Molecular Psychiatry

Major Depressive Disorder (MDD) frequently follows a recurrent trajectory of episodes and remissions, often culminating in treatment-resistance. Molecular differences defining state-specific changes during episode and remission have been explored. However, progressive differences--defined here as cross-sectional linear trends across clinical stages from first to recurrent episodes or remissions, reflecting increasing illness burden over time--remain poorly understood, limiting sustained therapeutic outcomes. Here, we analyzed RNA-seq data from postmortem sgACC to identify progressive differences across MDD episodes or remission relative to state-specific differences, using an integrative assessment of molecular and cellular specificity, genetic-risk, disease-comorbidity and potential therapeutic targets. Differential expression analysis showed greater overlap between progressive and state-specific differences during remission than episode. Pathway enrichment highlighted disruptions in extracellular-matrix pathways shared by state-specific and progressive episodes, while metabolic and catalytic pathways were restored during remission. Cell-type-specific analyses showed that progressive changes were linked to superficial-layer intra-telencephalic neurons, whereas state-specific changes were enriched in pyramidal neuron subtypes and deeper layer SST-positive interneurons. Genome-wide association-informed enrichment analysis further linked these transcriptomic changes to genetic risk factors and symptom dimensions. Anhedonia was associated with both state-specific episode and progressive-remission signatures, suggesting that it is a persistent trait-like feature of MDD. Finally, an integrative pharmacological analysis revealed shared molecular mechanisms between pro-disease and therapeutic targets, highlighting pleiotropic effects of key pathways depending on disease state and dosage. Together, these findings provide a novel perspective on biological underpinnings of MDD progression over episodes or remissions and identify pharmacological targets that account for pathological and/or compensatory/therapeutic processes.

BackgroundThe single nucleotide polymorphism (SNP) rs1053230 within the kynurenine 3-monooxygenase (KMO) gene encodes either an arginine (CGC) or cysteine (TGC) at amino acid residue 452. The rs1053230 genotype is associated with alterations in KMO expression and activity, and impaired cognition. Additionally, KMO intronic SNP rs2275163 is associated with schizophrenia endophenotypes. However, the direct functional consequences of these SNPs on KMO function have never been investigated. MethodsHere we performed the first in vitro cell-based examination of the rs1053230 genotype on KMO expression, activity, cellular localisation and KMO-protein interactions, as well as examination of the effects of rs1053230 on schizophrenia-relevant clinical measures. We also examined the effects of rs2275163 genotype on KMO pre-mRNA stability and alternative splicing. ResultsHEK293T cells expressing KMO-Arg452 or KMO-Cys452 with a red fluorescent protein (RFP) tag produced equivalent levels of KMO mRNA, protein and enzymatic activity, and localised to mitochondria to the same extent. However, cycloheximide-mediated inhibition of protein translation revealed a striking reduction in protein stability of KMO-Arg452-RFP. KMO-RFP-trap pull-down followed by tandem liquid-chromatography-mass spectrometry (LC-MS/MS) identified dramatic differences in protein partners between KMO variants. Indeed, gene ontology-term enrichment analysis revealed that terms associated with synaptic function were more highly enriched amongst KMO-Cys452 interacting proteins. rs1053230 genotype was found to associate with chronic, trait-like depressive mood symptoms in patients. rs2275163 genotype had no effect on KMO pre-mRNA. ConclusionsDifferences in protein stability and protein-protein interactions may underlie the mechanisms by which the KMO rs1053230 genotype influences neuronal function, leading to cognitive differences in psychiatric conditions.

