The Positive and Negative Syndrome Scale (PANSS) groups symptoms into three categories, but factor analyses suggest five dimensions with superior psychometric properties. Exploratory graph analysis (EGA) offers a novel network-based approach that provides additional information such as connection of domains, bridge symptoms, and centrality measures. We applied EGA to PANSS data from 1213 participants with schizophrenia at baseline and after six weeks of treatment. We identified symptom clusters with community detection algorithms, item stability with bootstrapping, and the connecting role of individual items with bridge centrality metrics. EGA consistently revealed five communities: positive symptoms, negative symptoms, cognitive disorganization, depression/anxiety, and hostility/excitement. The latter was less stable and its symptom P6 (suspiciousness) moved to the positive symptom domain at endpoint. Other item assignments were stable, except for items P5 (grandiosity), and G8 (uncooperativeness). P4 (excitement), P6, G8, and G15 (preoccupation) emerged as key bridge symptoms. Overall, the replication of five factors with a different method underlines their clinical importance.
Delays in seeking help are common in schizophrenia and are associated with negative outcomes. In addition to structural barriers, there is growing evidence that subjective interpretations of psychotic experiences, including delusions, voices, and religious or spiritual attributions, play a crucial role in recognizing symptoms and seeking care. This study explores how individuals diagnosed with schizophrenia describe the onset of psychosis, interpret their experiences, and navigate pathways toward or away from psychiatric care. We conducted semi-structured interviews with 16 individuals with schizophrenia. Data were analyzed using inductive thematic coding and narrative analysis to capture the experiential and interpretive dimensions of psychosis and help-seeking behaviors. We present three interconnected narrative themes that address the research question. First, participants’ experiences revolved around a moral dichotomy involving themes such as God and the devil, good and evil, and power and weakness. Second, participants described ‘nearly real’ sensory experiences, including voices and delusions ranging from familiar to imperative and fearsome. Third, the narratives revealed an ongoing struggle between private and shared realities, involving efforts to define boundaries and regain coherence. These experiential frameworks actively shaped the recognition of symptoms, trust in others, and the timing and direction of seeking help. Psychotic experiences function not only as symptoms but also as organizing narrative forces that influence pathways to care. Narrative-sensitive and metacognitive approaches may improve early engagement and reduce treatment delays.
Schizophrenia involves marked deficits in sensory-guided behavior, yet the behavioral consequences of N-methyl-D-aspartate (NMDA) receptor hypofunction for auditory decision-making, and whether they differ by sex, remain unclear. We trained female and male rats on an operant auditory oddball task requiring responses to rare deviant tones (go context) while withholding responses to frequent standard tones (no-go context) across three inter-stimulus intervals (ISIs), and tested performance after a single dose of the NMDA receptor antagonist MK-801 using signal detection theory. We subcutaneously injected MK-801 (0.1 mg/kg; 0.075 mg/ml) to generate the drug-induced group, and saline solution 0.9% to produce the control group, across female and male rats. MK-801 reduced discrimination sensitivity, but through sex-dependent response channels. In females, the deficit was carried mainly by reduced correct detections of deviant tones, alongside a more conservative response criterion. In males, the sensitivity loss was weaker and ISI-dependent but was accompanied by increased false alarms to standard tones and faster false-alarm responses, indicating diminished response withholding. These effects were most pronounced at the longer ISIs and were expressed as immediate post-injection shifts rather than progressive session-by-session drift. We quantified all effects with linear mixed-effects models and Holm-corrected planned contrasts. Together, these findings show that acute administration of the NMDA receptor blockade disrupts auditory-guided behavior through dissociable, sex-specific response channels, providing a behavioral framework relevant to abnormalities associated with schizophrenia.
