@article{pmid41872521,

title = {A genome-wide investigation of depression among individuals with and without irritability},

author = {Julien St-Pierre and Jacky Jang and Corina Nagy and Laura Fiori and Gustavo Turecki and Josée Dupuis and Sahir Rai Bhatnagar and Massimiliano Orri},

doi = {10.1038/s41380-026-03548-w},

issn = {1476-5578},

year  = {2026},

date = {2026-08-01},

journal = {Mol Psychiatry},

volume = {31},

number = {8},

pages = {4323--4331},

abstract = {Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N = 487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n = 35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n = 23,613, 8.1%) and compared them to controls with no depression or irritability (n = 268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P < 5×10; rs72795440 and rs1233494). The GWAS of depression with irritability (N = 292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (r = .77) and neuroticism for depression with irritability (r = .76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42427711,

title = {Multi-omics characterization of astrocyte subtypes reveals spatially coordinated astrocyte downregulation in depression},

author = {Haruka Mitsuhashi and Harish R Rao and Steffanie Amadei and Anjali Chawla and Maria Antonietta Davoli and Naguib Mechawar and Gustavo Turecki and Corina Nagy},

doi = {10.64898/2026.07.02.735636},

issn = {2692-8205},

year  = {2026},

date = {2026-07-01},

journal = {bioRxiv},

abstract = {Major depressive disorder (MDD) is a complex psychiatric disorder affecting millions of individuals worldwide. Astrocytes, which have been implicated in MDD by several studies, are the most abundant non-neuronal cells in the brain and play critical roles in synaptic regulation, blood-brain barrier maintenance, and immune modulation. While astrocytic molecular and morphological abnormalities are well-established features of MDD, these alterations have not been resolved within their spatial context. Here, we combine spatial transcriptomics with matched snRNA-seq and snATAC-seq datasets to spatially map molecularly distinct astrocyte subtypes and define their regional contributions to MDD pathology. This spatial context further enables the characterization of astrocyte interactions with neighboring cell populations, providing a more holistic assessment of how dysfunctional astrocytes influence local brain microenvironments and circuit function in MDD. We identified spatially localized astrocytic dysfunction in deep cortical layers of the MDD dlPFC, converging across transcriptomic, chromatin, and spatial modalities and centering on the PSAP-GPR37L1 signaling axis. Together, these findings identify astrocyte dysfunction as a key feature of MDD and demonstrate the value of spatially resolved molecular profiling for uncovering how altered astrocyte-neuron communication within deep cortical layers may contribute to disease pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42441714,

title = {Isolation of Small Extracellular Vesicles from Murine Skeletal Muscle and Bone Marrow by Size-Exclusion Chromatography},

author = {Reine Khoury and Laura Montermini and Nadim Tawil and Corina Nagy},

doi = {10.3791/70894},

issn = {1940-087X},

year  = {2026},

date = {2026-06-01},

journal = {J Vis Exp},

number = {232},

abstract = {Small extracellular vesicles (sEVs) are nanosized, lipid-bound particles that mediate intercellular communication through the transfer of proteins, lipids, and ribonucleic acids (RNAs). Isolation of sEVs from solid tissues such as skeletal muscle (SkM) and bone marrow (BM) remains challenging due to low yield and contamination from non-vesicular components. This protocol describes a reproducible workflow for isolating sEVs from mouse SkM and BM. SkM is enzymatically digested, whereas BM is processed directly and subsequently subjected to differential centrifugation and size-exclusion chromatography (SEC). For SkM, the void volume (~2.5 mL) is discarded, and the subsequent ~1.6 mL is collected as EV-enriched fractions, typically subdivided into 400 µL sequential fractions (F1-F4). For BM, a 700 µL void volume is discarded, followed by collection of an ~850 µL EV-enriched fraction, which can be subdivided into ~170 µL sequential fractions (F1-F5) and pooled based on EV marker enrichment. Using this approach, sEVs can be isolated from small tissue volumes (approximately 500 µL from a single quadriceps and 150 µL from pooled femur and tibia BM), yielding ~10 particles·mL·mg tissue with particle diameters predominantly <200 nm. Vesicle integrity and purity are validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for canonical EV markers, with additional characterization by single-particle interferometric detection to quantify tetraspanin-defined vesicle subpopulations. This method enables reproducible isolation of high-purity sEVs from structurally complex tissues using minimal input material, supporting downstream molecular and functional analyses of tissue-derived vesicles.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41942773,