Schizophrenia is a severe psychiatric disorder associated with altered dopaminergic signaling and hippocampal circuit dysfunction. Although antipsychotic medications remain the standard treatment, many are limited by incomplete efficacy and adverse effects. Cariprazine, a dopamine D2/D3 receptor partial agonist, has a favorable clinical profile, but its effects on neuronal excitability and network activity remain incompletely understood. Here, we integrated nationwide real-world clinical data with in vitro electrophysiology, computational modeling, and molecular analyses to define the neuronal actions of cariprazine. Among Hungarian patients diagnosed with schizophrenia and receiving index-drug monotherapy with one of the three prespecified D2/D3 targeting antipsychotics, haloperidol was associated with worse survival and a higher cumulative incidence of first registered suicide attempt than cariprazine or aripiprazole in matched observational cohorts. In primary mouse hippocampal cultures, multielectrode array recordings showed that acute cariprazine treatment moderately reduced spontaneous firing in a dose-dependent manner and prolonged burst intervals while largely preserving network synchronization. These effects were milder than those of haloperidol and aripiprazole. Whole-cell patch-clamp recordings revealed cell-type-dependent effects, with reduced intrinsic excitability and increased firing irregularity mainly in regular- and stuttering-type neurons. Conductance-based modeling identified enhanced Kv1-mediated D-type potassium currents as sufficient to reproduce these effects. Consistent with this mechanism, chronic cariprazine treatment altered Kv1.2 protein distribution without changing Kcna2/Kcna3 or Drd1/Drd2/Drd3 transcript expression. These findings identify modulation of intrinsic excitability via Kv1/D-type potassium currents as a candidate cellular mechanism of cariprazine and provide a translational link between real-world evidence and circuit-level drug effects.

Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 x 10-5) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.

Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimers and Huntingtons diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

Genomic insights into psychiatric disorders remain heavily skewed toward European populations. In European-ancestry studies, educational attainment is typically negatively genetically correlated with major depression but paradoxically positively correlated with schizophrenia, raising the question of whether these relationships generalize across ancestries. We investigated whether this cross-trait architecture extends to East Asian ancestry (EAS). Using EAS GWAS summary statistics for major depressive disorder (MDD), schizophrenia (SZ), and educational attainment (EDU), we applied multi-trait (MTAG) and pleiotropy-informed (PLEIO) analyses to characterize shared genetic architecture across these traits. Across MTAG and PLEIO analyses, we identified 32 unique genome-wide significant loci (p < 5 x 10-8), including seven novel loci revealed in depression analysis that overlapped schizophrenia-associated signals, consistent with shared cross-trait architecture. Results reinforce a convergent risk architecture for affective and psychotic disorders in this population. Fine-mapping analyses prioritized variants mapping to candidate genes, including serine/threonine kinase VRK2, nominating targets for future follow-up. Cross-trait analyses supported a positive genetic relationship between EDU and MDD (rg = 0.308, p = 9.63 x 10-17) in East Asian data, contrasting to the negative correlation typically observed in European ancestry. These findings suggest that the genetic relationship between educational attainment and psychiatric risk may not be fully transferable across ancestries. In an independent cohort of individuals at ultra-high risk for psychosis, MTAG-derived polygenic risk scores improved case-control discrimination relative to single-trait GWAS-based scores. These results underscore the importance of ancestry-specific genomic frameworks for interpreting cross-trait psychiatric architecture and improving polygenic prediction.

Thirty-five percent of people with schizophrenia-related disorders (SRD) form a high-inflammation subgroup defined by elevated anti-gliadin antibodies (AGA+) and inflammatory proteins and associated with an increased severity of negative symptoms. However, the immune mechanisms mediating these effects remain poorly defined. Here, we characterized transcriptional signatures of peripheral immune cells in AGA+ SRD (n=7) compared to AGA-negative (AGA-) SRD (n=3) and healthy controls (HC; n=5), using single-cell RNA-sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs). AGA+ SRD was associated with increased abundance of T-helper-17 cells (Th17), T-follicular helper-1 (Tfh1), CD5+ B cells, plasmacytoid dendritic cells (pDCs), and several CD8+ T cell subsets, including memory and Natural Killer-T-like activated subsets. In parallel, AGA-SRD exhibited a higher abundance of several monocyte subsets compared to either AGA+ SRD or HC. Pathway analysis revealed upregulation in AGA+ SRD of JAK/STAT, type I Interferon, and IL-6 signaling pathways in distinct subset of activated T-cells. Collectively, these results define a unique T cell predominant inflammatory signature in AGA+ SRD, as well as potential targets for therapeutic intervention.

