Schizophrenia is a chronic and disabling neuropsychiatric disorder traditionally defined by psychotic and cognitive symptoms. Increasing evidence suggests that neuroinflammatory mechanisms contribute to its pathophysiology and may also underlie common but underrecognized somatic manifestations. These include altered pain perception, characterized by both diminished sensitivity and chronic pain, with important implications for functional outcomes and rehabilitation. This narrative review examines clinical, preclinical, and translational studies addressing the role of neuroinflammation in schizophrenia, with a specific focus on microglial and astrocytic activation, cytokine signaling, oxidative stress pathways, and their interactions with central pain processing circuits. The review was informed by targeted searches of PubMed, Scopus, Web of Science, and Google Scholar, covering articles published from database inception to January 2026, with emphasis on studies relevant to pain modulation, symptom expression, and neurobiological heterogeneity in schizophrenia. Neuroinflammation represents a biologically plausible link between core schizophrenia pathology and altered pain perception. Recognition of pain as an integrated component of disease biology, rather than a secondary complaint, may improve clinical assessment and treatment planning. Investigating and targeting neuroinflammatory pathways holds promise for personalized interventions that address neuropsychiatric symptoms and pain, potentially enhancing rehabilitation outcomes and quality of life. Schizophrenia is a long-term mental health condition that is usually known for symptoms such as changes in thinking, perception, emotions, and memory. However, people with schizophrenia may also experience physical problems that receive less attention, including unusual pain responses. Some may seem less sensitive to pain, while others may live with ongoing pain that affects daily functioning and recovery.This review explores whether inflammation in the brain and body may help explain this pattern. Inflammation is part of the body’s defense system, but when it becomes persistent or unbalanced, it may affect how the brain works. Studies suggest that in schizophrenia, inflammatory changes may influence brain cells, chemical signals, stress pathways, and the systems involved in sensing and responding to pain. We reviewed findings from human and animal research on schizophrenia, inflammation, and pain-related processes. The evidence suggests that inflammation may be one of the biological mechanisms linking schizophrenia with altered pain experience. Understanding pain as part of the illness, rather than as a separate or secondary problem, may help clinicians provide better care. It may also support more personalized treatment and rehabilitation strategies. In the future, treatments that target inflammatory pathways may improve both mental health symptoms and pain-related outcomes, leading to better quality of life for people living with schizophrenia.
More than 20% of individuals with schizophrenia show minimal or no response to antipsychotic medications and little is known about genetic contributions to more severe forms of illness. This study sought to explore if cases with continuously-hospitalized, treatment-resistant schizophrenia (CH-TRS) carry a higher burden of common genetic variants compared to less severe forms. CH-TRS cases were recruited from Pennsylvania state psychiatric hospitals in the USA, with ≥ 5 years of continuous hospitalization, active treatment, and non-response to ≥ 3 antipsychotic medications. Three comparator groups were obtained from cohorts in the USA, Sweden, and the UK including TRS, general schizophrenia and non-psychiatric controls. Polygenic scores (PGS) of schizophrenia and cognitive ability were generated in individuals of European and African ancestry. Logistic regression assessed the association of PGS and CH-TRS cases (vs. comparators), with sex differences and sensitivity analyses excluding individuals with other diagnoses conducted to assess robustness. We included 18,571 individuals of European ancestry (346 CH-TRS, 10,757 TRS, 1148 general schizophrenia, 6320 non-psychiatric controls) and exploratory analyses of 476 individuals of African ancestry (78 CH-TRS, 398 non-psychiatric controls). For each standard deviation increase in the schizophrenia PGS, the odds of CH-TRS among individuals of European ancestry increased by 40-80% compared to general schizophrenia and TRS. Results in African ancestry participants mirrored those of European ancestry albeit with reduced levels of significance. Sex interactions and sensitivity analyses did not materially alter the estimates. This study demonstrates a greater burden of common genetic variants is associated with more severe forms of illness in schizophrenia.
