Schizophrenia Research

Apathy is a major driver of long-term disability in schizophrenia, yet existing accounts focus on how patients evaluate the cost of action while neglecting their capacity to generate options for action in the first place. Using a brief, culture-fair option generation task (OGT) within the international CHANSS study, we examined this process in 150 patients with different stages of schizophrenia and 100 healthy controls across the UK, Spain, and China. The OGT requires drawing as many different paths as possible between two points on a touchscreen, yielding two measures: fluency (the number of paths that they generate) and uniqueness (the distinctiveness of those paths). Patients drew as many paths as controls but produced options roughly half as unique. Across patients, uniqueness was positively associated with verbal fluency and depressive symptom severity, but negatively associated with self-reported behavioural apathy. This suggests that increased apathy is associated with reduced ability to generate unique options (paths on the task). To examine the cognitive mechanisms further, we decomposed uniqueness into four exploratory measures: roaming entropy (spatial breadth of exploration), option elaboration (within-path development), perseveration (local repetition), and novelty maintenance (sustaining diversity over time). Together these explained 69% of the variance in motor-residualised uniqueness and attenuated the group difference by 80%, with roaming entropy as the dominant contributor. K-means clustering revealed three distinct patient profiles, each with a different clinical signature. A small subgroup generated options much like the control group. A larger subgroup retained spatial exploration but developed each option less and reported more depressive symptoms. A third subgroup showed broadly impaired exploration and the lowest verbal fluency. These findings establish option generation as a measurable behavioural phenotype in schizophrenia that relates to apathy and can be decomposed into specific cognitive mechanisms. They suggest that an impoverished option space, marked by reduced generation of unique possibilities for action, may be a remediable component of apathy.

Background and Hypothesis Identifying which patients with schizophrenia will remain stable and which will relapse is relevant to both trial design and clinical practice. We hypothesized that higher negative and lower positive symptoms at baseline would predict longer time to relapse. Study Design This analysis pooled individual participant data on 557 patients with schizophrenia randomized to placebo from five placebo-controlled antipsychotic withdrawal relapse-prevention studies, each with a double-blind phase of at least 6 months. Relapse was defined as a [≥]12-point increase in Positive and Negative Syndrome Scale (PANSS) total score from double-blind baseline at any time during the double-blind phase. Cox regression analyses modeled time to relapse with the three PANSS subscales, age and sex. Study Results PANSS Negative and Positive symptom subscales predicted relapse in opposite directions and at almost equal magnitude in the pooled model. Higher negative symptoms predicted lower relapse risk (hazard ratio (HR)=0.94 per point, 95% confidence interval (CI)=0.90-0.99) and higher positive symptoms predicted higher relapse risk (HR=1.06, 95% CI=1.00-1.13). PANSS General Psychopathology did not predict relapse (HR=0.98, 95% CI=0.95-1.02). Based on the pooled estimates, a 4-point higher baseline PANSS Positive score corresponded to a 27% higher relapse risk, while a 4-point higher baseline PANSS Negative score corresponded to a 21% lower risk. Conclusions These results may help predict relapse risk in clinical care and in clinical trial samples but require prospective validation.

Background. Clinical meaningfulness in schizophrenia trials requires evidence that symptom change is recognizable in clinical practice. Established anchors include a 1 point minimal improvement on the CGI-S and a 7 to 10-point minimal improvement on the Personal and Social Performance scale (PSP), alongside a minimal improvement of 20% on the PANSS negative symptom factor score (NSFS) conventionally applied in negative-symptom trials. Methods. These clinically meaningful anchors were applied as benchmarks to pooled 12 week completer data from two randomized, placebo-controlled trials of roluperidone in adults with schizophrenia and moderate to severe negative symptoms. Results. Roluperidone was associated with higher responder rates than placebo on all three endpoints: at least 20% NSFS improvement (66/176 [38%] vs 39/182 [21%]; RR=1.75, 95% CI: 1.25 to 2.45; p=0.0008), at least 1 point CGI-S improvement (68/167 [41%] vs 48/177 [27%]; RR=1.50, 95% CI: 1.11 to 2.03; p=0.0077), and at least 10 point PSP improvement (63/176 [36%] vs 44/181 [24%]; RR=1.47, 95% CI: 1.06 to 2.04; p=0.018). Effects were consistent across symptoms, global-severity, and functional outcomes, with no evidence of heterogeneity between studies. Conclusions. Across all three anchor criteria, roughly 1.5 to 1.75 times as many patients treated with roluperidone as with placebo reached thresholds of improvement that clinicians and patients would recognize as clinically meaningful, supporting its relevance for persistent negative symptoms in schizophrenia.

