Schizophr. Res. [JOURNAL]
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200 papers
Why is it hard to assess thought disorder? Clarifying the third domain of psychosis.
Palaniyappan L, Sreeraj VS, Venkatasubramanian G … +1 more , Voppel A
Schizophr Res · 2026 Jun · PMID 41819768 · Publisher ↗
Formal Thought Disorder (FTD) presents psychiatry's central paradox: it is one of the robust predictors of poor outcomes and polygenic risk in psychosis yet remains poorly defined and rarely measured clinically. We syste...
Formal Thought Disorder (FTD) presents psychiatry's central paradox: it is one of the robust predictors of poor outcomes and polygenic risk in psychosis yet remains poorly defined and rarely measured clinically. We systematically reviewed 50 years of FTD assessment (16 rating scales, 32 factor analyses) to understand this paradox. Research to date has implicitly treated FTD as a natural kind, a latent entity that causes observable signs. Yet, empirical evidence contradicts this assumption: we find radical heterogeneity in construct definition, non-replicability of factor structures at the item level, and no universally essential properties across items. We propose measuring FTD as a Constituted Practical Entity: a probabilistic cluster of linguistic-cognitive features whose interaction produces communication failure. In this framework, no single feature is necessary or sufficient; dysfunction emerges from their relationships, not from a single latent process. This reconceptualization reconciles the multi-dimensional nature of FTD with our attempts to measure it and offers a clear research path: establish consensus constituents, measure their interactions, and develop computational tools. Without addressing the conceptual foundations, technical advances will only perpetuate existing confusions. Our framework clarifies what is being measured in the name of FTD and guides the development of computational tools and clinically meaningful targets for this third domain of psychosis.
Negative symptoms and resting state functional connectivity: Leveraging ecological momentary assessment and individual-specific techniques.
Dalloul N, Kandala S, Moran E … +1 more , Barch DM
Schizophr Res · 2026 Jun · PMID 41812485 · Full text
There are indications that motivational deficits in psychotic and mood disorders are related to differences in functional connectivity. However, the literature is mixed, partly due to the limitations of traditional metho...
There are indications that motivational deficits in psychotic and mood disorders are related to differences in functional connectivity. However, the literature is mixed, partly due to the limitations of traditional methods in accounting for individual variability. Ecological momentary assessment (EMA) and individual-specific techniques can account for such variability. By leveraging these methods, this study aims to elucidate transdiagnostic relationships between motivational deficits and resting-state functional connectivity. 144 participants (29 schizophrenia/schizoaffective; 38 bipolar, 37 major depressive, 40 controls) completed EMA on motivation and pleasure (MAP) and resting-state BOLD scans. Individual-specific network connectivity matrices were calculated with an empirically validated template-matching technique. Bayesian hierarchical regression models assessed relationships between anticipatory and consummatory MAP and within-network connectivity, participation coefficient, and number of vertices for eight networks (default mode, cingulo-opercular, dorsal attention, ventral attention, salience, fronto-parietal, dorsal somato-motor, ventral somato-motor). Analyses demonstrated intact MAP for bipolar and major depressive disorders, and elevated MAP for schizophrenia/schizoaffective disorder. Moreover, MAP was positively related to within-network connectivity of the dorsal attention network, positively related to participation coefficient of the ventral attention network in schizophrenia/schizoaffective disorder, negatively related to within-network connectivity of the salience network in schizophrenia/schizoaffective disorder, and positively related to spatial extent of the salience network in controls. Overall, the findings highlight the role of attentional processes in MAP and suggest that underlying neural mechanisms vary by diagnosis. The results emphasize the complexity of MAP deficits and underscore the need for research to consider inter-individual variability to fully understand their phenomenology and neural basis.
Patient expectations for outcome with psychological intervention for psychosis.
Freeman D, Rosebrock L, Waite F
Schizophr Res · 2026 Jun · PMID 41807890 · Full text
BACKGROUND: Initial patient perceptions of a treatment's credibility, and expectations for improvement, have been shown to predict to a small degree outcomes for common mental health disorders. This study aimed to discov...