Cognitive deficits are a leading cause of disability in schizophrenia and are linked to poor functional outcomes. There are no first line treatments for these deficits, and their neural basis is poorly understood. While schizophrenia is associated with widespread cognitive deficits, information processing speed is most profoundly impaired. Processing speed deficits have been associated with hyperconnectivity in the Default Mode Network (DMN). We therefore tested if modulating DMN connectivity with single or multiple sessions of transcranial magnetic stimulation (TMS) applied to an individualized DMN target would affect processing speed. In the first study, 10 individuals with schizophrenia received single TMS sessions and underwent resting-state neuroimaging and processing speed assessment (Brief Assessment of Cognition in Schizophrenia digit symbol coding) acutely before and after each session. These sessions included excitatory (intermittent theta burst stimulation, iTBS); inhibitory (continuous theta burst stimulation, cTBS); and sham stimulation sessions. In the second study, 29 individuals (17 schizophrenia, 12 non-psychosis controls) received 5 accelerated sessions of cTBS with resting-state neuroimaging and processing speed assessment before and after the course of TMS sessions. In the accelerated, multi-session DMN-targeted TMS trial, cTBS improved processing speed in the schizophrenia group (p = 0.0124). In individuals with schizophrenia, reduction in DMN connectivity was linked to improvement in processing speed (p = 0.021). These changes were dependent on age, where younger participants experienced greater processing speed improvements than older participants (p = 0.006). In sum, personalized network targeted TMS may be a novel method for reducing cognitive impairment associated with schizophrenia.
Treatment-resistant schizophrenia (TRS) is a clinically important subtype of schizophrenia, but its cognitive characteristics remain incompletely understood. The Wisconsin Card Sorting Test (WCST) is widely used to assess executive dysfunction in schizophrenia, although conventional summary analyses may overlook trial-by-trial behavioral adaptation. This study aimed to examine whether recent trial outcome modulates subsequent responding differently between TRS and non-TRS patients during the WCST. We analyzed WCST data from 41 outpatients with schizophrenia, including 13 patients with TRS and 28 with non-TRS. Conventional subject-level indices, including perseveration rate and outcome-dependent reaction time (RT) adjustment, were first compared between groups. We then performed trial-level linear mixed-effects analyses using log-transformed RT as the dependent variable, with previous trial correctness, treatment resistance, their interaction, age, and sex as fixed effects. Additional sensitivity analyses included models with by-subject random slopes for previous trial correctness and analysis in an age-matched sample. Conventional summary analyses showed no significant group differences in perseveration rate or RT measures. In the primary model, previous trial correctness significantly modulated subsequent RT, and the interaction between previous trial correctness and TRS suggested a group difference in outcome-dependent RT modulation. Specifically, the RT difference between trials following error and correct responses appeared smaller in TRS patients than in non-TRS patients. However, sensitivity analyses using by-subject random slopes and an age-matched sample showed similar directions and magnitudes of the interaction but did not reach statistical significance. Conventional WCST summary analyses did not distinguish TRS from non-TRS patients, whereas trial-level modeling provided preliminary evidence for possible alteration of outcome-dependent response adjustment in TRS. These findings suggest that dynamic behavioral phenotypes may provide a useful complement to standard neuropsychological indices in characterizing cognitive heterogeneity in schizophrenia, but replication in larger samples is needed.
Metabolic syndrome is common among patients with schizophrenia, but current treatment options are limited, with metformin being the most studied. While placebo-controlled studies suggest potential benefits of topiramate, comparative efficacy and safety data are lacking. This study aimed to compare the efficacy and safety of topiramate versus metformin for treating metabolic syndrome and reducing cardiovascular risks among patients with schizophrenia. A randomised, open-label, parallel-group clinical trial was conducted on 60 patients of schizophrenia with metabolic syndrome, randomised equally to receive either topiramate (50 mg/day) or metformin (1000 mg/day) for eight weeks. Primary outcome was cardiovascular risk score (QRISK3), and secondary outcomes were LDL∶HDL ratio, insulin resistance (HOMA-IR), positive and negative syndrome scale (PANSS), Montreal Cognitive Assessment (MoCA) and clinical global impression-Schizophrenia scale (CGI-SCH) scores. Over the study period, QRISK3 scores improved significantly in both groups [topiramate: MD = 0.61 (0.02 to 1.21), p = 0.04; metformin: MD = 0.45 (0.07 to 0.83), p = 0.02], with no significant between-group difference in unadjusted analysis (p = 0.648). However, ANCOVA adjusting for baseline QRISK3 revealed a significantly greater improvement in the topiramate group (β = -0.324, p = 0.043). Metformin showed significant within-group improvements in LDL: HDL ratio and HOMA-IR; however, ANCOVA adjusting for baseline HOMA-IR showed the between-group difference remained non-significant (β = -1.209, p = 0.078). Both groups showed significant improvements in PANSS and CGI-SCH scores, with no significant between-group differences in MoCA scores. A moderate correlation between the QRISK3 change, the PANSS change, and the CGI-SCH-I scores was observed in the topiramate group and the total population. Regression analysis identified PANSS change as a predictor of QRISK3 improvement. Topiramate demonstrated comparable, and on adjusted analysis superior, cardiovascular risk reduction compared to metformin, supporting its use as a viable alternative in the management of metabolic syndrome in patients with schizophrenia on atypical antipsychotics, particularly where metformin is contraindicated.
