@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{pmid41980683,

title = {Choroid plexus inflammation in bipolar disorder},

author = {Dario Figueroa Velez and Reza Rahimian and Christine Hehnly and Jordan C Benson and Isabella Sacharczyk and Gustavo Turecki and Naguib Mechawar and Maria K Lehtinen},

doi = {10.1016/j.bbi.2026.106598},

issn = {1090-2139},

year  = {2026},

date = {2026-08-01},

journal = {Brain Behav Immun},

volume = {136},

pages = {106598},

abstract = {Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology.},

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{pmid42094851,

title = {Comprehensive analysis of cytokines in depression: independent data from patient plasma and post-mortem ventromedial prefrontal cortex},

author = {Reza Rahimian and Jonas Hagenberg and Claudia Belliveau and Rebecca Chen and Stephanie Théberge and Gohar Fakhfouri and Marina Wakid and Elisabeth Binder and Gustavo Turecki and Janine Knauer-Arloth and Naguib Mechawar},

doi = {10.1016/j.bbih.2026.101245},

issn = {2666-3546},

year  = {2026},

date = {2026-07-01},

journal = {Brain Behav Immun Health},

volume = {54},

pages = {101245},

abstract = {Preclinical and clinical evidence has implicated inflammation in the pathophysiology of depression. Abnormal cytokine levels in blood, cerebrospinal fluid, and post-mortem brain samples have been associated with depression. To our knowledge, however, a comprehensive analysis of cytokine protein levels in brain samples from patients with depression has yet to be conducted in major components of the limbic system such as the ventromedial prefrontal cortex (vmPFC). This region plays a crucial role in depression, impacting cognitive control, emotional regulation, and executive functions. In the current exploratory study, we performed a comprehensive profiling of 72 cytokines, chemokines and growth factors in well-characterized vmPFC samples from 34 depressed suicides and 14 matched sudden-death controls. A human antibody array (RayBio®, chemiluminescent detection) was used to measure all markers. In depressed suicide samples, no significant increase in any cytokine, chemokine or growth factor was detected compared to controls. In comparison, in an independent cohort we measured the levels of 43 inflammatory markers in plasma samples from 141 depressed living subjects and 36 controls using the Mesoscale Discovery V-plex assay. Our analyses indicated no significant difference in the levels of pro- or anti-inflammatory markers in the plasma of cases vs controls. We also conducted a detailed morphological analysis of Iba1-immunostained microglia in vmPFC gray matter samples from 28 depressed suicides and 13 healthy controls. The distributions of the various morphological phenotypes assessed were similar between groups, suggesting that microglia/macrophages do not display signs of morphological changes in the vmPFC of depressed suicides. Taken together, these complementary experiments do not provide evidence of depression-associated neuroinflammatory changes in the vmPFC, at least in the samples analyzed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41935494,

title = {The association between body mass index and treatment outcomes in major depressive disorder: a CAN-BIND-1 study},

author = {Helena K Kim and Brett D M Jones and Margaret K Hahn and Sri Mahavir Agarwal and Faranak Farzan and Benicio N Frey and Sidney H Kennedy and Jane A Foster and Raymond W Lam and Roumen Milev and Daniel J Müller and Sagar V Parikh and Claudio N Soares and Valerie H Taylor and Gustavo Turecki and Rudolf Uher and Stefan Kloiber},

doi = {10.1016/j.jpsychires.2026.03.036},

issn = {1879-1379},

year  = {2026},

date = {2026-07-01},

journal = {J Psychiatr Res},

volume = {198},

pages = {252--256},

abstract = {Being overweight is commonly observed in patients with major depressive disorder (MDD). However, the relationship between body weight and treatment outcomes in MDD is less clear. In this context, we examined the association between BMI and treatment outcomes in patients treated with escitalopram with and without adjunctive aripiprazole. We tested this association using data from the Canadian Biomarker Integration Network in Depression-1 (CAN-BIND-1). The sample consisted of 180 participants who were treated with escitalopram for 8 weeks, followed by 8 more weeks of treatment with escitalopram alone (for responders) or escitalopram plus aripiprazole (for non-responders). Punishment/reward sensitivity and physical activity were also explored. Logistic regression analysis was used to examine the association between BMI, being overweight, and treatment response or remission after 8 or 16 weeks of treatment. BMI, being overweight, physical activity, behavioral inhibition, and behavioral activation were not associated with treatment outcomes. We also reviewed the recent literature on BMI, obesity, and antidepressant treatment outcomes, which showed mixed findings. Our results, which showed a lack of association between BMI and treatment outcomes, add to this complexity of the relationship between body weight and treatment outcomes in MDD. Larger studies with more diverse samples are needed to validate these results.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42064576,