Schizophrenia is associated with deficits in input processing, but the underlying neural dynamics of this deficit remain unclear. A recent model proposes temporal imprecision as a basic disturbance driving the input processing deficit. To address the question of whether temporal imprecision affects all three domains of the brain’s signal (e.g., phase, time, and frequency) as early as first episode schizophrenia, we analyzed magnetoencephalography (MEG) data from 25 first-episode schizophrenia (FESZ) participants and 24 healthy controls (HC) during a passive auditory oddball task with standard, pitch deviant, and duration deviant tones while watching a silent movie. We quantified temporal precision via (i) intertrial phase coherence (ITPC), (ii) intrinsic neural timescale (INT), and (iii) power spectral density (PSD) heterogeneity. For all three signal domains, we also calculated their temporal variability in sliding windows over the MEG recording. FESZ showed reduced intertrial phase coherence to both deviant tones, with a broader time and frequency range for the duration deviant ITPC reduction. Intrinsic neural timescales were prolonged in FESZ subjects. PSD profiles were more heterogeneous and broader during the auditory task in the FESZ group. FESZ subjects also showed increased temporal variability in all three signal domains across sliding windows. Finally, significant associations were observed between temporal variability in all three signal domains, including their association to impaired duration deviant mismatch negativity amplitude in first episode schizophrenia, whereas these associations were largely absent for healthy participants. We conclude that first-episode schizophrenia shows convergent temporal imprecision at specific time points as well as between time points in all three signal domains including phase, time, and frequency; this is consistent with temporal imprecision as a domain-general basic disturbance of input processing in schizophrenia.
There is growing interest in using digital health technologies to overcome limitations of traditional negative symptom assessment in schizophrenia spectrum disorders (SSD). For example, computerized speech analysis has been used to quantify speech and language changes associated with negative symptom severity in SSD. However, the large number of speech features and variability across studies make it difficult to determine the features with the greatest clinical utility. The present study aimed to identify the most robust speech-based markers of negative symptom severity by comprehensively evaluating their psychometric properties in a sample of individuals with SSD. Data were analyzed from 62 SSD participants who completed clinical assessments and speech tasks at baseline and follow-up visits. Thirty-eight acoustic and linguistic speech features were evaluated for test-retest reliability within visits, associations with clinician-rated negative symptoms, convergent and discriminant validity, specificity for negative symptom severity, and associations with participant clinical and demographic characteristics. Consistency of findings was evaluated across the two study visits, treating the second visit as a within-study replication sample. Three features (speech proportion, speech rate, unfilled pauses) consistently showed adequate or better reliability, correlations with negative symptoms across tasks and visits, and further demonstrated discriminant validity, specificity, and lack of associations with antipsychotic medication and extrapyramidal symptoms. Speech rate also consistently demonstrated convergent validity with an alternative negative symptom measure and was the most reliable feature when evaluated at the level of a single task administration. These findings advance the clinical validation of speech-based digital biomarkers for negative symptom assessment in SSD.
Treatment-resistant schizophrenia (TRS) affects roughly 20–30% of people diagnosed with schizophrenia and is linked to poorer clinical and functional outcomes. Its molecular basis, however, remains only partly understood. In this study, we integrated transcriptome-wide association study (TWAS) results from two large schizophrenia genome-wide association studies (GWAS): one reflecting broad schizophrenia liability and another using a clozapine-treated phenotype as a proxy for treatment resistance. These TWAS profiles were intersected with 48 curated ageing-related gene sets covering NAD metabolism, mitochondrial function, cellular senescence, synaptic plasticity, complement signalling and glial biology. In the original curated analysis, both general schizophrenia and TRS showed enrichment in long-term potentiation, mitochondrial bioenergetics, NAD and sirtuin pathways, complement-mediated pruning and glial signatures. This pattern is consistent with shared ageing-related vulnerability across schizophrenia phenotypes. At the same time, TRS showed selected quantitative and directional differences at key nodes within this shared architecture. Key differences included nominal shifts in PPP1R1B (DARPP-32), stronger influence of PPP3CC, DRD2, DRD3, DRD5 and synaptic vesicle genes, broader mitochondrial and oxidative phosphorylation burden, a stronger negative NAMPT signal with TFAM elevation, mixed mitochondrial sirtuin signals, elevated SLC2A1 and amplified complement enrichment. Sensitivity analyses showed that while most pathway enrichments were attenuated under stricter TWAS-filtered membership, formal matched-tissue key-gene tests confirmed significant differences for only four key genes: TFAM, SIRT5, SLC2A1 and C4A, and high concordance persisted in a broader Hallmark comparator set. The findings support a working model in which TRS shares broad ageing-related transcriptomic architecture with schizophrenia but shows selected quantitative and directional differences at key nodes, potentially constraining circuit adaptability under chronic D2 receptor blockade. The identified gene modules provide a hypothesis-generating foundation for future biomarker studies and stratified adjunctive trials targeting mitochondrial resilience, NAD metabolism and metabolic flexibility; however, extensive independent replication, functional validation and clinical testing would be required before any translational application.