Antipsychotics are the cornerstone of schizophrenia management, with antipsychotic polypharmacy commonly observed. This study aims to evaluate the trends of antipsychotic use and polypharmacy among individuals with schizophrenia in Hong Kong. This retrospective study used territory-wide electronic health records to identify all individuals aged ≥18 years diagnosed with schizophrenia in Hong Kong (2004-2024). Annual prevalence rates of antipsychotics and polypharmacy were calculated, with trend analysis using Joinpoint regression. The overall use of antipsychotics remained stable, with a slight decrease during the study period (average annual percentage change [AAPC] -0.40 [95% CI, -0.42 to -0.38]), though individual agents shifted substantially. There were opposing trends with a crossover from first to second-generation antipsychotics (SGA) predominance, while a less pronounced increase in SGA over the past decade. In 2024, olanzapine emerged as the most prevalent antipsychotic (20.6%), while clozapine utilisation grew but remained relatively limited (7.5%). Use of long-acting injectable antipsychotics (LAIA) declined (AAPC = -0.92 [-1.07 to -0.77]), except SGA-LAIA, which rose, primarily driven by LAIA-paliperidone and LAIA-aripiprazole. Antipsychotic polypharmacy prevalence decreased initially from 24.0% in 2004 to 22.4% in 2011, then increased to 28.0% in 2024 (AAPC = 0.74 [0.62 to 0.90]). In 2024, the most common combinations were oral aripiprazole and oral olanzapine (5.68%), oral amisulpride and oral olanzapine (4.22%), and LAIA-paliperidone and oral olanzapine (4.05%). Over the last two decades, overall antipsychotic use in schizophrenia remained stable in Hong Kong, though patterns shifted between agents. Antipsychotic polypharmacy became more prevalent, emphasising the need for further research on their safety and effectiveness.
Schizophrenia is a chronic psychiatric disorder associated with significantly elevated mortality. While antipsychotics are the cornerstone of treatment, their long-term effects on survival remain uncertain, particularly in non-Western populations. We aimed to assess the real-world association between antipsychotic treatment patterns and all-cause mortality among adults with schizophrenia in China. This population-based cohort study included 435,816 adults from the Community Schizophrenia Registry System of Guangdong Province, China. Patients were classified into four groups: antipsychotic monotherapy, polytherapy, non-antipsychotic treatment and non-drug treatment. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for mortality. Over a median follow-up of 7.2 years, 73,527 deaths (16.9%) occurred. Antipsychotic polytherapy (57.6%) was the most common regimen, followed by monotherapy (27.6%). Compared with the non-drug group, mortality risks were significantly lower for polytherapy (aHR: 0.18; 95% CI: 0.18-0.19), monotherapy (aHR: 0.24; 95% CI: 0.24-0.25) and non-antipsychotic treatment (aHR: 0.22; 95% CI: 0.21-0.23). Both first- and second-generation antipsychotics showed comparable mortality benefits. While most polytherapy regimens performed similarly to or better than monotherapy, combinations like risperidone-sulpiride were associated with higher mortality. Subgroup analyses showed stronger benefits in women, younger individuals, rural residents and those with less severe illness. Antipsychotic treatment is associated with significantly reduced mortality among patients with schizophrenia in China, with effects varying by patient characteristics and drug regimen.
