Transl Psychiatry [JOURNAL]
Sun
200 papers
Associations of modifiable risk factors with depression and anxiety in women and men: evidence from the UK Biobank.
Luo Z, Sun W, Shan S … +3 more , Wu J, Zhu Y, Song P
Transl Psychiatry · 2026 Jun · PMID 42331785 · Publisher ↗
Depression and anxiety are common mental disorders with substantial public health burden, yet the relative contributions of potentially modifiable physiological, psychosocial, and female-specific reproductive factors to...
Depression and anxiety are common mental disorders with substantial public health burden, yet the relative contributions of potentially modifiable physiological, psychosocial, and female-specific reproductive factors to their development remain incompletely understood, particularly across sex and age groups. We aimed to examine the associations of these factors with incident depression and anxiety in women and men and to estimate their population attributable fractions (PAFs). This prospective cohort study included 87,648 participants from the UK Biobank (44,383 women and 43,265 men) recruited between 2006 and 2010 and followed for a median of 13.7 years. Incident depression and anxiety were defined as the first recorded ICD-10 diagnosis or new-onset symptom positivity during follow-up among participants free of the respective condition at baseline. Sex-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and individual and combined PAFs were calculated separately in women and men. During follow-up, 5.65% of women and 4.21% of men developed depression, while 6.02% and 3.60% developed anxiety, respectively. Psychosocial factors contributed the largest population burden in both sexes. Neuroticism symptoms had the largest PAFs for depression (women: HR 2.61, 95% CI: 2.36, 2.88; PAF 48.61%, 95% CI: 44.71%, 52.68%; men: HR 3.50, 95% CI: 3.07, 3.98; PAF 59.93%, 95% CI: 55.41%, 64.13%) and anxiety (women: HR 2.82, 95% CI: 2.56, 3.11; PAF 51.75%, 95% CI: 47.93%, 55.68%; men: HR 2.94, 95% CI: 2.58, 3.36; PAF 53.80%, 95% CI: 48.89%, 58.62%). The additive combined PAF of psychosocial factors was 61.17% in women and 66.90% in men for depression, and 59.98% and 56.80% for anxiety. Among physiological factors, obesity contributed the largest PAF for depression in both sexes, while chronic inflammation was associated with both outcomes in both sexes. In women, reproductive factors provided additional contributions, with hormone replacement therapy showing the largest PAFs for depression (HR 1.48, 95% CI: 1.34, 1.62; PAF 13.43%, 95% CI: 10.15%, 16.84%) and anxiety (HR 1.32, 95% CI: 1.20, 1.44; PAF 9.43%, 95% CI: 6.38%, 12.80%). Age-stratified analyses showed that psychosocial contributions remained substantial across age groups, whereas physiological and reproductive contributions were more pronounced in later life. When all factors were considered jointly, the overall additive combined PAFs were 67.54% in women and 69.71% in men for depression, and 61.23% and 57.82% for anxiety. These findings support sex-informed and life course-oriented prevention strategies for depression and anxiety.
Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.
Gao TL, Geng S, Chen J … +4 more , Yang L, Nie YJ, Yu H, Chai GS
Transl Psychiatry · 2026 Jun · PMID 42331779 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless,...
Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.
A scoping review of the use of artificial intelligence as a psychological assessment tool.
Dev V, Consedine NS, Gao Y … +2 more , Narayanasamy R, Serlachius A
Transl Psychiatry · 2026 Jun · PMID 42331776 · Publisher ↗
Mental health disorders are highly prevalent worldwide, yet access to timely and effective mental health assessment (and care) remains limited. Artificial intelligence (AI) offers potential solutions, but the literature...
Mental health disorders are highly prevalent worldwide, yet access to timely and effective mental health assessment (and care) remains limited. Artificial intelligence (AI) offers potential solutions, but the literature on its use in psychological assessment contexts has not been comprehensively mapped. This review aimed to systematise existing research, identify gaps, evaluate methodological limitations, and outline future directions. Using a librarian-approved search strategy, 7595 records were retrieved from major databases and screened independently by two coders. Following the eligibility assessment, 320 peer-reviewed articles were included. Studies showed wide variability in sample sizes (1-19,400,000) with no clear temporal trend. Most recruited clinical (21%) or general population (16%) samples from China (24%) or the United States (21%), and focused on depression (54%), anxiety (14%), suicidality (12%) or stress (8%). Supervised (75%) and deep learning (47%) approaches predominated, often with multiple algorithms compared (77% of the studies). Validation commonly relied on cross-validation and convergence with screening instruments, with relatively little use of DSM or ICD diagnostic criteria (71% used neither). Area-Under-the-Receiver-Operating-Characteristics-Curve (AUC) was the most frequently used performance metric, and unsupervised models achieved the highest average AUC. A marginal improvement in performance was evident from 2014 to 2025. Overall, AI shows promise as a psychological assessment tool, but progress is constrained by limited transparency, heavy reliance on self-report data, inconsistent use of validated diagnostic standards, a narrow focus on outcomes, and insufficient demographic and cultural analyses. Future research should prioritise interpretability, ethical and cultural responsiveness, multi-modal data, diverse samples, and clinically meaningful validation.
