Schizophr. Res. [JOURNAL]
Sun
200 papers
Hyperlipidemia correlated with better neurocognition in patients with schizophrenia.
Miecznikowski KB, Blom TJ, Nasrallah HA
Schizophr Res · 2026 Jun · PMID 42259149 · Publisher ↗
BACKGROUND: Cognitive dysfunction is a core feature of schizophrenia and is associated with functional dysfunction. It is generally believed that metabolic abnormalities may further impair neurocognition in schizophrenia...
BACKGROUND: Cognitive dysfunction is a core feature of schizophrenia and is associated with functional dysfunction. It is generally believed that metabolic abnormalities may further impair neurocognition in schizophrenia. This study analyzed prospective data from the NIMH-funded schizophrenia CATIE study to examine the effects of hyperlipidemia on neurocognitive measures. We hypothesized that higher cholesterol and triglyceride levels are correlated with lower cognitive performance. METHODS: Screening data was collected on 1460 patients, including demographics, psychiatric history, and metabolic variables. Serum cholesterol and triglycerides were measured in a subsample (N = 741, mean age 40.4 years, 75% male, 61% white) who were in a fasting (≥ eight hours) state. Neurocognition was assessed at baseline using the Neurocognitive Composite (NC) Score, an average of five composite subscale z-scores: 1) Processing Speed 2) Verbal Memory 3) Vigilance Summary Score 4) Reasoning Summary Score 5) Working Memory Summary Score. Regression and analysis of variance models were used to examine the relationships between metabolic variables and neurocognition. RESULTS: Patients with low HDL cholesterol levels had significantly lower NC scores than patients with high HDL levels (p = 0.04). Conversely, contrary to our hypothesis, patients with elevated total cholesterol had significantly higher NC scores than patients with low total cholesterol (p = 0.002). Similarly, participants with elevated triglycerides had significantly higher NC scores when compared to participants with low triglycerides (p = 0.02). DISCUSSION: Our study found that high fasting cholesterol and triglyceride levels correlated with better neurocognition in patients with schizophrenia. The clinical and research implications of these unexpected findings are discussed.
Moderate to severe negative symptoms predict low risk of symptoms worsening in schizophrenia patients in CATIE.
Speyer H, Rabinowitz J, Luthringer R … +2 more , Tamba BI, Davidson M
Schizophr Res · 2026 Jun · PMID 42250382 · Publisher ↗
Understanding predictors of schizophrenia course is critical for long-term clinical management, yet prior findings have been inconsistent due to small samples, infrequent assessments, and non-standardized measures. Using...
Understanding predictors of schizophrenia course is critical for long-term clinical management, yet prior findings have been inconsistent due to small samples, infrequent assessments, and non-standardized measures. Using data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which includes a large cohort with monthly standardized evaluations, this study investigated whether baseline negative symptom severity predicts risk of symptom exacerbation over time. Participants were 1139 adults aged 18-65 years meeting DSM-IV criteria for schizophrenia. Symptoms worsening or exacerbation was defined as a ≥12-point increase from baseline on the PANSS total score. Cox regression survival models examined the association between baseline PANSS negative symptom tertiles and time to exacerbation, adjusting for age, sex, years since first prescribed antipsychotic medication, randomized antipsychotic treatment group, PANSS positive and general psychopathology subscales, and CGI-Severity. Overall, 25.5% of participants experienced exacerbation over an 18-month period of follow-up. Survival curves demonstrated significant separation across negative symptom tertiles (p < 0.05), with higher baseline negative symptoms associated with longer time to exacerbation. Compared with the lowest tertile, medium and high negative symptom groups showed reduced exacerbation risk (HR = 0.72 and HR = 0.70, respectively; both p < 0.04). Findings indicate that greater baseline negative symptom severity is associated with a lower likelihood of short-term symptom worsening, suggesting a relatively stable illness course among individuals with more severe negative symptoms. These results have implications for prognosis and treatment planning, while underscoring the persistent functional burden imposed by negative symptoms despite lower exacerbation risk.
Xanomeline/trospium and suicide-related events in schizophrenia: An early pharmacovigilance analysis.
Aboukaoud M, Amiaz R, Hoch B … +2 more , Davidson M, Weiser M
Schizophr Res · 2026 Jun · PMID 42250381 · Publisher ↗
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Digital therapeutics for negative symptoms of psychosis: Where do we go from here?
Luther L, Fulford D
Schizophr Res · 2026 Jun · PMID 42242066 · Publisher ↗
Some of the most pressing unmet needs in the treatment of psychosis spectrum disorders are negative symptoms. Digital therapeutics (DTx) have been touted as a transformative approach to advancing mental health treatment,...