This brief’s objective was to examine variation in first-episode psychosis (FEP) incidence rates by applying previously published study criteria to U.S. MarketScan claims data. Estimated FEP incidence rates ranged from 20 to 163 per 100,000 individuals, highlighting the need for standardization. Factors contributing to this variation included ICD coding definitions, age range, duration of continuous enrollment prior to the index diagnosis, minimum number of psychosis-related claims, and antipsychotic prescription requirements.
The early phase of schizophrenia is critical for rehabilitation outcomes: LAI antipsychotics can help in the clinical stabilization, but Evidence-Based Psychosocial Interventions (EBPI) are important to improve real-world psychosocial functioning. The present study aimed to assess the implementation and outcomes of EBPI in real-world clinical settings in people in the early phase of schizophrenia treated with LAI. Individuals diagnosed with Schizophrenia with an onset in the previous 5 years and stabilized with LAI treatment accessing 15 different centers were included in this prospective observation study with a 1-year observation follow-up. Rates of implementation of EBPI were recorded: participants receiving at least one EBPI were included in the “EBPI” group, and the others were included in the “Non-EBPI” group. Groups were compared on drop-out rates and clinical and functional outcomes at 3-, 6- and 12-months observations. A total of 116 participants were recruited in the study, 43 (37.07%) of which underwent at least one EBPI. A total of 68 (58.6%) participants completed the 1-year observation. No significant differences in drop-outs were observed between “EBPI” and “Non-EBPI” groups. Participants in the “EBPI” group showed superior improvements in real-world psychosocial functioning in longitudinal comparisons (12 months; p = 0.032) and at all time-points (all p < 0.05). Both groups showed improvements in core symptom domains, without other significant between-groups differences. EBPI are effective in improving psychosocial functioning in real-world clinical practice, but their dissemination is still limited. LAI antipsychotics are effective in clinical stabilization in the early phase of schizophrenia.
Social-affective changes are early indicators of psychosis relapse, yet their dynamic and subjective nature makes them difficult to capture between routine clinical assessments. Smartphone-based ecological assessments offer a method for capturing real-time social experiences in daily life. To address this gap, we examined whether social contact and social experience, measured through smartphone-based assessments, were associated with relapse following a First Episode of Psychosis (FEP), and evaluated whether smartphone data could predict relapse using machine learning. This longitudinal study included 256 individuals with FEP who completed at least one smartphone assessment, recruited from 10 Early Intervention Services across England and Wales between 2020-2023. Participants completed baseline clinical assessments and up to 30 days of daily smartphone surveys assessing social contact (alone vs with others) and social experience (a composite measure of emotional response to social contact). Relapse was assessed via structured interviews and electronic health records at 4, 8, and 12 months. Of 256 participants analysed (mean age 25.7 years [SD 5.3], 44.5% female), 8.2%, 13.5%, and 20.1% relapsed within 4, 8, and 12 months. Higher social experience consistently predicted reduced relapse risk across follow-ups, with similar effects for daily and momentary measures, while social contact showed inconsistent associations. Machine learning models using five smartphone assessments within 30 days achieved a validation accuracy of 0.790 (AUC 0.829) for predicting 12-month relapse, while data from a single smartphone assessment within 7 days achieved an accuracy of 0.715. These findings suggest that brief smartphone-based self-reports of social experience provide a low-burden, scalable tool for detecting early relapse risk and supporting more timely, personalised interventions in psychosis care.