BACKGROUND: Initial patient perceptions of a treatment's credibility, and expectations for improvement, have been shown to predict to a small degree outcomes for common mental health disorders. This study aimed to discover: how patients with psychosis initially perceive psychological therapy's credibility and likely success; whether there are predictors of these first views; and, primarily, if such ideas predict improvement in persecutory delusions. METHODS: We analysed first therapy session data on credibility and expectancy from 195 patients with non-affective psychosis taking part in clinical trials treating persecutory delusions. Baseline assessments before randomisation to therapy were used to identify potential predictors of credibility and expectancy. First session credibility and expectancy scores were tested as predictors of persecutory delusion severity six months later. RESULTS: Most patients were optimistic about therapy's potential. Baseline delusion severity did not predict credibility, β = -0.02, p = .742, or expectancy, β = -0.03, p = .632. Higher psychological well-being predicted higher levels of expectancy, β = 0.23, p = .001. Higher levels of credibility, β = -0.17, p = .021, and expectancy, β = -0.17, p = .020, predicted lower severity of persecutory delusions six months later. Credibility, β = 0.00, p = .970, and expectancy, β = -0.21, p = .074, did not significantly predict uptake of therapy sessions. CONCLUSIONS: Treatment credibility and expectancy may account for a small proportion of improvement when psychological interventions are used to treat severe paranoia. The results are comparable to those for common mental health disorders. There was little prediction of patient variability in credibility and expectancy. It will be helpful to understand a patient's initial views on intervention so that any concerns can be addressed.
Challenges and priorities in researching and managing altered perceptual experiences: Shared academic and lived experience perspectives.
Richards SE, Davis A, Blake C … +8 more , Errington H, Singh J, Fernyhough C, Moseley P, Ramachandran P, Thomas N, Rossell SL, Toh WL
Schizophr Res · 2026 Jun · PMID 41807889 · Publisher ↗
Within clinical environments and empirical research, discussions of atypical perceptual experiences (APE; i.e., hallucination) tend to centre on voice-hearing (auditory-verbal hallucinations) in psychotic disorders, with...
Within clinical environments and empirical research, discussions of atypical perceptual experiences (APE; i.e., hallucination) tend to centre on voice-hearing (auditory-verbal hallucinations) in psychotic disorders, with other sensory modalities and psychiatric conditions often neglected. Similarly overlooked are lived experience (LE) perspectives of APE, despite valuable insights that may be gleaned to advance research and clinical practice. The present paper presents a participatory collaboration between a panel of five people with lived experience of APEs and seven APE researchers who worked together on a review of the literature on APEs. LE perspectives were synthesised by researchers with thematic analysis of material generated in five LE consultation sessions held during the course of the project. This revealed six primary themes: (i) challenges during diagnosis and treatment; (ii) what is missing in clinical environments; (iii) underacknowledged cultural and subcultural factors; (iv) stigma; (v) priority areas for developing treatments and; (vi) priority areas for advancing research. Overall, a common sentiment emerged, in that the perception and treatment of APE within the mental health system can often be highly stigmatising, disempowering and distressing. It is hoped that recommendations outlined here may forge more positive and productive treatment experiences for persons distressed by their APE, irrespective of diagnosis.
Motor activity-based prediction of the presence of apathy in schizophrenia.
Deng W, Servaas MN, Kos C … +4 more , Marsman JC, Renken RJ, Aleman A, van Tol MJ
Schizophr Res · 2026 Jun · PMID 41785723 · Publisher ↗
OBJECTIVE: Apathy, a reduction in self-initiated goal-directed behavior, is a quality-of-life diminishing characteristic of schizophrenia, which often goes underrecognized and undertreated. Actigraphy-derived motor activ...
OBJECTIVE: Apathy, a reduction in self-initiated goal-directed behavior, is a quality-of-life diminishing characteristic of schizophrenia, which often goes underrecognized and undertreated. Actigraphy-derived motor activity measures provide potential objective markers for assessing apathy, but the value for assessing clinically relevant levels of apathy has yet to be determined in patients with schizophrenia. METHODS: Patients with schizophrenia with (SZ+; n = 42) and without (SZ-; n = 40) severe apathy symptoms and a group of age and education matched non-affected individuals (NAC; n = 40) were included. Activity indices derived from actigraphy recordings on two weekend days were compared between the three groups. Logistic regression analyses were conducted to examine whether actigraphy indices could predict presence of 1) a diagnosis of schizophrenia and 2) severe apathy. RESULTS: Lower levels and lower variability of activity and step counts during weekend days and the most active ten-hour period were associated with the presence of a schizophrenia diagnosis, and presence of severe apathy within patients. These associations were independent of sociodemographic, lifestyle status and clinical confounders. Backwards regression revealed that mean steps during the most active ten-hour period exhibited the strongest predictor of apathy severity. CONCLUSION: Results suggest that amount and variability of physical activity as measured with an actigraphy device can help to identify individuals with schizophrenia with high levels of apathy. Especially, the number of steps taken during the most active hours could be used to screen patients with a presence of severe apathy, therefore informing further diagnostics and treatment.