Some of the most pressing unmet needs in the treatment of psychosis spectrum disorders are negative symptoms. Digital therapeutics (DTx) have been touted as a transformative approach to advancing mental health treatment, including for negative symptoms. Although existing trials demonstrate that DTx are feasible, acceptable, and efficacious for improving negative symptoms in psychosis, in this review we argue that the field has yet to capitalize fully on their potential. We describe several opportunities for future directions, including leveraging the unique strengths of digital tools to deliver adaptive, engaging, personalized interventions in real-time, precisely when individuals need support. We also discuss pressing needs around identifying how to best integrate DTx into routine clinical care, including the level and type of clinical staff support needed to effectively support the integration of DTx into real-world settings. We also highlight the need for negative symptom DTx to move beyond feasibility and acceptability evaluations and more toward rigorous evaluation of effectiveness and implementation. This includes expanding traditional pharmaceutical evaluation models and using novel clinical trial designs such as micro-randomized trials (MRT), sequential, multiple assignment, randomized trials (SMART), quasi-experimental designs, or stepped wedge designs to optimize intervention content and timing, identify barriers and facilitators to sustainable adoption in clinical practice, and identify the most effective implementation clinical supports. Advancing each of these domains will help to push the field of DTx forward and optimize DTx to treat negative symptoms more effectively.
Altered mirroring and self-face processing in schizophrenia: A systematic review.
Poletti M, Bevione F, Iftime VN … +4 more , Lacidogna MC, Lavalle R, Preti A, Raballo A
Schizophr Res · 2026 Jun · PMID 42224837 · Publisher ↗
BACKGROUND: Anomalous experiences at the mirror have been classically described in patients with schizophrenia and conceptualized as "mirror sign". Mirror and self-face-based paradigms offer a unique window into the expe...
BACKGROUND: Anomalous experiences at the mirror have been classically described in patients with schizophrenia and conceptualized as "mirror sign". Mirror and self-face-based paradigms offer a unique window into the experiential and cognitive architecture of self-disturbances in schizophrenia, yet empirical findings in this area remain scattered and heterogeneous. METHODS: This systematic review synthesizes experimental studies investigating mirror, self-face recognition, and enfacement-illusion tasks in individuals with schizophrenia or at clinical high-risk for psychosis. Four electronic databases (MEDLINE, Embase, PsycInfo, and CINAHL) were searched with the keywords "Schizophrenia" OR "Psychosis" AND "Enfacement illusion" OR "Mirror gazing" OR "Double mirror" OR "Self face recognition" from inception until 31 December 2024. RESULTS: The search identified 16 experimental studies. Patients consistently exhibited impairments in self-face recognition, altered self-other boundary processing, and increased anomalous experiences during mirror exposure. Illusion-based paradigms revealed attenuated typical enfacement effects alongside heightened misattribution tendencies, suggesting instability in multisensory integration. Mirror-gazing tasks elicited frequent perceptual distortions and self-estrangement phenomena, in line with phenomenological accounts of diminished self-presence. Clinical correlates were generally weak and inconsistent, although some studies indicated associations with positive symptoms and anomalous self-experiences. Methodological quality was overall low, with common limitations including small sample sizes, insufficient blinding, and heterogeneous outcome measures. CONCLUSIONS: Evidence may preliminary support the view that schizophrenia involves fundamental alterations in the dynamic integration between embodied and reflective self-representations. Mirror tasks could provide a promising experimental platform to probe these vulnerabilities, but more rigorous, standardized, and longitudinal research is needed to clarify their diagnostic and mechanistic relevance.
Elevated impulsivity in psychosis is associated with mood, anxiety, and general symptoms.
Crabtree E, Brock E, Lewandowski KE
Schizophr Res · 2026 May · PMID 42214296 · Publisher ↗
Impulsivity is a trans-diagnostically relevant construct which includes five separable domains: negative urgency, (lack of) perseverance, (lack of) premeditation, sensation seeking, and positive urgency. Impulsivity may...
Impulsivity is a trans-diagnostically relevant construct which includes five separable domains: negative urgency, (lack of) perseverance, (lack of) premeditation, sensation seeking, and positive urgency. Impulsivity may be elevated in psychosis, and has been associated with increased aggression, suicidality, and substance use in this population. However, profiles of specific domains of impulsivity across the psychoses and their association with clinical symptoms and functioning has not been well-described. We aimed to examine impulsivity profiles across the psychosis spectrum, and the extent to which impulsivity correlates with clinical symptoms and functioning. Participants included 186 individuals with schizophrenia spectrum disorders (SSD; n = 93) or mood disorders with psychosis (MDP n = 93), and healthy controls (n = 50). Findings revealed elevated impulsivity across the psychosis spectrum, which was more pronounced in the MDP group. Linear regression revealed that positive and general symptoms of psychosis, depressive, manic, and anxiety symptoms were associated with impulsivity. When other domains were controlled, negative urgency, positive urgency, and lack of perseverence emerged as predictors of clinical symptoms across the psychosis spectrum. Results suggest that state clinical symptoms are associated with trait markers of impulsivity, and that individuals on the psychosis spectrum who report high levels of emotional urgency may be at risk for more severe mood, anxiety, and general psychosis symptoms. Understanding the role of the impulsivity domains in relation to clinical symptoms has clinical implications, both in understanding outcomes and identifying treatment targets. Mechanisms of these associations should be explored.
