Molecular Psychiatry最新文献

{"title":"Correction: DNA methylation profiles of long-term cannabis users in midlife: a comprehensive evaluation of published cannabis-associated methylation markers in a representative cohort.","authors":"Madeline H Meier, Karen Sugden, Terrie E Moffitt, Benjamin S Williams, Kyle J Bourassa, Renate Houts, Sandhya Ramrakha, Reremoana Theodore, Avshalom Caspi","doi":"10.1038/s41380-025-03107-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03107-9","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564982","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":"Characteristics of brain network connectome and connectome-based efficacy predictive model in bipolar depression.","authors":"Caixi Xi, Bin Lu, Xiaonan Guo, Zeyu Qin, Chaogan Yan, Shaohua Hu","doi":"10.1038/s41380-025-03099-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03099-6","url":null,"abstract":"<p><p>Aberrant functional connectivity (FC) between brain networks has been indicated closely associated with bipolar disorder (BD). However, the previous findings of specific brain network connectivity patterns have been inconsistent, and the clinical utility of FCs for predicting treatment outcomes in bipolar depression was underexplored. To identify robust neuro-biomarkers of bipolar depression, a connectome-based analysis was conducted on resting-state functional MRI (rs-fMRI) data of 580 bipolar depression patients and 116 healthy controls (HCs). A subsample of 148 patients underwent a 4-week quetiapine treatment with post-treatment clinical assessment. Adopting machine learning, a predictive model based on pre-treatment brain connectome was then constructed to predict treatment response and identify the efficacy-specific networks. Distinct brain network connectivity patterns were observed in bipolar depression compared to HCs. Elevated intra-network connectivity was identified within the default mode network (DMN), sensorimotor network (SMN), and subcortical network (SC); and as to the inter-network connectivity, increased FCs were between the DMN, SMN and frontoparietal (FPN), ventral attention network (VAN), and decreased FCs were between the SC and cortical networks, especially the DMN and FPN. And the global network topology analyses revealed decreased global efficiency and increased characteristic path length in BD compared to HC. Further, the support vector regression model successfully predicted the efficacy of quetiapine treatment, as indicated by a high correspondence between predicted and actual HAMD reduction ratio values (r_(df=147)=0.4493, p = 2*10^-4). The identified efficacy-specific networks primarily encompassed FCs between the SMN and SC, and between the FPN, DMN, and VAN. These identified networks further predicted treatment response with r = 0.3940 in the subsequent validation with an independent cohort (n = 43). These findings presented the characteristic aberrant patterns of brain network connectome in bipolar depression and demonstrated the predictive potential of pre-treatment network connectome for quetiapine response. Promisingly, the identified connectivity networks may serve as functional targets for future precise treatments for bipolar depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564981","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":"Central-peripheral neuroimmune dynamics in psychological stress and depression: insights from current research","authors":"Xiao Feng, Min Jia, Meng Cai, Tong Zhu, Jian-Jun Yang, Kenji Hashimoto","doi":"10.1038/s41380-025-03085-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03085-y","url":null,"abstract":"<p>Psychological stress plays a critical role in the onset of depression by activating neuroimmune and endocrine responses, leading to dysregulation of the hypothalamic-pituitary-adrenal axis and increased inflammation. This imbalance impacts key brain regions involved in mood regulation, such as the prefrontal cortex, hippocampus, and amygdala, contributing to the development of depressive symptoms. Moreover, stress induces immune dysregulation and inflammation in peripheral organs, including the gut, spleen, liver, lungs, and heart, which can result in metabolic disorders, cardiovascular disease, and immune dysfunction. Chronic stress also disrupts gut microbiota and alters the gut-brain axis via the vagus nerve, further exacerbating stress-related mental health issues. The cumulative effect of stress on peripheral organs significantly impacts both physical and mental health, linking systemic dysfunction to depression. This comprehensive review delves into the intricate mechanisms by which the immune system regulates mood and explores the etiological factors underlying dysregulated inflammatory responses in depression. We also summarize the