Background and Hypothesis Negative symptoms in schizophrenia spectrum disorder (SSD) are associated with poor functional outcomes and reduced quality of life; however, effective treatments remain limited. A better understanding of the underlying brain mechanisms is needed to develop better treatments. Neuroimaging studies implicate multiple brain networks in negative symptoms, though findings remain heterogeneous, potentially reflecting the multidimensionality of both symptoms and brain networks. Larger, more systematic dissections are required to identify the key hub(s) underlying negative symptoms. Study Design Structural MRI data from 394 participants (210 SSD, 184 healthy controls [HC]) were analyzed to identify cortical thickness and subcortical volume demonstrating both SSD-HC differences and associations with negative symptoms measured by the Brief Negative Symptom Scale (BNSS). Regions meeting both criteria were selected as seeds for resting-state functional connectivity analyses in 143 SSD patients to examine association with negative symptoms and their subdomains. Study Results The thalamus was the only region demonstrating significant structural abnormalities both in SSD and an association with BNSS total score (p-FDR<0.05). Functional-network-defined thalamic subregions were subsequently examined. Several thalamic hypoconnectivities were significantly corresponded with negative symptoms, involving thalamic subregions associated with the cortical default mode, somatosensory, medial temporal, and dorsal attention networks (p=0.001, corrected<0.05). Blunted affect showed the most extensive thalamic connectivity alterations, involving the striatum, cerebellum, and temporoparietal junction/superior temporal sulcus (TPJ-STS). Thalamic hypoconnectivity with TPJ-STS was also associated with overall negative symptoms and anhedonia. Conclusions This study identifies the thalamus as a central hub of negative symptom-related dysfunction in SSD and highlights specific thalamic subnetworks as potential targets for circuit-based interventions.

Objective: This study examined the prevalence of psychotic experiences (PE) and how early onset and persistence of PE contribute to risk and severity of mental disorders in adolescents at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and adolescents from a population-based control group (PBC). Methods: This is the second follow-up of a nationwide cohort study including 522 children at FHR-SZ (N=202), FHR-BP (N=120), and PBC (N=200). Participants were assessed at ages 7, 11, and 15 using a semi-structured interview to evaluate PE and mental disorders. Results: At age 15, adolescents at FHR-SZ reported more PE than PBC over the past six months (current) and the past four years, while adolescents at FHR-BP only reported more current PE. PE reported at two or three timepoints (persistent PE) predicted any Axis I disorder in mid-adolescence, corresponding to three- (OR 2.9, 95% CI [1.5-5.7]) and 21-fold (OR 21.4, 95% CI [2.8-162.3]) increased risks, respectively. Persistent PE also predicted multimorbidity, with three- (OR 2.8, 95% CI [1.0-7.6]) and four-fold (OR 4.1, 95% CI [1.2-14.1]) increased risks, respectively. This was after adjustment for sex, early mental disorders, and familial risk. Conclusions: This study demonstrates a strong link between persistent PE and mid-adolescence mental disorders. Our findings emphasize PE as important risk markers for mental disorders during mid-adolescence and highlight the importance of monitoring children with PE before age 7 who develop persistent symptoms.

Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

Background: Auditory verbal hallucinations (AVH) are among the most disabling symptoms of schizophrenia, yet the network-level mechanisms linking auditory dysfunction to hallucination severity remain poorly characterized, limiting targeted therapeutic development. Methods: Using resting-state fMRI and high-resolution surface-based parcellation (HCP-MMP), we examined auditory-language functional connectivity and mesoscale network organization in 56 patients with schizophrenia and 22 healthy controls (primary dataset, N=78). Pairwise auditory-language connectivity associations with hallucination severity (PANSS P3) were examined alongside auditory network community structure, assortativity, hub organization, and routing efficiency. To further characterize these parcel-level findings at the vertex level, we applied a region-growing approach to identify auditory-frontal connectivity patterns maximally associated with severity. In silico perturbation analyses tested the causal role of belt cortex connectivity. Key findings were independently replicated in 93 patients from the Human Connectome Project for Early Psychosis (HCP-EP), for a combined total of 171 participants. Results: Auditory-language connectivity disruptions were concentrated in belt cortex and specifically implicated ventral what-stream connections, with a vertex-wise analysis converging on the same anatomy. Auditory network segregation scaled with hallucination severity, with belt cortex emerging as the primary integrative hub governing auditory-to-language routing efficiency. Perturbation analyses showed that strengthening earlier hierarchy auditory regions reduced network segregation more than strengthening later-hierarchy regions. Reduced belt cortex coupling and elevated network segregation replicated independently in the HCP-EP sample. Conclusions: Auditory network disorganization scales with hallucination severity and replicates across independent samples, with belt cortex as the critical locus of connectivity disruption and network integration failure, identifying it as a candidate neuromodulatory target.

Individuals with schizophrenia show well-documented impairment in metaphor comprehension, often exhibiting a bias toward concrete, literal interpretations. While this tendency has traditionally been linked to psychopathological and cognitive factors, the contribution of perceptual processes remains underexplored. Here, we tested the hypothesis that figurative language impairment reflects altered perceptual processing, whereby the visual representations evoked by metaphors remain abnormally active and hinder abstraction. A sample of 143 individuals with schizophrenia and healthy controls was administered a novel paradigm where metaphors (e.g., Wisdom is a flashlight) served as primes for target words related to the metaphor vehicle based on visual (e.g., microphone), action (e.g., remote), or semantic features (e.g., lamp). While in healthy participants metaphors activated semantically associated words, individuals with schizophrenia showed sustained visual priming, emerging 1000 ms after metaphor presentation and persisting up to 1400 ms, with both groups showing reverse priming for action targets. Critically, greater visual priming predicted lower metaphor comprehension in patients, whereas greater semantic priming was correlated with better metaphor skills in controls. These results suggest that visual-perceptual representations are not only overactivated in patients compared to controls during metaphor processing but may also interfere with figurative comprehension. We argue that concretism arises from an imbalance between bottom-up sensory signals and top-down contextual priors, leading to the persistence of the visual representations and impaired abstraction. More broadly, these results support multimodal and predictive accounts of metaphor processing and point to altered perceptual dynamics as a previously unappreciated mechanism contributing to pragmatic impairment in schizophrenia.

Introduction: Disturbed interpersonal attunement is a core but poorly operationalised feature of the psychopathology of schizophrenia. Language Style Matching (LSM), the largely unconscious alignment of two speakers' function words during ordinary conversation, offers an observable, dialogue-derived index of this dyadic attunement. An open question is where altered alignment mark who a patient (a stable trait of inner experience) is or how they are (a fluctuating state that shifts with symptom severity)? Objective: To characterise LSM over 12 months in early psychosis relative to controls, and to test, at both between- and within-person levels, whether alignment covaries with core psychopathological dimensions across self-referential (autobiographical) and externally directed discourse. Methods: First-episode and recent-onset patients (n = 109) and controls (n = 60) completed semi-structured interviews at baseline and 12 months. LSM was computed per context and modelled with linear mixed-effects; a Mundlak decomposition partitioned the LSM-symptom association into between- and within-person components. Results: LSM is not a fixed trait: groups were indistinguishable at baseline but diverged by 12 months (Group x Timepoint {beta}=-0.018, p = .029), and the deficit was specific to autobiographical speech. Within individuals, autobiographical alignment tightened as formal thought disorder rose above a patient's own average and as negative symptoms worsened, independent of antipsychotic dose. Conclusion: Patients aligned less than controls when speaking about themselves, yet aligned more as symptoms deteriorated, a shift from self-generated toward partner-scaffolded speech when self-organisation fails. LSM indexes disordered self-anchoring and interpersonal attunement in the negative-disorganized dimension of psychosis.