Disentangling the relationship between psychiatric disorders, cardiometabolic abnormalities, and antipsychotics: A systematic review of genomic studies.
Shepherd R, Stacey D, Janetzki J … +3 more , Clark SR, Hyppönen E, Suppiah V
Schizophr Res · 2026 May · PMID 41780463 · Publisher ↗
Psychiatric disorders are often comorbid with metabolic syndrome (MetS), suggesting shared genetic architecture. This systematic review investigated the genetic connections between psychiatric disorders, antipsychotic us...
Psychiatric disorders are often comorbid with metabolic syndrome (MetS), suggesting shared genetic architecture. This systematic review investigated the genetic connections between psychiatric disorders, antipsychotic use, and MetS through genome-wide association studies and related genetic approaches. We systematically searched PubMed, Scopus, and Web of Science for relevant studies published between January 2005 and August 2025. Seventy-seven studies were included in the systematic review upon meeting the inclusion criteria. Substantial shared genetic architecture was found between psychiatric disorders and metabolic traits, particularly involving major depressive disorder (MDD), schizophrenia (SCZ), and body mass index (BMI). Key implicated pathways included lipid metabolism, glucose homeostasis, and inflammatory processes. Mendelian randomization studies provided evidence for causal relationships, notably a unidirectional effect of MDD on MetS, and bidirectional relationships between SCZ and BMI. Antipsychotic-induced weight gain showed a more specific genetic basis compared to broader psychiatric disorder-related MetS. Future research should focus on diverse populations, refined phenotype definitions, and translating genetic insights into clinical practice. The integration of pharmacogenomic scores with clinical data shows promise for personalizing treatment strategies in psychiatry.
Associations between Sleep Problems, Psychotic Experiences and Mental Disorders in Children at Familial High Risk of Schizophrenia or Bipolar Disorder and Population-based controls - The Danish High Risk and Resilience Study.
Søndergaard A, Hemager N, Wilms M … +7 more , Rohd SB, Krantz MF, Greve AN, Veddum L, Thorup AAE, Nordentoft M, Gregersen M
Schizophr Res · 2026 May · PMID 41775132 · Publisher ↗
BACKGROUND: Sleep problems are linked to schizophrenia or bipolar disorder and often precede the onset of manifest illness. Psychotic experiences and mental disorders during childhood are risk factors for later developme...
BACKGROUND: Sleep problems are linked to schizophrenia or bipolar disorder and often precede the onset of manifest illness. Psychotic experiences and mental disorders during childhood are risk factors for later development of schizophrenia and bipolar disorder. This study investigated whether nightmares, prolonged sleep latency, and nocturnal awakenings are associated with psychotic experiences and mental disorder in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and population-based controls (controls). METHOD: The study included 447 eleven-twelve-year-old children: 170 at FHR-SZ, 103 at FHR-BP, and 174 controls. Primary caregivers of the children provided information about nightmares, sleep latency, and nocturnal awakenings. Psychotic experiences and mental disorders were assessed with the semi-structured interview, The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children - present and lifetime version. RESULTS: Children with psychotic experiences had significantly higher odds of nightmares, prolonged sleep latency, and nocturnal awakenings, but only the association between psychotic experiences and nocturnal awakenings remained significant after adjustment for mental disorders. Children with mental disorder had significantly higher odds of nightmares, prolonged sleep latency and nocturnal awakenings. Associations between sleep problems and psychotic experiences and mental disorders were non-differential across familial risk-groups. CONCLUSIONS: Nightmares, prolonged sleep latency, and nocturnal awakening are associated with psychotic experiences and mental disorders in children at FHR-SZ and FHR-BP and controls. Sleep problems should be assessed in child and adolescent mental health services e.g. through anamnestic interviews or questionnaires. This may provide useful clinical information on an otherwise unrecognized marker of risk for mental health problems.
Prevalence of covert cerebrovascular changes in schizophrenia: A systematic review and meta-analysis.
Shi S, Wang J, Li H … +4 more , Qiu J, Zhu Y, Cao X, Li C
Schizophr Res · 2026 May · PMID 41775131 · Publisher ↗
BACKGROUND: Covert cerebrovascular changes, particularly cerebral small vessel disease (CSVD) and silent brain infarction (SBI), may contribute to neurobiological vulnerability in schizophrenia but remain underrecognized...