Poor adherence to oral antipsychotics is an important challenge in schizophrenia, highlighting long-acting injectables (LAIs) as an alternative. This study aimed to compare the clinical and demographic profiles of patients with schizophrenia with prior LAI exposure versus those maintained exclusively on oral antipsychotics. This cross-sectional, observational study enrolled eligible schizophrenia inpatients aged 18-65 diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria from June 2022 to October 2023. Participants were divided into two groups: those with prior LAI exposure and those who had maintained only oral antipsychotics. Demographic data, clinical history, and baseline laboratory parameters were collected. The primary outcome was the severity of psychotic symptoms, assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Severity (CGI-S) Scale upon admission. A total of 70 patients were included in the final analysis, with 36 patients having a history of LAI and 34 on only oral treatment. Demographically, both groups were comparable across most characteristics. Baseline PANSS score and its subscales, CGI-S scores, and laboratory markers showed no statistical difference. However, the LAI group showed a significantly longer duration of illness (P = 0.017), more hospitalizations (P < 0.001), and greater prior exposure to first-generation antipsychotics (P < 0.001) with higher chlorpromazine equivalent doses (P < 0.001) compared to the oral-only group. This study highlights treatment patterns among Iranian schizophrenia patients, showing that patients on LAIs generally have a history of longer illness durations, more hospitalizations, and more expose to first generation antipsychotics. Further studies should be conducted to investigate the efficacy of early versus delayed initiation of LAI and their long-term outcomes.
To identify correlations between the levels of platelet enzyme activity and clinical responses to antipsychotic pharmacotherapy in patients diagnosed with late-onset manifesting schizophrenia-like psychosis (late-onset schizophrenia, LOS) and very late-onset manifesting schizophrenia-like psychosis (VLOSLP). The mental health status of 76 hospitalized patients with LOS and VLOSLP was evaluated using standardized psychometric scales at two time points: prior to the initiation of treatment and after a 28-day course of psychotropic therapy. Prior to treatment commencement, the activity levels of platelet enzymes involved in glutamate metabolism, energy metabolism, and glutathione antioxidant metabolism were measured for all subjects. A statistical analysis of the database with clinical and biochemical examination results, was conducted. A comprehensive psychopathological assessment enabled the identification of patients exhibiting specific small-range delusions within their psychosis, notably «dwelling paranoid» delusions. It was observed that this type of delirium was predominantly present in patients with VLOSLP (X²=9.8, p=0.0018 with Yates correction). When participants were categorized into subgroups based on the presence or absence of «dwelling paranoid» delusions, a significant difference in platelet glutamate dehydrogenase activity was noted: patients exhibiting this type of delirium demonstrated significantly higher activity levels (p=0.009). Furthermore, several notable clinical and biological correlations were established between platelet enzyme activity levels and the clinical response to psychotropic therapy. The significant correlations identified between platelet enzyme activity levels prior to therapy and individual clinical responses to psychotropic interventions hold potential for prognostic applications in clinical psychiatry, particularly for patients with disorders along the schizophrenia spectrum in later life. Выявление корреляционных связей между уровнями активности тромбоцитарных ферментов и выраженностью клинического ответа на антипсихотическую фармакотерапию у пациентов с поздно манифестирующими шизофреноподобными психозами (поздней шизофренией, ПШ) и очень поздно манифестирующими шизофреноподобными психозами (ОПШП). Психическое состояние 76 госпитализированных пациентов с ПШ и ОПШП оценивалось по психометрическим шкалам дважды — до начала и после курса 28-дневной психотропной терапии. До начала курса терапии у всех пациентов определялись уровни активности тромбоцитарных ферментов, относящихся к глутаматному, энергетическому и антиоксидантному глутатионовому метаболизму. Проводился статистический анализ базы данных, созданной по результатам клинико-биохимических обследований. Углубленная психопатологическая оценка позволила выделить пациентов, у которых в структуре психоза присутствовал бред малого масштаба по типу «параноида жилья». Обнаружено, что пациенты с этим типом бреда преобладали среди пациентов с ОПШП (χ2=9,8, p=0,0018 с поправкой Йетса). При разделении пациентов по наличию или отсутствию этого типа бреда на две подгруппы обнаружено, что в них различается уровень активности тромбоцитарной глутаматдегидрогеназы (при наличии бреда «параноида жилья» активность значимо выше, p=0,009). Кроме того, в них обнаружены различные значимые клинико-биологические корреляции между уровнями активности тромбоцитарных ферментов и выраженностью клинического ответа на психотропную терапию. Обнаруженные значимые корреляции между уровнями активности тромбоцитарных ферментов до курса терапии с индивидуальной клинической реакцией на психотропную терапию могут применяться в клинической психиатрии для прогностических целей при расстройствах шизофренического спектра в позднем возрасте.