Psychometric analysis of speech-based digital biomarkers of alogia symptoms in treatment resistant schizophrenia: Comparison with clinical ratings of expressive negative symptoms.
Lindenmayer JP, Khan A, Insel BJ … +5 more , Kothare H, Neumann M, Nadim D, Mishkind R, Ramanarayanan V
Schizophr Res · 2026 May · PMID 42208341 · Publisher ↗
BACKGROUND: The measurement of expressive negative symptoms (ENS) is challenging due to reliance on subjective measurements with variable reliability. Digital speech assessments using a cloud-based multimodal dialog plat...
BACKGROUND: The measurement of expressive negative symptoms (ENS) is challenging due to reliance on subjective measurements with variable reliability. Digital speech assessments using a cloud-based multimodal dialog platform offer a promising objective alternative. This study evaluates psychometric properties of acoustic speech markers as complementary measures of ENS in treatment-resistant schizophrenia (TRS). We also examine whether speech markers differentiate TRS from healthy controls (HC) and their association with clinician-rated ENS severity. METHOD: 67 participants with DSM-5 TRS, and 63 HC completed two standardized, 10-min sessions using the Modality platform. Eight speech measures were retained. Trained raters assessed clinical measures. The analysis examined known-groups validity, test-retest reliability, and associations between speech measures and clinician-rated negative symptoms. RESULTS: Individuals with TRS demonstrated significant differences vs. HC in four speech measures. They required longer time to complete the reading passage (mean 44.09 vs. 31.90 s; p < 0.0001) and spoke less during spontaneous speech (mean 20.19 vs. 29.06 s; p < 0.0001). Higher Cepstral Peak Prominence was significantly associated with greater severity of ENS across 5 clinical measures. Speaking duration was significantly negatively associated with the PANSS ENS subfactor. Monotonous speech was significantly negatively associated with ENS. CONCLUSION: Specific acoustic speech measures differentiated TRS from HC and were associated with clinician-rated ENS, particularly alogia and blunted affect. These findings support speech-based digital markers as objective correlates of ENS, while also indicating that they reflect only part of broader clinical construct. Longitudinal studies are needed to determine sensitivity, and whether these markers reflect trait versus state features.
Can electroconvulsive therapy attenuate glial stress in schizophrenia? Longitudinal evidence from serum GFAP and S100B.
Ataov G, Balaban OD, Cirakli Z … +1 more , Yesilkaya UH
Schizophr Res · 2026 May · PMID 42190370 · Publisher ↗
BACKGROUND: Glial dysfunction has been implicated in schizophrenia, yet ECT's effects on glial biomarkers remain poorly understood. This study investigated longitudinal changes in serum GFAP and S100B in patients with sc...
BACKGROUND: Glial dysfunction has been implicated in schizophrenia, yet ECT's effects on glial biomarkers remain poorly understood. This study investigated longitudinal changes in serum GFAP and S100B in patients with schizophrenia treated with antipsychotic medication alone or combined with ECT. METHODS: Seventy-six patients with schizophrenia (37 ECT + medication; 39 medication alone) and 36 healthy controls were enrolled. Serum GFAP and S100B were measured at baseline, 24 h post-first ECT session, and at three-month follow-up. Symptom severity was assessed using PANSS. Longitudinal changes were analyzed using repeated measures ANOVA and paired t-tests. RESULTS: Both patient groups showed elevated baseline S100B compared with controls. In the ECT group, S100B increased acutely after the first session (p = 0.002) then normalized at three months. In the medication-only group, S100B significantly increased over follow-up (p = 0.047). Baseline GFAP was elevated in the ECT group with a decreasing trend at three months (p = 0.086), while remaining stable in the medication-only group. No significant correlations emerged between biomarker changes and PANSS improvement. CONCLUSIONS: Antipsychotic monotherapy may be insufficient to modify ongoing glial stress, whereas ECT is associated with transient glial activation followed by longer-term normalization. These distinct S100B trajectories suggest that ECT's therapeutic effects may involve dynamic modulation of glial function, providing preliminary evidence for glia-related mechanisms underlying ECT in schizophrenia.
Omega-3 polyunsaturated fatty acids for the management of metabolic syndrome in psychotic disorders: A systematic review and meta-analysis.
