Molecular Psychiatry

In-scanner head motion is a recognized source of bias in structural magnetic resonance imaging (sMRI), yet it remains under-addressed in psychiatric neuroimaging where structural difference in patient populations are considered foundational. We examined motion-related bias in grey matter volume estimates across eight independent cohorts comprising 9,664 individuals, including 8,979 neurotypical controls (NC), 497 patients with schizophrenia (SCZ), and 188 patients with bipolar disorder (BD). Mot...

Major depression (MD) is a disorder class that exhibits substantial phenotypic and clinical heterogeneity, yet many large-scale molecular genetic investigations treat MD as a unitary outcome. Here, we applied Genomic Structural Equation Modeling (Genomic SEM) to characterize the genetic variation in two clinically relevant MD subtypes, childhood-onset (child-onset) and treatment-resistant MD, that are independent of the field-standard GWAS of MD in all its forms. In addition, we fit a complement...

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...

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...

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...

Alcohol use disorder (AUD) is a serious psychiatric condition associated with negative health and psychosocial consequences, comprising core symptoms of compulsive heavy drinking that impairs daily functioning. Genetic factors play a major role in AUD etiology, estimated to explain around 50% of variation in risk. Despite being a major global public health concern, the vast majority of genetic and epidemiological studies of AUD have been restricted to samples of European ancestry living in high-...

IntroductionLactate plays dual roles in neuronal energy metabolism and signalling. The dorsal anterior cingulate cortex (dACC), a region with high baseline glycolytic activity implicated in psychiatric disorders, may exhibit dynamic lactate responses to graded cognitive-emotional demands. Because mitochondrial function declines with age, aging may model whether fMRS-derived lactate dynamics can detect latent neurometabolic vulnerabilities. MethodsUsing fMRS, we monitored dACC metabolite changes...

BackgroundBipolar disorder (BIP) frequently co-occurs with heightened substance use (SU) and substance use disorders (SUDs). Although the strong co-occurrence of these heritable traits points to shared genetic susceptibility, the extent to which there are differences in how SU and SUD overlap with BIP genetic architecture remains unclear. MethodsWe quantified the polygenic overlap between BIP and SUDs (alcohol, cannabis, opioid, and tobacco), and BIP and SU traits (drinks per week, lifetime can...

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...

IntroductionResearch has shown that social and physical stressors of early-life adversity (ELA) can negatively affect long-term health trajectories. Despite differences in types of ELA exposure, previous studies have identified common health-related outcomes in adults who had experienced less favourable conditions during developmentally sensitive periods. This meta-analysis investigates the potential role of DNA methylation in mediating these adverse health trajectories by identifying common bio...

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...

BackgroundImpaired glymphatic clearance, the perivascular system supporting cerebrospinal and interstitial fluid exchange, has been implicated in neurodegenerative and psychiatric disorders. Diffusion tensor imaging along the perivascular space (DTI-ALPS) provides a non-invasive proxy for glymphatic-related processes, yet its role in psychiatric conditions remains uncertain. MethodsFollowing PRISMA guidelines, we systematically searched PubMed, PsycNET, and Embase for articles published up to S...

BackgroundCerebellar transcranial magnetic stimulation (TMS) may serve as an adjuvant therapy for psychosis symptoms, most recently we have shown improvements in negative symptoms. Historically, cerebellum TMS has not utilized functional neuroanatomy for targeting, and the precision of TMS to the cerebellum is unclear. A classical view of the cerebellum as solely involved in motor computations has been updated with the discovery of rich non-motor connectivity including the default, dorsal attent...

Understanding the mechanisms underlying the response to antipsychotic medications is critical for refining targets for new interventions and predicting clinical outcomes. This study presents a mega-analysis of individual participant data (N = 1,189) from 18 {superscript 1}H-MRS datasets to examine differences in neurometabolites in antipsychotic non-responsive compared to antipsychotic-responsive psychosis, accompanied by complementary meta-analyses across the wider published literature (23 stud...

Disease heterogeneity presents a major challenge for genetic and epigenetic dissection of complex traits. Neuropsychiatric traits, such as opioid use disorder (OUD), arise from diverse genetic and environmental factors that uniquely combine in individuals, complicating efforts to identify causal genes and enhancers. We identified epigenetic variation linked to opioid overdose by profiling H3K27ac in the nucleus accumbens (NAc) of 91 cases and controls. While standard approaches identified only 1...

ObjectiveWe examined the clinical utility of resting state electroencephalography (rsEEG) by evaluating its temporal stability, discriminant validity for B-SNIP psychosis Biotypes, and suitability as a treatment target for brain stimulation. MethodsWe collected 5 minutes of eyes-open rsEEG from 1401 participants with psychosis and 750 healthy persons. A subset of participants was re-tested after 6 months and 12 months (N=109). In a pilot target engagement study (n=5) we collected rsEEG before a...

ObjectiveThe pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin, but the consistency and magnitude of effects are uncertain. We aimed to characterise brain iron and neuromelanin alterations in psychosis through a systematic review and meta-analysis of iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) studies. MethodsWe searched EMBASE, PubMed, and PsycINFO from inception to October 31, 2025, for case-control stud...

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...