RhoA-a member of the Rho family of GTPases-critically regulates synaptic plasticity and immune cell function, which have emerged as key mechanisms in schizophrenia pathogenesis. In this study, we measured RHOA mRNA expression levels in the peripheral blood mononuclear cells (PBMCs) from patients with acute schizophrenia and healthy controls. We also conducted integrative bioinformatics analyses to investigate transcription factors (TFs) and genetic variants in miRNAs predicted to regulate RHOA mRNA expression in schizophrenia. Quantitative real-time PCR (qPCR) revealed a significant upregulation of RHOA mRNA expression in the PBMCs from patients with acute schizophrenia compared with controls. Although sex-stratified analysis showed a significant association in males, the group × sex interaction was not significant. Moreover, multivariable robust regression adjusted for sex, educational level, age, BMI, and smoking confirmed a significant group effect, reflecting higher RHOA mRNA expression in patients than in controls. Integrative bioinformatics analyses identified five candidate miRNAs (hsa-miR-183-3p, hsa-miR-574-5p, hsa-miR-4429, hsa-miR-4686, and hsa-miR-5002-5p) that were differentially expressed in schizophrenia and predicted to target RHOA. Subsequent analysis revealed six variants within these candidate miRNAs with the highest predicted ΔG values and potential to affect mature miRNA expression. Moreover, 10 hub TFs (EP300, HDAC1, TP53, CREBBP, HDAC2, ESR1, MYC, JUN, SP1, and BRCA1) were predicted to regulate RHOA mRNA expression. These findings suggest that RHOA upregulation in PBMCs may be associated with the pathophysiology of schizophrenia. Further investigations are needed to validate these results and elucidate the mechanistic role of RHOA dysregulation in the disorder.
People with severe mental illness (SMI) have shorter life expectancy, largely driven by physical health conditions. While lifestyle and psychotropic side effects contribute, peripheral organ dysregulation is intrinsic to SMI. Clarifying these effects could reveal novel therapeutic targets. Mendelian randomization (MR) was used to test the causal effects of genetic liability to schizophrenia, bipolar disorder, and major depressive disorder (MDD) on magnetic resonance imaging (MRI)-derived measures of peripheral organ structure and composition. Multivariable MR assessed lifestyle and metabolic mediators. One-sample MR and observational analyses in the UK Biobank (UKB) explored sex-specific effects. Two-sample MR used the largest genome-wide association study (GWAS) for schizophrenia (N = 175,799), bipolar disorder (N = 2,954,535), and MDD (N = 5,053,033). MRI-derived GWASs included up to 38,923 participants. Genetic liability to all 3 SMIs associated with reduced peak diastolic strain rates, indicating impaired myocardial relaxation. Schizophrenia liability associated with smaller ventricular volumes, larger lung volumes, and higher liver iron levels. Bipolar disorder liability associated with lower right-sided cardiac volumes; higher left ventricular mass-to-volume ratio; and increased visceral, subcutaneous, and organ fat. MDD liability predominantly associated with greater abdominal and organ fat. Associations persisted after adjustment for body mass index, inflammation, insulin resistance, and smoking. One-sample MR in the UKB was directionally consistent and suggested sex-specific effects. SMI genetic liability exerts both shared and disorder-specific causal effects on peripheral organ structure, with myocardial stiffening (indicating poor cardiovascular prognosis) common to all, cardiopulmonary changes in schizophrenia, adipose-organ changes in MDD, and an intermediate phenotype in bipolar disorder. These cardiometabolic alterations support integrated screening and prevention strategies targeting cardiovascular and metabolic risk in SMI. People with severe mental illness (such as schizophrenia, bipolar disorder, and depression) often die earlier, mainly due to physical health problems. This study used genetic methods to test whether these conditions directly affect body organs. We found that all 3 conditions are linked to reduced heart function, suggesting stiffer heart muscle. Schizophrenia mainly affected the heart and lungs, while bipolar disorder and depression were linked to increased body and organ fat. These findings suggest that physical health monitoring and early prevention should be a routine part of care for people with severe mental illness.
