Molecular Psychiatry最新文献

{"title":"Neurophysiological signatures of Stanford Neuromodulation Therapy in treatment resistant depression.","authors":"Davide Momi, Derrick M Buchanan, Masataka Wada, Andrew D Geoly, Noriah J Johnson, Eleanor J Cole, Adi Maron-Katz, Claudia Tischler, Christopher C Cline, Diego A Pizzagalli, Manish Saggar, Daphne Voineskos, John D Griffiths, Camarin E Rolle, Corey J Keller, Nolan Williams","doi":"10.1038/s41380-026-03837-4","DOIUrl":"10.1038/s41380-026-03837-4","url":null,"abstract":"<p><p>Treatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder. Stanford Neuromodulation Therapy (SNT), a high-dose intermittent theta-burst transcranial magnetic stimulation protocol, produces rapid antidepressant effects, but its neurophysiological mechanisms remain unclear. Here, we used longitudinal TMS-EEG to characterize the progressive neurophysiological changes induced by SNT, assess their site-specificity, and explore whether baseline neural markers are associated with clinical response. We conducted a double-blind, randomized, sham-controlled trial at Stanford University (2017-2018; analysis August 2024-October 2025) in 24 TMS-naïve participants with TRD (Montgomery-Åsberg Depression Rating Scale ≥20; ≥1 failed antidepressant trial). Participants were randomized to active (n = 12) or sham (n = 12) SNT, consisting of 10 sessions per day over 5 consecutive days targeting the left dorsolateral prefrontal cortex (90,000 pulses). TMS-EEG was acquired at two baseline sessions, before and after each treatment session, and at 1-month follow-up (14 TMS-EEG sessions in total). Active SNT progressively reduced cortical excitability at the treatment site, with significant decreases by day 3 in the early window component (-27.9%; P < 0.01), while no changes were observed at the vertex control site. Site-specific comparisons confirmed early window reductions only at the left dorsolateral prefrontal cortex (t₂₂ = -3.82; P < 0.001). SNT also selectively decreased estimated medial prefrontal source activity consistent with the subgenual anterior cingulate cortex (sgACC) across sessions (F₁₃,₂₂₂ = 4.93; P < 0.001), with effects persisting at 1-month follow-up. In an exploratory analysis in the active group (n = 12), higher baseline estimated sgACC source activity was associated with greater clinical improvement (r = -0.67; P = 0.023); although promising, the latter preliminary finding requires replication in larger, adequately powered samples before predictive utility can be established. These findings indicate that SNT induces progressive, site-specific cortical modulation and selective downstream effects on estimated sgACC source activity. Early cortical excitability changes represent candidate neurophysiological markers of SNT response, while the observed association between baseline sgACC activity and clinical outcome, while preliminary, motivates prospective investigation of subcortical source activity as a potential predictor of treatment response in larger trials. ClinicalTrials.gov Identifier: NCT03068715.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881109","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":"Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.","authors":"Anu Korukonda, Harris E Blankenship, Korey Kam, Dilpreet Kour, Claudia Espinosa-Garcia, Wooyoung Eric Jang, Upasna Srivastava, Bernard Mulvey, Margaret M Tish, Ronit Witztum, Christina C Ramelow, Brittany S Pate, L Cameron Liles, Linyue Lu, Jake Atallah, Eugene Guo, Keri Martinowich, Amanda L Sharpe, Andrew W Varga, Srikant Rangaraju, Michael J Beckstead, David Weinshenker","doi":"10.1038/s41380-026-03852-5","DOIUrl":"10.1038/s41380-026-03852-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation, and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated \"pretangle\" tau (pTau) in the locus coeruleus (LC), the brain's primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, mechanisms underlying these phenomena remain unclear. We developed a translationally-relevant mouse model that recapitulates the 'LC-first' pattern using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety- and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6, suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. While pTau burden persisted at 6 and 9 months after viral infusion, the anxiety-like behaviors observed at 3 months abated at these later timepoints. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, with implications for future noradrenergic-based interventions to address neuropsychiatric manifestations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875336","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":"Dissecting the shared genetic architecture and biological mechanisms linking sleep traits and suicide attempts: from variants to genes.","authors":"Yan'e Lu, Yajing Xu, Yaoyao Sun, Yuying Li, Suhua Chang, Jianyu Que, Xikun Han, Ya Bin Wei, Catharina Lavebratt, Jia Jia Liu","doi":"10.1038/s41380-026-03858-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03858-z","url":null,"abstract":"<p><p>Comorbidities and genetic correlations between sleep traits and suicide attempts suggest potential shared genetic architecture, but pleiotropic genetic variants and functions remain unclear. This study aimed to identify shared genetic variants, genes, and biological mechanisms linking sleep traits with suicide attempts. We conducted a genome-wide pleiotropic analysis using GWAS summary statistics for 11 sleep traits and suicide attempts. Genetic correlations and overlaps were assessed using LDSC and GPA. Pleiotropic variants were identified via PLACO, functionally annotated with FUMA, and evaluated by Bayesian colocalization. SuSiE fine-mapping and SuSiE-based colocalization further refined variant-level signals. Gene-level associations were examined using MAGMA, followed by SMR integrating blood and brain cis-eQTL data. Prioritized genes were characterized through phenotype, pathway, cell-type enrichment, and DGIdb druggability analyses. Bidirectional causality was explored via Mendelian randomization. Six sleep traits exhibited significant genetic correlations with suicide attempts, while all 11 showed significant polygenic overlap. We identified 2,224 trait-pair-specific pleiotropic variants (1,640 unique) across 50 trait-pair-specific risk loci. Self-reported sleep duration and daytime napping contributed the most variants and loci, whereas least active 5 h timing and sleep efficiency showed the fewest. Colocalization supported shared causal variants at 15 loci. Thirty-two pleiotropic genes were prioritized, showing enrichment in metabolic, developmental, synaptic, immune, and H3K27me3-related pathways. Thirteen genes (40.63%) were druggable, including five with approved drug interactions. Genetically predicted morning chronotype was associated with lower odds of suicide attempts. These findings provide new insights into the shared genetic basis linking sleep traits and suicide attempts and highlight candidate druggable genes for future translational research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865944","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":"Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: a systematic review and network meta-analysis.","authors":"Michele Fornaro, Chiara Di Lorenzo, Nicolas Nunez, Alessandro Miola, Raffaella Calati, André Ferrer Carvalho, Luca Steardo, Brendon Stubbs, David Mischoulon, Christoph U Correll, Marco Solmi","doi":"10.1038/s41380-026-03759-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03759-1","url":null,"abstract":"<p><strong>Background: </strong>\"Nutraceuticals\" and \"phytoceuticals\" may have antidepressant activity, prompting an in-depth network meta-analysis of randomized clinical trials (RCTs).</p><p><strong>Methods: </strong>Systematic review and network meta-analysis (PubMed/MEDLINE/EMBASE/Scopus/PsycINFO/CENTRAL/ClinicalTrials.gov (until 01/07/2025) of RCTs vs. placebo or treatment as usual (TAU = antidepressants) testing nutraceuticals/phytoceuticals in major depressive disorder (MDD). Change in depressive symptomatology (standardized-mean-difference = SMD), treatment response, and all-cause discontinuation (acceptability) (risk ratio = RR) were co-primary outcomes. Secondary outcomes were anxiety symptom changes, adverse event-related discontinuation (\"tolerability\"), and symptom remission. We conducted subgroup, transitivity, and sensitivity analyses to explore/reduce heterogeneity, and assessed global/local inconsistency, publication bias, risk of bias (RoB), and confidence in the evidence (CINeMA/AMSTAR-Plus).</p><p><strong>Results: </strong>Across 163 studies (n = 15,757, distinct compounds' combinations n = 137), several molecules/classes outperformed placebo with very large effect sizes. Restricting analyses to compounds with ≥2RCTs/non-TAU antidepressants/low RoB/non-sponsored trials/non-outliers, higher-than-expected/unrealistic effect sizes emerged vs. placebo for eicosapentaenoic acid (EPA) (k = 20, n = 8483; SMD = -1.67;95%C.I. = -2.38;-0.97), vitamin D3 (k = 3, n = 344; SMD = -1.59;95%C.I. = -2.71;-0.46), and St. John's-wort-extract-ZE117 (k = 3,n = 207;SMD = -1.02;95%C.I = -1.90;-0.15) regarding depressive symptomatology. Substantial heterogeneity (I² = 85.3%;95%C.I. = 81.9%;88.0%) and global inconsistency (Q-between-designs = 186.91, p < 0.0001) emerged, explained by subgroup and sensitivity analyses, without publication bias. Additionally, a medium effect size emerged vs. placebo for curcumin (k = 2,n = 89;SMD = -0.58;95%C.I. = -0.99;-0.18) regarding anxiety reduction in low RoB analyses. Shugan granules, EPA, EPA+Docosahexaenoic Acid, ZE117, and fluoxetine+EPA response and St. John's wort extract WS5570/ZE117 remission significantly outperformed placebo. Citicoline was associated with significantly more dropouts than placebo. A meta-regression of efficacy effect sizes against adapted AMSTAR-Plus scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality. Confidence in the evidence was low to very low.