BACKGROUND: Covert cerebrovascular changes, particularly cerebral small vessel disease (CSVD) and silent brain infarction (SBI), may contribute to neurobiological vulnerability in schizophrenia but remain underrecognized. This meta-analysis aimed to estimate their prevalence and identify associated demographic and clinical factors. METHODS: Systematic searches of international and Chinese databases (through December 2024) were conducted to identify studies reporting CSVD and SBI prevalence in schizophrenia. Pooled prevalence estimates, sensitivity analyses, subgroup analyses, and meta-regressions were performed. RESULTS: From 6371 records, 124 studies (11,611 patients) were included. Pooled prevalence was: white matter hyperintensities (WMH) 26.3% (95% CI: 16.8-38.8), perivascular spaces 45.7% (95% CI: 1.3-98.2), brain atrophy (BA) 34.8% (95% CI: 31.0-38.8), and SBI 12.8% (95% CI: 6.2-24.7). Lacune ranged from 2.5% to 12.5%, and one study reported cortical superficial siderosis at 4.4%. Subgroup analyses indicated that age, imaging modality, exclusion of stroke/diabetes, and study region may influence prevalence. Meta-regression showed associations of BA prevalence with older age, family history, and more recent publication year. BA prevalence was significantly higher in patients than controls (PR = 6.5), whereas differences for WMH (PR = 1.3) and SBI (PR = 2.0) were not statistically significant. CONCLUSION: This meta-analysis synthesizes neuroimaging evidence on covert cerebrovascular changes in schizophrenia. WMH, SBI, and BA are frequently reported, although pooled estimates are highly heterogeneous. Case-control comparisons indicate a robust elevation in BA, whereas evidence for increased WMH or SBI relative to controls remains inconclusive. STRIVE-based definitions and systematic vascular risk assessment are needed to test schizophrenia-specific associations with covert vascular lesions.
Mediodorsal and pulvinar thalamus reductions across the psychosis spectrum.
Zeng V, Hoang D, Song SH … +23 more , Trotti R, Parker D, Raymond N, Iska N, Del Re EC, Coxon E, Rychagov N, Adhan I, Nisenson M, Hegde R, Reed A, Lai M, Ivleva E, Hill SK, McDowell J, Sweeney J, Lizano P, Tamminga C, Pearlson G, Gershon E, Keedy S, Clementz B, Keshavan M
Schizophr Res · 2026 May · PMID 41763163 · Publisher ↗
BACKGROUND: Abnormalities in thalamic structure and function are a consistent feature of psychosis spectrum disorders including schizophrenia (SZ), schizoaffective (SAD), and bipolar disorder with psychosis (BDP), yet th...
BACKGROUND: Abnormalities in thalamic structure and function are a consistent feature of psychosis spectrum disorders including schizophrenia (SZ), schizoaffective (SAD), and bipolar disorder with psychosis (BDP), yet the extent to which specific thalamic nuclei differ across diagnoses, and how these differences relate to cognition and psychopathology, remains unclear. We examined these questions, focusing on two nuclei - the mediodorsal (MD) and pulvinar (Pu), among individuals with psychosis (n = 2160) in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. METHODS: Whole thalamus, MD, and Pu were estimated using FreeSurfer. Group comparisons were performed to examine volumetric differences between neurotypical controls (NC) and: (1) traditional diagnostic groups and (2) biologically-defined Biotypes identified through unsupervised clustering of neurophysiological features. Spearman correlations were used to assess the associations between subthalamic nuclei volumes and cognitive performances. RESULTS: The MD volumes were significantly smaller in individuals with SZ, SAD, BDP and BT1 compared to controls (Cohen's d between -0.17 to -0.37). MD and Pu volumes positively correlated with some cognitive functions, notably in the right MD. CONCLUSIONS: This is the largest study to date examining thalamic nuclei volumes across both DSM diagnoses and psychosis Biotypes. We demonstrate that MD reductions are transdiagnostic yet most pronounced in BT1, supporting the Biotype framework over traditional nosology. The links between MD volume and cognitive performance suggest that nucleus-specific thalamic markers may help refine mechanistic models and stratify future treatment targets. Multimodal studies integrating electrophysiology and functional imaging are warranted to clarify nuclei-specific contributions to psychosis.
Phantom vibrations: An understudied marker of clinical risk for psychosis.
Pokorny VJ, Kaka T, Vargas T … +2 more , Pinkham AE, Mittal VA
Schizophr Res · 2026 May · PMID 41763162 · Full text
INTRODUCTION: Early identification of psychosis risk may lead to improved outcomes for those who go on to develop psychotic disorders. Despite significant advances in this domain, there remains a need for novel and valid...
