Schizophrenia Bulletin

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.

BackgroundSchizophrenia is associated with widespread cognitive impairments. Several early risk factors for schizophrenia have been identified, and some studies suggest associations between these early risk factors and cognition, yet the literature is sparse in psychosis. MethodsClinical cohorts of child/adolescent and adult patients with first-episode psychosis (FEP) and healthy controls (HC) were linked with register-based information (N=276). Gestational age, Apgar scores, birth weight and length, parental age, and season of birth were extracted from the Danish medical birth registry. Cognition was assessed at time of diagnosis using BACS, CANTAB, and WAIS-III/WISC-IV. Missing data was imputed using MICE. Canonical correlation analysis (CCA) was used to examine patterns of associations. Post hoc analyses explored group differences according to diagnosis, age, and sex. ResultsCCA resulted in two significant patterns of associations. CCA1 was stable across imputations (r=0.44, p=.036, pmin= .017, pmax= .055), and constituted by a risk profile of lower maternal age, lower birth length, being small for gestational age, and lower birth weight and a cognitive profile of lower estimated IQ and poorer working memory, mental flexibility, processing speed, verbal fluency, and motor latency. The pattern was more expressed in FEP compared to HC and in adults compared to children. CCA2 was more unstable across imputations (r=0.38, p=.033, pmin=.003, pmax=.168) and constituted by a broad pattern of minor loadings. ConclusionCognitive functioning later in life is associated with multiple early risk factors, underscoring the complexity of developmental processes and the importance of the early developmental context in shaping cognitive trajectories.

In the past two decades, the focus on genome-wide association studies in large samples of unrelated patients has overshadowed family genetic studies. Therefore, little is still known about the levels and effects of the transmission of polygenic risk scores (PRS) among familial cases of schizophrenia (SZ) or bipolar disorder (BD) and their unaffected relatives. Prior research has shown that PRS are elevated in both patients and young individuals at familial risk for BD and SZ. We sought to study the transmission of PRS in affected multigenerational families and non-affected adult relatives (NAARs) with or without other non-mood nonpsychotic DSM-IV diagnoses and unrelated non-affected individuals from the same population. We genotyped 1,117 participants divided in 48 families from the Eastern Quebec Schizophrenia and Bipolar Disorder Kindreds. PRSs for both SZ and BD were computed using Multivariate Lassosum. For both SZ PRS and BD PRS, SZ and BD cases present higher PRS compared to controls, replicating previous findings. Regardless of a diagnosis of other non-psychotic and non-mood conditions, NAARs presented higher PRS than the unrelated cohort. Crucially, a subset of families presented consistently low PRS transmission profiles across generations, falling below expectations from our polygenic inheritance model. When the effect of individual PRs is accounted for, we observed sex-specific associations between familial PRS and patients' symptom dimensions. Our results clearly demonstrate that polygenic inheritance alone does not adequately explain disease transmission in families. Such an approach may also clarify why some families exhibit dense clustering of cases despite minimal polygenic burden.

The most recent Psychiatric Genomics Consortium (PGC) genome-wide association study of schizophrenia used the statistical fine-mapping tool FINEMAP to identify 70 genes that were likely to mediate common genetic variant associations with the disorder. Here, we extended that study by using two fine-mapping methods, SuSiE and FINEMAP, applying the methods to loci whose causal variant structure was considered too complex by the PGC, and optimising the proportion of posterior probability required by credible sets of causal SNPs for gene prioritisation. Prioritised gene sets were validated for schizophrenia relevance by testing for enrichment of loss-of-function mutation intolerance (LoFI), and for enrichment of rare deleterious coding variants associated with generalised cognition in UK Biobank, both known characteristics of schizophrenia associated genes. Concordance between FINEMAP and SuSiE was high, with most prioritised genes supported by both methods. Genes prioritised by both methods using a relaxed 80% posterior probability (PP) threshold for defining credible sets (N=98) were as enriched for LoFI and for rare deleterious missense variants associated with generalised cognition as genes prioritised using a more conservative 95% PP threshold (N=87). Loosening the credible set threshold combined with the joint application of SuSiE and FINEMAP increased the yield of prioritised genes by 40%, without reducing the orthogonal evidence for validity. Newly prioritised genes included calcium channel genes, CACNA1I and CACNB2, a glutamate receptor gene, GRM3, and TCF4, which has been previously implicated in schizophrenia.