Postmortem brain single-nucleus and bulk gene expression analyses identify shared and distinct abnormalities in bipolar disorder and major depressive disorder.
Gao R, Otsuka I, Shirai T … +7 more , Miyachi M, Minami K, Okada S, Tsukamoto R, Tanifuji T, Okazaki S, Hishimoto A
Transl Psychiatry · 2026 Jun · PMID 42324251 · Publisher ↗
Bipolar disorder (BD) and major depressive disorder (MDD) are severe and chronic mood disorders which impairs the psychosocial functioning of patients. Besides manic or hypomanic episodes, many patients with BD also expe...
Bipolar disorder (BD) and major depressive disorder (MDD) are severe and chronic mood disorders which impairs the psychosocial functioning of patients. Besides manic or hypomanic episodes, many patients with BD also experience depressive episodes similar to those seen in MDD, suggesting the similarities and differences between the two diseases. However, the shared and distinct abnormalities of gene expression and cellular function in the brain underlying the disorders remain to be elucidated. Here we analyzed publicly available single-nucleus and bulk RNA expression datasets of postmortem brain samples from BD patients, MDD patients, and healthy donors. For single-nucleus gene expression profiling of postmortem orbitofrontal cortex (OFC), differential abundance testing, differential gene expression analysis and gene set enrichment analysis performed on each cell type showed abnormal gene expression profiles in both neuronal and non-neuronal cells. Cell-cell communication inference revealed the dysfunction of parvalbumin interneurons, as well as enhanced interactions among certain subtypes of neurons, in both diseases. Gene co-expression network analysis identified the overall alterations in both diseases, as well as the differences in co-expression modules between BD and MDD. Compared to MDD, most neurons in BD exhibited particularly downregulated expression of modules related to translation and mitochondrial ATP production. Transcription factor network analysis revealed the regulatory relationships among the modules. Further analyses of two additional datasets supported the main findings of the postmortem OFC analyses. Overall, our findings clarified the molecular mechanisms underlying BD and MDD, which highlight distinct molecular pathways that may inform therapeutic strategies for mood disorders.
Associations of stable psychological traits with multi-omic subtypes of Alzheimer's dementia.
Zammit AR, Yu L, Poole VN … +9 more , Tasaki S, Vialle R, Arfanakis K, Schneider JA, Petyuk VA, De Jager PL, Kaddurah-Daouk R, Iturria-Medina Y, Bennett DA
Transl Psychiatry · 2026 Jun · PMID 42324246 · Publisher ↗
Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biological mechanisms remain largely unknown. Using multi-omic da...
Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biological mechanisms remain largely unknown. Using multi-omic data from the dorsolateral prefrontal cortex of 822 decedents in the Religious Orders Study and Rush Memory and Aging Project, we utilized a previously derived multi-omic brain molecular pseudotime representing molecular distance from no cognitive impairment (NCI) to AD dementia, and three distinct multi-omic brain molecular subtypes of AD dementia. We first confirmed generalizability of pseudotime and subtypes in two independent samples. We then annotated the subtypes, and explored whether they differed by neuropathologic burden, brain morphology or genetic risk, and found that while these indices differentiated all subtypes from NCI they did not differentiate amongst them. Finally, we tested for differential associations between the psychological traits and the subtypes, adjusting first for age, sex, education, and time to death, and then additionally for 9 common AD and Related Dementias pathologies. We found that in fully adjusted models, neuroticism, loneliness and purpose in life remained differentially associated with some AD subtypes relative to NCI. Our results are consistent with a two-stage model in which (i) upstream genetic risk influences overall disease liability, while (ii) intermediary psychological predispositions align more directly with subtype differentiation capturing AD-related heterogeneity not explained by neuropathology or brain atrophy. These results indicate that psychological risk factors may be associated with AD dementia via multi-omic molecular pathways, predominantly informed by metabolomic dysregulation, capturing heterogeneity not explained by neuropathology.
Hydrogen sulfide mitigates spatial learning deficits in angiotensin II-Induced hypertension via inhibition of endothelial NOX2 and neuroinflammation.
Kumar G, Mishra S, Goswami S … +1 more , Sharma M
Transl Psychiatry · 2026 Jun · PMID 42323339 · Publisher ↗
Hypertension (HTN), when prolonged, extends beyond the cardiovascular system, impairs neurovascular function, and progresses into cognitive impairment. Thus, it is essential to understand the mechanism that drives HTN-in...
