Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition.

In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method.

The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = −0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship.

Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Poverty is associated with the severity of common mental health disorders and increased physical comorbidities. However, its effects on severe mental illness (SMI), beyond increasing their incidence, are less understood, especially in low- and middle-income countries. We here examined the relationship between baseline household income and subsequent mental and physical health outcomes in a large cohort of individuals diagnosed with schizophrenia or bipolar disorder in Colombia.

Retrospective cohort and case–control study using electronic health records from over 5 million Colombians. We identified individuals diagnosed with schizophrenia or bipolar disorder and their baseline household income. Mental health outcomes included third-line antipsychotic treatments (clozapine or antipsychotic polypharmacy) and psychiatric hospitalizations. Physical outcomes included diagnoses of hypertension, type 2 diabetes, and HbA1c levels, compared with rates in individuals without SMI.

We included 12,216 (6,485 women) participants newly diagnosed with bipolar disorder or schizophrenia between 2019 and 2023. Compared to middle-income participants (between $700–1,750USD/month), patients on a low income (less than $700USD/month) were more likely to require third-line antipsychotic treatment (OR 1.84 [1.64, 2.08]) and psychiatric hospitalization (incidence rate ratio 1.30 [1.21, 1.41]). Low-income participants with SMI had hypertension and diabetes rates like middle-income participants without SMI who were 20 years older. However, the combined effect of SMI and low income together posed a less-than-additive risk. Lower income was associated with higher HbA1c levels in diabetes, while a diagnosis of SMI was associated with lower levels.

Low income at SMI onset is associated with worse mental and physical health outcomes.

This study aimed to investigate leptin (LEP) (G-2548A) and leptin receptor (LEPR) (668A>G) gene polymorphisms in SCZ patients with and without suicide attempts, compared to controls

The study included 120 patients with SCZ and 130 healthy volunteers. Sociodemographic characteristics, suicidal behavior, and symptom severity were assessed using data collection forms. Gene polymorphisms were analyzed from DNA samples using the polymerase chain reaction–restriction fragment length polymorphism.

The LEP genotype distribution in SCZ patients differed significantly from controls, with the heterozygous GA genotype more frequent in controls (p = .026). Within SCZ, LEPR genotype distribution differed by suicide attempt history; the heterozygous AG genotype was more frequent in non-attempters (p = .048). Logistic regression showed that the LEPR polymorphism (p = .023), number of hospitalizations (p = .036), and PANSS-psychopathology score (p = .023) predict suicide attempt history in SCZ.

Our findings suggest that LEP polymorphism may contribute to SCZ susceptibility, while LEPR polymorphism may be linked to suicide attempts in SCZ.

The co-occurrence of psychotic disorders and borderline personality disorder (BPD) complicates clinical management, with overlapping symptoms exacerbating morbidity and impairing therapeutic outcomes. This systematic review and meta-analysis aimed to estimate the prevalence of psychotic disorders and BPD co-occurrence, including with first-episode psychosis (FEP) and to describe associated sociodemographic and clinical characteristics.

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, four databases were systematically searched from inception to June 2025. Eighteen studies met the inclusion criteria. Data extraction and quality appraisal (Effective Public Health Practice Project tool) were conducted independently by two reviewers. Random-effects meta-analyses estimated pooled prevalence rates.

The pooled prevalence of BPD in people with psychotic disorders was 22.7% (95% CI: 14.2–34.3%), while 14.3% (95% CI: 5.5–32.1%) of individuals with BPD had a comorbid psychotic disorder. In FEP samples, 40.0% (95% CI: 21.9–61.3%) met the criteria for BPD. People with both conditions, often young women, showed greater emotional dysregulation, suicidality, psychotic symptoms, and social dysfunction. Trauma, dissociation and substance use emerged as frequent vulnerability factors. However, most studies were cross-sectional, with small samples and high heterogeneity (I2 > 80%), limiting generalizability.

This co-occurrence constitutes a distinct clinical subgroup with complex needs. Categorical diagnostic approaches may fail to capture the dimensional nature of overlapping affective and psychotic symptoms. Integrative and personalized care pathways, especially in early intervention settings, are warranted. This review was registered in PROSPERO (CRD42024577525).