title = {Characterization of the chromosome 7 locus associated with suicidal behavior},

author = {Laura M Fiori and Anjali Chawla and Vikram Nathan and Malosree Maitra and Corina Nagy and Gustavo Turecki},

doi = {10.1038/s41380-026-03600-9},

issn = {1476-5578},

year  = {2026},

date = {2026-04-01},

journal = {Mol Psychiatry},

abstract = {Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the underlying genetic factors has been challenging. Recent genome-wide association studies for suicidal behavior identified a SNP on chromosome 7, rs62474683, which was the most significantly associated SNP. As this SNP is intergenic, the mechanism by which it may be related to suicidal behaviors is unclear. In order to determine the potential functional effects of the rs62474683 genotype, and how it may be related to suicidal behavior, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two brain regions in individuals with depression who died by suicide, and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility. While we found several genes displaying differential expression, Forkhead box P2 (FOXP2) was the most consistently altered in brains of individuals who died by suicide and its expression was related to rs62474683 genotype. Furthermore, the association between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for an association between the region containing rs62474683 and FOXP2, and identified Homeobox family transcription factors as potential mediators of this relationship. In conclusion, our study provides evidence suggesting a potential functional association between the most significant suicide attempt-associated locus to date and genes displaying differential expression in individuals with depression who died by suicide.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41951638,

title = {Astrocyte fatty acid metabolism as a driver of risk for major depressive disorder},

author = {Eamon Fitzgerald and Nicholas O'Toole and Irina Pokhvisneva and Eric J Nestler and Gustavo Turecki and Corina Nagy and Michael J Meaney},

doi = {10.1038/s41467-026-71542-5},

issn = {2041-1723},

year  = {2026},

date = {2026-04-01},

journal = {Nat Commun},

abstract = {Genome-wide association studies (GWAS) have successfully identified genetic loci associated with major depressive disorder (MDD), yet the complex gene networks underpinning this polygenic risk remain largely uncharacterised. Here, we elucidate the neurobiological mechanisms of MDD by analyzing co-expression networks of 94 risk genes in the human prefrontal cortex. By linking these networks to individual symptoms, we identify the FADS1 (fatty acid desaturase 1) network as a central integrator across symptom clusters. We find that the FADS1 network functions primarily in astrocytes to regulate fatty acid metabolism and influence oligodendrocyte-related cell states. Furthermore, we identify FGF2 as a synaptic effector of this pathway and highlight PPARα (peroxisome proliferator-activated receptor alpha) as a putative therapeutic target. These results establish astrocyte fatty acid metabolism as a critical mechanistic contributor to MDD and a promising avenue for treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41593764,

title = {Identification of antidepressant response-related changes to DNA methylation and gene expression},

author = {Laura M Fiori and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyag001},

issn = {1469-5111},

year  = {2026},

date = {2026-02-01},

journal = {Int J Neuropsychopharmacol},

volume = {29},

number = {2},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a debilitating condition that is commonly treated with antidepressants. However, many people do not respond to treatment, and the molecular mechanisms underlying antidepressant response remain poorly understood. Baseline DNA methylation differences have been observed between individuals who respond to treatment compared to those who do not respond; however, little is known regarding DNA methylation changes that occur during treatment or how they may relate to clinical response.nnMETHODS: We assessed peripheral levels of DNA methylation and gene expression at baseline and after 8 weeks of treatment in 154 individuals with MDD who were treated with escitalopram or desvenlafaxine, using the Infinium MethylationEPIC Beadchip and RNA sequencing. We identified methylation sites whose levels changed over time in relation to changes in depressive symptoms, as well as corresponding changes to gene expression levels after 8 weeks of treatment.nnRESULTS: We identified 2 sites, in sodium voltage-gated channel alpha subunit 7 and IQ Motif and ankyrin repeat containing 1, whose methylation changes over time were correlated with changes in depressive symptoms at the epigenome-wide level. Gene ontology analyses of genes displaying response-related methylation changes highlighted several processes previously implicated in depression, including small GTPase-related signaling and the Wnt signaling pathway. Additionally, we identified methylation sites in 10 genes that displayed significant changes in methylation over time in relation to improvement of depressive symptoms, whose expression levels at week 8 were correlated with the level of depressive symptoms, and for which methylation levels were functionally related to gene expression.nnCONCLUSIONS: Antidepressant treatment response is associated with changes in peripheral DNA methylation over time, as well as corresponding alterations in gene expression. Significance Statement Major depressive disorder (MDD) is commonly treated with antidepressants; however, many people do not respond to treatment. In order to better understand the molecular changes that occur during antidepressant treatment, we analyzed DNA methylation and gene expression in the blood of 154 individuals with MDD who were treated with escitalopram or desvenlafaxine. We found 10 methylation sites within 10 genes whose methylation levels changed over time in relation to clinical improvement, and whose levels of expression were related to both methylation and antidepressant response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41108682,