Rainford A, Connor J, Lochtenberg J … +1 more , Hallahan B
Schizophr Res · 2026 May · PMID 42190369 · Publisher ↗
BACKGROUND: Individuals with psychotic disorders, particularly schizophrenia, experience significantly elevated rates of metabolic syndrome, often linked to antipsychotic treatment. Omega-3 polyunsaturated fatty acids (P...
BACKGROUND: Individuals with psychotic disorders, particularly schizophrenia, experience significantly elevated rates of metabolic syndrome, often linked to antipsychotic treatment. Omega-3 polyunsaturated fatty acids (PUFAs) have demonstrated cardiovascular and mood benefits, but their effects on metabolic outcomes in psychotic disorders remain unclear, with no prior systematic review dedicated to this population. METHODS: A systematic bibliographic search of randomised controlled trials and comparative studies assessing the effect of omega-3 PUFAs on metabolic outcomes in individuals with psychotic disorders was conducted. Outcomes included body mass index (BMI), waist circumference, serum triglycerides, low- and high-density lipoproteins, total cholesterol, blood glucose, and blood pressure. Seven randomised placebo-controlled trials were included in meta-analyses, with four additional open-label or non-randomised trials reviewed narratively. RESULTS: Omega-3 PUFAs demonstrated no statistically significant effect on several metabolic parameters including BMI, waist circumference, serum glucose, lipid profiles, or blood pressure. Heterogeneity was moderate to high across outcomes (I range of 31-99%), reflecting variability in study design, treatment duration, and populations. Isolated benefits were observed in first-episode psychosis, but these were not significant in pooled analyses. CONCLUSIONS: Current evidence does not support a consistent metabolic benefit of omega-3 PUFA supplementation in psychotic disorders. Given methodological variability across studies and promising subgroup findings, further large-scale, standardised RCTs with metabolic outcomes as primary endpoints are warranted. While the heterogeneity of results limits interpretability, at present, omega-3 PUFAs cannot be recommended as a metabolic risk-reduction strategy in psychosis. PROSPERO REGISTRATION: CRD420251067935.
Motivation and pleasure deficits reflect altered network embedding of normal brain deviations in schizophrenia.
Holker J, Clouse A, Gilday SAJ … +12 more , Jensen J, Cimmino D, Humble B, Johnston J, Madrid K, Reading M, Johnson S, Lee B, Ehrlich S, Smith MJ, Wang L, Cobia D
Schizophr Res · 2026 May · PMID 42176687 · Publisher ↗
BACKGROUND: Negative symptoms in schizophrenia are associated with significantly worse outcomes, and their factor structure (i.e., diminished motivation and pleasure [MAP] and diminished expressivity [EXP]) has only rece...
BACKGROUND: Negative symptoms in schizophrenia are associated with significantly worse outcomes, and their factor structure (i.e., diminished motivation and pleasure [MAP] and diminished expressivity [EXP]) has only recently been clarified. Studies investigating structural imaging correlates of negative symptoms have largely focused on cortical regions involved in motivation, reward processing, affect expression, and language. Structural covariance network modeling provides a framework for examining covariance among these cortical regions in a network-like manner. METHODS: Clinical and imaging data from 203 individuals with schizophrenia were obtained from three independent data sites. Cortical thickness measures based on the Desikan-Killiany atlas were standardized using a normative modeling algorithm developed by the ENIGMA Lifespan Working Group. Structural covariance networks were constructed using a priori cortical regions of interest related to MAP and EXP. Linear regression models tested whether MAP and EXP severity predicted network embeddedness. RESULTS: Both the MAP-related (F = 22.76, p < 0.001, adjusted R = 0.4848) and EXP-related networks (F = 14.43, p = 0.001, adjusted R = 0.3673) were significant. Howerver, only MAP severity predicted network embeddedness within the MAP network (β = 0.085, p = 0.03, 95% CI [0.009, 0.162]). DISCUSSION: Results suggest that MAP is selectively associated with network-level over-coupling of cortical morphology, whereas EXP may reflect more distributed network properties. These findings underscore the potential role of cortical network rigidity in the pathophysiology of negative symptoms.
A network analysis of psychotic symptoms, neurocognition, alexithymia, empathy, and suicidal intent in patients with chronic schizophrenia.
Wu M, Li Z, Wang Y … +7 more , Zhang X, Yan K, Xu H, Wang X, Liu T, Wu Q, Zhang X
Schizophr Res · 2026 May · PMID 42176686 · Publisher ↗
BACKGROUND: Chronic schizophrenia represents a major global health burden. However, the symptom-level interrelationships among its multiple clinical features remain insufficiently understood. This study aimed to examine...