Background: Major depressive disorder (MDD) is characterized by disrupted information flow among brain regions. While effective connectivity (EC) captures these causal interactions, the underlying structural and molecular basis remain unclear. This study aims to investigate direction-specific EC alterations in MDD and their associations with laminar structural covariance (SC) and transcriptional and neurotransmitter profiles. Methods: Resting-state fMRI and structural MRI data were analyzed from the REST-meta-MDD consortium (Discovery, N=1627) and an independent cohort (Validation, N=226). We calculated the unsigned and signed EC using Liang Information Flow and laminar SC based on cortical depth, and compared them between MDD patients and healthy controls. The EC alterations were further associated with molecular profiles integrating gene expression (AHBA) and neurotransmitter receptors (PET/SPECT). Then, Chain mediation analyses were performed to map the hierarchical pathways from molecular basis to EC. Finally, we evaluated the clinical potential of EC in its therapeutic responses to medication and neuromodulation in a longitudinal dataset (N = 16 for medication, N = 11 for neuromodulation). Results: Our analysis revealed no significant changes in the EC of first-episode MDD but observed a hyper-driven cerebellar-cerebral EC pattern in recurrent MDD (RMDD), characterized by a direction-specific excitation-inhibition imbalance featuring enhanced inhibitory cerebellar output alongside a concurrent increase in both inhibitory input and excitatory output within sensorimotor/cognitive regions. These alterations were physically constrained by specific laminar SC patterns, particularly involving the middle cortical lamina. Moreover, the input EC changes in RMDD patients were primarily enriched in biological processes related to the modulation of chemical synaptic transmission, whereas output EC changes were linked to synapse structure regulation. These EC alterations were closely associated with serotonergic, GABAergic, and glutamatergic neurotransmitter systems. Importantly, we identified oligodendrocyte precursor cells (OPCs) as a key cellular mediator bridging microscale molecular features to macroscale connectional alterations in RMDD. These findings were reproducible in the validation dataset. Clinically, medication treatment primarily evoked a pattern of decreased input coupled with increased output, whereas neuromodulation elicited a reciprocal shift characterized by enhanced input and attenuated output. Conclusions: These findings underscore a direction-specific gene-neurotransmitter-cell type-laminar SC-EC pathological model in RMDD. By integrating multi-scale biological mechanisms with clinical phenotypes, this study highlights the potential of directional EC as a biomarker for stratifying refractory depression and guiding precision therapeutics.

GABAergic deficit is associated with key neuropsychiatric disorders, such as major depressive disorder (MDD), anxiety, schizophrenia, and autism spectrum disorder (ASD). However, it is not known whether these disorders are causal to or a result of GABAergic dysfunction. We previously showed that the Solute carrier 38 member 1 (Slc38a1) accumulates glutamine in subpopulations of GABAergic neurons and sustains neurotransmitter GABA synthesis. Genetic inactivation of Slc38a1 in mice caused lowered GABA levels, altered synaptic vesicle morphology, slowed {gamma}-oscillations, and reduced cortical processing and plasticity, selectively at GABAergic synapses. We now demonstrate a significant reduction in learning and memory performance in the Morris water maze and increased signs of despair in the forced swim test in Slc38a1-/- mice compared to Slc38a1+/+ mice, implicating cognitive impairments and depressive-like behavior. Examination in the open field maze also indicates anxiety and/or reduced interest in exploration. There are no signs of impaired sociability or recognition of social novelty in the three-chambered test, speaking against involvement in schizophrenia- or ASD-like disorders. Metabolic phenotyping and measurement of the locomotion do not segregate the Slc38a1 genotypes, suggesting that the cognitive impairments, depressive-like behavior and anxiety are brain-dependent. Our data is further supported by a pathologic variant of Slc38a1 in a family with depression and suicidal behavior. Altogether, we demonstrate that dysfunction of Slc38a1-dependent GABA synthesis and the ensuing impaired {gamma}-oscillations underpin the pathogenesis of neurocognitive deficits, anxiety and depression.