Schizophrenia spectrum disorders (SSD) have been linked to immune dysregulation and altered intestinal barrier function, although findings across studies remain inconsistent. The present study investigated circulating markers of intestinal permeability and immune activation in individuals with early-stage SSD and healthy controls and examined their associations with clinical outcomes. Serum concentrations of intestinal fatty acid-binding protein (iFABP), zonulin, soluble CD14 (sCD14), bactericidal/permeability-increasing protein (BPI), and lipopolysaccharide-binding protein (LBP) were measured in 36 patients with SSD at baseline and one-year follow-up and in 36 matched healthy controls. Linear mixed-effects models adjusted for age, sex, and body mass index (BMI) were used to evaluate group differences and longitudinal changes. No biomarker differences between patients and controls, and no longitudinal changes within patients, remained statistically significant after correction for multiple testing. Similarly, biomarker concentrations were not associated with symptom severity, global functioning, or neutrophil-to-lymphocyte ratio (NLR). Exploratory analyses identified a robust positive association between BMI and zonulin concentrations and additional associations among iFABP, LBP, and sCD14. Exploratory mixed-effects models identified a negative non-significant association between iFABP and sCD14 after adjustment for age, sex, and BMI. Overall, the findings do not support a generalized alteration of gut permeability or immune activation markers in SSD. Instead, they suggest that variation in gut-related biomarkers may be more strongly influenced by metabolic and individual factors than by diagnosis or current symptom severity.

Schizophrenia may involve a fundamental disruption in the ability to construct a shared understanding of social reality, yet conventional neuroimaging studies have largely examined social cognition using simplified and highly structured paradigms that may not capture how individuals interpret complex and ambiguous interpersonal events in everyday life. Using an ecologically valid naturalistic fMRI paradigm, we examined shared and paranoia-related neural representations during ambiguous social narrative processing in 38 patients with schizophrenia and 46 healthy controls. Intersubject correlation was used to quantify neural convergence across individuals, whereas intersubject representational similarity analysis was used to examine how individual differences in paranoid ideation were reflected in neural representations. Compared with healthy controls, patients with schizophrenia showed reduced neural convergence within distributed systems supporting social inference, contextual integration, and salience attribution, including temporoparietal, temporal, insular, and inferior frontal regions. Furthermore, paranoid ideation was associated with altered neural representational structure. In healthy controls, higher paranoia was linked to reduced neural similarity across social-cognitive and affective regions, suggesting reduced convergence toward shared interpretations of ambiguous social information. In schizophrenia, paranoia-related representations showed sparse within-group associations but elevated patient-control differences across a distributed social-affective circuit, indicating a reorganization rather than a simple amplification of paranoia-related processing. Together, these findings demonstrate that schizophrenia involves both impaired alignment of neural responses during shared social meaning construction and organization of paranoia-related representations, providing an ecologically grounded framework for understanding abnormal social inference in psychosis.

BackgroundSocial dysfunction is a major source of disability in schizophrenia, yet the neural mechanisms that contribute to impaired social understanding remain poorly understood. Converging evidence points to the role of the default mode network (DMN) in integrating social information over time to construct interpretations of social behaviors. Here, we tested the hypothesis that individuals with schizophrenia show reduced stimulus-driven coordination between brain regions within the DMN during free viewing of naturalistic social stimuli. MethodsA sample of 124 adults (schizophrenia: n=63; healthy controls: n=61) viewed naturalistic video clips during fMRI. Inter-subject functional connectivity (ISFC) was computed within the two groups. Group differences were identified via permutation testing. We also explored group differences in other brain networks to examine whether effects were specific to the DMN. ResultsIndividuals with schizophrenia showed weaker stimulus-driven coupling within the DMN compared to healthy controls, specifically between areas such as the parahippocampal gyrus, precuneus, and medial prefrontal cortex. Group differences in ISFC were specific to the DMN. Furthermore, no between-group differences emerged for within-participant functional connectivity in the DMN, suggesting that the observed effects reflect reduced stimulus-driven coordination among DMN regions when processing social stimuli rather than a more general decline in DMN connectivity. ConclusionsSchizophrenia is characterized by impaired coordination within the DMN as it dynamically integrates social information over time, which could contribute to difficulties in constructing coherent interpretations of real-world social situations. These findings suggest that disrupted stimulus-driven network coordination might underlie social cognitive impairments in schizophrenia, highlighting the value of naturalistic paradigms for revealing network-level dysfunction under conditions that closely approximate real-world experience.