Hypertension (HTN), when prolonged, extends beyond the cardiovascular system, impairs neurovascular function, and progresses into cognitive impairment. Thus, it is essential to understand the mechanism that drives HTN-induced brain pathogenesis for devising novel therapy. This study explored spatial learning, vessels-associated microglia and neuroinflammation during angiotensin II (Ang II) induced HTN with the hypothesis that after HTN induction, endogenous HS level contributes to neuropathology in HTN. Male Sprague Dawley rats received Ang II (600 ng/kg/min) or saline using an implanted osmotic pump, and NaHS (4 mg/kg), an HS donor was given intraperitoneally 10 days prior and during Ang II infusion. We employed HS estimation by amperometric probe, spatial learning was assessed through the Morris water maze task, and synaptic proteins were probed in a synaptosomal fraction of hippocampus homogenate using Western blot. Additionally, rat cytokine array and immunofluorescence were used to screen for chemokine and cytokine, and the endothelium microglial phenotype, respectively. The pretreatment of NaHS attenuated Ang II-induced spatial learning and perturbation of synaptic protein in the hippocampus. It is associated with significant reduction in endothelial activation and microglia pro-inflammatory phenotype in both parenchymal and vessel-associated microglia. Moreover, above observation is accompanied by decreased proinflammatory cytokines and chemokines, such as, TNF-α, MCP-1, VEGF, and IL-1ɑ, among others. In summary, our data demonstrated that maintenance of HS level attenuated HTN induced spatial learning deficit by suppressing neuroinflammation and endothelial NOX2 expression. Therefore, reinforcing the role of HS in alleviating oxidant-induced inflammatory injury and eventually maintaining brain function.
Impact of NRSN2 deficiency on memory: Altered excitatory synaptic plasticity associated with reduced expression of NMDA receptor subunits and impaired LTP in the hippocampus.
Wei J, Wu Y, Yi Y … +6 more , Gan Y, Li H, Wang L, Shen Y, Dong Y, An Y
Transl Psychiatry · 2026 Jun · PMID 42323322 · Publisher ↗
Our earlier human studies identified NRSN2 (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of NRSN2 deficiency in th...
Our earlier human studies identified NRSN2 (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of NRSN2 deficiency in the nervous system remain poorly understood. To explore the role of Nrsn2 in neurodevelopment and cognitive function, we utilized previously generated homozygous Nrsn2 knockout mice (Nrsn2) and performed a series of behavioral, morphological, and electrophysiological analyses. Behaviorally, Nrsn2 mice exhibited mild locomotor impairment, as assessed by gait analysis at 4 and 8 weeks of age, as well as significant deficits in spatial learning and memory (Morris water maze) and fear memory (passive avoidance test) at 8 weeks. Morphometric analysis suggested no overt alterations in dendritic complexity or spine density in hippocampal CA1 pyramidal neurons or cerebellar Purkinje cells without developmental malformation. Electrophysiological recordings and immunoblotting analyses may reflect region-specific synaptic alterations. In the hippocampus, expression levels of the NMDA receptor subunits GluN1 and GluN2A were reduced at 4 weeks of age. Consistently, CA1 pyramidal neurons displayed decreased sEPSC frequency with unchanged amplitude under the conditions examined. In addition, an imbalance in hippocampal excitatory/inhibitory transmission was observed, as reflected by altered sEPSC frequency in the absence of changes in sIPSC frequency. In cerebellar Purkinje cells, GluA1-containing AMPA receptors were selectively downregulated, accompanied by reduced frequency and amplitude of sEPSCs and a selective decrease in sIPSC frequency, indicating both excitatory and inhibitory synaptic dysfunction in this region. Collectively, these findings indicate that Nrsn2 deficiency is accompanied by altered excitatory synaptic transmission and reduced long-term potentiation (LTP) at 8 weeks of age, despite preserved dendritic architecture as assessed by Golgi staining. These synaptic and plasticity deficits occur alongside the observed cognitive and motor impairments in Nrsn2 mice. This study provides a descriptive phenotypic characterization of Nrsn2 deficiency and offers initial insights into the neurobiological role of NRSN2 and its contribution to neurodevelopment, learning, and memory.
Rethinking EEG biomarkers of brain disorders: a transdiagnostic dimensional view.
Zebhauser PT, Heitmann H, Henningsen P … +1 more , Ploner M
Transl Psychiatry · 2026 Jun · PMID 42323306 · Full text
Developing clinically useful brain-based biomarkers remains a central challenge in translational psychiatry and neurology. Traditional approaches focusing on disorder-specific signals have shown limited clinical utility....