INTRODUCTION: Early identification of psychosis risk may lead to improved outcomes for those who go on to develop psychotic disorders. Despite significant advances in this domain, there remains a need for novel and valid markers of risk. In the present manuscript, we report on a novel candidate indicator of risk: phantom phone vibrations. METHODS: We administered a phantom vibrations questionnaire to 83 clinical high-risk individuals (CHR) and 76 healthy controls. The primary dependent variables of interest were lifetime occurrence, severity, and frequency of phantom vibrations. Convergent validity was assessed via the Launay Slade Hallucinations Scale (LSHS). In a subset of participants, we also estimated relationships between North American Prodrome Longitudinal Study (NAPLS) risk scores and phantom vibrations. RESULTS: We found that the odds of experiencing phantom cell phone vibrations were 3 times higher for CHR compared to controls (b = 1.11, p = 0.003, OR = 3.03, 95% CI [1.48,6.51]). Furthermore, CHR reported greater frequency (b = 1.07, p = 0.001, OR = 2.92, 95% CI [1.52,5.69]) and bothersomeness of the phantom vibrations (b = 1.48, p < 0.001, OR = 4.39, 95% CI [2.09,9.62]). Greater severity of self-reported hallucinations (LSHS) and greater NAPLS risk scores were also associated with phantom vibration experiences. CONCLUSION: Our results suggest that phantom cell phone vibrations are an understudied marker of clinical risk for psychosis. Future work should assess neural mechanisms and longitudinal predictive utility of these experiences.
Response to Gama-Marques et al. commentary: Re-rethinking psychosis.
Keshavan M, Good M
Schizophr Res · 2026 May · PMID 41759283 · Publisher ↗
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Predictors of violence against others in non-affective psychosis: A systematic review and meta-analysis.
Ahle G, Henriksen MG, Mølstrøm IM … +3 more , Rasmussen AR, Christensen MB, Nordgaard J
Schizophr Res · 2026 May · PMID 41747436 · Publisher ↗
INTRODUCTION: The risk of committing violence against others is increased in patients with non-affective psychosis compared to the background population. However, the profile of patients with non-affective psychosis, who...
INTRODUCTION: The risk of committing violence against others is increased in patients with non-affective psychosis compared to the background population. However, the profile of patients with non-affective psychosis, who commit violence against others, is not fully known. Prior reviews and meta-analyses have included heterogenous psychosis populations and operated with broad definitions of violence. In this study, we narrowed the focus to patients with non-affective psychosis and restricted the definition of violence to physical violence committed against others. METHODS: Following the PRISMA guidelines, we searched PubMed, PsycInfo, and Ovid Embase for studies comparing patients with non-affective psychosis with and without a history of violence against others. RESULTS: 13 studies with a total of 1446 patients were included. Few predictors of violence were identified across the studies. In the meta-analysis, only higher score on Hare Psychopathy Checklist-Revised (PCL-R) and shorter years of education significantly predicted belonging to the violence group across studies. None of these predictors were robust after Bonferroni correction. No differences were found in psychopathology on the Positive and Negative Syndrome Scale (PANSS), substance use, cognition, duration of illness, marital status, employment status, and age of onset of illness between patients with a history of physical violence against others and those without such a history. CONCLUSIONS: Predictors of violence previously identified in other studies proved non-significant in our more narrowly focused and stringent review and meta-analysis. More research is needed to improve characterization and identification of patients with non-affective psychosis at risk of committing violence against others.
MC4R methylation and antipsychotic-related metabolic changes in early psychosis: findings from two prospective cohorts.
Loureiro CM, Fachim HA, Bissoli GC … +7 more , Corsi-Zuelli F, Shuhama R, Menezes PR, Louzada-Junior P, Dalton CF, Reynolds GP, Del-Ben CM
Schizophr Res · 2026 May · PMID 41740308 · Publisher ↗
Metabolic side effects represent a major long-term concern in antipsychotic (AP)-treated early psychosis. We evaluated the weight gain and changes in related metabolic parameters in patients followed up for 12 months. We...
Metabolic side effects represent a major long-term concern in antipsychotic (AP)-treated early psychosis. We evaluated the weight gain and changes in related metabolic parameters in patients followed up for 12 months. We also explored DNA methylation of four genes associated with weight gain (ADRA2A, INSIG2, LEP, MC4R). We included patients aged 15-64 years followed in the Ribeirão Preto Early Intervention in Psychosis Program from two different cohorts (Clinical sample, n = 147; Epigenetic sample, n = 59). DNA methylation was analysed by pyrosequencing only at baseline, after several weeks of AP exposure. In both cohorts, 40% of patients initially received second-generation antipsychotics (SGAs), increasing to over 70% after one year. Clinical sample: At follow-up, patients exhibited significant increases in body mass index (p < 0.001), triglycerides (p < 0.001), HDL-c (p = 0.001) and LDL-c (p < 0.001). Patients predominantly on SGAs during the 12 months had almost three times higher chance of weight gain than those using haloperidol. Other factors associated with weight gain included non-white skin colour (OR = 2.6), fewer years of schooling (OR = 2.5) and a weight gain of at least 7% at three months (OR = 3.1). Epigenetic sample: Patients receiving SGA treatment (median = 23.4 weeks) at baseline showed hypermethylation within the MC4R promoter region in relation to patients using haloperidol (median = 18.6 weeks). No changes in the baseline methylation of other genes related to weight gain or AP drugs were observed longitudinally. MC4R promoter hypermethylation in SGA-treated patients suggests drug-induced metabolic alterations and a potential role of MC4R as a biomarker for predicting AP-related metabolic risk.
