Molecular Psychiatry最新文献

{"title":"Noradrenergic modulation of glymphatic clearance: implications for neuropsychiatric disorders and mortality","authors":"Ting-Ting Zhu, Jian-Jun Yang, Kenji Hashimoto","doi":"10.1038/s41380-025-03051-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03051-8","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"136 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113888","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":"Towards clinical subtypes in schizophrenia: integrating cognitive, functional, and digital phenotyping assessments","authors":"Andrew Jin Soo Byun, Erlend Lane, Carsten Langholm, Matthew Flathers, Mei-Hua Hall, John B. Torous","doi":"10.1038/s41380-025-03054-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03054-5","url":null,"abstract":"<p>Heterogeneity in the clinical presentation of schizophrenia impairs both proper and preventative care. The digital phenotyping data gathered from an international multi-site cohort study in people with schizophrenia (SZ) offers a novel opportunity to explore clinically meaningful subtypes in the context of clinical, functional, and cognitive data. Using a set of behavioral features derived from smartphone digital phenotyping, clinical assessment of symptoms including PANSS, clinical assessment of cognition with BACS, and clinical assessment of functioning with the social functioning assessments over the target period of twelve months, we found that the international cohort of 74 patients were categorized into three well-defined clusters that suggest clinically actionable targets from differential correlations in each. Namely, the identified clusters seemed to share phenotypic traits with the affective psychosis with more severe symptomatic presentation, a non-affective SZ with functional impairment, and a higher functioning non-affective SZ cluster. Partial correlation analysis further highlighted the emergence of different features per cluster, where anxiety symptoms were most notable for one group, whereas psychotic symptoms were most notable for the other two. Importantly, we showcase an analysis pipeline that transparently addresses challenges of missing data and potential skew so that this research methodology can be applied to future prospective validation studies. This study hopes to build a foundation for future digital phenotyping clustering work by scaling up to new sites, and populations to uncover the nature and extent of heterogeneity in schizophrenia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104686","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 event-related potential components across psychiatric disorders: a systematic review and network meta-analysis","authors":"Zhe Lu, Jing Guo, Junyuan Sun, Yaoyao Sun, Ying Zhang, Yuyanan Zhang, Yundan Liao, Zhewei Kang, Xiaoyang Feng, Guorui Zhao, Rui Yuan, Yunqing Zhu, Weihua Yue","doi":"10.1038/s41380-025-03062-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03062-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This study aims to compare and rank event-related potentials (ERP) components among healthy individuals and patients with various psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), anxiety disorder (AD), and obsessive-compulsive disorder (OCD).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A comprehensive search was conducted in PubMed, Embase, PsycINFO, and Web of Science up to March 20th, 2024. Original studies reporting ERP component data in patients with psychiatric disorders were included. Network meta-analyses were conducted to compare ERP components, including P300, mismatch negative (MMN), P50, N1, N2, P1, and P2.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>From 47,391 citations, 687 studies were included, with sample sizes ranging from 893 to 16,879. Compared to healthy controls (HC), significant reduction in amplitudes and latency delay of P300, and reduced MMN amplitude were observed in SCZ, BD, and MDD. Additionally, SCZ displayed significant abnormalities in all P50 components. Reductions in N1, N2, and P2 amplitudes were noted in SCZ, with increased N2 latencies in SCZ and BD. The most significant difference across psychosis in EPR components was the MMN amplitude and ERN amplitude between OCD and SCZ. Finally, the composite ERP-score suggested SCZ rank the first in ERP abnormalities. Most primary outcomes were stable in sensitivity analyses.