Delayed diagnosis and treatment are a major burden to patients with bipolar disorder. While lithium is the most effective treatment against mania, depressive episodes, and suicide, only 30% of patients respond to it fully. Currently there are no reliable methods to predict lithium responsiveness. To address these challenges, we aimed to identify potential diagnostic and treatment response biomarkers for BD, in addition furthering understanding of BD pathophysiology. Here, we leveraged human induced pluripotent stem cell (hiPSC) derived neurons from lithium responsive (LR), lithium non-responsive (LNR), and healthy age-matched controls (CTL). We found extracellular vesicle (EV) cargos from hiPSC-derived neurons are indicative of disease state and treatment-response. Unbiased proteomic and miRNA profiling identified 10 proteins and 13 miRNAs that were differentially expressed in BD EVs relative to CTL, as well as distinct molecular signatures separating LR ad LNR groups. These differences converged on pathways related to synaptic function, neurotrophic signalling, and cellular stress responses. Additionally, we found the BD neuronal secretome alters activity in non-BD neuronal networks. Chronic treatment of CTL cultures with BD neuron-conditioned media modified the proportion of active neurons and the frequency and amplitude of calcium transients in individual neurons. We demonstrate that neuronal EVs contain molecular signatures of disease state and treatment response in BD and identify the BD secretome as an active regulator of neuronal network homeostasis. This study provides novel insights into the pathophysiology of BD and candidate biomarkers for personalized BD diagnosis and treatment selection.

Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.

Bipolar disorder (BD) is associated with widespread white matter microstructural alterations, yet their cellular and metabolic underpinnings remain poorly understood. Here, we asked whether in vivo magnetic resonance imaging (MRI) signatures of BD spatially align with the distribution of glial and mitochondrial cell populations, whether these patterns are specific to BD across the affective-psychotic spectrum, and whether lithium attenuates them. In individuals with BD (n = 104), major depressive disorder (MDD; n = 135), and psychotic disorders (PY; n = 87) from the UK Biobank, each matched to healthy controls, we mapped multimodal MRI alterations (radial diffusivity [RD], fractional anisotropy [FA], voxel-based morphometry [VBM]) onto reference maps of five glial cell types and six mitochondrial markers. BD showed a reproducible spatial alignment between elevated radial diffusivity and glial-rich regions (astrocytes, microglia, endothelial cells, oligodendrocyte precursors), together with a separable alignment between regional gray-matter loss and mitochondrial respiratory capacity. Across diagnostic groups, psychotic disorders partially shared the glial signature but lacked the mitochondrial one, while MDD diverged on both, supporting a degree of BD specificity for the combined glial-mitochondrial pattern. Within BD, lithium-treated patients showed an attenuation of glial alignment most prominently for astrocytes and oligodendrocyte precursors, consistent with a glial mechanism of lithium action. While effect magnitudes were modest, as is typical for cross-modal spatial alignment studies, they were consistent across markers and modalities. The findings identify glial-mitochondrial coupling as a tractable cellular axis in BD pathophysiology and point to glial pathways as a candidate substrate for lithium's therapeutic effect.