BACKGROUND: Chronic schizophrenia represents a major global health burden. However, the symptom-level interrelationships among its multiple clinical features remain insufficiently understood. This study aimed to examine the interconnections among psychotic symptoms, neurocognition, alexithymia, and empathy (PNAE), and to further explore their associations with suicidal intent in patients with chronic schizophrenia. METHODS: A total of 845 patients with chronic schizophrenia were recruited in China. Participants were assessed using the 19-item Beck Scale for Suicidal Ideation, the 20-item Toronto Alexithymia Scale, the Interpersonal Reactivity Inventory, the Repeatable Battery for the Assessment of Neuropsychological Status, and the Positive and Negative Syndrome Scale (PANSS). A symptom network of PNAE was constructed, and expected influence (EI) and bridge expected influence (BEI) were calculated to identify central and bridge symptoms. RESULTS: The prevalence of suicidal intent in this sample was 13.1% (n = 111). Within the PNAE network, difficulty identifying feelings (DIF) emerged as the most central symptom, followed by immediate memory (IM). Personal distress (PD) was identified as the primary bridge symptom, with DIF serving as a secondary bridge symptom. The PNAE network showed good stability and accuracy. In addition, the PANSS mood factor (PMF), PANSS positive factor (PPF), and PD showed the strongest associations with suicidal intent. CONCLUSION: These findings underscore the importance of carefully assessing DIF, PD, and IM in patients with chronic schizophrenia. Mood-related symptoms, positive psychotic symptoms, and personal distress may serve as clinically relevant indicators for the identification of suicidal intent in this population.
Subjective perceptions of negative symptoms among outpatients with schizophrenia and their relatives or caregivers: Definitions, importance, measurement, and desired improvement.
Strauss GP, Zhang Z, Arnold LE … +7 more , Hutcheson AL, Barolette JT, Luck JE, Carter ZA, Knippenberg AR, Allen DN, Kirkpatrick B
Schizophr Res · 2026 May · PMID 42160904 · Full text
Despite advances in the assessment of negative symptoms in schizophrenia (SZ), little is known about how patients and their relatives/caregivers (REL/CARE) subjectively perceive these symptoms and the tools used to measu...
Despite advances in the assessment of negative symptoms in schizophrenia (SZ), little is known about how patients and their relatives/caregivers (REL/CARE) subjectively perceive these symptoms and the tools used to measure them. The current study used a combined qualitative and quantitative approach to obtain subjective perceptions on negative symptoms. Participants included 52 outpatients with SZ and 22 REL/CARE who completed structured online surveys with quantitative and qualitative questions evaluating agreement with standard definitions of 6 negative symptom domains (anhedonia, avolition, asociality, blunted affect, alogia, lack of normal distress), the perceived importance of each of the domains, clarity of interview probes used on the Brief Negative Symptom Scale (BNSS), and the level of symptom improvement required for meaningful change on the BNSS. Clinician-rated BNSS scores were compared with SZ and REL/CARE subjective perceptions of negative symptom severity. A subset of participants completed follow-up live, one-on-one qualitative interviews to probe responses further. Participants showed high agreement with BNSS definitions for the five core domains, but less agreement for lack of normal distress. Both groups rated anhedonia, avolition, and asociality as most important to improve. Most BNSS items were considered clear, though lack of normal distress was sometimes misunderstood. Participants rated negative symptom severity higher than clinicians and reported that a 1-2 point reduction on BNSS anchors would reflect meaningful change. Findings provide important insight into subjective perceptions of negative symptoms from stakeholders and suggest that the BNSS assessment approach captures the construct in ways that are meaningful to people with SZ and their REL/CARE.
A mixed methods study of program-level factors influencing patient and family engagement in first episode psychosis coordinated specialty care.
Foo CYS, Leonard CJ, McLaughlin MM … +4 more , Johnson KA, Öngür D, Mueser KT, Cather C
Schizophr Res · 2026 May · PMID 42160903 · Full text
BACKGROUND: Poor patient retention and family engagement compromise the effectiveness of coordinated specialty care (CSC) for first-episode psychosis (FEP). This mixed methods study aimed to identify program-level charac...