Cerebellar dysconnectivity has been repeatedly linked to psychosis and is often accompanied by disruptions in thalamic and cortical regions. These disturbances are broadly consistent with the triple network model, which conceptualizes psychopathology as arising from abnormal interactions among the salience (SAL), default mode (DMN), and executive control (ECN) networks. However, how the cerebellum interacts with thalamic and cortical components of these networks across different psychosis risk stages and early psychosis remains unclear. Resting-state functional MRI from 37 first-episode psychosis (FEP) patients, 63 clinical high-risk (CHR) individuals, 41 unaffected relatives (URs) of schizophrenia patients, and 100 healthy controls (HCs) were analyzed. The cerebellum and thalamus were parcellated according to their functional connectivity with cortical functional networks, and the DMN, SAL, and ECN subdivisions across all three regions were used to estimate cerebellar-cortical and cerebellar-thalamic connectivity across groups. Compared with HCs, FEP patients showed widespread increases in cerebellar-cortical connectivity across all three networks, together with reduced cerebellar-thalamic connectivity, most prominently within SAL-related circuits. CHR individuals exhibited predominantly increased connectivity, with localized disruptions across cerebellar, thalamic, and cortical regions. URs did not show significant connectivity differences relative to HCs. By extending the triple network framework to include cortico-thalamo-cerebellar pathways, this study characterized how cerebellar network connectivity differs across familial risk, CHR, and FEP groups. The observed pattern suggests that early changes in CTC circuits correspond to disruptions described within the triple network model, and highlights the potential relevance of cerebellar and thalamic involvement when characterizing network alterations across the psychosis spectrum.
The Clinical High-Risk for Psychosis (CHR-P) paradigm underpins early detection strategies and informs the DSM-5 construct of Attenuated Psychosis Syndrome (APS), yet its discriminative predictive validity relative to CHR-P-negative help-seekers has not been systematically quantified. We conducted a systematic review and meta-analysis of longitudinal studies comparing transition to psychosis among help-seeking individuals according to CHR-P status. PubMed/MEDLINE and the Cochrane Library were searched from inception to June 22, 2026. Eligible studies included help-seeking samples assessed with validated CHR-P instruments and reporting psychosis transition outcomes separately for CHR-P-positive and CHR-P-negative participants. Random-effects meta-analyses estimated transition prevalence and relative risks (RRs), while heterogeneity, publication bias, and moderators were examined. 14 studies including 4477 participants (2220 CHR-P-positive and 2257 CHR-P-negative) met inclusion criteria. Estimated transition rates were 14.7% [95% CI, 9.7-21.7%) among CHR-P-positive individuals and 1.6% (95% CI, 0.8-3.2%) among CHR-P-negative individuals. CHR-P status was associated with an almost ten-fold increased risk of transition to psychosis (RR, 9.8; 95% CI, 4.5-21.82), with no significant moderation by follow-up duration or sample characteristics. These findings demonstrate strong discriminative and predictive validity of CHR-P criteria among help-seekers, supporting attenuated psychotic symptoms as a clinically meaningful pre-psychotic phenotype. Results support consideration of APS in DSM-6 within a prognostically grounded, stepped-care framework rather than as a categorical disorder.