Developing clinically useful brain-based biomarkers remains a central challenge in translational psychiatry and neurology. Traditional approaches focusing on disorder-specific signals have shown limited clinical utility. EEG, a scalable and non-invasive measure of brain function, illustrates the value of an alternative perspective: transdiagnostic and dimensional biomarker development. Here, we use low-frequency activity (LFA) as an illustrative example to demonstrate this framework. We synthesize evidence from 176 EEG studies across chronic pain, migraine, fatigue, and depression and identify increased low-frequency activity (LFA) as the most consistent alteration across studies. Crucially, this absence of disorder specificity does not diminish its clinical value. Instead, it points to shared neural dysfunction, consistent with frameworks of thalamo-cortical dysrhythmia and excitation-inhibition imbalance. These processes may underlie shared symptom dimensions, such as negative affect, cognitive dysfunction, and somatic manifestations. Accordingly, such transdiagnostic, dimensional markers could support prevention, monitoring, stratification, and neuromodulation across disorders, exemplifying precision neuroscience via mechanistically grounded, clinically actionable biomarkers.
Vagus nerve-dependent antidepressant effects of ineupatorolide B via gut microbiota modulation in a mouse model of depression.
Wang S, Zhang Y, Wu N … +6 more , Wang S, Ma Y, Zhang W, Li G, Hashimoto K, Ni Z
Transl Psychiatry · 2026 Jun · PMID 42323297 · Publisher ↗
Ineupatorolide B (InB), a sesquiterpene lactone with anti-inflammatory and anti-tumor properties, has not previously been evaluated for antidepressant effects. Given the central role of the gut-brain axis in stress-relat...
Ineupatorolide B (InB), a sesquiterpene lactone with anti-inflammatory and anti-tumor properties, has not previously been evaluated for antidepressant effects. Given the central role of the gut-brain axis in stress-related mood disorders, we investigated whether InB alleviates depression-like phenotypes in mice exposed to chronic social defeat stress (CSDS) through microbiota- and vagus-dependent mechanisms. CSDS-susceptible mice received vehicle, fluoxetine, or InB and were assessed using behavioral paradigms, plasma inflammatory cytokine measurements, and analyses of synaptic-related protein expression in the medial prefrontal cortex (mPFC). CSDS induced robust depression-like behaviors, elevated interleukin-6 and tumor necrosis factor-α, caused splenomegaly, and reduced PSD-95 and BDNF expression in the mPFC. Repeated InB administration significantly reversed these behavioral, inflammatory, and synaptic abnormalities. 16S rRNA gene sequencing revealed that CSDS disrupted gut microbial α- and β-diversity, whereas InB treatment largely normalized these alterations and restored depression-associated short-chain fatty acids, including isobutyric and valeric acid, consistent with reestablishment of microbial metabolic homeostasis. Importantly, subdiaphragmatic vagotomy abolished the antidepressant-like, anti-inflammatory, and synaptic effects of InB, demonstrating that its efficacy requires intact vagus nerve-mediated gut-brain signaling. Together, these findings identify vagus-dependent modulation of the microbiota-immune-synaptic axis as a mechanistic pathway through which InB exerts antidepressant effects and highlight this compound as a potential microbiota-targeted therapeutic strategy for depression.
Mapping behavioural mechanisms linking childhood maltreatment, cognition, impulsivity, and suicidality in bipolar disorder: A network approach.
Fares-Otero NE, Iversen AE, Gutiérrez-Zotes A … +8 more , Zarp J, Jiménez E, Sánchez-Moreno J, Pomarol-Clotet E, Vieta E, Kjærstad HL, Vilella E, Miskowiak KW
Transl Psychiatry · 2026 Jun · PMID 42323292 · Full text
Childhood maltreatment (CM) has been consistently associated with increased risk and poorer outcomes in bipolar disorder (BD). However, the behavioural and cognitive mechanisms linking CM and suicidality remain poorly un...