connections between the brain and peripheral organs—bone marrow, spleen, gut, adipose tissue, heart, liver, lungs, and muscles—highlighting their coordinated regulation of immune function in response to psychological stress. Additionally, we investigate specific brain regions and neuronal populations that respond to stress stimuli, transmitting signals through autonomic and neuroendocrine pathways to modulate immune function. Finally, we discuss emerging therapeutic strategies that leverage the interaction between endocrine signaling and inflammatory responses for the effective treatment of depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"3 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546977","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":"Stress-induced reduction of sodium leak currents causes social deficits by impairing dorsal dentate gyrus-medial septum glutamatergic projection","authors":"Jinping Wang, Lanyu Zhang, Jin Liu, Yaoxin Yang, Xinchuan Wei, Xiaoqin Jiang, Yusi Hua, Tao Zhu, Guo Chen, Cheng Zhou","doi":"10.1038/s41380-025-03101-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03101-1","url":null,"abstract":"<p>Stress-induced social deficits are related with the malfunction of dentate gyrus (DG). However, the exact molecular mechanism and/or neural circuit of DG participated in social impairments induced by chronic stress is not fully known. Here, we report that the sodium leak channel (NALCN) reduction in the dorsal DG (dDG) but not the ventral DG (vDG) induces social deficits of chronic stress through lowering the excitability and the firings of the glutamatergic neurons. Furthermore, the present study reveals that the medial septum (MS) is an important downstream projection region of dDG glutamatergic neurons involved in the social impairments of chronic stress; and activating the dDG-MS glutamatergic projection significantly relieves these social deficits. In summary, these findings indicate that NALCN in dDG glutamatergic neurons presents a promising molecular target for social deficits of chronic stress <i>via</i> influencing the activity of the dDG glutamatergic neurons (dDG^Glu) and their projection to the MS.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546975","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":"Long term safety of ADHD medication in patients with schizophrenia spectrum disorders","authors":"Jurjen J. Luykx, Olivier Corbeil, Olli Kärkkäinen, Antti Tanskanen, Ellenor Mittendorfer-Rutz, Jari Tiihonen, Heidi Taipale","doi":"10.1038/s41380-025-03080-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03080-3","url":null,"abstract":"<p>Attention-deficit hyperactivity disorder (ADHD) is frequently comorbid with schizophrenia spectrum disorders (SSDs) and is associated with poorer outcomes. Yet, its pharmacological treatment in patients with SSDs has been hampered by safety concerns. We therefore examined whether psychiatric, cardiovascular and other medical outcomes are associated with the use of ADHD medications in people with SSDs (<i>N</i> = 131,476). The main outcome was all-cause hospitalization/mortality. Secondary outcomes were hospitalization for psychosis, somatic hospitalization, and cardiovascular hospitalization. Adjusted hazard ratios (aHRs) were calculated for the association between the outcomes and the different exposure categories (compared with non-use of ADHD medication) using within-individual Cox regression analyses. Lisdexamphetamine was associated with a decreased risk of all-cause hospitalization/mortality (aHR = 0.89, 95%CI = 0.84–0.94) and methylphenidate with a slightly increased risk (aHR = 1.04 [1.01–1.08]), while for the other exposures the 95%CI of the HRs encompassed 1. Atomoxetine was associated with a reduced risk of hospitalization for psychosis (aHR = 0.87 [0.78–0.98]), lisdexamphetamine with a reduced risk of somatic hospitalizations (aHR = 0.70 [0.58–0.84]), and ADHD polytherapy with an increased risk of somatic hospitalizations (aHR = 1.37 [1.07–1.74]). No other statistically significant associations were found between the exposures and outcomes (including cardiovascular hospitalizations). Furthermore, increased all-cause hospitalization/mortality risks for methylphenidate were only found with doses ≥95 mgs/day (aHR 1.08 [1.03–1.14]) or during use periods of this agent without concomitant use of an antipsychotic (aHR = 1.06 [1.01–1.12]). Finally, for methylphenidate and lisdexamphetamine, we found evidence of U-shaped associations between doses used and risks of all-cause hospitalization/mortality and psychosis. In conclusion, we find that for people with SSDs, the use of ADHD medication (particularly lisdexamphetamine in all dosages and long-acting methylphenidate in low to medium doses) is safer than generally conceived. The benefits of its use for patients with SSD and comorbid ADHD should therefore be weighed against the risks in a shared decision-making process aimed at improving patients’ chances of recovery.