Background and Hypothesis: Environmental exposures linked to schizophrenia may play a role in shaping long-term clinical outcomes among individuals with psychotic disorders. This study examined whether the Maudsley Environmental Risk Score (ERS), a cumulative measure of five established environmental risk factors, predicts trajectories of symptoms, cognition, and psychosocial functioning over 25 years following first hospitalization for psychosis. Study Design: Participants were drawn from the Suffolk County Mental Health Project, a longitudinal cohort of individuals with first-admission psychosis assessed six times over two decades. A total of 516 participants had sufficient ERS data and repeated assessments of symptoms (SAPS, SANS), cognitive ability, and functioning (GAF). Study Results: Linear mixed-effects models showed that higher ERS was significantly associated with lower global functioning ({beta} = -0.104, p = 0.008), an effect that remained consistent over time. ERS also predicted more severe and worsening reality distortion ({beta} = 0.082, p = 0.023 for intercept; {beta} = 0.005, p = 0.032 for slope of time). No significant associations were observed between ERS and cognitive ability, disorganization, or negative symptoms. Conclusions: These findings highlight the contribution of environmental risk to functional impairment and persistent positive symptoms across the course of psychotic illness. Incorporating ERS into clinical risk models may aid the identification of individuals likely to experience a more severe illness trajectory, and inform long-term treatment planning.

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.

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.

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. Something in discourse with a person experiencing psychosis often "feels off" before formal assessment is completed, yet this disturbance has not been quantified at the level of ongoing dyadic conversation. Prior work has largely treated patient speech in isolation, limiting our capacity to measure how communicative disruption emerges within clinical exchange. Methods. We applied a three-level decomposition of conversational alignment in 109 patients with psychotic disorders (26 female) and 60 healthy controls (22 female) at baseline and 12 months (n = 115). Register divergence (dAUCnorm) captured lexical distance between interviewer and patient; embedding-based synchrony (rembed) measured semantic trajectory coupling; within-speaker coherence was computed separately for each speaker. We used linear mixed-effects models adjusted for timepoint and participant clustering. Results. Patients showed significantly greater lexical-semantic divergence from the interviewer (d = 0.48, p < .001) and reduced embedding-based synchrony (d = -0.59, p < .001), both effects replicating at each time point. Critically, the interviewer's within-speaker coherence was reduced during conversations with patients (d = -0.33, p = .016), indicating that the disruption extends beyond the patient to the interaction itself. Register divergence tracked impoverished thinking and synchrony tracked disorganized thinking (both FDR-corrected q = .038). Group differences were persistent at 12 months, indicating a partially stable profile. Conclusions. Conversational alignment in psychosis reveals a dyadic failure of semantic coordination that destabilizes the interviewing clinician's coherence even when patient narrative continuity is preserved. These transcript-derived alignment metrics offer a scalable approach to quantifying interpersonal communicative function from routine clinical encounters.

Objective. Persistent, distressing psychotic-like experiences (PLEs) are associated with neurobiological alterations and increased psychosis risk. We combined individual-level neuroimaging measures with effect sizes from large neuroimaging studies to create a summary score ('Psychosis Neuroscore') reflecting neuroanatomic liability for psychosis, and examined its ability to predict PLE trajectories in young adolescents. Method. Using latent growth mixture models, we estimated PLE trajectories from four annual visits of the Adolescent Brain Cognitive Development Study (N=9584, ages 9-10 at baseline). Using baseline T1-weighted and diffusion-weighted imaging data, we calculated Psychosis Neuroscores, as well as Neuroscores for two psychiatric disorders with late adolescent/adult onset (Major Depressive Disorder, Bipolar Disorder). We compared Psychosis Neuroscores to i) other psychiatric Neuroscores, ii) modifiable risk factors, and iii) established risk factors in predicting trajectory membership. Results. We identified four trajectories of distressing PLEs: Persistent Elevated (N=1,968, 21%), Gradual Decreasing (N=3,424, 36%), Rapid Decreasing (N=1,593, 17%) and Low/No Distress (N=2,599, 27%). Adolescents with Persistent Elevated PLEs had significantly higher Multimodal (combined T1 and diffusion-weighted) and T1-weighted Psychosis Neuroscores than all other trajectories (Odds Ratios [ORs] 1.27-1.34,pFDR<.01). Bipolar Disorder Neuroscores showed a similar pattern (ORs 1.16-1.23,pFDR<.01). Psychosis Neuroscores showed comparable associations with established risk factors in predicting trajectory membership, but smaller associations than modifiable risk factors, including screen time, physical activity, and sleep disturbances. Conclusion. Psychosis Neuroscores differentiate youth with persistent PLEs from those with decreasing, remitting or low PLEs, demonstrating their potential utility for early risk stratification. Integration with established risk factors may enhance psychosis risk prediction in youth.