title = {Alterations of microRNAs across human and mouse limbic brain areas: molecular mechanisms and biological processes involved in major depressive disorder},

author = {Samantha Saleri and Moira Marizzoni and Patrizia Genini and Chiara Galbiati and Annamaria Cattaneo and Gustavo Turecki and Henning Grosskopf and Petra Steinacker and Markus Otto and Giulia Poggi and Christopher R Pryce and Naguib Mechawar and Nadia Cattane},

doi = {10.1016/j.ynstr.2026.100816},

issn = {2352-2895},

year  = {2026},

date = {2026-06-01},

journal = {Neurobiol Stress},

volume = {42},

pages = {100816},

abstract = {The etiology of major depressive disorder (MDD) is multifactorial with both genetic and environmental factors, such as adverse/stressful life events, contributing to risk. There is some evidence suggesting that microRNAs (miRNAs) mediate environmental-genetic interaction leading to the brain dysfunctions that underlie MDD. However, changes in miRNAs expression in human brain regions due to stress and associated with MDD are unclear. To increase the evidence in this regard, miRNA sequencing was performed on tissue samples of subgenual anterior cingulate cortex (sgACC) obtained from depressed patients and control subjects, as well on tissue samples of medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) from mice exposed to chronic social stress (CSS) and control animals. DESeq2 was applied to identify differentially expressed miRNAs (DEMs) and weighted co-expression network preservation analysis to uncover conserved molecular mechanisms between species. Finally, pathways obtained from DESeq2 and preservation analyses were overlapped to robustly identify MDD-related processes across bioinformatic approaches.Eighteen DEMs were identified in the human sgACC, 11 in the mPFC and 9 in the BLA of mice. The human sgACC DEMs were involved mainly in intracellular signaling and immune system-related pathways. The mouse mPFC and BLA DEMs were mainly involved in, respectively, intracellular signaling and nervous system functions. Preservation patterns between humans and mice indicated an over-representation of processes related to cellular signaling. Transcriptional regulation by MECP2 and Protein Kinase A signaling were the two pathways consistently altered across species, brain regions, and bioinformatic approaches. Although further studies are needed, they could represent a novel target for intervention strategies and confirm the dysregulation of intracellular signaling, immune, neuronal and synaptic functions in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42162419,

title = {Dopamine drives persistent remodelling of the maternal brain},

author = {Jennifer C O'Chan and Giuseppina Di Salvo and Ashley M Cunningham and Sohini Dutta and Elizabeth Brindley and Benjamin H Weekley and Winnie Chen and Rasika R Iyer and Ethan Wan and Cindy Zhang and Naguib Mechawar and Gustavo Turecki and Ian Maze},

doi = {10.1038/s41586-026-10509-4},

issn = {1476-4687},

year  = {2026},

date = {2026-05-01},

journal = {Nature},

abstract = {Pregnancy and postpartum experiences represent transformative physiological states that impose lasting demands on the maternal body and brain, resulting in lifelong neural adaptations. However, the precise molecular mechanisms that drive these persistent alterations remain poorly understood. Here we used brain-wide transcriptomic profiling to define the molecular landscape of neuroplasticity induced by reproductive experience, identifying the dorsal hippocampal formation (dHF) as a key site of transcriptional remodelling. Combining single-cell RNA sequencing with a maternal-pup separation paradigm, we additionally found that chronic postpartum stress significantly disrupts dHF adaptations by altering dopamine dynamics, leading to changes in the dopamine-dependent histone post-translational modification, H3 dopaminylation, which causally mediates downstream alterations in gene expression and behaviour. In human dorsal subiculum, a brain structure within the dHF, we uncovered conserved patterns of parity-dependent alterations in H3 dopaminylation and transcription. We further established the sufficiency of dopamine modulation in regulating these adaptations via chemogenetic suppression of dopamine release into the dHF, which recapitulated key epigenomic and behavioural features of reproductive experience in virgin female mice. In sum, our findings establish dopamine as a central regulator of parity-induced neuroadaptations in humans and mice, revealing a fundamental transcriptional mechanism by which female reproductive experience remodels the brain to sustain long-term behavioural adaptations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42127906,