title = {Protocol for antibody-based m6A sequencing of human postmortem brain tissues},

author = {Haruka Mitsuhashi and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1016/j.xpro.2025.104149},

issn = {2666-1667},

year  = {2025},

date = {2025-10-01},

journal = {STAR Protoc},

volume = {6},

number = {4},

pages = {104149},

abstract = {Here, we present an optimized N6-methyladenosine (m6A) immunoprecipitation sequencing for human postmortem brain tissue, building on previously established approaches. We describe steps for RNA extraction, RNA shearing, RNA immunoprecipitation, and library preparation. The protocol includes optimization data for each step, such as m6A profiles from total RNA versus poly(A) RNA as an input, a comparison of different commercial m6A antibodies, and immunoprecipitation with varying RNA/antibody ratios. This protocol allows reliable capture of m6A peaks from human postmortem brain tissue. For complete details on the use and execution of this protocol, please refer to Mitsuhashi et al..},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40519638,

title = {Peripheral MicroRNA Signatures in Adolescent Depression},

author = {Alice Morgunova and Nicholas O'Toole and Fatme Abboud and Saché Coury and Gary Gang Chen and Maxime Teixeira and Eamon Fitzgerald and Gustavo Turecki and Anthony J Gifuni and Ian H Gotlib and Corina Nagy and Michael J Meaney and Tiffany C Ho and Cecilia Flores},

doi = {10.1016/j.bpsgos.2025.100505},

issn = {2667-1743},

year  = {2025},

date = {2025-07-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {5},

number = {4},

pages = {100505},

abstract = {BACKGROUND: Adolescent depression is linked to enduring maladaptive outcomes, chronic severity of symptoms, and poor treatment response. Identifying epigenetic signatures of adolescent depression is urgently needed to improve early prevention and intervention strategies. MicroRNAs (miRNAs) are epigenetic regulators of adolescent neurodevelopmental processes, but their role as markers and mediators of adolescent depression is unknown.nnMETHODS: Here, we examined miRNA profiles from dried blood spot samples of male and female adolescents with clinical depression and psychiatrically healthy male and female adolescents ( = 62). We processed and sequenced these samples using a small RNA protocol tailored for miRNA identification.nnRESULTS: We identified 9 differentially expressed (DE) miRNAs (adjusted  value < .05), all of which were upregulated in adolescents with depression. At future follow-ups post blood collection, expression of miR-3613-5p, mir-30c-2, and miR-942-5p were positively associated with depression severity but not anxiety, suggesting a stronger link to persistent depression symptoms. Expression of miR-32-5p inversely correlated with hippocampal volume, highlighting a potential neurobiological basis. Common predicted gene targets of the DE miRNAs are involved in neurodevelopment, cognitive processing, and depressive disorders.nnCONCLUSIONS: These findings lay the groundwork for identifying adolescent peripheral miRNA markers that reflect neurodevelopmental pathways that shape lifelong psychopathology risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40482843,

title = {Sex-dependent gene expression during puberty has potential mechanistic implications for the development of major depressive disorder},

author = {Zoe Zhuoling Li and Georgia Kruck and Gladi Thng and Corina Nagy},

doi = {10.1016/j.bbi.2025.05.023},

issn = {1090-2139},

year  = {2025},

date = {2025-06-01},

journal = {Brain Behav Immun},

volume = {129},

pages = {244--266},

abstract = {Major Depressive Disorder (MDD) is a complex illness with heterogeneous symptom profiles, affecting 5% of the global population. Recent molecular studies across biological systems suggest that the manifestations of MDD are significantly shaped by sex. In response, this narrative review organizes up-to-date findings on sex-specific, MDD-related gene expression into multiple biological systems-primarily available from adult human and rodent studies. This adult-centric focus highlights a critical gap: when and how sex-dependent, MDD-associated gene expression patterns emerge, and contribute to adult manifestations. We identify puberty as a sensitive developmental window during which sex-dependent gene expression and regulatory patterns may emerge and carry their impacts into adulthood. We define this as a sex-specific framework established during puberty. To address the "how," we synthesize empirical evidence on the molecular mechanisms associated with the emergence and long-term influence of this framework. Finally, we explore how perturbations acting on this framework may further bifurcate expression patterns and ultimately give rise to the sex-divergent manifestations of MDD observed in adulthood. Overall, this review positions puberty as a key developmental window and calls for future sex-stratified functional genomic studies that span the pubertal timeline.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39989284,