Tardive dyskinesia (TD) is a persistent, iatrogenic movement disorder arising from long-term use of dopamine receptor antagonists, particularly antipsychotics; however, its clinical and economic impact among adults with schizophrenia remains poorly characterized in real-world settings. This retrospective, matched-cohort analysis used two large U.S. claims databases (PharMetrics Plus and MarketScan Medicaid) to evaluate treatment patterns, healthcare resource utilization (HCRU), and costs among adults with schizophrenia with and without TD. Patients were propensity score matched 1:5 for age, sex, index year, and comorbidity burden. TD was identified in 2.2-2.6% of records, with affected patients being older, more often female, and exhibiting greater medical complexity than those without TD. Following matching, TD was associated with greater use of higher-risk antipsychotic regimens, including nearly double the use of first-generation agents and long-acting injectables, and a twofold to fourfold greater anticholinergic burden. Adherence to antipsychotic therapy was comparable between groups. Across both databases, patients with TD demonstrated substantially greater HCRU and costs, with all-cause expenditures elevated by 56-66% and schizophrenia-related costs by 49-103% versus patients without TD. Approximately one in five individuals with TD received a vesicular monoamine transporter 2 inhibitor, with these patients exhibiting the highest HCRU and costs, suggesting greater disease burden and treatment intensity. TD imposes a considerable clinical and economic burden in schizophrenia underscoring the need for earlier recognition, evidence-based treatment, and preventative strategies, including rational antipsychotic selection and proactive monitoring, to mitigate the long-term impact of TD.
Clozapine is the preferred treatment for refractory schizophrenia. However, clozapine use is constrained by the risk of clozapine‑induced seizures (CISs). The molecular mechanisms behind CISs are complex and poorly understood. The objective of this study was to identify the core targets and signaling pathways contributing to CISs using network pharmacology and molecular docking. Potential targets for clozapine and seizures were screened using multiple databases, and overlapping targets were identified. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualized in Cytoscape to identify core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the core targets were performed, and a disease-target-pathway-drug network was constructed. The docking of clozapine with the core targets was evaluated to determine the stability of their interactions. Of the 656 potential targets for clozapine and 1260 targets for seizure, 104 targets overlapped. PPI analysis of the overlapping targets yielded 12 core targets. KEGG pathway enrichment analysis demonstrated that glutamatergic, dopaminergic, and GABAergic synapses may be key pathways mediating CIS. The molecular docking results showed that clozapine had strong binding affinities for the core targets, BDNF, GRIN2B, GRIN2A, and GAD1. Thus, clozapine may interfere with the glutamatergic, dopaminergic, and GABAergic synaptic pathways by modulating BDNF, GRIN2B, GRIN2A, and GAD1. Modulation of these core targets may contribute to excitatory-inhibitory imbalance in the central nervous system, thereby potentially increasing seizure susceptibility. This study provides an integrative perspective on the potential pathophysiology of CIS and suggests directions for future experimental validation and risk intervention strategies.
Stressful life events (SLEs) are a risk factor for psychosis; however, evidence on the impact of SLEs in individuals with first-episode psychosis (FEP) is limited. The current study draws on longitudinal data from the social mind study (ISRCTN85485447) and examines whether SLEs predict subsequent symptom severity, functioning, and relapse among individuals with first-episode psychosis (FEP). We hypothesised that greater exposure to SLEs at baseline would be associated with poorer clinical outcomes at follow-up. Data from 265 FEP participants across 10 sites in the United Kingdom were examined to investigate the associations between baseline SLEs and changes in symptom severity, functioning, and relapse over a 1-year follow-up. Statistical models were adjusted for age, sex, ethnicity, and site. Greater baseline SLE exposure predicted more severe general psychopathology both across assessment timepoints (p < 0.05) and at 12 months (p < 0.05). Baseline SLEs predicted poorer functioning (measured using GAF symptoms and disability) across assessment timepoints (p < 0.05). Baseline SLE exposure was not associated with increased odds of relapse. In conclusion, this study shows that FEP individuals who were exposed to SLEs prior to baseline exhibited more severe general psychopathology and poorer functioning. SLEs assessment should be integrated into early psychosis care and inform early intervention strategies addressing social stress.
