Schizophrenia

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.

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.

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.

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.

BackgroundA high proportion of autistic people receive off-license antipsychotic medication, often in the absence of a mental illness, primarily for behaviours that challenge, which is a public health concern. Although meta-analyses have been published recently, there is a lack of a comprehensive network meta-analysis to inform clinicians about the relative efficacy and safety of antipsychotic medications. AimsTo conduct a network meta-analysis of available RCTs of antipsychotic medications involving autistic participants to assess the relative efficacy of different antipsychotics and their adverse effects. MethodWe searched seven databases and hand-searched ten relevant journals. Two authors independently screened titles, abstracts, and full papers, extracted data, and assessed their quality. ResultsWe analysed data from 22 RCTs involving 1562 autistic people. The largest mean difference with 95% confidence interval in the Aberrant Behaviour Checklist-Irritability (ABC-I) score compared with placebo was from the combined intervention with risperidone and parent training: -11.16 (-15.13, -7.18), followed by risperidone: -7.59 (-9.22, -5.95), and aripiprazole: -5.59 (-7.18, -4). The largest effect on Clinical Global Impression-Improvement (CGI-I) scores was from risperidone, 7.65 (2.17, 27.04), followed by aripiprazole, 7.02 (1.92, 25.72), compared with placebo. Risperidone (4; 1.57, 10.21) and aripiprazole (2.77; 1.20, 6.39) had significantly higher odds ratios for adverse effects, but aripiprazole showed the least weight gain. ConclusionsCombined parent training and risperidone followed by risperidone and aripiprazole showed the best effects on the ABC-I score, whereas risperidone and aripiprazole showed the greatest effect on the CGI-I score. However, risperidone and aripiprazole showed significantly increased adverse effects.

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.

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.

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.

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.

Prader-Willi syndrome (PWS) is a rare multisystemic disorder characterized by obesity, endocrine dysfunctions, and psychiatric comorbidities, which imply frequent use of psychotropic medications. They account for atypical responses to standard dosages of psychiatric drugs. Pharmacogenetics could be part of the reason for this situation, potentially offering a valuable tool for individualized treatment. This study analyzed allelic and phenotypic frequency distributions of five of the main cytochrome P450 enzymes (CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A4) involved in psychiatric drug metabolism in 47 patients with genetically confirmed diagnosis of PWS and compared them to reference frequencies in the general European population. Allelic frequency comparisons between the European reference population and the overall PWS cohort revealed a significant global difference for CYP2B6, with CYP2C19 and CYP2D6 showing trends toward significance. Although no global allelic differences remained significant after false discovery rate correction, post-hoc analyses consistently identified an enrichment of reduced- or non-functional alleles CYP2B619 and CYP2D610 in patients with PWS. Predicted metabolizer phenotype analyses showed a significant shift toward intermediate metabolizers of CYP3A4 in the PWS cohort, with corresponding depletion of normal metabolizers. Subgroup analyses indicated that allelic differences were more pronounced in maternal uniparental disomy and non-deletion subtypes, particularly for CYP2B6, although no significant differences were observed between PWS genetic subtypes. Overall, results imply potential differences in metabolizing activity in PWS patients, and subsequent implications in drug efficacy and tolerability. These results support the idea that pharmacogenetic testing may improve therapeutic decision-making in PWS for psychiatric treatment. Larger studies are needed to confirm these preliminary results.

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.

BackgroundWhile resting-state fMRI demonstrated that brain networks are spatially dynamic (expanding, shrinking, and changing complexity over time), understanding the transient spatial network interactions that remain poorly characterized is critical for revealing the mechanisms underlying brain disorders. MethodsWe introduce DESINE (Dynamic Estimation of Spatially Interactive Networks), a novel framework using joint density distributions (2D histograms) of voxel-wise activity to quantify 4D spatial network interactions across sliding windows. We analysed transient deviations from the average functional state using root-mean-square error (RMSE) and mean absolute deviation (MAD), and characterized recurring interaction patterns using k-means clustering. We applied DESINE to 91 network pairs (14 networks) in a cohort of 508 subjects (315 healthy controls; 193 patients with schizophrenia, SZ). ResultsSZ is characterized by a significantly "constrained dynamic repertoire" of network interactions. SZ patients showed markedly lower means and standard deviations for both RMSE and MAD metrics across network pairs, particularly in regions of high activity, indicating systematic rigidity. Cluster analysis revealed significant alterations in state affinity metrics, suggesting a global breakdown in the brains capacity to preserve diverse, high-fidelity spatial configurations. Critically, these interaction metrics were associated with cognitive performance, symptom scores on the positive and negative syndrome scale, and chlorpromazine equivalent drug scores. ConclusionsThis work introduces DESINE as a global, voxel-agnostic framework for characterizing time-varying spatial interactions. Our findings highlight spatial rigidity as a fundamental feature of psychopathology, suggesting that the inability to express a diverse range of spatial interactions is a factor underlying cognitive deficits in schizophrenia.