BACKGROUND: Poor patient retention and family engagement compromise the effectiveness of coordinated specialty care (CSC) for first-episode psychosis (FEP). This mixed methods study aimed to identify program-level characteristics (CSC fidelity and engagement strategies) associated with patient retention and family engagement in Massachusetts' CSC programs. METHODS: Primary outcomes were rates of patient retention and family engagement (≥1 evidence-based family intervention session), based on CSC program census (October 2022-September 2023). Quantitative analyses explored program characteristics (EPINET Program-Level Core Assessment Battery) and fidelity ratings (Massachusetts Psychosis Fidelity Scale) as predictors using t-tests or univariate linear regressions. Thematic analysis of program interviews compared patient and family engagement strategies employed by high versus low performing programs. RESULTS: Across nine programs, mean patient retention was 86% (range: 58-97%) and family engagement was 40% (range: 12-100%). Higher fidelity to evidence-based services (e.g., individual therapy, family intervention, and supported education/employment) was significantly associated with both outcomes (p < .05; R range: 0.51-0.72). Mixed-methods analysis showed that high performing programs used case management-related supports to meet service users' practical needs. Factors associated with higher patient retention included having comprehensive intake assessments, provider visits during hospitalization, and periodic treatment reviews. Programs that conducted benefits counselling and proactively recommended family services as standard care had higher family engagement. CONCLUSIONS: Higher fidelity CSC programs had better patient retention and family engagement. Case management-related supports addressed treatment barriers. Strategies designed to strengthen therapeutic alliance and goal alignment may promote patient engagement, while family engagement may benefit from proactive recommendation of family intervention.
Negative symptoms in the Hierarchical Taxonomy of Psychopathology: Nosology, etiology, and pathophysiology.
Williams TF, Freilich CD, Cowan HR … +4 more , Docherty AR, Jonas KG, Martin EA, Kotov R
Schizophr Res · 2026 May · PMID 42160902 · Publisher ↗
This review examines negative symptoms in the context of the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychopathology. The HiTOP model was developed as an alternative to traditional psychiatric diagnoses...
This review examines negative symptoms in the context of the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychopathology. The HiTOP model was developed as an alternative to traditional psychiatric diagnoses-improving reliability, parsing heterogeneity, and accounting for patterns of comorbidity--thus advancing the ability of researchers and clinicians to understand negative symptoms. In the current HiTOP model, negative symptoms are components of the psychoticism (thought disorder) spectrum alongside positive symptoms and disorganization, though recent HiTOP consortium publications suggest it may be more closely associated with the detachment spectrum. The primary objective of this review is to determine which placement is correct and the implications of this placement for HiTOP and negative symptoms research. In particular, factor analytic research that has emerged since the initial publication of the HiTOP model suggests that negative symptoms can be fully accounted for by the detachment spectrum, alongside personality traits and disorders related to detachment (avoidant, schizoid, extraversion, etc.). In addition, the etiological, developmental, neurobehavioral, and treatment research literatures are reviewed from the perspective of how existing evidence may fit this revised conceptualization of negative symptoms and psychosis. Overall, these research areas provide support for distinctions between psychoticism and detachment in the HiTOP model. Finally, recommendations are offered regarding how the HiTOP model may be further advanced and how researchers and clinicians may benefit from this approach to understanding negative symptoms.
Plasma metabolomic signature of frailty and risk of late-onset schizophrenia: A prospective cohort study.
Sun L, Bo Y, Li D … +9 more , Yao P, Sun Z, Cai Q, Chang H, Cheng M, Xue M, Yu Z, Zhu Y, Zhao X
Schizophr Res · 2026 May · PMID 42155165 · Publisher ↗
BACKGROUND: With population aging, late-onset schizophrenia is attracting increasing attention. The prospective association between frailty and late-onset schizophrenia, along with its underlying mechanisms, remains uncl...
BACKGROUND: With population aging, late-onset schizophrenia is attracting increasing attention. The prospective association between frailty and late-onset schizophrenia, along with its underlying mechanisms, remains unclear. This study aimed to investigate the relationship between frailty and late-onset schizophrenia, and assess the potential role of metabolic mechanisms on this association. METHODS: A total of 489,302 participants without late-onset schizophrenia at baseline were included from UK biobank. Cox proportional hazard regression model was utilized to investigate the association between frailty and late-onset schizophrenia. Elastic net regression was used to determine the metabolic signature associated with frailty. Mediation analysis was employed to assess the mediating role of metabolic signature and specific metabolites on the relationship between frailty and late-onset schizophrenia. RESULTS: During a median follow-up of 13.49 years, 705 late-onset schizophrenia cases were identified. Compared to individuals with nonfrailty, the risk of late-onset schizophrenia was increased in those with prefrailty (HR: 1.82, 95% CI: 1.52, 2.19) and frailty (HR: 3.10, 95% CI: 2.44, 3.95). Eighty-three metabolites were identified as being related to frailty (38 positively, 45 negatively). The metabolic signature mediated the association between frailty and late-onset schizophrenia (proportion of mediation effects (PM%): 4.57, 95% CI: 2.22, 7.36). The mediation effect of metabolites from fatty acids, inflammation and lipid metabolism on the relationship between frailty and late-onset schizophrenia was significant, with PM% ranging from 2.41 to 5.93. CONCLUSIONS: Physical frailty was associated with an increased risk of late-onset schizophrenia, partly by disrupting metabolic signatures (fatty acids, inflammation, and lipid metabolism).