</p><p><strong>Conclusions: </strong>Upon filtering low-quality evidence, only a few nutraceutical/phytoceuticals showed potential for depressive symptoms, warranting more rigorous trials.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875259","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":"Closed-loop transcranial alternating current stimulation (tACS) reduces cue reactivity and improves inhibitory control in methamphetamine use disorder with frequency and timing specificity.","authors":"Lei Guo, Yue Ding, Tianzhen Chen, Jiajun Xu, Hang Su, Shiyan Qu, Ruitong Yan, Hong Gan, Xiandong Lin, Wei Shao, Dan Luo, Yingying Tang, Valerie Voon, Gang Wang, Haifeng Jiang, Min Zhao","doi":"10.1038/s41380-026-03846-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03846-3","url":null,"abstract":"<p><p>Methamphetamine use disorder (MUD) involves persistent cue reactivity and impaired inhibitory control, posing major treatment challenges. Closed-loop noninvasive neuromodulation can tailor stimulation to dynamic brain states, but its application in MUD remains largely unexplored. This study developed a cue reactivity biomarker-guided closed-loop transcranial alternating current stimulation (tACS) system, examined its optimal stimulation frequency, and preliminarily evaluated its efficacy in improving inhibitory control and reducing cue reactivity. Three cohorts of individuals with severe MUD were enrolled. Drug-cue exposure increased parietal-occipital theta power in Cohort 1. Based on this biomarker, a closed-loop tACS system targeting the left dorsolateral prefrontal cortex was developed. In Cohort 2, a within-subject crossover design examined closed-loop tACS at 6, 10, and 40 Hz. Random-time and open-loop continuous stimulation at the identified optimal frequency served as controls. In Cohort 3, an open-label, single-arm study of five consecutive daily closed-loop stimulation sessions assessed preliminary clinical efficacy. The results showed that closed-loop tACS at 40 Hz was the only condition that simultaneously reduced cue-related electroencephalographic (EEG) activity (P = 0.007) and improved inhibitory control (P = 0.031). Random-time stimulation reduced cue-related activity but did not improve inhibitory control, whereas open-loop continuous stimulation showed no significant effects. Repeated 40 Hz closed-loop tACS over five days in severe MUD significantly reduced craving and improved inhibitory control. These findings suggest that biomarker-guided 40 Hz closed-loop tACS can modulate neural and behavioral dysfunction in MUD and support the feasibility, safety, and preliminary efficacy of this neuromodulation strategy.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875292","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":"Organoid intelligence: a promising paradigm for autism spectrum disorder research.","authors":"Xitong Zuo, Xinggao Zhang, Yulong Liu, Xin Li, Meiling Xia, Yuanyuan Ma, Xiaotang Fan","doi":"10.1038/s41380-026-03850-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03850-7","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition marked by heterogeneity in its clinical presentations, which complicates both its diagnosis and treatment. Despite advancements, the molecular mechanisms underlying ASD remain largely unclear. In recent years, two independent yet highly promising technological domains have made significant advancements: organoids and artificial intelligence (AI). Brain organoids can simulate critical processes of human neurodevelopment in both physiological and pathological states, providing an unprecedented window into the mechanisms and potential therapeutics of ASD. Simultaneously, AI has demonstrated formidable capabilities for processing and analyzing large-scale, high-dimensional biomedical data, and has been effectively applied to ASD imaging analysis, genomics research, and behavioral data interpretation. However, these two fields have developed mainly in parallel, leaving their potential for cross-disciplinary integration untapped in ASD research. This review aims to fill this gap by reviewing the current status and limitations of both fields in the context of ASD, and to elucidate a promising research paradigm that integrates AI with brain organoids, called \"organoid intelligence\", to enhance our understanding of predictive models, unravel ASD pathogenesis, and develop more effective and individualized therapies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865947","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":"Gut microbiota and blood biomarkers as correlating factors in patients with postoperative delirium: analysis of three prospective observational studies","authors":"Wenyu Song, Shrishti Singh, Wang Xiang, Kathryn Baldyga, Kali Stevens, Wei Qi, Júlio Ken Matsubara, Chang Ge, Hao Deng, Ji-Eun Kim, Edward R. Marcantonio, Shiqian Shen, Zhongcong Xie, Yiying