Childhood maltreatment (CM) has been consistently associated with increased risk and poorer outcomes in bipolar disorder (BD). However, the behavioural and cognitive mechanisms linking CM and suicidality remain poorly understood, limiting the development of targeted preventive interventions. We estimated a regularised partial correlation network to explore the interplay between CM subtypes (emotional, physical, or sexual abuse; emotional and physical neglect), cognitive domains (attention/processing speed, executive function/working memory, socio-emotional cognition, decision-making), impulsivity traits (attentional, motor, non-planning), and suicidal behaviours (ideation, planning, attempts) in 249 euthymic individuals with BD (mean age = 46.14, SD = 8.60; 59.84% female; 71.89% BD type I). CM was assessed using the Childhood Trauma Questionnaire (CTQ), cognition with a comprehensive neuropsychological battery, impulsivity with the Barratt Impulsiveness Scale (BIS-11), and suicidality with the Columbia Suicide Severity Rating Scale (C-SSRS) and structured interview. Age, sex, and social desirability (CTQ minimisation/denial subscale) were included as covariates. CM was associated with both cognitive functioning (poorer executive function and working memory, attention/processing speed, and socio-emotional cognition) and suicidality (suicidal ideation and, to a lesser extent, suicide attempts). Emotional abuse was linked to suicidal ideation (strongest association among CM subtypes; r = 0.27, p <0.001) and showed the highest centrality within the network (strength z = 1.76; expected influence z = 1.95). All CM subtypes were associated with impulsivity traits. Motor impulsivity emerged as a behavioural bridge between CM and suicidality (bridge expected influence z = 0.21), whereas higher socio-emotional cognition, particularly the ability to manage emotions, was associated with fewer suicide attempts. These findings highlight specific cognitive and behavioural mechanisms linking CM and suicidality in BD. Emotional abuse and socio-emotional cognition represent promising targets for trauma-informed and personalised interventions.
A systematic narrative review of the form, process, and function of sensory hyposensitivity in depression.
Sharpley CF, Odierna GL, Bitsika V … +1 more , Watson CB
Transl Psychiatry · 2026 Jun · PMID 42321224 · Publisher ↗
As well as the key diagnostic symptoms that define Major Depressive Disorder (MDD), there is also evidence that some aspects of sensory sensitivity may decrease concurrently with MDD. However, although various individual...
As well as the key diagnostic symptoms that define Major Depressive Disorder (MDD), there is also evidence that some aspects of sensory sensitivity may decrease concurrently with MDD. However, although various individual studies have reported sensory hyposensitivity as a correlate of depression, most studies have focused upon single senses (i.e., vision, hearing, taste, touch, olfaction) and no comprehensive review of all five senses has been published to date. By applying a systematic narrative review methodology to identify research on loss of each these senses and their association with depression, a total of 51 individual studies and five reviews (of olfaction) were identified and examined for their methodology, major findings, and explanation of those findings. Following that summary of the form of sensory hyposensitivity, the neurobiological processes underlying it are described as being based in peripheral hyposensitivity or dysfunction of central cognitive processes. From these bases, an explanation is provided of how sensory hyposensitivity can be understood from the perspective of providing an 'escape' from a noxious environment, thus representing a functional benefit for the depressed individual. Translation of these findings to clinical practice, and avenues for future research, are described.
Blood IL-6 is a critical trigger of depressive symptoms in a mouse model for human atopic dermatitis.
Matsuda K, Muko R, Moon C … +12 more , Shin T, Arkwright PD, Pennock JL, Endo S, Yanai S, Jensen-Jarolim E, Shibuya A, Tominaga M, Takamori K, Oikawa MA, Tanaka A, Matsuda H
Transl Psychiatry · 2026 Jun · PMID 42321187 · Publisher ↗
Patients with atopic dermatitis (AD) often suffer from mental health issues such as depression. Crosstalk between proinflammatory cytokines and hippocampal circuits may be a potent risk factor for behavioral abnormalitie...
Patients with atopic dermatitis (AD) often suffer from mental health issues such as depression. Crosstalk between proinflammatory cytokines and hippocampal circuits may be a potent risk factor for behavioral abnormalities in depression, including anxiety, and mood disorders, which negatively controlled hippocampal neurogenesis via the upregulation of several proinflammatory cytokines. However, the mechanisms by which AD notably contribute to the development of depression are poorly understood. We found that increased IL-6 and soluble IL-6Rα (sIL-6Rα) in the peripheral blood specifically disrupted the blood-brain barrier and triggered depressive symptoms in NC/Tnd mice with spontaneous AD. The skin severity and depressive behavior correlated with markedly reduced numbers of doublecortin (DCX)-positive immature neurons in the hippocampus. Parabiotic pairs of mice with AD and unaffected mice showed disruption of hippocampal neurogenesis in the unaffected mice. Injection of neutralizing mAb against IL-6 significantly improved depressive behavioral signs and hippocampal neurogenesis. Furthermore, house dust mite-induced dermatitis gave rise to no depressive phenotypes in IL-6-deficient mice. Single-cell RNA sequencing analysis showed high expression of IL-6Rβ, unlike IL-6Rα, in hippocampal cells isolated from NC/Tnd mice. Addition of IL-6 and sIL-6Rα to neuronal progenitor cells cultured from the murine hippocampal dentate gyrus significantly reduced the number of DCX-positive cells, whereas IL-6 alone had no effect. Overall, these findings suggest that increased peripheral blood IL-6 and sIL-6Rα following atopic inflammation inhibits hippocampal immature neurogenesis via IL-6Rβ and is a critical risk factor for the development of mood and behavioral disorders in AD.