Childhood adversity and benevolent childhood experiences associated with attenuated psychotic symptoms: The role of depression and anxiety.
Kearns J, Davidson G, Shannon C … +3 more , Mullholand C, Bunting L, Shevlin M
Schizophr Res · 2026 May · PMID 42150254 · Publisher ↗
BACKGROUND: Psychotic Experiences (PEs) represent subclinical experiences that may precede psychotic disorders and reflect broader psychopathology. Guided by the affective pathway hypothesis, this study examined potentia...
BACKGROUND: Psychotic Experiences (PEs) represent subclinical experiences that may precede psychotic disorders and reflect broader psychopathology. Guided by the affective pathway hypothesis, this study examined potential indirect effects of depression and anxiety on associations between adverse childhood experiences (ACEs), bullying, and PEs in adolescents. Secondary aims were to assess the role of benevolent childhood experiences (BCEs) and the influence of parental mental health. METHODS: Data were drawn from the Northern Ireland Youth Wellbeing Survey (N = 1299; aged 11-19 years). Using structural equation modelling (SEM) with bootstrapped standard errors, bullying, ACEs, BCEs, and parental psychological distress were entered as predictors of PEs through depression and anxiety latent variables. BCEs were modelled using linear and quadratic terms to test potential curvilinear protective effects. RESULTS: The SEM demonstrated good fit (Comparative fit index = 0.921, Tucker-Lewis index = 0.901, Root Mean Square Error of Approximation = 0.054, Standardized Root Mean Residual = 0.042). Bullying and ACEs significantly predicted higher depression and anxiety, while BCEs protective effects. Depression and anxiety significantly predicted PEs and served as indirect pathways linking bullying and ACEs to PEs. BCEs and parental distress demonstrated smaller protective and negative effects, respectively. CONCLUSIONS: Findings are consistent with the affective pathway to psychosis, suggesting early adversity may contribute to PEs via internalising symptoms. Depression showed the largest indirect association, underscoring the need for early detection and intervention targeting comorbid affective symptoms. Fostering benevolent experiences and adopting trauma-informed, intergenerational approaches may mitigate risk and strengthen resilience.
Changes in neurovascular coupling of cerebral blood flow and functional connectivity strength in first-episode schizophrenia patients after antipsychotic treatment.
Wang J, Yang M, Wang Z … +6 more , Xue K, Song X, Han S, Wen B, Zhang Y, Wei Y
Schizophr Res · 2026 May · PMID 42143979 · Publisher ↗
Previous studies have identified abnormalities in neurovascular coupling in chronic schizophrenia patients based on functional connectivity strength (FCS) and cerebral blood flow (CBF). Pharmacological treatment remains...
Previous studies have identified abnormalities in neurovascular coupling in chronic schizophrenia patients based on functional connectivity strength (FCS) and cerebral blood flow (CBF). Pharmacological treatment remains the cornerstone of schizophrenia management. However, it remains unclear whether antipsychotic treatment influences these findings. This study aimed to investigate potential abnormalities in neurovascular coupling in patients with first-episode schizophrenia (FES) and to explore changes before (FES-pre) and after antipsychotic treatment (FES-post). Here, we recruited 133 FES patients and 149 normal controls and used CBF-FCS correlation of the entire gray matter and CBF/FCS ratio of each voxel to evaluate changes in coupling changes in FES patients at baseline and after treatment. Compared with normal controls, FES patients exhibited significantly reduced whole-brain CBF-FCS correlation coefficients, significantly reduced CBF/FCS ratio in bilateral parahippocampal gyri, the medial part of bilateral superior frontal gyri, and left anterior cingulate gyrus, and enhanced CBF/FCS ratios in the left calcarine sulcus, left lingual gyrus, left superior temporal gyrus, and bilateral postcentral gyri. FES-post showed increased FCS in the left postcentral gyrus but decreased FCS in the left anterior cingulate gyrus, increased CBF in the visual cortex, and increased CBF/FCS ratio in the left middle occipital gyrus and right middle temporal gyrus but decreased ratio in the inferior frontal gyrus. Significantly decreased PANSS scores were found between FES-pre and FES-post. These findings suggest that neurovascular decoupling may represent a potential pathophysiological index in schizophrenia, and antipsychotic treatment not only ameliorate clinical symptoms but also modulate brain function, perfusion, and neurovascular coupling.
Atypical semantic priming in individuals at clinical risk for psychosis.
Rich HM, Pokorny VJ, Osborne KJ … +4 more , Geiger M, Horne S, Kappenman ES, Mittal VA
Schizophr Res · 2026 May · PMID 42143525 · Publisher ↗
BACKGROUND: Loosening of the associative connections between words and concepts is a core feature of psychotic disorders and is consistently related to disrupted semantic processing and impairments in real-world function...