title = {Traumatic life experiences during critical periods lead to diverse developmental trajectories},

author = {Giovanni Morelli and Greta Visintin and Elisa Gelli and Angelo Serani and Martina Bartolucci and Sara Uccella and Maria D'Apruzzo and Deborah Preiti and Mariam Marie Chellali and Alessandra Cucinelli and Mohit Rastogi and Matteo Falappa and Andrea Scalabrini and Gustavo Turecki and Andrea Petretto and Valter Tucci and Laura Cancedda},

doi = {10.1016/j.xcrm.2026.102798},

issn = {2666-3791},

year  = {2026},

date = {2026-05-01},

journal = {Cell Rep Med},

pages = {102798},

abstract = {Traumatic events can disrupt neurodevelopment, increasing the risk for neuropsychiatric disorders. However, the relationships between specific types of traumas and the emergence of particular neuropsychiatric traits remain elusive. Here, we examine the long-term consequences of different life-threatening events experienced during four distinct developmental periods in mice. Our findings at the behavioral and molecular/cellular levels in adulthood suggest a crucial role for timing (rather than type) of stress during development in shaping long-term outcomes. Our parallel analysis of individuals exposed to trauma at diverse life stages reveals similar results. Finally, our proteomic data suggest the brain-derived neurotrophic factor (BDNF)-pathway as a promising therapeutic target for ameliorating psychopathology related to trauma experienced specifically in early adulthood in mice and potentially in individuals. Our results point to the existence of critical periods for trauma exposure that uniquely influence adult behavioral outcomes and induce time-specific molecular/cellular patterns in the brain, which may have therapeutic implications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42082796,

title = {Characterizing neuronal cell bodies in white matter tracts of the human brain},

author = {Drew VanderBerg and Kelly Perlman and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1007/s00429-026-03112-w},

issn = {1863-2661},

year  = {2026},

date = {2026-05-01},

journal = {Brain Struct Funct},

volume = {231},

number = {5},

abstract = {Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders.},

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{pmid42003427,

title = {A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations},

author = {Kelly Perlman and Chuck T Chen and Mackenzie E Smith and John Kim and Gustavo Turecki and Richard P Bazinet and Naguib Mechawar},

doi = {10.1111/jnc.70428},

issn = {1471-4159},

year  = {2026},

date = {2026-04-01},

journal = {J Neurochem},

volume = {170},

number = {4},

pages = {e70428},

abstract = {The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditions such as aging, epilepsy, and the vulnerability to psychopathology posed by a history of childhood abuse (CA). Since the myelin sheath is highly enriched in lipids, changes in white matter (WM) microstructure observed via neuroimaging may reflect alterations in the myelin lipid profile. Given that the UF does not exist in rodents, its molecular properties are highly understudied. Therefore, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and evaluate any lipid-related or myelin-constituent gene/protein changes associated with age and history of CA. UF samples were analyzed from individuals with depression who died by suicide with (DS-CA) or without (DS) severe CA, and control individuals (CTRL), with an age span of 15 to 85 years. Phospholipids were separated by thin-layer chromatography; FAs and nonderivatized cholesterol were quantified by gas chromatography-flame ionization detection. The relative expression of myelin-constituent genes and proteins was measured by RT-qPCR and immunoblotting, respectively. We found no robust relationships between CA or depression and lipid measures or myelin-constituent gene/protein levels. In contrast, phospholipids showed pronounced age effects that differed by fraction, with an overall trend of monounsaturated FAs increasing and long-chain omega-6 polyunsaturated FAs decreasing with age. The expression of most myelin-constituent genes and proteins declined with age; PLP1 and MAG showed significant decreases. Therefore, changes in lipid composition and lipid-protein interactions likely contribute to age-related myelin deficits and may in part underlie age-associated cognitive decline.},