Prenatal tobacco exposure and adult offspring brain health: the mediating role of leukocyte telomere length in a large population-based cohort.
Wang Z, Zhang X, Meng X … +4 more , Xie J, Xu Q, Xu J, Wang J
Transl Psychiatry · 2026 Jun · PMID 42321180 · Publisher ↗
Maternal smoking during pregnancy (MSDP) has been linked to adverse effects on offspring brain health. However, the underlying mechanisms remain unclear. Given that offspring exposed to MSDP exhibit shortened leukocyte t...
Maternal smoking during pregnancy (MSDP) has been linked to adverse effects on offspring brain health. However, the underlying mechanisms remain unclear. Given that offspring exposed to MSDP exhibit shortened leukocyte telomere length (LTL)-a potential biomarker of accelerated biological ageing-we hypothesized that LTL may mediate the association between MSDP and long-term brain health consequences in adult offspring. Using data from the UK Biobank cohort, we performed association analyses to assess the effects of MSDP (almost 100 000 patients) on LTL, 363 imaging derived phenotypes (IDPs) from structural MRI, 11 kinds of cognitive performances, and 4 mental health outcomes in adult offspring. Mediation analysis was further conducted to evaluate whether LTL mediates the relationship between MSDP and these brain health outcomes. Offspring exposed to MSDP exhibited significantly shorter LTL, greater atrophy in 30 IDPs, poorer performance on 3 cognitive tests, and higher scores on 4 mental health questionnaires compared to unexposed offspring. Mediation analysis revealed that shortened LTL partially mediated the association between MSDP and atrophy in 11 IDPs-particularly in the hippocampus and its subregions-as well as reduced fluid intelligence performance and increased depressive symptoms. In conclusion, this study demonstrates that MSDP may contribute to long-term adverse brain health outcomes in adult offspring. Crucially, we identify accelerated telomere shortening as a partial mediator reflecting cumulative aging that partially explains the link between MSDP and specific adverse outcomes in adult offspring, particularly hippocampal atrophy, declines in fluid intelligence, and increased depressive symptoms. These results underscore the importance of reducing prenatal tobacco exposure to improve population-level brain health.
Discovery of a potential novel pharmacogenomic biomarker on ANK3 gene for liafensine, a triple reuptake inhibitor for treatment-resistant depression.
Luo W, Wang G, Whitaker JW … +6 more , Dhali Z, Sun H, Lu H, Li X, Shi T, Zhang J
Transl Psychiatry · 2026 Jun · PMID 42321177 · Publisher ↗
Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in...
Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in two Phase 2b studies. We utilized the blood samples from the patients enrolled in these two studies and extracted genomic DNA to conduct a genome‑wide association study aiming to find a biomarker which can predict liafensine response. A single single-nucleotide polymorphism (SNP), rs12217173, at ANK3 gene was identified as strongly associated with treatment response to liafensine (p = 6.61 × 10) in the discovery set (n = 186) and was further confirmed in the replication sample set (n = 47, p = 0.05, combined p = 1.27 × 10). In addition, this SNP was not associated with the efficacy of the duloxetine or escitalopram, suggesting it is a liafensine-specific biomarker. This finding was subsequently confirmed in a prospective clinical study. Thus, this study represents a novel approach to translating precision medicine into psychiatric diseases.
Multimodal predictors of spoken vocabulary development in autism: the role of early childhood brain and behavior.
Surgent O, Naigles L, Dakopolos A … +8 more , Sierakowski VK, Andrews DS, Lee JK, Heath B, Rogers SJ, Amaral DG, Solomon M, Nordahl CW
Transl Psychiatry · 2026 Jun · PMID 42321164 · Publisher ↗
Many autistic children have spoken vocabulary delays that impact communication abilities during critical developmental periods. Behavioral and brain predictors of spoken language development in autism have been independe...
Many autistic children have spoken vocabulary delays that impact communication abilities during critical developmental periods. Behavioral and brain predictors of spoken language development in autism have been independently identified but rarely evaluated simultaneously. Here, we examined how fine motor skills, joint attention, and white matter microstructure of speech-related tracts are associated with spoken vocabulary development in autistic children with a broad range of speech abilities. Spoken vocabulary was assessed longitudinally in 122 autistic children (38% female) first between 2-4 years (Time 1) and again approximately two years later. Children were divided into groups based on their Time 1 spoken vocabularies: larger, average, or smaller. Fifty-eight autistic children (47% of the sample) were in the smaller vocabulary group, which represented both emergent speakers and non-speaking individuals. Within this smaller vocabulary group, faster rates of spoken vocabulary development were associated with better Time 1 fine motor and joint attention skills, and lower Time 1 fractional anisotropy (FA) in the occipital inferior longitudinal fasciculus, central arcuate fasciculus, and inferior corticospinal tract. Rates of spoken vocabulary development were best predicted by models that included both brain and behavior metrics, which each individually explained significant variance and together accounted for roughly half of the model variability. Results suggest that together early childhood fine motor skills, joint attention skills, and white matter microstructure contribute to a developmental cascade supporting spoken language. Findings demonstrate the potential clinical utility of early brain scanning, indicating that microstructure is predictive of language development above and beyond salient behavioral predictors.