</p><h3 data-test=\"abstract-sub-heading\">Conclution</h3><p>The findings suggested that SCZ exhibited pronounced electrophysiological abnormalities, particularly in the P300 and P50 components. Moreover, the results provided a comprehensive overview of the varying electrophysiological profiles across different psychoses. These insights support the potential of ERPs as neurophysiological markers reflecting the neural dysfunctions associated with these disorders. Prospero registration: CRD42022361158</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"236 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104715","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":"Cholinergic system in schizophrenia: A systematic review and meta-analysis","authors":"Zacharie Saint-Georges, Julia MacDonald, Roya Al-Khalili, Rami Hamati, Marco Solmi, Matcheri S. Keshavan, Lauri Tuominen, Synthia Guimond","doi":"10.1038/s41380-025-03023-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03023-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background/Objectives</h3><p>Studies have shown widespread alterations in different components of the cholinergic system in schizophrenia, but to date the evidence has not been systematically reviewed and summarized. Here, we systematically review imaging and post-mortem studies on the central cholinergic system in schizophrenia/schizoaffective disorder.</p><h3 data-test=\"abstract-sub-heading\">Subjects/Methods</h3><p>Searches were performed in Embase and Medline. Study designs included cross-sectional case control studies comparing individuals with schizophrenia/schizoaffective disorder to control population. Risk of bias was assessed with the NIH/NHLBI tool for Quality Assessment of Case-Control Studies. The current study followed the PRISMA 2020 guidelines (PROSPERO: CRD42023402126).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 3259 studies were screened and 61 met eligibility criteria for the systematic review, including 8 in vivo neuroimaging and 53 post-mortem studies. About 74% of these studies described significant alterations, most often reductions in either muscarinic or nicotinic receptor levels in schizophrenia. We also conducted 3 meta-analyses showing reductions in M1/M4 muscarinic receptors in the striatum (<i>g</i> = −0.809, <i>k</i> = 3, <i>n</i> = 108), hippocampus (<i>g</i> = −0.872, <i>k</i> = 3, <i>n</i> = 84), and fronto-cingulate cortex (<i>g</i> = −0.438, <i>k</i> = 4, <i>n</i> = 295). Six neuroimaging studies reported associations with clinical symptom severity measures, and four investigations with cognitive dysfunction.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Our review demonstrates a widespread decrease in muscarinic and nicotinic receptor levels in schizophrenia, evident in both neuroimaging and post-mortem studies. Our meta-analyses show large to moderate effects for the reductions in M1/M4 muscarinic receptors in the striatum, hippocampus, and fronto-cingulate cortex. Limitations and future directions for the field are discussed.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104683","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":"Reduced glymphatic clearance in early psychosis","authors":"Lin Hua, Xinglin Zeng, Kaixi Zhang, Zhiying Zhao, Zhen Yuan","doi":"10.1038/s41380-025-03058-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03058-1","url":null,"abstract":"<p>Psychosis involves neuroinflammation and oxidative stress, both affecting the glymphatic system, the lymphatic-like, fluid-transport system in the brain. However, it is unclear whether early psychosis is related to impairments in glymphatic functions. In resting-state fMRI, it has been recently established in a number of neurodegenerative diseases that the coupling relationship between cortical blood-oxygen-level-dependent (BOLD) signal and ventricular cerebrospinal fluid (CSF) flow is associated with brain waste clearance, a key glymphatic function that has not been examined in psychosis or any other psychiatric populations. In a large dataset (total <i>n</i> = 137, age = 23.86 ± 4.16), we demonstrated that glymphatic clearance marked by BOLD-CSF coupling was weaker and more delayed in patients with early psychosis compared to healthy controls. BOLD-CSF coupling also varied between the non-affective and affective psychosis groups with group differences most prominent in high-order but not low-order cortical regions. Finally, reduced global BOLD-CSF coupling was associated with cognitive decline and more severe psychotic symptoms. We provided novel evidence highlighting dysregulated coupling between cortical activity and macroscopic CSF flow as a biomarker for early psychosis. Similar to recent observations in neurodegenerative disorders, the association between reduced BOLD-CSF coupling and psychotic symptoms suggested that waste clearance is disrupted in psychosis which shed light on the pathophysiology of this disease from a glymphatic point of view.