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"41 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520567","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":"Response to: \"Circular reasoning concerning red flags for predicting rituximab response in OCD\".","authors":"Maike Gallwitz, Isa Lindqvist, Annica J Rasmusson, Simon Cervenka, Joachim Burman, Janet L Cunningham","doi":"10.1038/s41380-025-03012-1","DOIUrl":"10.1038/s41380-025-03012-1","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"3323-3324"},"PeriodicalIF":9.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence of bidirectional relationship between type 2 diabetes and depression; a Mendelian randomization study","authors":"Renu Bala, Dale Handley, Alexandra Gillett, Harry Green, Jack Bowden, Andrew Wood, Inês Barroso, Cathryn M. Lewis, Jessica Tyrrell","doi":"10.1038/s41380-025-03083-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03083-0","url":null,"abstract":"<p>Major depressive disorder (MDD) and type 2 diabetes (T2D) represent two global health challenges with a high degree of co-occurrence. Here, we aim to investigate the causal relationship between MDD and T2D in diverse ancestries using Mendelian randomization (MR) in GWAS summary statistic and individual level (UK Biobank (UKB)) data. We assessed the bi-directional causal relationship between: (a) MDD and T2D and (b) MDD and glycaemic biomarkers (e.g. TG:HDL-C ratio, a measure of insulin resistance, fasting glucose) in non-diabetic individuals. In UKB we also tested the role of T2D on treatment resistant depression (TRD). We used multivariable MR (MVMR) to assess the role of body mass index (BMI) in the MDD to T2D relationship. Our results demonstrated that a doubling in MDD genetic liability was associated with 1.14 higher odds of T2D (95% CI:1.09, 1.19), whilst a doubling in T2D genetic liability associated with 1.02 higher odds of MDD (95% CI:1.01, 1.03). Consistent effect estimates were observed in the UKB when stratifying by sex and suggested a role for T2D in TRD. T2D GWAS derived clusters of genetic variants highlighted the importance of specific pathways in the MDD relationship, including variants raising T2D risk via body fat (OR:1.04; 95% CI:1.02, 1.06), obesity mediated insulin resistance (OR:1.06; 95% CI:1.04, 1.09) and residual glycaemic (OR: 1.02; 95% CI:1.00, 1.04) pathways. MVMR with BMI attenuated the bidirectional relationship between MDD and T2D, particularly from MDD to T2D. Genetic liability to MDD was also associated with higher TG:HDL-C ratio in individuals without T2D (β:0.11; 95% CI:0.08, 0.14). We provide evidence of bidirectional causal association between MDD and T2D, with MDD strongly predicting insulin resistance and T2D. T2D predicted both MDD and TRD and highlighted the importance of obesity and body fat pathways in the T2D to MDD relationship.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533875","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":"Comparative effects of 10-Hz rTMS and iTBS on cortico-striatal connectivity in major depressive disorder: a sham-controlled study","authors":"Cheng-Ta Li, Wan-Chen Chang, Chih-Ming Cheng, Tung-Ping Su, Ya-Mei Bai, Pei-Chi Tu","doi":"10.1038/s41380-025-03091-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03091-0","url":null,"abstract":"<p>Abnormalities in the prefrontal cortex (PFC)-related network play an important role in the pathophysiology of major depressive disorder (MDD). Accumulating evidence indicated that fronto-striatal dysconnectivity is critical to MDD pathogenesis. Whether non-invasive brain stimulation, including 10-Hz repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS), may change cortico-striatal functional connectivity (FC) in MDD patients is unclear. Whether the change of cortico-striatal FC is associated with the antidepressant effects is also unknown. In total, 68 adult MDD subjects were randomly assigned to one of three groups: iTBS, 10-Hz rTMS, or sham group. Functional connectivity was analyzed using MRI and seed-based methods. Seeds included left and right dorsal caudate (DC), dorsal rostral putamen (DRP), and ventral rostral putamen (VRP). The results revealed that significant group-by-time interactions in FC were found in all the striatal seeds. Post-hoc analyses revealed significant increases in FC of the left DRP and VRP for both iTBS and rTMS treatments, particularly with the right frontal pole. Greater FC changes of the fronto-striatal networks correlated with the antidepressant effects. The effects of rTMS and iTBS on FCs of the intra-striatal network, default mode network, and other cortico-striatal networks were distinct. In conclusion, the first study demonstrated that iTBS and rTMS had common but unique effects on the cortico-striatal and intra-striatal networks. These results suggest that both treatments regulate brain reward systems and might be used to treat various striatum-related neuropsychiatric illnesses.