People with schizophrenia develop more chronic diseases at a younger age and die younger than people in the general population. It has been hypothesized that this excess morbidity and mortality could be partially due to accelerated aging in schizophrenia. If true, this would motivate the development of ‘gero-protective’ interventions to reduce chronic disease burden in schizophrenia. However, it has been difficult to test this hypothesis, in part, due to the limited ability to measure aging in samples of people with schizophrenia.

We utilized a novel neuroimaging biomarker of the longitudinal pace of aging, DunedinPACNI, to test for accelerated whole-body aging in schizophrenia across four neuroimaging datasets (total N = 2,096, 48% female) accessed through the Lieber Institute for Brain Development, the University of Bari Aldo Moro, and the North American Prodrome Longitudinal Study – 3.

We found consistent evidence of faster DunedinPACNI in schizophrenia compared with controls. In contrast, youth at clinical-high risk for psychosis did not have faster DunedinPACNI compared to controls. Unaffected siblings of patients also did not have faster DunedinPACNI than controls. Faster DunedinPACNI in schizophrenia was not explained by tobacco smoking or antipsychotic medication use.

The results support the hypothesis that schizophrenia is accompanied by accelerated aging. Results were inconsistent with some of the most obvious explanations for accelerated aging in schizophrenia (familial risk, smoking, and iatrogenic medication effects). Research should aim to uncover why people who have schizophrenia age rapidly, as well as the utility of early disease-risk monitoring and anti-aging interventions in schizophrenia.

Volumetric changes in the superior temporal gyrus and anterior cingulate cortex have been repeatedly reported in studies on schizophrenia. Tractography and functional magnetic resonance imaging studies have suggested that alterations in connectivity involving the superior temporal gyrus and the anterior cingulate cortex are relevant to psychotic symptoms of schizophrenia.

We analyzed nanometer-scale three-dimensional structures of brain tissues of the superior temporal gyrus and the anterior cingulate cortex in eight schizophrenia and eight control cases and evaluated structural parameters of their neurons. We then examined the relation between the neuronal parameters and clinical information including auditory hallucination score.

The obtained results indicated that 1) neurites become thin and tortuous in schizophrenia and that 2) somata become small in schizophrenia. The frequency distribution of neurite curvatures had a broad profile in the schizophrenia cases, whereas the control cases showed sharp peaks. In the scatter diagram of the standard deviation of neurite curvatures, the schizophrenia and control cases formed separate clusters, indicating that all 16 cases analyzed in this study can be assigned to either the schizophrenia or control group simply by using the diagram. The cingulate/temporal ratio of the standard deviation of neurite curvatures showed a strong positive correlation with the auditory hallucination score.

The structural alteration of neurites observed in the schizophrenia cases should influence the function of affected brain areas by hindering communication between distant neurons. We suggest that the interplay of the temporal and cingulate cortices in the whole-brain network is relevant to auditory hallucination.

Schizophrenia (SCZ) shows marked biological heterogeneity, with negative symptoms linked to poor outcomes and hypothesised immune dysregulation. This study examined whether a peripheral cytokine–long non-coding RNA (lncRNA) panel could distinguish patients with SCZ and Brief Negative Symptom Scale (BNSS)-defined subgroups from healthy controls (HC).

Forty-one hospitalised patients with SCZ completed the BNSS and the Positive and Negative Syndrome Scale (PANSS). Twenty HCs, frequency-matched for age and sex, served as comparison samples. Severe negative-symptom subgroups were defined using two BNSS criteria: a broader (SNS1) and a more restrictive (SNS2) threshold. Serum cytokines – interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-10 (IL-10) – and leukocyte lncRNAs (MALAT1, NEAT1, MEG3) were quantified by enzyme-linked immunosorbent assay and quantitative RT-PCR. Covariate-adjusted logistic and multinomial models (adjusting for age, sex, body mass index, and smoking) assessed discrimination using area under the receiver-operating-characteristic curve (AUC) and interquartile-range odds ratios (OR_IQR).

IL-6 correlated with PANSS Total (ρ = 0.48, p = 0.001) and Negative (ρ = 0.34, p = 0.032) scores and was higher in SCZ than HC (p = 0.033), with further increases in SNS subgroups. NEAT1 was significantly reduced only within BNSS-defined subgroups (p ≤ 0.025). The dual-marker pattern (IL-6 ↑, NEAT1 ↓) showed the strongest discrimination for SNS1 versus HC (AUC = 0.85) and the steepest multinomial contrasts for SNS2 (IL-6 OR_IQR = 4.98; NEAT1 OR_IQR = 0.11).