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{pmid41670991,

title = {One-Year Actigraphy Study of Sleep and Rest-Activity Rhythms as Markers of Relapse in Depression},

author = {Andre C Tonon and Adile Nexha and Jasmyn E A Cunningham and Jason d'Eon and Trisha Chakrabarty and Faranak Farzan and Jane A Foster and Kate L Harkness and Stefanie Hassel and Keith Ho and Raymond W Lam and Roumen Milev and Luciano Minuzzi and Daniel J Müller and Abraham Nunes and Sagar V Parikh and Lena C Quilty and Susan Rotzinger and Claudio N Soares and Valerie H Taylor and Gustavo Turecki and Rudolf Uher and Sidney H Kennedy and Benicio N Frey},

doi = {10.1001/jamapsychiatry.2025.4453},

issn = {2168-6238},

year  = {2026},

date = {2026-04-01},

journal = {JAMA Psychiatry},

volume = {83},

number = {4},

pages = {379--388},

abstract = {IMPORTANCE: Given its recurrent nature and burden, major depressive disorder (MDD) warrants reliable methods of relapse prediction.nnOBJECTIVE: To determine whether actigraphy-derived parameters, measured over 1 to 2 years, are associated with relapse.nnDESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study with data collection from July 2016 to January 2019. The setting was multicentric. A referred sample of participants from outpatient psychiatric and primary care clinics across Canada were followed up for 1 to 2 years. Participants had a diagnosis of MDD and Montgomery-Åsberg Depression Rating Scale (MADRS) score less than or equal to 14 at baseline.nnEXPOSURES: Actigraphy-derived parameters measured over 1 to 2 years.nnMAIN OUTCOME AND MEASURES: The primary outcome was relapse, defined as any of the following: MADRS score greater than or equal to 22 for 2 consecutive weeks, psychiatric hospitalization, emergence of suicidal intent or behavior, or antidepressant treatment escalation-all adjudicated by an independent panel. Continuous actigraphy data were averaged every 2 weeks.nnRESULTS: From a referred sample of 102 adults, 93 participants (mean [SD] age, 39.1 [12.7] years; 58 female [62%]) contributed approximately 32 000 complete actigraphy days (median, 46 weeks). In Cox models adjusted for age, sex, season, and baseline MADRS score, baseline lower sleep regularity (hazard ratio [HR], 0.46; 95% CI, 0.28-0.74; P = .002), lower relative amplitude (RA; HR, 0.45; 95% CI, 0.29-0.70; P < .001), lower sleep efficiency (HR, 0.57; 95% CI, 0.38-0.85; P = .005), higher wake after sleep onset (HR, 1.77; 95% CI, 1.12-2.80; P = .01), and higher nighttime activity (HR, 1.86; 95% CI, 1.32-2.62; P < .001) were associated with relapse. In time-varying models, greater composite phase deviation (HR, 1.76; 95% CI, 1.04-2.98; P = .04) and lower RA (HR, 0.45; 95% CI, 0.21-0.97; P = .046) were associated with relapse, with RA remaining significant even after adjusting for concurrent MADRS scores (HR, 0.60; 95% CI, 0.36-0.98; P = .04). Actigraphy significantly differentiated individuals experiencing relapse from those with an ultrastable (MADRS score <14 throughout) and unstable (transient MADRS score, 14-22 without relapse) clinical course.nnCONCLUSIONS AND RELEVANCE: Actigraphy measures of sleep phase variability and daily activity amplitude were associated with depressive relapse, supporting actigraphy as a potential scalable biomarker to identify high-risk individuals and enable timely, personalized relapse prevention in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41452049,

title = {Modulation of Brain Temporal Complexity During Treatment for Depression: A CAN-BIND-1 Study Report: Modulation de la complexité temporelle du cerveau pendant le traitement de la dépression: rapport de l'étude CAN-BIND-1},

author = {Chloé Stengel and Benjamin Schwartzmann and Raaj Chatterjee and Sravya Atluri and Yasaman Vaghei and Stephen R Arnott and Pierre Blier and Prabhjot Dhami and Jane A Foster and Benicio N Frey and Raymond W Lam and Roumen Milev and Daniel J Müller and Sagar V Parikh and Claudio N Soares and Rudolf Uher and Gustavo Turecki and Susan Rotzinger and Sidney H Kennedy and Faranak Farzan},