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"3 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513151","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":"Integrated multi-omics analyses of synaptosomes revealed synapse-associated novel targets in Alzheimer’s disease","authors":"Subodh Kumar, Enrique Ramos, Axel Hidalgo, Daniela Rodarte, Bhupender Sharma, Melissa M. Torres, Davin Devara, Shrikanth S. Gadad","doi":"10.1038/s41380-025-03095-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03095-w","url":null,"abstract":"<p>Synapse dysfunction is an early event in Alzheimer’s disease (AD) caused by various factors, including amyloid beta, p-tau, inflammation, and aging. However, the precise molecular mechanism underlying synapse dysfunction in AD remains largely unknown. To understand this, we comprehensively analyzed the synaptosomes fraction in post-mortem brain samples from AD patients and cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes in microRNA (miRNA) and mRNA levels in synaptosomes extracted from the brains of unaffected individuals and those with AD. Additionally, we performed mass spectrometry analysis of synaptosomal proteins in the same sample group. These analyses revealed significant differences in the levels of miRNAs, mRNAs, and proteins between the two groups. To gain further insights into the pathways or molecules involved, we employed an integrated omics approach to study the molecular interactions of deregulated synapse miRNAs, mRNAs, and proteins in samples from individuals with AD and the control group, demonstrating the impact of deregulated miRNAs on their target mRNAs and proteins. Furthermore, the DIABLO analysis revealed complex relationships among mRNAs, miRNAs, and proteins that could be key in understanding the pathophysiology of AD. Our study identified novel synapse-associated candidates that could be critical in restoring synapse dysfunction in AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"643 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503397","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":"Single-cell transcriptomics reveals Sox6 positive interneurons enriched in the prefrontal cortex of female mice vulnerable to chronic social stress","authors":"Guojing Ma, Jing Wu, Yiyuan Wu, Jie Yang, Jianping Zhang, Yu Huang, Ruimin Tian, Xingyu Zhou, Xunmin Tan, Yifan Li, Ping Liu, Minghao Yuan, Xiaodong Song, Ma-Li Wong, Julio Licinio, Peng Zheng","doi":"10.1038/s41380-025-03088-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03088-9","url":null,"abstract":"<p>Major depressive disorder (MDD) is a prevalent mental illness that significantly impacts global health, with women showing twice the prevalence of men. This study employed the chronic social defeat stress (CSDS) model in female mice to investigate cellular and molecular changes in the prefrontal cortex (PFC) associated with depressive-like behaviors. Using single-nucleus RNA sequencing (snRNA-Seq), we examined transcriptomic alterations across various cell types in the PFC. Our results revealed that interneurons exhibited the most significant transcriptomic changes among all analyzed cell types. Notably, we found the Sox6⁺ interneurons (Sox6⁺Int) were enriched in the CSDS susceptible group. This enrichment was associated with enhanced inflammatory and immune responses, as well as alterations in synaptic function and mitochondrial pathways. Furthermore, we observed significant changes in cell-cell communication patterns, particularly between Sox6⁺Int and oligodendrocyte precursor cells (OPC). Weighted gene co-expression network analysis (WGCNA) identified several gene modules in Sox6⁺Int associated with specific depressive-like behaviors, implicating pathways related to inflammation, autophagy, and synaptic function. In particular, specific knockdown of Sox6 in neurons reversed the depressive-like behaviors. These findings provide novel insights into the cellular and molecular mechanisms underlying MDD in females, highlighting the potential role of Sox6⁺Int in stress-induced depression. Our study not only extends our understanding of the neurobiological basis of depression but also identifies potential therapeutic targets for sex-specific interventions in MDD treatment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"59 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503407","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}