title = {Altered proteomics in brain extracellular vesicles from depressed individuals who died by suicide implicates synaptic processes},

author = {Pascal Ibrahim and Haruka Mitsuhashi and Lorne Taylor and Jenna Cleyle and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyaf012},

issn = {1469-5111},

year  = {2025},

date = {2025-05-01},

journal = {Int J Neuropsychopharmacol},

volume = {28},

number = {5},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a common and debilitating disorder whose molecular neurobiology remains unclear. Extracellular vesicles (EVs) are small vesicles that are released by cells and are involved in intercellular communication. They carry bioactive molecules, such as proteins, that reflect the state of their cell of origin. In this study, we sought to investigate the proteomic cargo of brain EVs from depressed individuals as compared to EVs from matched neurotypical individuals. In addition, we investigated how the EV proteomic cargo compares to the proteomic profile of bulk tissue.nnMETHODS: Using mass spectrometry and label-free quantification, we investigated the EV and bulk tissue protein profile from anterior cingulate cortex samples from 86 individuals. We performed differential expression analysis to compare cases and controls, followed by in silico analysis to determine potential implicated functions of dysregulated proteins.nnRESULTS: Extracellular vesicles display distinct proteomic profiles compared to bulk tissue. Differential expression analysis showed that 70 proteins were differentially packaged in EVs in MDD, while there was no significant difference in protein levels between groups in bulk tissue. In silico analysis points to a strong role of these differential EV proteins in synaptic functions.nnCONCLUSION: To our knowledge, this is the first study to profile EV proteins in depression, providing novel information to better understand the pathophysiology of MDD. This work paves the way for discovering new therapeutic targets for MDD and prompts more investigations into EVs in MDD and other psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39650737,

title = {Altered m6A RNA methylation profiles in depression implicate the dysregulation of discrete cellular functions in males and females},

author = {Haruka Mitsuhashi and Rixing Lin and Anjali Chawla and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1016/j.isci.2024.111316},

issn = {2589-0042},

year  = {2024},

date = {2024-12-01},

journal = {iScience},

volume = {27},

number = {12},

pages = {111316},

abstract = {Adverse environmental stress represents a significant risk factor for major depressive disorder (MDD), often resulting in disrupted synaptic connectivity which is known to be partly regulated by epigenetic mechanisms. N-methyladenosine (m6A), an epitranscriptomic modification, has emerged as a crucial regulator of activity-dependent gene regulation. In this study, we characterized m6A profiles in the ventromedial prefrontal cortex (vmPFC) of individuals with MDD. Using m6A sequencing, we identified a total of 30,279 high-confidence m6A peaks, exhibiting significant enrichment in genes related to neuronal and synaptic function. The m6A peaks between males and females with MDD that passed the significance threshold showed opposite m6A patterns, while the threshold-free m6A patterns were concordant. Distinct m6A profiles were found in MDD for each sex, with dysregulation associated with microtubule movement in males and neuronal projection in females. Our results suggest the potential roles of m6A as part of the dysregulated molecular network in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39128570,

title = {Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb},

author = {Reza Rahimian and Kelly Perlman and Gohar Fakhfouri and Refilwe Mpai and Vincent R Richard and Christa Hercher and Lucy Penney and Maria Antonietta Davoli and Corina Nagy and René P Zahedi and Christoph H Borchers and Bruno Giros and Gustavo Turecki and Naguib Mechawar},

doi = {10.1016/j.bbi.2024.08.016},

issn = {1090-2139},

year  = {2024},

date = {2024-11-01},

journal = {Brain Behav Immun},

volume = {122},

pages = {110--121},

abstract = {The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1 cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38457375,

title = {Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression},

author = {Pascal Ibrahim and Ryan Denniston and Haruka Mitsuhashi and Jennie Yang and Laura M Fiori and Dariusz Żurawek and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyae013},

issn = {1469-5111},

year  = {2024},

date = {2024-03-01},

journal = {Int J Neuropsychopharmacol},

volume = {27},

number = {3},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile.nnMETHODS: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico.nnRESULTS: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity.nnCONCLUSION: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38128342,