Abstract Schizophrenia has been associated with disturbances in perceiving affordances, i.e. action possibilities offered by the environment. However, empirical research has largely relied on static laboratory tasks that poorly capture the dynamic perception-action loops of everyday environments. In this exploratory study, we used immersive virtual reality (VR) to examine environmental exploration and interaction in patients with schizophrenia and healthy controls ( n = 19 each). Participants completed baseline questionnaires including self-report measures of anomalous world experience and were exposed to natural and urban 360° video environments and an interactive VR game. Their field of view was recorded and manually coded using a predefined coding scheme. Subjective affect, stress, and presence were assessed before and after VR exposure. Patients with schizophrenia showed reduced visual exploration of the environments, reflected by fewer gaze shifts per minute compared with controls, particularly in urban scenes. In the interactive VR game, overall object interaction patterns were comparable, although patients showed a tendency toward longer latencies before initiating social interaction with a virtual non-player character. Reduced fixation of the character’s face was strongly associated with domains of anomalous world experience related to other persons, language, and atmosphere. Qualitative observations further suggested that immersive environments could interact with the sense-making of psychotic experiences in a few participants. Although preliminary given the limited sample size, these findings indicate subtle alterations in how patients with schizophrenia explore their surroundings, while basic object interaction remains preserved. Immersive VR paradigms may provide a promising experimental platform to investigate altered subject-world relations in psychosis.
Research suggests a need for more ecologically valid assessments of emotion recognition in aggressive individuals with psychotic spectrum disorder (PSD). We employed a task featuring dynamic, multimodal (visual and auditory) expressions of a broad range of positive and negative emotions. Emotion recognition accuracy and misclassification patterns were compared between individuals with PSD and a history of interpersonal aggression (PSD+AGG; n = 79), individuals with PSD without such a history (PSD-AGG; n = 72), and healthy controls (HC; n = 86). Analyses of variance investigated effects of presentation modality (visual, auditory, multimodal), emotion category (12 emotions), valence (positive, negative), and arousal (high, low). Across analyses, the PSD+AGG group showed significantly lower accuracy than the PSD-AGG group, which in turn showed significantly lower accuracy than the HC group. Misclassification patterns revealed that the PSD+AGG group was more likely to misclassify negative emotions as positive emotions compared to the PSD-AGG group. Multiple regression analyses indicated that accuracy was most strongly predicted by fluid intelligence and semantic understanding of emotion words in individuals with PSD, with significant additional effects of gender, history of substance use disorders in remission, and educational attainment. PSD group remained a significant predictor of accuracy after controlling for these factors. In summary, individuals with PSD and a history of interpersonal aggression exhibit more pronounced deficits in emotion recognition than those with PSD alone. This underscores the potential value of incorporating emotion recognition assessment and training into clinical interventions to reduce aggression risk and improve social functioning in individuals with PSD.
BACKGROUND:Schizophrenia is a severe mental disorder with significant impact on quality of life (QoL). Reliable measurement of QoL is essential for evaluating treatment outcomes. METHODS:We applied the COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) systematic review guideline to evaluate the psychometric properties of Lehman's Quality of Life Interview (QOLI), the Lancashire Quality of Life Profile (LQOLP), and the Manchester Short Assessment of Quality of Life (MANSA) as patient-reported outcome measures (PROMs). RESULTS:The combined search of PubMed and EMBASE yielded 19 included studies: 4 for QOLI, 10 for LQOLP, and 4 for MANSA. The overall results of the measurement properties across all three scales are largely insufficient or indeterminate. Evidence for several measurement properties is missing for the individual scales, with studies on content validity in particular being absent for all three scales. CONCLUSION:All three scales fall in COSMIN category B, meaning they have potential to be recommended but certain important evidence for recommendation is missing. However, newer scales - such as the Schizophrenia Quality of Life Scale - have been developed using more modern approaches. Consequently, prioritizing the further evaluation of these newer instruments may prove more productive than continued research into older scales.