Zhang","doi":"10.1038/s41380-026-03825-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03825-8","url":null,"abstract":"Postoperative delirium is associated with both gut microbiota alterations and Tau phosphorylation; however, how these factors interact and jointly contribute to postoperative delirium remains poorly understood. This prospective observational cohort study screened 491 patients aged ≥65 years undergoing elective laminectomy or hip or knee replacement under general or spinal anesthesia at Massachusetts General Hospital (2016–2020). The study aimed to assess the correlation between plasma Tau protein levels, specific gut microbiota, and the gut microbiota-derived metabolite indole-3-propionic acid (IPA) in participants with and without postoperative delirium. Exclusion criteria included major neurological disease, smoking history, sensory impairment, and recent antibiotic use. Delirium was assessed 24–48 h postoperatively. Out of 491 screened participants, 139 had blood biomarker data, and 86 had gut microbiota data included in the final analysis. Ten percent of the participants experienced postoperative delirium. Co-occurrence network analysis demonstrated that microbial interactions differed between postoperative delirium and non-postoperative delirium groups. Significant associations among gut microbiota, IPA, and Tau biomarkers were observed only in postoperative delirium participants. Additionally, three machine learning classifiers distinguished postoperative delirium cases from non-postoperative delirium cases with Area Under the Curve values above 50%. The results suggest that plasma Tau may interact with gut microbiota, and this interaction is associated with postoperative delirium, suggesting the involvement of a gut–blood-brain axis in postoperative delirium vulnerability. These findings implicate a microbiota–Tau interaction that may represent both a potential pathogenic mechanism and a therapeutic target for postoperative delirium pending confirmative studies. Furthermore, machine learning classifiers utilizing microbiome-derived features demonstrate a potential in distinguishing patients with and without postoperative delirium.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853521","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":"Spatial lipidomics of the human brain: systematic review of current state and future perspectives.","authors":"Cecilia Cabasino, Paolo Enrico, Federico Bottaro, Dalia De Santis, Cinzia Cagnoli, Rita Garbelli, Italia Bongarzone, Yvan Torrente, Giuseppe Delvecchio, Paolo Brambilla","doi":"10.1038/s41380-026-03793-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03793-z","url":null,"abstract":"<p><strong>Background: </strong>Lipids represent a significant component of the human brain, exerting crucial functions in both physiological and pathological conditions. Mapping brain lipids distribution is an emerging area of research, with mass spectrometry imaging allowing the detection of lipid species and their localization within tissue sections. However, comprehensive spatial mapping of lipids in the human brain remains to be achieved. This systematic review addresses this gap by critically synthesizing the available literature in the field.</p><p><strong>Methods: </strong>A bibliographic search on PubMed, Scopus and Web of Science for original articles employing mass spectrometry imaging to analyze lipids and their distribution in the human brain was performed. The included articles were grouped according to the clinical characteristics of the studied populations, including healthy subjects and selected neurological and psychiatric disorders. Studies on human brain tissue from tumoral specimens, animals, or in vitro models such as organoids were excluded to maintain focus on translational findings directly applicable to human neurological and psychiatric diseases.</p><p><strong>Results: </strong>Following the inclusion criteria, 34 articles were selected. Alzheimer's disease, schizophrenia and multiple sclerosis were the most frequently investigated conditions, alongside studies in healthy subjects describing lipid distribution under physiological conditions. We observed considerable heterogeneity across studies in terms of research questions and methodological approaches. Nevertheless, our critical synthesis allowed us to identify both consistencies and discrepancies in experimental strategies and in the lipid signatures reported.</p><p><strong>Conclusions: </strong>Studying lipids by mass spectrometry imaging enables the identification of spatially defined profiles in distinct brain areas, providing valuable insights into both human neurobiology and brain disorders' pathophysiology. In this context, spatial information is crucial for linking lipid alterations to specific structures or lesions, thereby supporting translational applications. Finally, we identified key methodological issues that must be addressed to advance this emerging field.