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.

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; {rho}=.40, q=.030) and vesicular acetylcholine transporter (VAChT; {rho}=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT ({rho}=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

Working memory depends on gamma oscillations generated across sensory and prefrontal cortices. In sensory cortices such as primary visual cortex (V1), stimulus-locked gamma oscillations encode stimulus information, while in prefrontal cortex (PFC), persistent gamma oscillations maintain this information after the stimulus is removed. In schizophrenia (SZ), gamma power is reduced in both V1 and PFC, consistent with deficits in sensory encoding and working memory maintenance in the illness. These two regimes of gamma oscillations arise from a canonical microcircuit involving pyramidal neurons (PNs) and parvalbumin-expressing interneurons (PVIs). Yet, whether stimulus-locked and persistent gamma oscillations are similarly or differentially vulnerable to synaptic alterations within this circuit in SZ remains unknown. To investigate this question, we used a mean-field model of the PN-PVI circuit generating either stimulus-locked or persistent gamma oscillations. We then assessed the effects of three synaptic alterations found in SZ: lower excitatory drive to PVIs (E[-&gt;]I), lower inhibitory drive to PNs (I[-&gt;]E), and greater variability in E[-&gt;]I synaptic strength. Each alteration produced larger gamma power deficits in the persistent regime than in the stimulus-locked regime. When applied together, these alterations interacted synergistically to reduce gamma power in both regimes, with the persistent regime exhibiting a more pronounced deficit. Among the three parameters, E[-&gt;]I synaptic strength was the strongest contributor to the synergistic loss of gamma power. Two-dimensional bifurcation analyses further revealed that this differential vulnerability arises from a narrower margin of oscillatory stability in the persistent regime, where the parameter values producing maximum gamma power sit closer to the Hopf bifurcation boundary. Together, these findings identify the persistent regime as intrinsically more fragile than the stimulus-locked regime, with the implications for understanding regional patterns of synaptic pathology and cortical gamma oscillations with distinct dynamics in SZ. Author summaryWorking memory depends on stimulus-locked gamma oscillations in sensory cortices such as primary visual cortex (V1) for encoding stimulus information, and persistent gamma oscillations in prefrontal cortex (PFC) for maintaining this information after stimulus offset. In schizophrenia (SZ), gamma power is reduced in both V1 and PFC, and postmortem human brain studies suggest that the underlying synaptic alterations are more severe in V1 than in PFC. Our computational modeling results suggest that this regional pattern arises because persistent gamma oscillations are intrinsically more fragile than stimulus-locked gamma oscillations, so that smaller synaptic alterations are sufficient to disrupt gamma oscillations in PFC while larger alterations are required to produce comparable disruption in V1. Together, these findings give rise to a differential vulnerability model of cortical gamma oscillations in SZ, linking the regional patterns of synaptic pathology to the deficits in gamma oscillations observed across sensory and prefrontal cortices in the illness.

Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.

Schizophrenia (SCZ) is a severe and debilitating neurodevelopmental disorder with lifelong impact on everyday life. Disruptions in synapse functions play a key role in its complex and poorly understood etiological and pathological mechanisms. Here, we investigated both the molecular composition and the spontaneous and stimulated functional properties of synapses in neural organoids from SCZ individuals. Air-liquid interface forebrain organoids (ALI-FOs) were generated from induced pluripotent stem cells (iPSCs) derived from three individuals with SCZ and three healthy controls. At day 170 synaptosomes were enriched and analyzed by data-independent acquisition mass spectrometry to profile the proteome, alongside with TMT-labeled phosphoproteomics both before and after acute KCl-induced depolarization. In parallel, we characterized the PTMome of the surrounding cellular environment, comprising phosphorylation, peptides with free and reversibly modified cysteines, and sialylated N-linked glycopeptides. Functional glutamatergic and GABAergic activity was assessed using calcium imaging to capture spontaneous neuronal signaling. Both conditions exhibited mature synaptic structures, while growth cones were observed only in SCZ-derived ALI-FOs, indicative of ongoing or delayed synaptogenesis. Proteomic analysis of synaptosome preparations revealed 358 differentially regulated proteins between SCZ and controls and 125 phophoproteins with altered phosphorylation, which clustered into three major categories: (1) synaptogenesis and synapse signaling; (2) cytoskeleton and cell junctions; (3) growth cone dynamics and neurite outgrowth. Analysis of the PTMs in the surrounding cellular environment revealed regulation of key regulatory mechanisms in 526 proteins, supporting the synaptic alterations observed. Notably, components of the Wnt signaling pathway were consistently dysregulated across both the synaptosome preparation and the PTMome in SCZ-derived ALIFOs as compared to controls. Depolarization-induced phospho-signaling revealed SCZ-specific response enriched in synaptic vesicle trafficking pathways. Together, these findings provide new insights into early synaptic alterations in SCZ, highlighting changes not only in protein composition, but more in protein regulatory mechanisms underlying synaptic signaling.

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

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.