The association between daily reports of psychotic experiences and life worthiness in early risk stages for psychosis and across gender.
Muller MK, de Almeida ER, van der Tuin S … +9 more , Balafas SE, van den Berg D, Núñez D, Eisma MC, Schoevers RA, Wang YP, Veling W, Booij SH, Wigman JTW
Schizophr Res · 2026 May · PMID 41719812 · Publisher ↗
AIM: Explore the temporal and contemporaneous associations between daily reports of psychotic experiences (PEs) and life worthiness (LW) in individuals in early risk stages for psychosis, and to examine whether these ass...
AIM: Explore the temporal and contemporaneous associations between daily reports of psychotic experiences (PEs) and life worthiness (LW) in individuals in early risk stages for psychosis, and to examine whether these associations differ across risk stages and gender. METHOD: We analyzed 90-day daily diary data from a prospective cohort study. N = 96 individuals (mean age = 24.7 years; range = 18-35; 77% female) were divided into four subgroups with each group having increasing levels of risk for psychosis: increased risk no current symptoms (subgroup 1; n = 25), low risk (subgroup 2; n = 27), mild risk (subgroup 3; n = 24), and ultra-high risk (subgroup 4; n = 20). Multilevel vector autoregressive models were used to assess the associations between PEs and LW, and compare across subgroup and gender. RESULTS: PEs and LW were negatively associated, temporally (PEsₜ₋₁➔LWₜ: B = -0.08, p < 0.01; LWₜ₋₁➔PEsₜ: B = -0.02, p < 0.001) and contemporaneously (PEs➔LW: B = -0.50, p < 0.001; LW➔PEs: B = -0.10, p < 0.001). Small subgroup differences were observed, although no clear patterns could be distinguished. The contemporaneous association was stronger in males compared to females (B = -0.03, p < 0.01). CONCLUSION: Analyses showed associations between PEs and LW. Findings highlight LW as a potential protective factor already in early stages of psychosis, underscoring the value of targeting LW in early interventions.
Novel positive allosteric modulators of alpha 5 subunit-containing GABA receptors (α5-GABARs) reverse the hyperdopaminergic state in a neurodevelopmental model of schizophrenia.
Uliana DL, Popa MO, Paradowski M … +5 more , Elvers KT, Hanley M, Baldwin A, Atack JR, Grace AA
Schizophr Res · 2026 May · PMID 41707438 · Full text
Dysfunction in the GABAergic system has been described in schizophrenia, including decreased expression of α5 subunit-containing GABA receptors (α5-GABARs) in patients with schizophrenia. This study explores the therapeu...
Dysfunction in the GABAergic system has been described in schizophrenia, including decreased expression of α5 subunit-containing GABA receptors (α5-GABARs) in patients with schizophrenia. This study explores the therapeutic potential of positive allosteric modulators (PAMs) of the α5-GABAR to reduce the hyperdopaminergic state produced by the neurodevelopmental methylazoxymethanol acetate (MAM) model of schizophrenia. Male offspring rats generated from pregnant females injected with saline or MAM at gestational day 17 were used for the electrophysiological recordings as adults. In vivo electrophysiological recordings were performed to assess the effects of 10 mg/kg of the novel α5-GABAR-preferring PAM alogabat on dopamine (DA) neuron activity in the ventral tegmental area (VTA); a dose shown to produce sustained, ≥80% α5-GABAR occupancy over a time period of 0.5-3.5 h post-dose. A less extensive confirmatory study was also performed with a second α5-GABAR PAM, Compound 100. The primary outcome was that at a dose of 10 mg/kg, which corresponded to an α5-GABAR occupancy of ≥80% for alogabat and 70% for Compound 100, reversed the increased number of spontaneously active DA neurons in MAM rats. Alogabat data showed that these effects were driven by a reduction in the central and lateral (but not medial) portions of the VTA; regions that project to the associative striatum. These findings suggest that selective targeting of α5-GABARs may help normalize aberrant DA activity. The study highlights α5-GABARs as a promising therapeutic target, potentially addressing positive symptoms by restoring excitatory-inhibitory balance in a key region of the brain implicated in the pathophysiology of schizophrenia.