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.

Background: Schizophrenia, bipolar disorder, and depression share substantial genetic liability. However, the molecular mechanisms underlying this shared architecture remain poorly characterized. In particular, the role of circulating proteins as potential mediators and therapeutic targets is not well understood. Methods: Based on large-scale genome-wide association studies, we constructed a latent psychiatric common factor using genomic structural equation modeling. We then performed proteome-wide Mendelian randomization to estimate the associations between circulating proteins and this shared liability, based on four independent proteomic cohorts. Protein-psychiatric common factor associations were prioritized through comprehensive sensitivity analyses and colocalization. We additionally performed tissue- and single-cell expression enrichment analyses and a systematic druggability assessment. Results: We identified 36 circulating proteins with evidence of association with the psychiatric common factor that withstood multiple sensitivity analyses. Several proteins showed distinct tissue-specific expression patterns, with enrichment in brain, immune, or liver tissues, highlighting convergent neuroimmune and systemic pathways. For instance, genetically predicted higher levels of MAPK3, FES, MRE11A, HS6ST3, OLFM1, BTN3A1, BTN3A2 and BTN3A3 were associated with increased psychiatric risk, whereas higher levels of CD40, ITIH3, and ITIH4 were associated with decreased risk. Druggability assessment identified CD40, MAPK3, FES, MRE11A and BTN3A1 as established or potential therapeutic targets. Conclusions: By integrating genetic, proteomic, and transcriptomic data, this study identifies circulating proteins that associated with the shared genetic effects on three major psychiatric disorders. These findings provide biologically grounded candidates for therapeutic targeting and offer insights into shared disease mechanisms.

Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex polygenic architectures. Genome-wide association studies (GWASs) have identified numerous common variant associations, but rarer variants detectable through whole-genome sequencing (WGS) remain underexplored. We conducted rare variant association analysis using WGS data from the Portuguese Island Collection (PIC), including 28 families with SCZ (n = 53) and 41 families with BPD (n = 83) cases, and population controls (n = 62). Following ANNOVAR and CADD annotation, burden analysis of deleterious variants showed that both affected and unaffected family members from SCZ and BPD pedigrees had significantly higher burdens of rare deleterious variants compared to controls (p < 0.0001), with no significant differences observed between affected and unaffected relatives, consistent with shared familial genetic liability. Polygenic Risk Score (PRS) analysis confirmed significant genetic contributions to both disorders within PIC. Association analyses were subsequently performed using SAIGE-GENE+ identifying 483 and 583 nominally significant (suggestive associations) gene sets (p-value [&le;] 0.05; FDR > 0.05) for SCZ and BPD, respectively, including gene sets related to neurotransmission, synaptic function and structure, neurodevelopment, and neuroinflammation as well as major signaling pathways. Cross disorder overlaps also identified shared suggestive enrichment of GABA and glutamate signaling, synaptic signaling, and Wnt signaling gene sets in both SCZ and BPD. These findings support shared rare variant burden within multiplex psychiatric families and highlight the role of gene-set based rare variant analysis in identifying neurobiological pathways relevant to SCZ and BPD. Keywords: WGS, Rare Variants, Schizophrenia, Bipolar Disorder

Background: Psychotic disorders such as schizophrenia have been associated with older-appearing brain structure, commonly quantified using the brain-age paradigm. However, it remains unclear whether these alterations are present at illness onset and whether antipsychotic treatment modifies their trajectory. Methods: In this study, 61 (28 females and 33 males) antipsychotic-naive people with first-episode psychosis were randomised to receive either a second-generation antipsychotic (risperidone or paliperidone) or placebo over a 6-month treatment period, alongside intensive psychosocial therapy. A healthy control group (n = 27, 17 females, 10 males) was also recruited. Structural MRI scans were collected at baseline, 3 months, and 12 months. Brain age was estimated using two pretrained and validated models (Pyment and CentileBrain). Results: Brain-predicted age difference (brain-PAD) did not differ between patients and healthy controls at baseline (F(1,80) = 1.30; p = 0.26). There were also no significant effects of time, treatment group (antipsychotic, placebo, healthy control), or their interaction on brain-PAD across the first year (all p > 0.26). Findings were consistent across both brain-age models, and brain-PAD was not associated with clinical and lifestyle measures. Conclusion: These findings suggest that altered structural brain ageing is not evident during the earliest stages of psychosis and is not modified by early antipsychotic exposure over the first year of illness. Longer follow-up and approaches that account for illness heterogeneity may be needed to clarify when brain-age alterations emerge in psychotic disorders.