title = {Elevated triglycerides and low triiodothyronine: Key risk factors for coronary artery calcification in patients with schizophrenia},

author = {Tan-Yu Huang and Li-Chang Chen and Xiao-Ping Li and Wu-Hao Li and Shu-Xian Xu and Corina Nagy and Pascal Ibrahim and Zhao-Wen Nie and Nai-Yan Yang and Lun Zeng and Hua-Wei Huang and Gustavo Turecki and Xin-Hui Xie},

doi = {10.1016/j.schres.2023.12.007},

issn = {1573-2509},

year  = {2024},

date = {2024-02-01},

journal = {Schizophr Res},

volume = {264},

pages = {113--121},

abstract = {OBJECTIVE: Coronary artery calcification (CAC) is a well-established independent predictor of coronary heart disease, and patients with schizophrenia have significantly higher rates compared to the general population. We performed this study to examine the population-specific risk factors associated with CAC in patients with schizophrenia.nnMETHODS: In this cross-sectional study, patients with schizophrenia who underwent low-dose chest CT scans between January 2020 and December 2021 were analyzed. Ordinary CAC scores and results of routine blood tests were obtained. Logistic regression was used to calculate the odds ratio (OR) for potential risk factors in patients with and without CAC, while the negative binomial additive model was used to explore the dose-response relationship between risk factors and CAC score.nnRESULTS: Of the 916 patients, 233 (25.4 %) had CAC, while 683 (74.6 %) did not. After adjusting for confounding factors, higher triglyceride levels (OR = 1.20, 95 % confidence interval (CI): 1.04 to 1.38, p = 0.013) and low triiodothyronine levels (OR = 0.50, 95 % CI: 0.29 to 0.84; p = 0.010) were identified as risk factors for CAC. Both triglycerides (p = 0.021) and triiodothyronine (p = 0.010) were also found to have significant dose-response relationships with CAC scores according to the negative binomial additive model in the exploratory analysis.nnCONCLUSIONS: This study highlights elevated serum triglycerides and decreased triiodothyronine levels as population-specific risk factors for CAC in patients with schizophrenia, suggest the need for close monitoring of CAC in patients with schizophrenia and further prospective trials to provide additional evidence on this topic.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39414359,

title = {Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain},

author = {Sophie Simard and Reza Rahimian and Maria Antonietta Davoli and Stéphanie Théberge and Natalie Matosin and Gustavo Turecki and Corina Nagy and Naguib Mechawar},

doi = {10.1503/jpn.240026},

issn = {1488-2434},

year  = {2024},

date = {2024-01-01},

journal = {J Psychiatry Neurosci},

volume = {49},

number = {5},

pages = {E319--E333},

abstract = {BACKGROUND: Adult hippocampal neurogenesis has been extensively characterized in rodent models, but its existence in humans remains controversial. We sought to assess the phenomenon in postmortem human hippocampal samples by combining spatial transcriptomics and multiplexed fluorescent in situ hybridization.nnMETHODS: We computationally examined the spatial expression of various canonical neurogenesis markers in postmortem dentate gyrus (DG) sections from young and middle-aged sudden-death males. We conducted in situ assessment of markers expressed in neural stem cells, proliferative cells, and immature granule neurons in postmortem DG sections from infant, adolescent, and middle-aged males.nnRESULTS: We examined frozen DG tissue from infant ( = 1, age 2 yr), adolescent ( = 1, age 16 yr), young adult ( = 2, mean age 23.5 yr), and middle-aged ( = 2, mean age 42.5 yr) males, and frozen-fixed DG tissue from middle-aged males ( = 6, mean age 43.5 yr). We detected very few cells expressing neural stem cell and proliferative markers in the human DG from childhood to middle age. However, at all ages, we observed a substantial number of DG cells expressing the immature neuronal marker . Most   cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature.nnLIMITATIONS: The study was limited by small sample sizes and included samples only from males.nnCONCLUSION: Our findings indicate very low levels of hippocampal neurogenesis throughout life and the existence of a local reserve of plasticity in the adult human hippocampus. Overall, our study provides important insight into the distribution and phenotype of cells expressing neurogenesis markers in the adult human hippocampus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37931511,