Virtual reality (VR)-assisted avatar therapy has shown promising effects for reducing voice-related distress and overall severity of persistent auditory verbal hallucinations (AVH) in psychosis, yet the mechanisms underlying these improvements remain unclear. Emotional processes may play a role during therapeutic encounters with simulated voices, but it is unknown whether treatment effects involve broader changes in emotion regulation. We conducted secondary analyses of the CHALLENGE randomized clinical trial (N = 270), comparing a seven-session immersive VR-based avatar therapy with enhanced treatment as usual (standard care plus additional supportive counseling). Mediation models tested whether changes in cognitive reappraisal or expressive suppression, assessed using the Emotion Regulation Questionnaire (ERQ), mediated treatment effects on AVH severity and frequency at treatment end. Randomization to VR-assisted therapy did not significantly change ERQ reappraisal or suppression. Although higher reappraisal at follow-up was associated with lower AVH severity, no significant indirect effects were observed. These findings suggest that improvements following VR-assisted avatar therapy are unlikely to be explained by changes in self-reported trait emotion regulation strategies and may instead reflect more context-specific processes during voice confrontation.
Schizophrenia (SCZ) is a chronic brain disorder with significant impacts on patients, families, and society, affecting health, social life, and economic well-being. Despite extensive research, the biological basis of SCZ remains unclear. However, evidence suggests that disruptions in brain development, including neurogenesis, neuronal migration, synaptogenesis, and circuit maturation, may contribute to the risk of developing SCZ later in life. This review integrates findings from in vivo and in vitro studies on SCZ tissues, providing a comprehensive overview of neurodevelopmental alterations, with a particular focus on neurogenesis. We examine alterations in brain trophic support, inflammatory states, and alterations in cell markers, molecular pathways, and genetic factors implicated in both neurogenic and broader developmental processes. Additionally, we explore anomalies in miRNAs and genetic variations, such as single nucleotide polymorphisms (SNPs) and chromosome structure alterations, linked to SCZ. This review provides a framework to guide future research on the genetic, cellular, and molecular mechanisms underlying SCZ, with particular emphasis on neurogenesis within a broader neurodevelopmental context.
While schizophrenia (SZ) etiology remains unclear, accumulating evidence implicates mitochondrial dysfunction, particularly complex-I of the respiratory chain and its essential free-electron scavenger subunit, NDUFV2, as a contributor to neuronal and behavioral impairments observed in SZ. Our recent studies suggest a potential role for the NDUFV2 pseudogene (NDUFV2P1) in NDUFV2 deficits. Here, we describe a mechanism by which NDUFV2P1 negatively controls NDUFV2 mRNA transport and its protein levels in SZ-derived lymphocyte cell lines (SZ-LCLs). We found increased NDUFV2P1 transcript levels in SZ frontal cortex postmortem specimens (SZ-FCX) and across all studied SZ-LCLs subcellular fractions. However, NDUFV2 levels were reduced in SZ-FCX and in all cell compartments, except for the nucleus, as compared to healthy subjects-derived LCLs (CTL-LCLs), suggesting its impaired nuclear export. Concomitantly, we observed increased NDUFV2P1, yet decreased NDUFV2 mRNA binding to NXF1, a key player in nuclear mRNA export. Overexpression of NDUFV2P1 in CTL-LCLs mimicked the SZ-state, reducing NDUFV2 levels and its binding to NXF1. The interactome of both mRNAs revealed an opposite binding profile for most RNA-binding proteins (RBPs) in SZ-LCLs compared to CTL-LCLs. Pathway enrichment analysis of the differentially bound RBPs to both transcripts revealed additional potential interference sites for NDUFV2 and NDUFV2P1, including ribosomal-, spliceosome-, and RNA transport-related RBPs. This study uncovers a new mechanism in which NDUFV2P1 interferes with RBPs involved in regulating NDUFV2 transport from the nucleus to mitochondrial-bound ribosomes. While further validation is necessary to substantiate this mechanism, the findings highlight NDUFV2P1 potential as a means for regulating mitochondrial function and consequently energy metabolism in SZ.