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.

Background. There is growing evidence to suggest a clinically significant overlap between autism spectrum conditions and psychotic disorders. Preliminary evidence suggest that autism diagnoses and autistic traits are associated with poorer outcomes following a first episode of psychosis. Methods. This study used data from the Cambridgeshire and Peterborough National Health Service Foundation Trust (CPFT) Research Database to examine clinical outcomes in autistic and non-autistic people following a first episode of psychosis. We describe patterns of community and inpatient service use, using descriptive statistics , Cox regression, binomial logistic regression, and negative binomial regression. Results. Data from 282 autistic and 7127 non-autistic people with psychosis were analysed. Autism was associated with greater community service use (use of mental health emergency lines, mental health detentions by police), as well as greater likelihood of psychiatric hospital admission (adjusted hazard ratio 1.34, 95% confidence interval 1.05 -1.7, p<0.05) and longer inpatient stays (median 111 versus 48 days, p<0.0001). Learning disability played a significant role in the utilisation of community and inpatient services, with lower rates of community service use but longer inpatient admissions. Conclusions. This study indicates a differing pattern of service use between autistic and non-autistic people following psychosis that warrants further research into how best to support autistic people with psychosis.

Social withdrawal is a key component of the negative symptom domain of schizophrenia, and pharmacological blockade of the N-methyl-D-aspartate receptor (NMDAR) is widely used to model schizophrenia-relevant phenotypes in animals. However, findings on social behaviour are inconsistent across paradigms and laboratories. We therefore conducted a systematic review and meta-analysis to synthesise the effects of dizocilpine, ketamine, and phencyclidine on social interaction and social preference, to evaluate whether clinically approved antipsychotics modify these outcomes, and to examine locomotor activity measured within the same social tests to aid interpretation. We searched Embase, PubMed and Web of Science without language or date restrictions. Controlled in vivo studies in laboratory animals administering an eligible NMDAR antagonist and reporting social interaction and/or social preference outcomes were included. Two reviewers independently screened records, extracted data and assessed risk of bias. Effect sizes were computed as standardised mean differences and synthesised using correlated multilevel random-effects models with cluster-robust variance estimation. In total, 264 studies met the inclusion criteria. Overall, NMDAR antagonists were associated with reduced social interaction and reduced social preference relative to controls, although the social preference literature appeared vulnerable to small-study effects and imprecision. Locomotor activity measured during social interaction tests tended to be higher following NMDAR antagonists, whereas during social preference no consistent overall change was observed. In animals exposed to NMDAR antagonists, antipsychotics increased social behaviour, but these changes commonly co-occurred with reduced locomotion during social interaction tests, suggesting that improvements in social measures may partly reflect altered behavioural competition and time allocation rather than selective restoration of social functioning. Taken together, the evidence supports an overall link between NMDAR antagonism and reduced social behaviour, but the strength and interpretability of this signal depend on the paradigm and are constrained by heterogeneity and limitations in reporting.

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.

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.

Apathy is a leading driver of functional disability in schizophrenia, yet effective mechanism-based therapies are lacking. We evaluated whether cerebellum-ventral tegmental area functional connectivity (CB-VTA FC) meets the criteria for clinical translation as a therapeutic neuromodulation target. Using resting-state fMRI in three independent repeated-imaging cohorts (healthy controls, early psychosis or chronic schizophrenia patients, minutes-months inter-scan intervals), CB-VTA FC was always stable and individual-specific (stability r=0.52-0.69; differential identifiability {Delta} r=0.21-0.35; all p<10-5). In paravermal cerebellar territories, it tracked apathy severity in two patient cohorts (early psychosis, Crus I/II: n=99; r97=0.36, p=2.65 {middle dot} 10-4; chronic schizophrenia, Lobules VIIB/VIIIA: n=87 scans [65 patients]; t85=4.06, p=1.1 {middle dot} 10-4). In a meta-analysis of 39 randomized controlled transcranial magnetic stimulation trials (n=1,624; 867 active), connectivity of neighboring areas to stimulation site predicted negative symptoms improvement. CB-VTA FC thus emerges as a stable, individual-specific, and symptom-related therapeutically relevant circuit, constituting a mechanism-informed precision neuromodulation target in schizophrenia, ready for prospective clinical trials.