BackgroundSchizophrenia (SCZ) is a severe neurodevelopmental disorder with numerous genetic risk loci. However, little is known about the molecular alterations that occur during brain development in SCZ, particularly regarding the role of microRNA (miRNA) mediated regulatory mechanisms. This gap in knowledge is largely due to the limited availability of developing human brain tissue. Patient-derived brain organoids offer a promising alternative model. Here we use 3D dorsal forebrain organoids (DFOs) to investigate miRNA dysregulation in SCZ. MethodsDFOs were generated from human induced pluripotent stem cells (hiPSCs) derived from six SCZ patients and five matched controls and cultured for 120 days. Multi-omics analyses, immunohistochemistry, and in situ hybridization were employed to characterize molecular and spatial features. ResultsDFOs recapitulated key molecular hallmarks of human cortical development. Nineteen miRNAs were differentially expressed in SCZ: nine associated with neural progenitor proliferation were downregulated and ten linked to neuronal differentiation and synaptic maturation were upregulated, reflecting a compressed developmental timeline. Among 77 dysregulated mRNAs, 55 were predicted miRNA targets. SCZ DFOs exhibited significant upregulation of GABAergic pathway genes accompanied by altered expression of their regulatory miRNAs, indicating premature GABAergic lineage specification. The disrupted miRNA-mRNA network converged on glutamatergic and dopaminergic development, synaptic organization, and extracellular matrix remodeling. ConclusionDysregulated miRNAs in SCZ DFOs disrupt neuronal differentiation, excitatory-inhibitory balance, and early circuit formation, implicating miRNA-mediated post-transcriptional regulation as a key mechanism linking molecular alterations to cellular and network-level deficits in SCZ.

The past decade has seen tremendous progress in the identification of genes associated with complex neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. Expression patterns of these genes in single cell data strongly implicate excitatory and inhibitory neurons; however, there are limited data on the brain regions involved - a critical question for neurobiology. Spatial transcriptomics provide an opportunity to perform systematic multiregional analyses to provide insights into this question. Here, we have generated a spatial transcriptomics dataset encompassing the diverse anatomical territories of the adult mouse brain sagittal midsection. We compare neuropsychiatric gene enrichment by applying Gene Fraction Enrichment Score (GFES), a novel statistic method that controls for differing neuronal proportions across regions. ASD-associated genes identified by exome sequencing were most enriched in the thalamus followed by the cortex. Schizophrenia genes from genome-wide association studies were also enriched in the thalamus, along with the hippocampus and cortex. These findings add to the evidence that the thalamus plays a major role in neuropsychiatric disorders whilst supporting roles for the cortex and hippocampus. The results highlight shared and distinct patterns for pleiotropic brain disorders that could elucidate common underlying mechanisms and circuitry.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by symptoms that emerge in childhood and often improve or even disappear in adulthood, providing a model for understanding how altered brain development shapes neural structure and function. We investigate brain structural alterations in TS and Chronic Tic Disorders (TS/CTD) across development, presenting the largest structural neuroimaging analysis for TS/CTD to date (1,803 individuals from the ENIGMA-TS Working Group), and integrating with large-scale genomewide association studies. Nonlinear age effects were observed in cortical thickness across development and in thalamic volume in children, indicating altered trajectories of brain maturation . Pediatric and adult TS/CTD showed distinct structural patterns, with widespread alterations in childhood and more focal changes in adulthood. Children also showed the most prominent effects highlighting the involvement of orbitofrontal cortex and putamen, alongside additional regions such as frontal and paralimbic areas. Genetic pleiotropy analyses identified overlap between TS/CTD-associated genetic effects on brain structure and neuroanatomical differences. Cross-disorder comparisons revealed correlations with ADHD and OCD and age-related patterns. These findings demonstrate altered neurodevelopmental trajectories in TS/CTD and implicate systems underlying inhibitory control and urge regulation.

Abnormalities in the gut microbiome, intestinal permeability, and the gut-immune-brain axis are increasingly linked to neuropsychiatric disorders, neurodegenerative disorders, inflammatory bowel disease (IBD), and other immunologic/autoimmune conditions. We investigated these phenomena in 128 youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and individuals with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD) characterized by profound, unexplained deteriorations/regressions in developmental, neuropsychiatric, and behavioral functioning. Previous studies we have carried out showed that immune dysregulation and DNA damage response (DDR) gene mutations are implicated in a subset of these patients. The current study examines the role of genetic variants affecting intestinal homeostasis. We report a series of patients exhibiting both neuropsychiatric deterioration and gastrointestinal symptoms. Genetic analysis identified ultrarare (minor allele frequency < 0.001) pathogenic or likely pathogenic variants in eight genes primarily expressed in the intestines and associated with IBD, dysbiosis, or intestinal permeability. Across thirteen patients, mutations were identified in DUOX2 (n=4), SLC10A2 (n=2), UNC45A, TTC7A, LGALS4, SI, CCR9, MEP1B, and BACH2. While these findings suggest a potential role for genetic variants governing intestinal homeostasis in these cases of neuropsychiatric decline, their presence in only a small subgroup necessitates larger, prospective cohorts to determine whether these variants are statistically significant and play a definitive role in the pathogenesis of these disorders.