BACKGROUND: Loosening of the associative connections between words and concepts is a core feature of psychotic disorders and is consistently related to disrupted semantic processing and impairments in real-world functioning. Both behavioral and neural indices of altered semantic processing have been studied in psychotic disorders but are underexplored in clinical high-risk (CHR) individuals. METHODS: We analyzed behavioral responses and EEG from 73 participants (CHR = 35 [female = 19], HC = 38 [female = 24]) completing the N400 Word Pair Judgement Task. In each trial, participants viewed a prime word followed by a target word and judged whether the pair was semantically related or unrelated. RESULTS: Behaviorally, the CHR group exhibited disrupted unrelated-related semantic priming (t(63.22) = 2.84, p = .006). Neurophysiologically, CHR had slightly smaller N400 semantic priming effects on average, but this difference was not significant (t(60.0) = 0.84, p = .40). Reduced N400 semantic priming effects were related to greater disorganization symptoms, specifically bizarre thinking (r(66) = 0.26, p = .035). Furthermore, smaller N400 semantic priming effects predicted lower Global Functioning: Social Scale (r(70) = -0.35, p = .002) and Global Functioning: Role Scale (r(70) = -0.33, p = .003). DISCUSSION: While we observed disrupted behavioral semantic priming in CHR, we did not replicate previously observed group differences in N400 semantic priming. Associations between N400 and bizarre thinking are consistent with disrupted semantic processing, driving associative loosening. Moreover, associations between N400 and global social/role functioning suggest that atypical semantic processing may contribute to downstream impairments in real-world functioning.
Foreign body airway obstruction in schizophrenia: Findings from a prospective multicenter registry.
Igarashi Y, Norii T, Ohno E … +2 more , Wakisaka R, Yokobori S
Schizophr Res · 2026 May · PMID 42140069 · Publisher ↗
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A systematic review on the effects of clozapine on B-lymphocytes and immunoglobulins.
Kang JT, Shields AM, Mizuno Y … +3 more , De Biase M, Ibrahim MAA, MacCabe JH
Schizophr Res · 2026 Aug · PMID 42134210 · Publisher ↗
BACKGROUND: Treatment-resistant schizophrenia (TRS) patients have been reported to exhibit distinct immunological characteristics compared with treatment-responsive patients, which have been hypothesised to relate to dif...
BACKGROUND: Treatment-resistant schizophrenia (TRS) patients have been reported to exhibit distinct immunological characteristics compared with treatment-responsive patients, which have been hypothesised to relate to differential illness course or treatment response. Clozapine treatment has been associated with an increased risk of secondary antibody deficiency and a recent prospective observational study found reductions in immunoglobulin concentrations after clozapine initiation in individuals with treatment resistant schizophrenia. Researchers have hypothesised that hypogammaglobulinaemia may be associated with clozapine use in TRS, although it remains unclear whether this reflects treatment effects, underlying disease factors, or their interaction. AIMS: This systematic review primarily aimed to investigate reported associations between clozapine exposure, immunoglobulin levels, and B-lymphocyte populations in clinical studies. Preclinical findings were summarised separately. METHOD: A systematic literature search using terms related to clozapine, immunoglobulins, and B-lymphocytes was conducted on Ovid Embase Classic+Embase, Ovid Medline, Ovid APA PsycInfo, Scopus, Cochrane Library Search, and Web of Science Core Collection. Reference lists of key papers were also hand-searched for relevant studies. The search yielded 1373 records to screen. Human clinical studies, preclinical studies, and mechanistic hypotheses were analysed and discussed as separate domains. RESULTS: 16 studies were included, including 15 human clinical and 1 animal study. CLINICAL STUDIES: (1) frequently reported lower immunoglobulins, including total serum immunoglobulins and specific autoantibodies, (2) showed mixed findings for B-lymphocyte absolute counts and some evidence of subset shifts. The animal study reported lower immunoglobulin concentrations in clozapine-exposed animals relative to untreated disease-model controls. CONCLUSIONS: Current in vivo and animal studies report a diverse range of immunoglobulin and B-lymphocyte findings in clozapine-treated populations, with substantial variability and limited reproducibility across studies. Across the reviewed literature, confounding by indication remains the dominant interpretive constraint, and no immune alteration identified can be confidently ascribed to clozapine exposure independent of treatment-resistant illness. Future research should prioritise prospective human studies with baseline immune phenotyping, active comparators, longitudinal sampling, and complementary mechanistic work to evaluate whether observed immune alterations represent treatment-associated epiphenomena, illness-related features, or biologically meaningful processes, rather than inferring therapeutic mechanisms. Additional studies should also consider the relationship between these measures and changes in clinical severity scores as well as adverse effects, including infection rates and antibiotic use.
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