A genomic study of trichotillomania and excoriation disorder in families.
Greenspun SR, Milanes I, Farhat LC … +8 more , Abdallah S, Bok D, Chen D, Liu W, Teefe E, Bloch MH, Fernandez TV, Olfson E
Transl Psychiatry · 2026 Jun · PMID 42315517 · Publisher ↗
Trichotillomania and excoriation disorder are obsessive-compulsive related disorders that are often subclassified together as body-focused repetitive behavior (BFRB) disorders. While previous research suggests shared gen...
Trichotillomania and excoriation disorder are obsessive-compulsive related disorders that are often subclassified together as body-focused repetitive behavior (BFRB) disorders. While previous research suggests shared genetic factors, the genetic architecture of these BFRBs remains incompletely understood. Probands with trichotillomania and/or excoriation disorder and both of their biological parents were recruited for an ongoing genetic study of parent-offspring trios with BFRBs. Genome-wide array data were generated in 110 families (334 individuals total) to investigate the role of both common single-nucleotide polymorphisms and rare copy-number variants (CNVs). Polygenic scores were calculated using summary statistics from genome-wide association studies of related psychiatric conditions, including obsessive-compulsive disorder (OCD), depression, anxiety, and attention-deficit/hyperactivity disorder. Using the polygenic transmission disequilibrium test (pTDT), we observed a significant over-transmission of the OCD polygenic score in probands of European ancestry from their parents (mean pTDT = 0.36, p = 0.01, n = 92), and a non-significant enrichment for the other conditions. Our results suggest that common variants associated with OCD may contribute to risk for BFRBs, consistent with their current classification as obsessive-compulsive related disorders. We also identified several rare CNVs in probands that overlapped genes intolerant to loss-of-function (LoF) mutations and those previously associated with neurodevelopmental disorders. The LoF-intolerant genes were enriched in biological processes relevant to synapse organization and neurodevelopment. This work provides new insight into the genetic underpinnings of these BFRB disorders, paving the way for larger genomic studies of these understudied conditions.
Exploration of NMDA and GABA receptor-mediated plasticity induced by 10-Hz repetitive transcranial magnetic stimulation.
Kweon J, Kim H, Ganesh P … +5 more , Vigne MM, Fukuda AM, Ren B, Carpenter LL, Brown JC
Transl Psychiatry · 2026 Jun · PMID 42310013 · Publisher ↗
Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we do not understand the mechanisms through which rTMS induces therapeutic change. Two competing theories su...
Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we do not understand the mechanisms through which rTMS induces therapeutic change. Two competing theories suggest that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), and/or removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in six healthy subjects. We tested plasticity with motor-evoked potentials (MEPs) and learning with serial reaction time task (SRTT) before and after 10-Hz rTMS in the presence of four drugs separated by 1 week each: placebo, d-cycloserine (DCS 100 mg), DCS 100 mg + NMDAR partial antagonist dextromethorphan (DXM 150 mg), and lorazepam (LZP 2.5 mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability relative to placebo. This facilitation was specifically blocked by combining DCS with DXM. LZP administration resulted in a significant reduction of MEP amplitudes after rTMS. Results suggest that 10-Hz rTMS-induced plasticity works primarily through NMDAR dependent modulation with LTP-like mechanisms as opposed to GABAergic reduction. Our pilot study is the first to compare NMDAR v. GABAR in rTMS-induced plasticity and found the safety and feasibility of a 4-arm crossover protocol with each drug combined with the full 3000 pulse 10-Hz rTMS protocol. Our results may guide future clinical translation leveraging mechanistic understanding to improve therapeutic efficacy.
Effects on hippocampal activity following novel 5-HT4 receptor agonism in unmedicated patients with depression: the RESTAND study.
de Cates AN, Gillespie AL, Scaife J … +8 more , Martens MAG, Carson J, Godlewska BR, Howard W, Guru A, Cowen PJ, Harmer CJ, Murphy SE
Transl Psychiatry · 2026 Jun · PMID 42309998 · Publisher ↗
Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT receptor (5-HTR) agonists rapidly improve learning and memory, consiste...
Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT receptor (5-HTR) agonists rapidly improve learning and memory, consistent with this receptor's role in hippocampal neuroplasticity. However, their effects in clinically depressed patients, remain unexplored. In this double-blind, randomised experimental medicine study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HTR agonist PF-04995274 (15 mg, once daily) or placebo. Participants subsequently underwent fMRI scanning during a memory encoding task and completed behavioural measures of auditory verbal learning and spatial working memory. Compared to placebo, PF-04995274 significantly increased activity in the hippocampus (ROI analysis) in response to novel versus familiar images, particularly in the left hemisphere. Whole brain analysis also revealed greater activation in the left inferior parietal lobule, a key region for memory processing. In contrast with previous studies using the 5-HTR agonist prucalopride, PF-04995274 had notably limited effects on behavioural measures of memory. The results demonstrate that short term 5-HTR agonism enhances hippocampal and parietal activity during memory encoding in patients with depression. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HTRs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HTR activation in modulating memory-related brain circuits in MDD and previously identified beneficial effects of another 5-HT4 receptor agonist, prucalopride, on cognitive performance.
Dynamic relationship and pleiotropic loci of attention deficit hyperactivity disorder with sleep traits.
Zu Y, Pang T, Luo L … +5 more , Liufu C, Xu Z, Lv L, Li W, Chang S
Transl Psychiatry · 2026 Jun · PMID 42297780 · Publisher ↗
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder modulated by genetic and environmental factors. Approximately 20-55% of individuals with ADHD experience concurrent sleep disturbanc...
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder modulated by genetic and environmental factors. Approximately 20-55% of individuals with ADHD experience concurrent sleep disturbances, yet the dynamic relationship between the two and their shared genetic mechanisms remain unclear. This study analyzed 11,288 participants (52.1% male) from the Adolescent Brain Cognitive Development Study using the Sleep Disturbance Scale for Children. We found a robust positive correlation between ADHD and sleep traits, though ADHD medication weakened this relationship. Latent growth curve modeling revealed that ADHD symptoms significantly impacted sleep traits with a lag effect. Polygenic risk score analyses showed significant but very small associations (explained variance ~0.28-0.30%). Pleiotropic analyses identified two loci associated with ADHD and excessive somnolence (implicating 30 genes), and cross-cohort comparisons with UK Biobank insomnia data uncovered 12 additional pleiotropic loci (98 genes) enriched in brain tissue. Functional enrichment analysis highlighted excitatory and inhibitory neuronal subtypes in visual and frontal cortices, suggesting roles in synaptic transmission and neural circuit development. Protein-protein interaction network analysis identified 10 hub genes involved in cell growth regulation and neurodevelopmental processes. This study demonstrates robust ADHD-sleep associations, with medication moderating this link, and provides preliminary insights into their shared genetic architecture.
Polygenic risk for schizophrenia is associated with psychomotor vigilance performance impairment during sleep deprivation in women.
Liuhanen J, Skeiky L, Kantojärvi K … +5 more , Laitinen P, Hansen DA, Satterfield BC, Van Dongen HPA, Paunio T
Transl Psychiatry · 2026 Jun · PMID 42297777 · Publisher ↗
Schizophrenia (SZ) is a highly heritable psychiatric disorder with gender-specific etiology profiles. SZ may involve altered synaptic plasticity, as supported by genetic studies, and individuals with elevated polygenetic...
Schizophrenia (SZ) is a highly heritable psychiatric disorder with gender-specific etiology profiles. SZ may involve altered synaptic plasticity, as supported by genetic studies, and individuals with elevated polygenetic risk may show prodromal characteristics such as increased sensitivity to sleep deprivation. We examined whether polygenic risk for SZ is associated with vulnerability to sleep deprivation-induced psychomotor vigilance impairment in healthy young adults. A total of 120 healthy non-Hispanic Caucasian volunteers (62 women, 58 men; aged 20-40 years) participated in one of six in-laboratory total sleep deprivation (TSD) studies. Performance was assessed using the psychomotor vigilance test (PVT) every 2-3 h during 38 h of TSD. Each participant's SZ polygenic risk score (PRS) was computed using the PRS-CS method, utilizing published GWAS statistics. Gender-specific associations between SZ PRS and PVT performance across 6 h time intervals during hours 3-38 of TSD were investigated using mixed-effects statistical methods. SZ PRS was associated with vulnerability to PVT performance impairment during TSD in women, but not in men. The early morning hours (04:00-10:00) emerged as the most sensitive period for the association with SZ PRS, aligning with peak impairment in PVT performance during acute TSD. Our findings suggest that SZ genetic risk may heighten vulnerability to sleep deprivation-induced psychomotor vigilance impairment in young adult women, but no such effect was observed in men. Future research is needed to determine whether vulnerability to sleep deprivation reflects SZ-related genetic or neurobiological liability and whether this extends to men and older individuals.
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