Improved quality of life with semaglutide in schizophrenia: Secondary analyses from a randomized controlled trial.
Uhrenholt N, Ganeshalingam A, Arnfred S … +5 more , Gæde P, Pedersen AK, Larsen PV, Frystyk J, Bilenberg N
Schizophr Res · 2026 May · PMID 41702353 · Publisher ↗
BACKGROUND: People with schizophrenia experience markedly reduced health-related quality of life (QoL), partly driven by obesity and metabolic dysregulation. Glucagon-like peptide-1 receptor agonists such as semaglutide...
BACKGROUND: People with schizophrenia experience markedly reduced health-related quality of life (QoL), partly driven by obesity and metabolic dysregulation. Glucagon-like peptide-1 receptor agonists such as semaglutide induce substantial weight loss in the general population and in patients receiving antipsychotic medication. However, the extent to which semaglutide-associated weight loss mediates changes in QoL and symptom severity in schizophrenia remains unclear. METHODS: This secondary analysis of a randomized, double-blind, placebo-controlled trial included 154 adults with schizophrenia spectrum disorder, prediabetes, and overweight or obesity. Participants were randomized 1:1 to once-weekly semaglutide or placebo for 30 weeks. Outcomes were the SF-36v2 Physical and Mental Component Summary scores (PCS, MCS) and the Positive and Negative Syndrome Scale, 6-item version (PANSS-6). Causal mediation analyses estimated natural direct and indirect effects of semaglutide via weight loss at weeks 15 and 30. RESULTS: Semaglutide improved PCS at weeks 15 and 30, with effect sizes exceeding the minimally important difference. Indirect effects via weight loss were positive but not statistically significant, although at week 30 approximately half of the total PCS effect was estimated to be mediated through weight change. No total or mediated effects were found for MCS. For PANSS-6, no meaningful mediation was observed. CONCLUSIONS: Semaglutide improved physical QoL in patients with schizophrenia, and weight loss may partially contribute to this effect. Longer-term studies are needed to determine whether mental QoL or symptom effects emerge beyond 30 weeks.
The impact of CNV burden on age at onset of schizophrenia.
Muntané G, Valle A, Ramon-Cañellas P … +2 more , Martorell L, Vilella E
Schizophr Res · 2026 May · PMID 41690160 · Publisher ↗
BACKGROUND: Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a complex genetic architecture influenced by both common and rare variants. Disease age at onset (AAO) is a critical clinical feature, with earli...
BACKGROUND: Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a complex genetic architecture influenced by both common and rare variants. Disease age at onset (AAO) is a critical clinical feature, with earlier onset associated with greater severity and poorer functional outcomes. While copy number variants (CNVs) are well-established contributors to SCZ risk, their role in modulating AAO remains less explored. METHODS: This study investigates the association between CNV burden and CNV length with AAO, leveraging a cohort of 836 individuals, including 323 patients with SCZ (31.6% female) and 513 healthy controls (52.1% female). RESULTS: Patients with SCZ exhibited a significantly higher CNV burden than the control group (P = 9.3e-03). Linear regression analyses revealed that the number of deletions, but not duplications, was significantly associated with earlier AAO (P = 9.28e-04). Patients with earlier onset of the disorder had the highest CNV load, with a trend toward decreasing burden with increasing AAO. CONCLUSIONS: These findings suggest that an increased burden of CNV deletions may disrupt neurodevelopmental pathways, contributing to earlier onset of SCZ. This study highlights the importance of CNV burden in elucidating the genetic architecture underlying SCZ and AAO, and emphasizes the value of using genetic tests to detect CNVs in informing future therapeutic approaches.
Radiomics-based prediction of early antipsychotic treatment response for first-episode schizophrenia.
Jin M, Li H, Yan L … +9 more , Wang H, Ren H, Zhang X, Hu W, Hao Y, Xie M, Yang Y, Wang N, Yu Q
Schizophr Res · 2026 May · PMID 41687365 · Publisher ↗
BACKGROUND: This study aims to develop and validate cranial CT-based radiomics models for predicting early antipsychotic response in first-episode schizophrenia (SCZ). METHODS: We retrospectively enrolled 530 antipsychot...