Elevated IL-6 and decreased NEAT1 define a peripheral signature linked to negative-symptom severity in SCZ and may support biologically informed stratification and longitudinal research.

People diagnosed with schizophrenia can have functional impairments in multiple domains. Cognitive impairment is central to schizophrenia and has substantial prognostic value compared with other symptoms of schizophrenia. However, no study has previously investigated directed relationships in a complex system of cognitive, sociodemographic, clinical and quality of life (QOL) variables in people diagnosed with schizophrenia.

To identify the complex relationships of components of cognition with other cognitive components, as well as with clinical and QOL variables.

This study included data from 1450 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The present study reconstructed a Bayesian network from this data using cognition, clinical, sociodemographic and QOL variables.

Processing speed was centrally associated with all other cognitive domains. Cognitive domains were conditionally independent of positive symptoms but moderately associated with negative symptoms (β = −0.25; P < 0.001). The positive symptoms subscale was independent of QOL, conditioning on third variables. Negative symptoms were moderately associated with QOL (β = −0.33; P < 0.001), and processing speed had a weak association with QOL (β = −0.12; P < 0.001). Processing speed was a central variable in the network.

Intervening with respect to processing speed may be the most beneficial way of improving other cognitive functions. More research is needed on directed networks that include social cognition and global levels of functioning.

Understanding the neuroanatomical correlates of treatment response in schizophrenia is crucial for improving clinical stratification and clarifying underlying pathophysiological mechanisms.

To examine subcortical volumetric differences across clinically defined schizophrenia treatment-response subgroups.

T1-weighted structural magnetic resonance imaging data were analysed from 109 participants, including 79 individuals with schizophrenia and 30 healthy controls. Patients were categorised into three distinct treatment response groups: ultra-treatment-resistant (UTR; n = 22), clozapine-responsive (n = 28) and first-line antipsychotic responsive (FLR; n = 29). Group differences were examined across 33 regions of interest, including subcortical, ventricular and hippocampal subfield regions.

The UTR group had higher antipsychotic dosages and exhibited greater symptom severity than other patient groups. Across all schizophrenia subgroups, hippocampal and amygdala volumes were smaller relative to controls. Treatment-resistant patients (UTR and clozapine-responsive) also showed reduced nucleus accumbens volumes, whereas FLR patients demonstrated larger pallidal volumes. In addition, the UTR subgroup exhibited enlarged lateral ventricles. Hippocampal subfield analyses revealed widespread reductions in treatment-resistant patients, most prominently in the CA4/dentate gyrus, subiculum and stratum, whereas FLR patients showed more focal reductions in the CA4/dentate gyrus and left subiculum.

These results suggest that smaller hippocampal and amygdala volumes represent a shared neuroanatomical signature of schizophrenia, whereas reduced accumbens and enlarged pallidal volumes may differentiate treatment-resistant and treatment-responsive profiles, respectively. The findings underscore the heterogeneity of schizophrenia and highlight the need for longitudinal research to disentangle illness-related pathology from medication effects.

Evidence regarding the effects of antipsychotic medication on cognitive functioning after a first-episode psychosis (FEP) remains inconclusive. This study examined whether dopamine D2 receptor occupancy, affinity, and antipsychotic dose are related to cognitive functioning in people in remission from FEP.

278 remitted FEP participants from the HAMLETT-trial were included. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia, 3–6 months after remission. D2 receptor occupancy was estimated based on antipsychotic type and dose. Antipsychotics were categorized into partial agonists, or antagonists with high or low D2 receptor affinity. Linear regression analyses were performed with inverse probability of treatment weighting to control for differences in characteristics between groups.

D2 receptor occupancy was negatively related to global cognition (β = −0.18), verbal fluency (β = −0.22), and attention and processing speed (β = −0.17, all p < 0.003). The interaction between daily dose and D2 receptor affinity category was significant for global cognition (p = 0.0046) and working memory (p = 0.0019), but not for verbal fluency after correction for multiple testing (p = 0.029). Interactions showed that higher daily dose was related to lower cognitive functioning, with significantly stronger negative effects in high-affinity antagonists compared to other antipsychotics.

The current findings underscore the importance of antipsychotic D2 receptor occupancy and affinity for cognitive functioning and suggest better cognitive functioning in users of partial agonists and low D2 receptor affinity antipsychotics. This can be important when selecting antipsychotics for individuals with FEP.