Multiple sclerosis (MS) can present with neurological and psychiatric symptoms that may overlap with those of schizophrenia, making differentiation difficult particularly because their typical onset ages are similar. We present the case of a woman in her 50s who developed persecutory delusions and a subjective sense of being under surveillance in Year X-31 and was diagnosed with schizophrenia. Despite the long-term antipsychotic treatment, the patient's symptoms persisted and worsened. In Year X-1, brain magnetic resonance imaging revealed multiple white matter lesions, and then cerebrospinal fluid analysis revealed oligoclonal bands, leading to a diagnosis of MS. Treatment with ofatumumab was initiated. Owing to persistent psychiatric symptoms, clozapine was administered, which showed partial effectiveness. This case highlights the clinical overlap between schizophrenia and MS and suggests that comorbid MS pathology may be clinically relevant in the context of treatment resistance and cognitive impairment. Similarities in symptoms and disease course raise the possibility that a subset of patients with schizophrenia may share pathophysiological features with MS. In addition, postmortem studies, including our previous and current observations, provide hypothesis-generating support for partially overlapping MS-like changes in some patients with schizophrenia. Clinicians should consider the possibility of comorbid MS in patients with treatment-resistant schizophrenia, particularly when atypical clinical or neurological features are present.
This study aimed to explore core and bridge elements in the network structure linking family functioning and cognitive insight among community-dwelling individuals with schizophrenia. The NodeIdentifyR (NIRA) algorithm was applied to simulate node-level perturbations within this cross-sectional network. Findings were interpreted as hypothesis-generating evidence for potential targets rather than as proof of preventive intervention effects. Individuals with schizophrenia receiving community follow-up care in Pengzhou City, China, were recruited using convenience sampling. Data were collected through an online questionnaire platform and included demographic and clinical characteristics, the Family Intimacy and Adaptability Scale, and the Beck Cognitive Insight Scale. Because all scale items were ordinal Likert-type responses, ordinal item handling and node coding were specified before network estimation. Gaussian graphical models were estimated using polychoric correlations, while Ising/NIRA simulations were conducted on dichotomized, consistently risk-coded nodes. Sensitivity analyses were performed to examine the robustness of the main network findings after adjustment for available demographic and clinical covariates. A total of 785 participants, including 414 males and 371 females, were analyzed. In the Gaussian graphical model, F13, representing lower family democratic decision-making, and F26, representing a lower atmosphere of free expression, showed the highest expected influence and were identified as core elements in the risk-coded network. B4, representing cognitive impulsivity, had the highest bridge expected influence, indicating its key role in linking family functioning and cognitive insight. Ising-model simulations showed that mitigating activation of F6, representing reduced intergenerational equal expression, produced the greatest reduction in overall network activation, suggesting this node as a promising hypothesis-generating prevention target. In contrast, exacerbation simulations showed no significant differences in cognitive insight scores across intervention targets after multiple-comparison correction. The covariate-adjusted sensitivity network yielded the same leading expected-influence and bridge-expected-influence nodes. Network centrality indices, including core and bridge elements, should be interpreted cautiously when identifying intervention targets, because they do not necessarily correspond to the most effective simulated intervention nodes. Reduced intergenerational equal expression within families may represent an important hypothesis-generating focus for future early intervention and prevention research aimed at improving cognitive insight among community-dwelling individuals with schizophrenia.
Anhedonia and related motivation and pleasure (MAP) deficits are prevalent in schizophrenia and psychosis spectrum disorders, are generally persistent over time and show limited treatment response. These symptoms are of clinical importance as they contribute to the profound social impairment and reduced quality of life in schizophrenia and psychosis spectrum disorders. This selective narrative review examines methods for assessing anhedonia and MAP deficits followed by a summary of current research on factors that contribute to these symptoms with a focus on identifying continued gaps in our understanding. Literature spanning affect and hedonic responding is reviewed with an examination of the role of cognitive deficits, neural mechanisms, dysfunctional beliefs, behavior, sleep and environmental factors. Current treatment approaches are highlighted including recent advances in pharmacotherapy and psychosocial treatments.