doi = {10.1177/07067437251408188},

issn = {1497-0015},

year  = {2026},

date = {2026-03-01},

journal = {Can J Psychiatry},

volume = {71},

number = {3},

pages = {185--198},

abstract = {ObjectivesCurrent pharmacological antidepressant treatments suffer from low remission rates and slow initiation of therapeutic effects. In addition, the development of new antidepressant treatments is confounded by the lack of consensus on efficient and valid neurophysiological targets. Temporal complexity is an alternative measure of dynamic brain activity that estimates brain signal variability at several timescales. It can be easily extracted from non-invasive brain recordings and provides new insights into pathophysiological mechanisms. We aim to assess the potential of brain temporal complexity as a novel neuromarker to predict the effectiveness of antidepressant treatments.MethodWe measured longitudinal changes in temporal complexity of electroencephalography signals in patients undergoing 8 weeks of escitalopram treatment through a Canadian Biomarker Integration Network in Depression (CAN-BIND) trial.ResultsAs early as 2 weeks after the start of treatment, reduction of complexity in fine timescales was associated with improvement in depressive symptoms. After 8 weeks of treatment, the treatment-related effect shifted towards an increase in coarse timescale complexity, linked to symptom improvement.ConclusionsThese results suggest a relative shift away from local, segregated information processing, measured by complexity at fine timescales, in the short term, potentially in favour of a higher long-range communication across networks, as indicated by higher complexity measures at coarse timescales in the long term. Further research into the modulation of multiscale temporal complexity by antidepressant treatments could open new possibilities for faster-acting and more efficient treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41509590,

title = {Socioeconomic Status Is Associated With Reward Processing, Interleukin 1β, Striatal Connectivity, and Antidepressant Outcomes in Individuals With Major Depressive Disorder: A CAN-BIND-1 Report},

author = {Sara Jani and Stefanie Hassel and Jane A Foster and Gustavo Turecki and Nicholas Bock and Nathan Churchill and Daniel J Mueller and Raymond W Lam and Valerie H Taylor and Roumen Milev and Claudio Soares and Susan Rotzinger and Sakina J Rizvi and Sidney H Kennedy and Benicio N Frey and Katharine Dunlop},

doi = {10.1016/j.bpsgos.2025.100649},

issn = {2667-1743},

year  = {2026},

date = {2026-03-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {6},

number = {2},

pages = {100649},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a common condition with heterogeneous risk factors. Socioeconomic status (SES) is one such risk factor, which is negatively linked to MDD treatment outcomes and symptom severity. SES is associated with altered resting-state functional connectivity (RSFC) in reward-processing circuitry and elevated proinflammatory cytokine levels in individuals without depression. However, how the negative consequences of low SES exacerbate MDD psychopathology is poorly understood.nnMETHODS: Data on SES (household income and education), depression severity, self-reported reward processing, serum proinflammatory cytokine levels, and neuroimaging for 323 adult participants (211 patients with MDD receiving open-label escitalopram, 112 control participants without depression; 63.4% female) were obtained from the CAN-BIND-1 (Canadian Biomarker Integration in Depression Study-1) dataset. General linear models assessed the effects of MDD diagnosis and SES on self-reported reward processing and proinflammatory cytokine levels. Whole-brain seed-to-voxel RSFC analyses were performed for the dorsal and ventral striatum leveraging 249 participants (150 patients with MDD, 99 control participants; 62.2% female). We also assessed the impact of SES on response to open-label escitalopram.nnRESULTS: Participants with MDD from households with lower incomes displayed lower goal pursuit behaviors, decreased interleukin 1β levels, and slower improvement to escitalopram relative to those from households with higher incomes. Using a lenient  > 2.3 threshold, MDD household income correlated with striatal RSFC with the dorsolateral prefrontal and posterior cingulate cortices.nnCONCLUSIONS: Our results elucidate the role of SES and its negative consequences in altering reward processing and antidepressant treatment efficacy in MDD, corroborating previous literature suggesting that SES significantly impacts health outcomes. Better characterizing the relationship between SES and MDD psychopathology may inform future treatment approaches and intervention development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41663375,

title = {Cerebellar astrocytic alterations in depression},

author = {Christa Hercher and Gina Abajian and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1038/s41398-026-03866-1},