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"55 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088292","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":"Cannabinoid CB1 receptor-sensitive neurodevelopmental processes and trajectories","authors":"Kuei Y. Tseng, Hanna M. Molla","doi":"10.1038/s41380-025-03057-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03057-2","url":null,"abstract":"<p>As high-potency cannabis (with high Δ⁹-Tetrahydrocannabinol content) becomes easily accessible and widespread, it is of extreme importance for public health that a scientific platform is used to implement practical guidelines, particularly for at-risk populations. Many reviews have been written in the past decade summarizing the impact of cannabis in the developing brain. One critical concept frequently mentioned but not discussed in detail is whether there are sensitive neurodevelopmental events driving the age-specific sensitivity to cannabis, particularly those mediated by cannabinoid type 1 receptor signaling. By integrating available data from humans and animal models, the goal of the present expert review article is to provide a mechanistic overview on how cannabis exposure during sensitive periods of neural circuit plasticity and development can result in lasting consequences. Here we used the frontal cortex as a proxy to align the trajectory of the brain cannabinoid system between humans and rodents. Both the strengths and limitations of available mechanistic studies on the effects of cannabis and cannabinoids were discussed using a developmental framework from which neural circuit adaptations during sensitive periods are considered. Such an approach is needed to align key neurodevelopmental variables through the lifespan, which in turn will provide valuable insights applicable to the human brain by defining the underpinning mechanisms of sensitive periods and how the impact of cannabis changes from childhood to adolescence, and thereafter through young adulthood.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"142 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097240","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":"Elevated NEGR1 in brain induces anxiety or depression-like phenotypes and synaptic dysfunction","authors":"Ya-Qi Zhang, Qing Zhang, Yi Yang, Li-Li Yu, Ning-Lin Fan, Yong Wu, Jun-Yang Wang, Xing-Lun Dang, Ying-Qi Guo, Cong Li, Guo-Lan Ma, Lu Wang, Yong-Bo Guo, Shi-Wu Li","doi":"10.1038/s41380-025-03052-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03052-7","url":null,"abstract":"<p>Single nucleotide polymorphisms (SNPs) within 1p31.1 region have shown significant associations with depression, and our prior functional genomics pinpointed a regulatory variant rs3101339 among them. However, its precise role in depression pathogenesis remains elusive. In this study, we employed a series of analytical and functional approaches, including regulatory element annotation, brain expression quantitative trait loci (eQTL), reporter gene assay, electrophoretic mobility shift assay (EMSA), and precise genome editing. Our results confirmed that rs3101339 is a causal variant within 1p31.1 with its risk allele C upregulating <i>NEGR1</i> expression. To further investigate the consequences of <i>NEGR1</i> upregulation, we overexpressed <i>NEGR1</i> in specific region of the mouse brain (including medial prefrontal cortex (mPFC) and ventral hippocampus (vHIP)) using stereotaxic injection. Behavioral assessments revealed that elevated <i>NEGR1</i> levels in the brain, particularly in the vHIP, resulted in working memory impairment as well as anxiety- and depression-like behaviors in mice. Neuronal sparse labeling assay and transmission electron microscopy revealed that <i>NEGR1</i> overexpressing in the vHIP leads to dendritic spine loss and synaptic ultrastructure abnormality. Immunoprecipitation-mass spectrometry (IP-MS) further identified 67 high-confidence proteins that interacted with NEGR1, many of which are involved in neurotransmitter exocytosis and synaptic vesicle endocytosis. Transcriptomic profiling revealed 94 differentially expressed genes in NEGR1-OE (vHIP) mice compared to control mice (<i>P</i> adj &lt; 0.05), which were enriched in myelination-related signaling pathways (such as myelination, ensheathment of neurons, axon ensheathment in central nervous system, etc.). Together, our findings implicated that the overexpression of the <i>NEGR1</i> gene in the mouse brain as a potential driver of anxiety- or depression-like phenotypes potentially through impairing synaptic function and myelination.