Background: Approximately 25% of individuals with 22q11.2 deletion syndrome (22q11DS) develop a psychotic disorder, and the syndrome shares key neurodevelopmental features with psychosis in the general population. The olfactory system develops early in utero, providing a window into gestational disruptions relevant to psychosis risk. We hypothesized that 22q11DS would show impairments in olfactory function and structural anomalies of the olfactory system relative to psychosis spectrum (PS) youth without a known genetic syndrome and typically developing controls (TD). Methods: Participants included individuals with 22q11DS (n=101), PS (n=56), and TD (n=52). Sinonasal symptoms, odor identification, and discrimination (Sniffin' Sticks) behaviorally. Structural 3T MRI measured olfactory bulb volume, sulcus depth, and sulcus length. Sample sizes vary per analysis. Results: Relative to TD, 22q11DS showed elevated sinonasal burden (p<.001), lower odor identification (p<.001), and lower odor discrimination (p<.001). PS showed elevated sinonasal burden (p<.001) and marginally lower odor identification (p=.06), but no discrimination deficit. Olfactory bulb volume was significantly smaller in 22q11DS versus TD (p=.007, r=.39); PS showed a non-significant trend (p=.07). Olfactory sulcus depth (p=.52) and length (p=.82) did not differ across groups. Conclusions: 22q11DS is associated with elevated sinonasal burden, robust olfactory identification and discrimination deficits exceeding those of PS and reduced olfactory bulb volume. The co-occurrence of functional deficits and reduced bulb volume without sulcal anomalies may distinguish the 22q11DS olfactory phenotype from that of PS. These hypothesis-generating findings are consistent with partially dissociable neurodevelopmental mechanisms and support the utility of 22q11DS as a genetic model for psychosis risk.

Background: Schizophrenia has been conceptualised as a disorder of brain disconnectivity, with white matter abnormalities contributing to altered neural communication. However, fibre-specific white matter alterations in early illness and their potential sex-related differences remain insufficiently characterised. We applied fixel-based analysis to investigate sex-stratified white matter microstructural alterations in first-episode schizophrenia (FES). Methods: Diffusion MRI data from individuals with FES and healthy controls were stratified by biological sex. The male cohort included 79 patients and 29 controls, and the female cohort included 48 patients and 46 controls. Fixel-based analysis was performed separately in males and females to assess fibre density, fibre-bundle cross-section, and their combined measure. Head motion was included as a covariate in the fixel-based analyses. A descriptive follow-up voxel-scale analysis extracted mean fibre density from a binary mask derived from significant male fixels and applied the same region to the female cohort. Results: Males with first-episode schizophrenia showed significantly reduced fibre density compared with male controls, primarily in bilateral frontal white matter and a thin segment of the anterior corpus callosum. The voxel-scale follow-up confirmed lower mean fibre density in males within the significant fixel-derived mask. In contrast, females showed no significant group differences in any fixel-based metric or within the male-derived region. Conclusions: Early white matter microstructural alterations were detected in males with FES but not in females. These findings highlight a differential pattern emerging from sex-stratified analyses and support further investigation of sex-related differences in white matter alterations during the early stages of schizophrenia.

Background: Interoception refers to the processing, integration, interpretation, and regulation of bodily signals by the brain. It is crucial to motivational and affective functioning such as subjective experience of arousal (i.e., intensity of emotion). Previous studies found altered self- report of arousal in people with schizophrenia, but the underlying biological mechanism is unclear. This study aimed to investigate interoceptive processing and emotional experience in schizophrenia by triangulating self-report, cardiac dynamics, and heartbeat-evoked potential (HEP; an event-related potential that reflects cortical processing of heartbeats). Methods: A total of 39 participants with schizophrenia spectrum disorders (SZ; 36% female) and 31 healthy controls (HC; 35% female) reported subjective arousal level when viewing images of varying emotional intensity while electroencephalogram and electrocardiogram were being recorded. Results: We found that intense images led to larger heartrate decelerations and higher subjective arousal ratings in HC, but did not modulate heartrate changes in SZ and were less predictive of their subjective ratings. Subjective ratings were predictive of cardiac dynamics in HC, but not in SZ. SZ showed a less negative HEP amplitude than HC when viewing less intense images. Lastly, SZ with less severe positive and negative symptoms exhibited cardiac dynamics more similar to those of HC. Conclusions: These findings suggest both reduced cardiac reactivity to emotional stimuli and a disconnect between interoceptive afferent signals and cortical processing, leading to different subjective emotional experience in people with schizophrenia. Studying interoception using a multimodal approach may reveal important insights into the underlying mechanisms of altered emotional experience in schizophrenia.