title = {Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons},

author = {Swapnali Barde and Julio Aguila and Wen Zhong and Anna Solarz and Irene Mei and Josee Prud'homme and Miklos Palkovits and Gustavo Turecki and Jan Mulder and Mathias Uhlén and Corina Nagy and Naguib Mechawar and Eva Hedlund and Tomas Hökfelt},

doi = {10.1016/j.euroneuro.2023.09.004},

issn = {1873-7862},

year  = {2024},

date = {2024-01-01},

journal = {Eur Neuropsychopharmacol},

volume = {78},

pages = {54--63},

abstract = {Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38101468,

title = {Altered in vivo early neurogenesis traits in patients with depression: Evidence from neuron-derived extracellular vesicles and electroconvulsive therapy},

author = {Xin-Hui Xie and Shu-Xian Xu and Lihua Yao and Mian-Mian Chen and Honghan Zhang and Chao Wang and Corina Nagy and Zhongchun Liu},

doi = {10.1016/j.brs.2023.12.006},

issn = {1876-4754},

year  = {2024},

date = {2024-01-01},

journal = {Brain Stimul},

volume = {17},

number = {1},

pages = {19--28},

abstract = {BACKGROUND: The neurogenesis hypothesis is a promising candidate etiologic hypothesis for depression, and it is associated with electroconvulsive therapy (ECT). However, human in vivo molecular-level evidence is lacking.nnOBJECTIVE: We used neuron-derived extracellular vesicles (NDEVs) as a "window to the neurons" to explore the in vivo neurogenesis status associated with ECT in patients with treatment-resistant depression (TRD).nnMETHODS: In this study, we enrolled 40 patients with TRD and 35 healthy controls (HCs). We isolated NDEVs from the plasma of each participant to test the levels of doublecortin (DCX), a marker of neurogenesis, and cluster of differentiation (CD) 81, a marker of EVs. We also assessed the plasma levels of brain-derived neurotrophic factor (BDNF), a protein that is known to be associated with ECT and neuroplastic processes.nnRESULTS: Our findings indicated that both the levels of DCX in NDEVs and BDNF in plasma were significantly lower in TRD patients compared to HCs at baseline, but increased following ECTs. Conversely, levels of CD81 in NDEVs were found higher in TRD patients at baseline, but did not change after the ECT treatments. Exploratory analyses revealed that lower levels of BDNF in plasma and DCX in NDEVs, along with higher CD81 levels in NDEVs, were associated with more severe depressive symptoms and reduced cognitive function at baseline. Furthermore, higher baseline CD81 concentrations in NDEVs were correlated with greater decreases in depression symptoms.nnCONCLUSIONS: We first present human in vivo evidence of early neurogenesis using DCX through NDEVs: decreased in TRD patients, increased after ECTs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37675893,

title = {Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy},

author = {Shu-Xian Xu and Xin-Hui Xie and Lihua Yao and Wei Wang and Honghan Zhang and Mian-Mian Chen and Siqi Sun and Zhao-Wen Nie and Corina Nagy and Zhongchun Liu},

doi = {10.1111/pcn.13596},

issn = {1440-1819},

year  = {2023},

date = {2023-09-01},

journal = {Psychiatry Clin Neurosci},

abstract = {AIM: This study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma.nnMETHODS: A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein (GFAP) and S100β), an EV marker cluster of differentiation (CD) 81, and nine inflammatory markers in ADEVs were measured as main analyses. Additionally, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis.nnRESULTS: At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100β, as well as CD81 compared to the HCs. Inflammatory markers interferon (IFN)-γ, interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor (TNF)-α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECTs, there was a significant reduction in the levels of GFAP, S100β, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100β, CD81 and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function.nnCONCLUSION: This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert anti-inflammatory effect through inhibition of such activation of astrocytes. This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37549631,

title = {Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing},

author = {Eamon Fitzgerald and Danusa Mar Arcego and Mo Jun Shen and Nicholas O'Toole and Xianglan Wen and Corina Nagy and Sara Mostafavi and Kelly Craig and Patricia Pelufo Silveira and Nirmala Arul Rayan and Josie Diorio and Michael J Meaney and Tie-Yuan Zhang},

doi = {10.1016/j.ebiom.2023.104749},

issn = {2352-3964},

year  = {2023},

date = {2023-09-01},

journal = {EBioMedicine},

volume = {95},

pages = {104749},

abstract = {BACKGROUND: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established.nnMETHODS: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region).nnFINDINGS: We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS).nnINTERPRETATION: Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS.nnFUNDING: This work was supported by funding from the Hope for Depression Research Foundation (MJM).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}