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066790","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 evidence of influenza A virus infection during pregnancy as a risk factor for neuropsychiatric disorder in offspring","authors":"Jean-Paul Selten, Vera A. Morgan","doi":"10.1038/s41380-025-03059-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03059-0","url":null,"abstract":"<p><b>To the Editor</b>,</p><p>With interest we read the paper about the effects of infection with Influenza A virus on pregnant mice: disruption of maternal intestinal immunity and of foetal cortical development in a time- and dose-dependent manner [1]. However, we were surprised to read in the introduction of the paper that “epidemiological studies demonstrate that influenza A virus infection during pregnancy increases the prevalence of offspring neurodevelopmental disorders like schizophrenia, bipolar disorder and autism spectrum disorder (as reviewed in [2])”. The authors cite three papers that support an association with schizophrenia, one paper that does the same for bipolar disorder and one for autism spectrum disorder. Importantly, they do not mention dozens of studies that obtained negative results. The review cited by the authors [2] describes possible mechanisms that can lead to neuropsychiatric illness and is not a critical or systematic review of the existing epidemiological literature. The authors fail to mention two meta-analyses of studies on the relationship between maternal influenza during pregnancy and risk of schizophrenia or bipolar disorder in the child [3, 4], and a systematic review of studies on a wider range of neuropsychiatric outcomes, including autism spectrum disorder and intellectual disability [5]. Let us very briefly summarize the findings.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979519","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":"Correction: Cardiovascular diseases and depression: A meta-analysis and Mendelian randomization analysis.","authors":"Jun Zeng, Yuting Qiu, Chengying Yang, Xinrong Fan, Xiangyu Zhou, Chunxiang Zhang, Sui Zhu, Yang Long, Kenji Hashimoto, Lijia Chang, Yan Wei","doi":"10.1038/s41380-025-03049-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03049-2","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079137","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":"Association between autism and dementia across generations: evidence from a family study of the Swedish population","authors":"Zheng Chang, Honghui Yao, Shihua Sun, Le Zhang, Shengxin Liu, Isabell Brikell, Brian M. D’Onofrio, Henrik Larsson, Paul Lichtenstein, Ralf Kuja-Halkola, Sara Hägg, Francesca Happé, Mark J. Taylor","doi":"10.1038/s41380-025-03045-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03045-6","url":null,"abstract":"<p>There is emerging evidence to suggest that autistic individuals are at an increased risk for cognitive decline or dementia. It is unknown whether this association is due to shared familial influences between autism and dementia. The main purpose of this study was, thus, to investigate the risk of dementia in relatives of autistic individuals. We conducted a family study based on linking Swedish registers. We identified all individuals born in Sweden from 1980–2013, followed until 2020, and clinical diagnoses of autism among these individuals. We linked these index individuals with their parents, grandparents, and aunts/uncles. The risk of dementia (including any type of dementia, Alzheimer’s disease, and other types of dementia) in relatives of autistic individuals was estimated using Cox proportional hazards models. Analyses were then stratified by sex of the relatives and intellectual disability in autistic individuals. Relatives of autistic individuals were at an increased risk of dementia. The risk was strongest in parents (hazards ratio [HR] = 1.36, 95% confidence intervals = 1.25–1.49), and weaker in grandparents (HR = 1.08, 1.06–1.10) and aunts/uncles (HR = 1.15, 0.96–1.38). Furthermore, there were indications of a stronger association between autism in index individuals and dementia in mothers (HR = 1.51, 1.29–1.77) compared to dementia in fathers (HR = 1.30, 1.16–1.45). There was only a small difference in relatives of autistic individuals with and without intellectual disability. Our results provide evidence of familial co-aggregation between autism and different types of dementia, and a potential genetic link. Future research now needs to clarify the risk of dementia in autistic individuals.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"43 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979454","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}