Background: Nicotine dependence is a major contributor to early mortality in individuals with schizophrenia, yet effective treatments remain limited. Drug cue-reactivity is a key contributor to nicotine use. Although transcranial magnetic stimulation (TMS) can reduce nicotine use and cue-reactivity, conventional left dorsolateral parietal (DLPFC)-targeted TMS is less effective in those with schizophrenia, highlighting the need for alternative, circuit-based targets. Because default node network (DMN) function is implicated in schizophrenia, cue-reactivity, and nicotine use, we investigated whether DMN-targeted TMS modulates cue-elicited brain activity in nicotine-using individuals with schizophrenia. Study Design: 63 nicotine-using individuals (schizophrenia: n=31, non-psychosis control: n=32) participated in a randomized, crossover study comparing DMN-targeted and DLPFC-targeted TMS with pre/post-TMS neuroimaging and craving assessment. A nicotine cue-reactivity task was used concurrently with neuroimaging. Mixed-effect models were used to determine effects of TMS target and diagnosis, and model relationship between baseline craving and cue-reactivity change. Study Results: At baseline, we found a Cue Reactive Network composed of regions overlapping with the DMN, including clusters in the posterior cingulate cortex, medial prefrontal cortex, and bilateral lateral occipital cortex (voxel-wise p<0.005, cluster p<0.05). Baseline cue-reactivity in schizophrenia did not differ from controls. DMN-targeted TMS decreased cue-reactivity in schizophrenia across Cue Reactive Network (estimate=-0.180, p=0.009). DLPFC-targeted TMS did not impact cue-reactivity. We did not observe an effect of either TMS target in controls. Higher baseline unprovoked craving predicted larger decrease in cue-reactivity across the Cue Reactive Network (estimate=-0.034, p=0.004). Conclusion: DMN-targeted TMS is a promising intervention that modulates nicotine cue-elicited brain activity in schizophrenia.

Objective: Cognitive models of psychosis implicate maladaptive core schemas in the development and emergence of psychotic symptoms, but no study has tested temporal dynamics between schemas and psychotic symptoms in a large sample of clinical high-risk (CHR) youth. Given their sizable role in cognitive behavioral therapies, the first-line treatment for CHR youth, core schemas may be key to both symptom development and treatment in this population. Methods: Participants were 578 CHR individuals from the second North American Prodrome Longitudinal Study (NAPLS-2) assessed across five timepoints. Time-lagged mixed-effects models tested forward and reverse paths for each Brief Core Schema Scales subscale with both psychotic symptom and functioning changes, controlling for autoregressive effects, time-varying depression, and linear time. Results: Twenty of 36 schema outcome pairs showed significant prospective associations. Negative-other schemas were prospectively associated with worsening across nearly all psychosis symptom and functioning domains. Suspiciousness exhibited bidirectional associations with all four schema subscales. Grandiose ideas were uniquely prospectively associated with positive-self and negative-other schemas. Positive schemas were prospectively associated with decreases in suspiciousness, negative symptoms, and improvements in functioning. Effects were largely independent of depressive symptoms and robust across sensitivity analyses, with partial attenuation of self-schema effects on suspiciousness. Conclusions: Core schemas were prospectively associated with psychosis symptom and functioning change in CHR youth, with symptom-domain specificity and bidirectionality. These findings extend cognitive models of psychosis into CHR syndromes and highlight schemas as potentially modifiable treatment targets to improve outcomes in this population.