In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.

Circular RNAs (circRNAs) remain an underexplored layer of transcriptomic regulation in psychiatric disorders. We quantified circRNA expression from 1,022 [518 neurotypical, 365 schizophrenia (SCZ) and 139 bipolar disorder (BIP)] postmortem cortex samples from PsychENCODE consortium cohorts and integrated these profiles with matched linear RNA and genotype profiles. We identified 23 SCZ-associated and 3 BIP-associated differentially expressed circRNAs (FDR<0.05; FDR-circDEG). We trained genetically regulated circRNA expression (circGReX) models using neurotypicals and applied them to SCZ and BIP GWAS to perform Transcriptomic Wide association analysis (TWAS) which identified 22 and 4 circGReX trait associations (circGTAs), respectively. Pathway enrichment of circDEGs and circGTAs implicated neuronal and synaptic processes for both disorders. In UK Biobank, circGReX-imaging associations were predominantly negatively correlated with SCZ and BIP circGTAs, but positively correlated with Alzheimers disease circGTAs. circKLHL24 isoforms showed the most prominent imaging associations. Many co-expression modules containing our FDR-circDEGs were enriched for psychiatric and neurodegenerative risk genes, including our identified circGTAs, and these modules were enriched for cognitive and neurodevelopmental traits. To conclude, circRNAs represent a distinct regulatory layer in psychiatric disorders, linking genetic risk to synaptic biology, brain structure and cognition through disease-specific expression, TWAS prioritization, and imaging associations.

Suicidality phenotypes, including suicidal ideation (SI), non-fatal suicide attempt (SA), and suicide death (SD), are heritable and exhibit both shared and phenotype-specific genetic influences. Using genomic structural equation modelling, we estimated the shared genetic architecture across GWAS of SI (176,147 cases, 1,010,300 controls), SA (53,919 cases, 1,063,988 controls), and SD (7,584 cases, 652,070 controls) and conducted a multivariate GWAS of a latent suicidality factor capturing their shared liability. This analysis identified 36 genome-wide significant loci, including seven not previously reported in any suicidality GWAS. Follow-up analyses identified residual genetic variance specific to each phenotype, including three SD-specific genomic risk loci. Conditioning suicidality phenotypes on genetic liability to psychiatric disorders revealed significant residual genetic variance across SI, SA, SD, and the suicidality common factor. Together, these results suggest that suicidality reflects both shared genetic liability and phenotype-specific contributions.

Genetic risk for schizophrenia (SCZ) has been linked to cognitive performance before the onset age. We examined how SCZ-related polygenic risk and resilience variants, and their co-expression patterns in the human brain, were associated with cognitive abilities across development in 16,520 non-psychiatric European and African ancestry children and adults. SCZ risk showed significant negative associations with spatial, verbal, and working memory across ancestries (all t<-2, pFDR<0.05). In Europeans, risk and resilience variants had opposing effects on attention, working and spatial memory ({Delta}t>4, pFDR<0.05). Polygenic scores filtered through perinatal co-expression networks showed stronger links with cognition than adult ({Delta}AIC>5.75, p=0.02) or juvenile ({Delta}AIC>5.8, p=0.03) networks. Cross-ancestry correlations (R=0.52, p<0.01) highlight replicability. These findings support the neurodevelopmental basis of SCZ, suggesting that risk and resilience variants influence cognition from early life, independent of symptoms and elucidate biological pathways through which SCZ risk may influence early cognitive development.