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857194","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":"Iron dyshomeostasis and its neurobiological mechanisms in psychiatric disorders.","authors":"Chuyue Li, Shuangyi Tan, Zuqiang Wu, Zhuo Wang","doi":"10.1038/s41380-026-03854-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03854-3","url":null,"abstract":"<p><p>Brain iron homeostasis is indispensable for sustaining central nervous system development, neural circuit stability, and core neurobiological processes including neurotransmission, mitochondrial energetics, and synaptic plasticity. Compelling clinical and preclinical evidence has established that iron dyshomeostasis represents a pervasive, convergent pathological driver of multiple psychiatric disorders, spanning anxiety, depression, schizophrenia, and neurodevelopmental and affective spectrum conditions. Nevertheless, current literature remains fragmented by disease-specific investigation, with persistent unresolved contradictions regarding regional iron deficiency versus overload in disease pathogenesis. Moreover, the cell-type- and circuit-specific mechanisms linking iron imbalance to psychiatric phenotypes, lacks systematic integration-hindering mechanistic consensus and translational advancement. In this comprehensive review, we synthesize multimodal evidence from human neuroimaging, post-mortem tissue analysis, clinical cohorts, and preclinical animal studies to delineate the distinct regulatory logics governing peripheral and cerebral iron metabolism. We systematically dissect how disrupted iron homeostasis triggers a cascade of neurobiological impairments, encompassing oxidative stress, ferroptosis, neuroinflammation, myelination defects, neurotransmitter dysfunction, and maladaptive synaptic remodeling. Synthesizing these findings, we construct a unified mechanistic framework illustrating how diverse etiological factors-genetic predisposition, chronic psychosocial stress, neuroinflammatory insult, and developmental influences-converge to drive region- and cell-specific iron perturbations and subsequent circuit dysfunction. We further summarize the translational potential and inherent limitations of existing iron-targeted intervention strategies. Collectively, this synthesis positions brain iron dyshomeostasis as a core convergent node in the pathophysiological network of psychiatric disorders, bridges basic iron neurobiology with translational neuroscience, and provides a conceptual framework and practical roadmap for biomarker discovery, mechanistic dissection, and next-generation therapeutic development in psychiatry.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857248","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":"In vivo imaging of synaptic density in psychotropic-free adults with autism spectrum disorder: a [¹¹C]UCB-J PET study.","authors":"Masamichi Yokokura, Taishi Tamayama, Yosuke Kameno, Toshiki Iwabuchi, Takafumi Goto, Ichiro Murata, Taeko Harada, Noritaka Ichinohe, Yasuomi Ouchi, Hidenori Yamasue","doi":"10.1038/s41380-026-03812-z","DOIUrl":"https://doi.org/10.1038/s41380-026-03812-z","url":null,"abstract":"<p><p>Synaptic dysfunction has been proposed as a key biological mechanism underlying autism spectrum disorder (ASD), yet findings from animal, genetic, postmortem, and molecular imaging studies remain inconsistent. Using positron emission tomography with [¹¹C]UCB-J, a radioligand that binds to synaptic vesicle glycoprotein 2 A and serves as an index of synaptic density, the present study investigated standardized uptake value ratio (SUVR) of [¹¹C]UCB-J in 20 unmedicated adult males with high-functioning ASD and 21 typically developed control adult males. Both voxel-wise whole-brain and region-of-interest analyses across multiple brain regions revealed no significant group differences in [¹¹C]UCB-J SUVR. These results remained unchanged after adjusting for potential confounders (i.e., full-scale IQ, trait and state anxiety, and depressive tendency) that differed between groups. Within the ASD group, [¹¹C]UCB-J SUVR in the left anterior and medial temporal lobe showed a significant positive correlation with the scores of restricted and repetitive behaviors (RRB), a core symptom of ASD, in the Autism Diagnostic Observation Schedule-2nd Edition. Contrary to previously reported pervasive reduction of synaptic density in individuals with ASD-most of whom were taking psychotropic medications-the current results, obtained using the same radioligand ([¹¹C]UCB-J) as in the previous study, suggest potential heterogeneity in the contribution of synaptic pathology to ASD. Although this exploratory finding requires replication in larger cohorts, the observed association between [¹¹C]UCB-J SUVR and RRB severity serves as a hypothesis-generating indicator of synaptic involvement of the behavioral rigidity in ASD. Together, these findings highlight the complexity of ASD-related synaptic pathology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841055","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}