressing mitochondrial genes from the nuclear genome, is currently being evaluated in clinical trials but remains controversial, due to issues related to mitochondrial import and functional integration in the respiratory complexes. The clinical translation of AAV-mediated therapies for mitochondrial diseases still confronts several interrelated challenges, including efficient targeting of multiple affected organs, scalable and cost-effective vector manufacturing, and minimizing vector-associated toxicity. By integrating advanced genome editing technologies with sophisticated vector engineering and delivery strategies, AAV-based gene therapy stands as a transformative approach for addressing the broad and heterogeneous spectrum of primary mitochondrial disorders. Continued progress in overcoming current biological and technical barriers will be essential to realize the full therapeutic potential of AAVs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777020","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":"Cognitive impairment preceding the onset of the first psychosis episode in schizophrenia.","authors":"Abraham Reichenberg, René S Kahn","doi":"10.1038/s41380-026-03625-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03625-0","url":null,"abstract":"<p><p>Adults with schizophrenia exhibit substantial and widespread cognitive impairment, with subtle cognitive deficits already apparent in childhood and adolescence - many years prior to the onset of psychosis. Here, we focus on evidence from population-based research highlighting findings specific to cognitive impairment (as indexed by IQ) that precedes the onset of schizophrenia. We illustrate that (i) cognitive impairment worsens from early childhood onwards through to the onset of psychosis; (ii) this early and progressive cognitive impairment is rarely present in other psychotic disorders. At the same time, (iii) early cognitive impairment is not universal in schizophrenia; and (iv) a substantial role for genes affecting both schizophrenia and early life cognitive impairment has not been unequivocally proven. We suggest that a subgroup of patients with schizophrenia is characterized by progressive premorbid cognitive impairment. This group is developmentally distinguishable from the rest of patients with psychoses. Future studies should focus on understanding the (possibly unique) etiology in this neurodevelopmental subgroup of schizophrenia patients.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776977","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}