Individuals with schizophrenia have shown distinct cancer incidence patterns. We aimed to assess whether their cancer-related mortality differs from the general population overall, by gender and by specific cancer types. We systematically searched Scopus, Web of Science, PsycINFO, PubMed and Embase, up to December 2025. Each record was independently screened by two reviewers, and data were independently extracted by two investigators. Two authors assessed the quality of the included articles with the Newcastle-Ottawa Scale. Analyses were conducted using Stata version 16; between-study heterogeneity was evaluated with Cochran's Q-statistic and the I2-statistic, and potential sources of heterogeneity were further examined through exploratory meta-regression. Meta-analysis of cohort studies showed that individuals with schizophrenia had a 55% higher risk of cancer-related death than the general population (standardised mortality ratio (SMR) 1.55; 95% CI 1.16-2.07). In gender-stratified analyses, SMRs for all cancers combined were 1.37 (95% CI 1.01-1.87) in men and 1.43 (95% CI 1.15-1.79) in women. Site-specific SMRs were 1.77 (95% CI 1.17-2.68) for breast, 2.40 (95% CI 2.35-2.45) for respiratory, 1.54 (95% CI 1.35-1.76) for gastrointestinal, 2.32 (95% CI 0.72-7.45) for haematologic, 4.43 (95% CI 0.71-27.62) for skin and soft tissue, 3.03 (95% CI 1.96-4.69) for urogenital and 1.01 (95% CI: 0.36-2.83) for other cancers, although precision varied considerably across cancer sites. Schizophrenia was associated with substantially elevated cancer-related mortality compared with the general population. These findings underscore the need for earlier cancer detection and guideline-concordant, integrated physical and mental healthcare for this high-risk group.
This study was designed to evaluate the genetic association of three specific intronic Single Nucleotide Polymorphisms (SNPs) within the Dopamine Receptor D2 (DRD2) gene-rs2005313, rs4274224, and rs4938019-with schizophrenia susceptibility in a Pakistani population. The primary objective was to identify population-specific biomarkers that could inform early intervention and personalized treatment strategies. Genotyping was conducted on a matched case-control cohort of 208 participants (104 cases; 104 controls) using High-Resolution Melting (HRM) PCR. Genetic associations were quantified using Odds Ratios (OR) and 95% Confidence Intervals (CI), representing the standard coefficient and its margin of error to ensure statistical precision. Functional annotation of the investigated polymorphisms was performed using GTEx, FORGEdb and RegulomeDB to assess regulatory potential and tissue-specific expression effects. The research identified highly significant associations across multiple inheritance models, validating the technical robustness of the findings. The rs4938019 polymorphism emerged as the most potent genetic risk factor, particularly under the recessive model (OR: 9.60; 95% CI: 3.92-23.52; p < 0.0001), where the rare GG genotype was found in 44% of cases compared to only 7.2% of controls. Conversely, rs4274224 demonstrated a significant protective effect, with a co-dominant OR of 0.23 (95% CI: 0.09-0.59; p = 0.0022), suggesting that the T allele confers genetic resilience. Furthermore, among the investigated DRD2 variants, rs2005313 demonstrated significance primarily under the over-dominant inheritance model, whereas rs4938019 exhibited the strongest association under the recessive model (OR: 2.13; 95% CI: 1.15-3.94; p = 0.014). All variants in the control group maintained Hardy-Weinberg Equilibrium (p > 0.05), confirming the absence of population bias. Functional annotation revealed that rs4274224 showed the strongest direct regulatory evidence for DRD2 (FORGEdb score: 6; RegulomeDB Rank 1f), while rs4938019 demonstrated the highest overall regulatory potential (FORGEdb score: 9), with rs2005313 exhibiting substantial regulatory evidence (FORGEdb score: 7) supported by extensive GTEx cis-eQTLs across multiple tissues including brain regions. These findings establish DRD2 intronic polymorphisms as critical determinants of schizophrenia risk. The high-risk rs4938019 GG genotype provides a clear translational biomarker for rapid genetic screening, potentially improving clinical outcomes through genotype-guided therapeutic interventions.