Recent computational approaches to speech in psychosis generate large multidimensional feature spaces capturing semantic and acoustic aspects of language production. However, the clinical relevance of individual measures often becomes difficult to interpret due to redundancy, interaction effects, and high intercorrelation among features. Building upon previous work constructing a single composite index derived from semantic features based on language model embeddings, we here build a second acoustic index derived from speech acoustic features. Our aim was to evaluate the differential performance of both indices in conjunction in PANSS symptom prediction in psychosis in a cross-linguistic setting, including positive symptoms (P1, P2, P3), negative symptoms (N1, N4, N6), and general measures (G5, G9). The dataset comprised five languages and 221 patients with schizophrenia spectrum disorder (SSD). Both indices showed predictive power for individual PANSS scores, while also demonstrating clinically important complementarity: semantic indices were more strongly associated with positive symptom dimensions (P2, P3, Total Positive), whereas acoustic indices showed stronger relationships with negative and general symptoms (N1, N4, G5, G9). Both domains shared predictive overlap for global measures, such as PANSS Total scores. These findings suggest that both indices capture complementary and partially overlapping dimensions of psychopathology. The proposed composite index framework contributes to the advancement of low-dimensional speech-derived markers of symptom severity variation, potentially informing vulnerability to relapse and remission in psychosis.

We conducted an open-label pilot study of bilateral nucleus accumbens-anterior limb of the internal capsule (NAc-ALIC) deep brain stimulation (DBS) in three patients with treatment-resistant schizophrenia (TRS). Clinical symptoms, global functioning, cognition, stimulation parameters and intracranial local field potential (LFP) were assessed over 24 weeks. Two patients met the prespecified clinical response criterion, defined as a [&ge;]40% reduction in Positive and Negative Syndrome Scale (PANSS) total score, by week 8 and showed PANSS reductions of 69.0% and 69.4%, respectively, at week 24. The third patient showed a 18.7% reduction at week 24. Responders showed improvements in global functioning and selected cognitive domains. Longitudinal LFP recordings revealed increased gamma-band relative power and reduced theta-band activity in responders, whereas these changes were less consistent in the non-responder. DBS was generally well tolerated, with transient stimulation-related adverse effects resolving after reprogramming. These findings provide preliminary clinical evidence supporting further investigation of NAc-ALIC DBS in TRS and suggest that individualized programming and intracranial physiological measures may contribute to the identification of treatment-response signatures.

Background: Schizophrenia Spectrum Disorders (SSD) is associated with spatially heterogeneous structural abnormalities across distributed brain systems, but the longitudinal evolution and neurochemical context of subcortical subregional changes remain poorly understood. We investigated longitudinal volume changes across thalamic, hippocampal, amygdalar, and brainstem subregions and their relationships with clinical characteristics and normative neurotransmitter distribution. Methods: A total of 357 SSD individuals with first-episode and 196 healthy controls were included. Clinical assessments were performed at baseline and at 1, 3, 5, 10, 15, and 20 years of follow-up. Using T1-weighted structural MRI, subregional volumes were quantified across the thalamus, hippocampus, amygdala, and brainstem. We examined baseline group differences, longitudinal volume changes, and associations with clinical variables, including symptom severity. Spatial patterns of regional associations were compared with normative maps of neurotransmitter receptor and transporter distributions. Results: Patients showed heterogeneous structural alterations across the examined subcortical subregions. The hippocampus showed prominent early volume deficits in specific subfields and demonstrated a strong association with antipsychotic medication doses. Amygdalar volumetric reductions were more widespread and were strongly associated with positive symptom severity. Localised structural abnormalities were also observed in the thalamus and brainstem, although these showed weak associations with clinical symptomatology. The spatial co-location of normative neurotransmitter maps with the structural and clinical associations revealed distinct overlapping with dopaminergic, GABAergic, glutamatergic, serotonergic and cholinergic systems. Conclusions: Longitudinal structural alterations in SSD showed marked anatomical heterogeneity across thalamic, limbic, and brainstem systems. Their spatial correspondence with normative neurochemical architecture suggests that regional and subregional structural vulnerability and clinical heterogeneity may be organized along distinct, partially overlapping neurotransmitter profiles.