BACKGROUND: This study aims to develop and validate cranial CT-based radiomics models for predicting early antipsychotic response in first-episode schizophrenia (SCZ). METHODS: We retrospectively enrolled 530 antipsychotic-naïve first-episode SCZ patients and split them 7:3 into training and independent test sets. Early response was defined as ≥25% Brief Psychiatric Rating Scale (BPRS) reduction at week four. CT images were resampled, registered to MNI space, and parcellated using the Harvard-Oxford atlas. Radiomic features (RFs) were extracted and selected via a multi-stage pipeline (ANOVA, mutual information, LASSO-SVM, and interaction screening). An XGBoost classifier was trained to generate radiomics-only predictions. A radiomics score (Rad-Score) was derived by logistic regression and combined with clinical predictors in a nomogram. Spearman's correlations between RFs and symptoms were tested with FDR control. RESULTS: Among the RFs of 530 patients (313 responders and 217 non-responders), we retained 11 radiomic features and one interaction term, predominantly from temporal regions and the thalamus. In the test set, AUCs were 0.72 for the clinical-only model and 0.86 for the radiomics-only model; the nomogram integrating Rad-Score with age, duration of untreated psychosis, marital status, and education achieved AUC = 0.92. Sensitivity analyses using ≥30% and ≥40% response thresholds showed consistent discrimination. Rad-Score correlated with symptom improvement (rs = 0.504; q < 0.001). CONCLUSION: Baseline cranial CT radiomics, particularly when combined with routine clinical factors, enables accurate early prediction of antipsychotic response and yields interpretable biomarkers linked to symptom change in first-episode schizophrenia.
Chicken or the egg: The relationship between cognitive deficits and negative symptoms in first episode psychosis.
Au-Yeung C, Christophe NK, Lavigne KM … +2 more , Raucher-Chéné D, Lepage M
Schizophr Res · 2026 Apr · PMID 41687329 · Publisher ↗
BACKGROUND: Cognitive impairments and negative symptoms (NS) represent an unmet therapeutic need in psychotic disorders. Both NS and cognitive impairments, are key predictors of functioning. Both also appear during the i...
BACKGROUND: Cognitive impairments and negative symptoms (NS) represent an unmet therapeutic need in psychotic disorders. Both NS and cognitive impairments, are key predictors of functioning. Both also appear during the illness prodrome, highlighting their relevance to the etiology of psychosis. Cross-sectional and longitudinal links between NS and cognition have been established, suggesting a common underlying foundation. Thus, investigating the relationship between cognition and NS is particularly relevant, especially given the clinical fluctuations seen in the early stages of psychosis and the marked cognitive deficits present throughout the illness. OBJECTIVE: The following study aims to investigate the longitudinal relationship between NS and cognition and whether, over the first two years following psychosis onset, 1) NS influences cognition, 2) cognition influences NS, or 3) the relationship is bidirectional. METHODS: We used data from the Recovery After an Initial Schizophrenia Episode Early Treatment Program (2010-2014). Participants underwent early treatment intervention, with assessments at baseline, 12, and 24 months using the Brief Assessment of Cognition in Schizophrenia and the Positive and Negative Syndrome Scale (n = 404). Random intercept cross-lagged panel models, which consider the temporal sequence of effects, were created to model the relationship between cognition and NS through the three timepoints over two years. RESULTS: We found a unidirectional relationship- declines in cognitive function predicted increased NS severity, while NS did not predict future cognitive function. CONCLUSION: This suggests that cognitive deficits may contribute to the development or exacerbation of NS. These findings underscore the role of cognition on NS trajectories and open new avenues for early psychosis treatments.
Asociality in schizophrenia: A review of historical foundations, measures, mechanisms, and treatments.
Toda-Thorne K, Luther L
Schizophr Res · 2026 Apr · PMID 41679113 · Publisher ↗
Asociality - diminished desire for social connection and reduced initiation of social interaction - has profound effects on a person's occupational and interpersonal functioning. Although asociality has long been describ...
Asociality - diminished desire for social connection and reduced initiation of social interaction - has profound effects on a person's occupational and interpersonal functioning. Although asociality has long been described in those with schizophrenia, only recently has asociality been defined as a core negative symptom. This has resulted in measurement and conceptual advances that have made it possible to more clearly delineate the underlying mechanisms of asociality and to identify targeted treatment strategies. This review synthesizes the historical foundations of asociality, advances in its measurement, prevalence and course, clinical correlates, proposed psychological and neurobiological mechanisms, and current available interventions. Continued progress in understanding asociality has the potential to substantially improve outcomes in schizophrenia by addressing one of the most understudied negative symptom domains, yet one that exerts a disproportionately large impact on functional recovery and well-being.
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