issn = {2158-3188},

year  = {2026},

date = {2026-02-01},

journal = {Transl Psychiatry},

volume = {16},

number = {1},

abstract = {Accumulating evidence suggests dysfunction of cerebellar-cerebral circuits in depression. However, the potential cellular and molecular alterations associated with depression in the cerebellum remain largely uncharacterized. While postmortem findings in the cerebral cortex indicate astrocyte dysregulation in depressed individuals who died by suicide (DS), the extent to which depression potentially alters cerebellar astrocytes is not well understood. In this study, two canonical astrocyte markers, glial fibrillary acidic protein (GFAP) and aldehyde Dehydrogenase-1 Family member L1 (ALDH1L1) were used to quantify cerebellar astrocyte subtypes, Bergmann glia (BG) in the Purkinje cell layer (PCL), velate astrocytes in the granule cell layer (GCL), and fibrous astrocytes in the white matter (WM). Purkinje cells (PCs) were also quantified due to their close association with BG. To assess potential dysregulation of astrocyte communication, we examined connexins, channel proteins essential in forming a functional network between astrocytes. Astrocytic connexins were visualized using single molecule in situ hybridization targeting connexin 30 (Cx30) and connexin 43 (Cx43), followed by immunolabeling for ALDH1L1. Our analysis revealed significant increases in ALDH1L1+ astrocyte densities in DS specific to the PCL compared to control individuals. Astrocytic connexins were significantly downregulated in DS, with Cx43 showing marked reductions in both PCL and GCL. Overall, our findings suggest that BG in the PCL and velate astrocytes in the GCL are particularly vulnerable in the depressive phenotype. Furthermore, this study supports previous findings in the cerebral cortex and extends astrocytic dysfunction to the cerebellum suggesting a widespread disruption of astrocyte-mediated communication across the brain in depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41654494,

title = {The Habenula's role in major depressive disorder: recent insights from preclinical and human studies},

author = {Feiteng Lin and Kayleigh Casmey and Sierra A Codeluppi-Arrowsmith and Gustavo Turecki},

doi = {10.1038/s41398-026-03867-0},

issn = {2158-3188},

year  = {2026},

date = {2026-02-01},

journal = {Transl Psychiatry},

volume = {16},

number = {1},

abstract = {The habenula is a small epithalamic structure composed of two distinct subregions, the medial (MHb) and lateral (LHb) habenula. It serves as a critical hub for integrating fronto-limbic and brainstem signals to regulate motivation, mood, and reward processing. Therefore, it is unsurprising that dysfunction of the habenula has been implicated in several mood disorders including major depressive disorder (MDD), a debilitating mood disorder marked by low mood and feelings of hopelessness. This review synthesizes recent advances in understanding the habenula's neurocircuitry, molecular landscape, and role in MDD pathophysiology, while evaluating its potential as a therapeutic target. Specifically, emerging evidence highlights subregion-specific pathology. Indeed, in MDD and in animal models of depression, the MHb has been shown to exhibit marked downregulation of calcium-dependent activator protein for secretion 2 (CAPS2) and deficits in nicotinic acetylcholine receptor-mediated signaling. While in the LHb, dysregulated expression profiles of inward-rectifying potassium channel Kir4.1, the β isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIβ), protein phosphatase 2 A (PP2A), and small nucleolar RNA SNORA69 have been found in animal models of depression and MDD postmortem studies. Structural imaging and postmortem neurohistological studies in MDD patients have further revealed habenular volume changes, reduced neuronal cell counts, diminished cell area, and abnormal functional connectivity. As research unravels the habenula's complexities, its potential in treating mood disorders grows increasingly salient, offering new avenues for intervention in mental health.},

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{pmid42475341,

title = {Early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter predicts cognitive functions at age five: Evidence from the Parents as Teachers intervention in the ZEPPELIN study},

author = {Elena Silvia Gardini and Alex Neuhauser and Simone Schaub and Isabelle Kalkusch and Patsawee Rodcharoen and Ulrike Ehlert and Andrea Lanfranchi and Gustavo Turecki and Peter Klaver},

doi = {10.1371/journal.pone.0344401},

issn = {1932-6203},

year  = {2026},

date = {2026-01-01},

journal = {PLoS One},

volume = {21},

number = {7},

pages = {e0344401},

abstract = {BACKGROUND: The present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions.nnMETHODS: Participants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples collected at age three using sodium bisulfite next-generation sequencing (NGS). Cognitive functions were assessed at age five using the SON-R 2.5-7 Intelligence Test.nnRESULTS: (a) DNA methylation at age three was associated with lower IQ at age five through increased concentration problems (indirect effect = -0.083, p = .012); (b) parental disagreement was associated with concentration difficulties through DNA methylation (indirect effect = 0.064, p = .023); and (c) participation in the three-year PAT program was associated with lower methylation levels (β = -0.375, p = .041). The serial pathway from parental disagreement to IQ via methylation and concentration was not significant.nnCONCLUSIONS: These findings provide preliminary evidence for an association between early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter and later cognitive functions in children and highlight the potential role of early life stressors and the PAT intervention in shaping these associations. However, given the exploratory nature of this study, replication in larger independent samples is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}