Translational Psychiatry

BackgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. ObjectivesTo identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through h...

BackgroundSchizophrenia (SCZ) is a highly heritable and heterogeneous disorder with diverse clinical presentations and cognitive deficits. The specific genetic variants contributing to this variability remain largely unknown. This study aims to uncover the genetic bases of various clinical phenotypes such as age at onset (AAO), positive/negative symptoms, self-harm and aggression in SCZ using genome-wide association studies (GWAS). Few large-scale GWAS have explored these phenotypes, especially ...

BackgroundMajor depressive disorder (MDD) is a neuro-immune-metabolic-oxidative (NIMETOX) disorder. Nevertheless, the effects of alterations in immune responsiveness, oxidative stress, antioxidant defenses, gut-derived short-chain fatty acids (SCFAs), metabolic hormones and adipokines on metabolomic modules and the MDD phenome have remained elusive. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed using high-resolution metabolomics assays (liquid chromatography...

BackgroundMajor depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDDs marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. ObjectivesTo identify lipidomic profile differences between MDD patients and healthy controls and examine a...

Background: Circadian rhythm disturbances represent a core feature of bipolar disorder (BD), with evening chronotype as a marker for poorer outcomes. We hypothesized that BD psychopathology combined with evening chronotype is associated with structural alerations in circadian-related hypothalamic regions - particularly the suprachiasmatic nucleus (SCN) - specific to BD relative to other psychiatric diagnoses. Methods: We investigated structural neuroimaging data from the UK Biobank (113 BD, 205 ...

BackgroundMajor depressive disorder (MDD) involves immune-metabolic dysregulation, psychosocial adversity, and multidomain cognitive disturbances, yet single cognitive indices often show small and inconsistent effects. We derived a multivariate Cambridge Neuropsychological Test Automated Battery (CANTAB)-based cognitive phenotype ("cognitype") and tested whether it adds explanatory value beyond adverse childhood experiences (ACEs) and an acute-phase protein (APP) index in acute-phase MDD. Metho...

BackgroundThe predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder (BD) remains limited. AimTo enhance prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or BD aetiology. MethodsWe analysed data collected from BD patients who had received lithium treatment for at least six months and participated in the International Consortium on Lithiu...

Depression is a heterogeneous disorder, often diagnosed based on symptom co-occurrence. However, individuals may present with markedly different symptom profiles, potentially reflecting distinct underlying mechanisms. Identifying common patterns of symptoms using data-driven approaches could help clarify the heterogeneity of depression. Furthermore, examining the sociodemographic and lifestyle characteristics, health status, and polygenic scores of individuals with specific symptom profiles may ...

BackgroundMajor depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune-metabolic processes. AimsTo identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune-metabolic biomarkers of MDD. MethodsShotgun metagenomics with taxonomic profiling was performed in MDD versus controls us...

BackgroundAdolescence and young adulthood are critical periods for the emergence of bipolar disorder (BD). Instability in sleep and rest-activity rhythms is associated with elevated risk for BD, yet little is known about the neural correlates of this vulnerability. White matter organization in fronto-limbic pathways, which support mood regulation and show sensitivity to sleep/rest-activity rhythm disruption, offers a promising avenue for investigation. MethodsParticipants (16-24y;N=112) recruit...

BackgroundTransdiagnostic genetic factor models organize shared liability across psychiatric disorders, but they may leave systematic pairwise genetic overlap unexplained. MethodsUsing publicly available PGC cross-disorder LD score regression genetic correlations and published five-factor genomic SEM parameters, we computed model-implied disorder correlations and derived edge-level residual genetic correlations (observed minus model-implied) for all disorder pairs. We summarized residual misfit...

BackgroundLipidomic alterations have been reported across schizophrenia (SCZ) and bipolar disorder (BD), but findings are heterogeneous and often overlap across diagnoses, limiting diagnostic specificity. Associations between lipid profiles and illness severity have also been inconsistent when assessed using single symptom scales, raising the possibility that unidimensional measures fail to capture biologically relevant variation. Whether plasma lipidomic alterations relate to multidimensional p...

Enzyme-mediated RNA modifications provide a versatile and dynamic regulatory layer that fine-tunes gene expression programs throughout brain development and in mature neural function. More than 100 RNA modification proteins (RMPs) have been identified to drive the dynamics of RNA modifications; yet how genetic variation in human RMP genes contributes to the risks of neurological disorders has not been systematically examined. Here we have curated 123 RMPs corresponding to 31 RNA modifications on...

BackgroundAdverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. MethodsWe compared 36,772 individuals with records of adverse life events and leukocytosis in ...

Major psychiatric disorders typically emerge in youth and exhibit shared and disorder-specific behavioral phenotypes and neuroanatomical alterations, yet the transdiagnostic neurobehavioral gradients and environmental interactions contributing to this heterogeneity remain poorly understood. Here, we present a transdiagnostic cohort of 1,755 youths aged 10-24 years, including 1,040 patients with bipolar disorder (BD), major depressive disorder (MDD), or schizophrenia spectrum disorder, and 715 he...

Prenatal alcohol exposure (PAE) disrupts embryonic development and gives rise to a variable fetal alcohol spectrum disorder (FASD) phenotype characterized by neurodevelopmental and dysmorphological defects. We investigated the effects of PAE on placental gene regulation by performing genome-wide DNA methylation (DNAm) microarray and gene expression (mRNA sequencing) analyses in 87 PAE, 77 unexposed control, and 11 smoking-exposed-only placentas. Significant alterations were identified in genes i...

ObjectiveTo identify immunomodulatory drug targets with genetic evidence in major depressive disorder (MDD), probe symptom-level heterogeneity in their effects, and identify drug repurposing opportunities. MethodsWe used cis-Mendelian randomisation to evaluate the targets of 204 immunomodulatory compounds, including immunosuppressants, cytokine inhibitors, and anti-infectives. As exposures, we selected genetic instruments from nine genome-wide association studies (GWASs) of protein or gene tran...

Psychotic disorders are increasingly recognized as the extreme end of a progressive psychopathology continuum, with less advanced stages including the asymptomatic familial high-risk state (FHR), the help-seeking clinical high-risk state (CHR), and first episode psychosis (FEP). However, we lack a comprehensive study of clinical, cognitive, functional, and neuroanatomical markers across all three early stages of psychosis, limiting our understanding of how the multimodal phenotypes which define ...

Neurodevelopmental conditions (NDCs) arise from complex genetic-environmental interactions, yet their molecular underpinnings remain poorly defined. We applied an integrative multi-omics approach within a deeply phenotyped twin cohort to identify systemic molecular signatures and pathways associated with NDCs. Our study included 237 twins between the age of 8-28 years from the Roots of Autism and ADHD Twin Study in Sweden (RATSS), combining one or more omics layers, including serum and cerebrosp...

BackgroundAntenatal depressive symptoms (ADS) are common and underdiagnosed, particularly in low- and middle-income countries, and are associated with adverse maternal and offspring outcomes. Current screening relies on subjective symptom reporting, limiting early identification and prevention. Epigenetic modifications, particularly DNA methylation, offer a promising avenue for objective, early biomarkers of depression risk during pregnancy. MethodsIn this nested case-control design within the ...