To evaluate the validity of the six-factor model of the Positive and Negative Syndrome Scale (PANSS) using network analysis and to examine the relationships between depression, anxiety, and symptoms associated with schizophrenia. The study included a cohort of 150 inpatients diagnosed with schizophrenia. The severity of psychopathological symptoms was assessed using the PANSS based on a six-factor model. The study also utilized the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Network analysis was performed using the R statnet package. The findings revealed that the highest centrality rates were attributed to the disorganized, negative, and excitation factors within the PANSS scale. Anxiety scores derived from HARS were found to be significantly associated with G16 (active social avoidance), G6 (depression), N2 (emotional withdrawal), and G3 (guilt feelings), which correspond to elements within the negative, depressive, and disorganized factors. In addition, HDRS depression scores demonstrated associations with G6 and N2, representing the depressive and negative factors. A correlation was also observed between the scores from both assessment scales. The network analysis indicated that depressive symptoms evaluated through the HDRS, alongside anxiety symptoms assessed via HARS, hold substantial significance among the psychopathological presentations observed in patients with schizophrenia. These symptoms exhibit a close interrelationship with components of the negative, depressive, and disorganized factors as identified within the PANSS model. In addition, the analysis substantiated the validity of the PANSS six-factor model. Провести оценку валидности 6-факторной модели шкалы позитивных и негативных синдромов (PANSS) с использованием сетевого анализа, а также изучить связи между депрессией, тревогой и симптомами шизофрении. Обследованы 150 стационарных пациентов с шизофренией. Тяжесть психопатологической симптоматики у пациентов оценивалась с помощью PANSS на основе 6-факторной модели. В исследовании также применялась шкала Гамильтона для оценки депрессии (HDRS) и тревоги (HARS). Проведение сетевого анализа осуществлялось с использованием пакета R statnet. Самые высокие показатели центральности отмечались по дезорганизованному фактору, негативному фактору и фактору возбуждения шкалы PANSS. Показатели тревоги по HARS имели связи с пунктами G16 (активная социальная отстраненность), G6 (депрессия), N2 (эмоциональная отгороженность) и G3 (чувство вины), т.е. компонентами негативного, депрессивного и дезорганизованного фактора. Показатели депрессии по HDRS также имели связи с G6 и N2 — депрессивный и негативный факторы. Кроме того, показатели по обеим шкалам были связаны друг с другом. Проведенный сетевой анализ показал, что депрессивные симптомы, оцениваемые с помощью HDRS, а также тревожные симптомы по HARS занимают значимое место среди психопатологических проявлений у пациентов с шизофренией. Эти симптомы проявляют тесную связь с компонентами негативного, депрессивного и дезорганизованного факторов, выделенных в модели PANSS. Кроме того, анализ подтвердил обоснованность 6-факторной модели PANSS.
Schizophrenia is a severe neuropsychiatric disorder characterized by positive, negative, cognitive, mood-related, and motor symptoms. Sub-chronic ketamine administration is widely used to induce schizophrenia-like behavioral and cognitive alterations in rodents. Chlorogenic acid (CGA) is an abundant dietary phenolic acid with reported anti-inflammatory, antioxidative, and neuroprotective properties. The present study examined the effects of CGA on behavioral disturbances in male and female rats exposed to sub-chronic ketamine administration, together with brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex. Ketamine was injected for 7 consecutive days (30 mg/kg, i.p.), and CGA was orally administered once (150 mg/kg) 24 h after the last ketamine injection. Ketamine increased locomotor activity in both sexes, with a greater effect in females; CGA partially reduced this effect only in males. Rearing was reduced only in ketamine-treated males, and CGA did not reverse this change. Grooming was increased in both sexes after ketamine administration, whereas CGA attenuated this effect only in females. Novel object recognition memory was impaired in both sexes after ketamine administration, and CGA partially attenuated this impairment. Immobility in the forced swim test was reduced only in ketamine-treated females, and CGA attenuated this effect. Prefrontal BDNF expression was decreased after ketamine administration in both sexes, and CGA partially attenuated this reduction. Overall, CGA showed partial and sex-dependent protective effects against selected ketamine-induced behavioral and molecular alterations. These findings should be interpreted in light of the absence of independent DMSO-only vehicle-control cohorts.
Cognitive symptoms represent a major determinant of long-term disability in chronic schizophrenia and only partially respond to pharmacotherapy. Evidence is growing about the potential effect of cognitive interventions to promote functional recovery. Immersive virtual reality (IVR) offers a simulated, adaptive, and ecologically valid real-world-like scenarios in safe and controlled environments. The present study aimed to evaluate the feasibility, acceptability, and efficacy of IVR-based cognitive rehabilitation in schizophrenia. We performed a single-blind, randomized, waiting list (WL) controlled trial (Clinicaltrials.gov:NCT07427485). Forty clinically stable outpatients with schizophrenia were allocated (1:1) to IVR or WL. The intervention consisted of 12 weekly IVR-sessions through the CEREBRUM-VR tool. Primary outcome was the change in psychotic symptoms (Positive and Negative Symptoms Scale/PANSS). Secondary outcomes included global functioning (GAF), Digital Symbol Substitution Test (DSST), Animal Naming Test (ANT), Trail-Making Test A (TMT-A). Simple Reaction Choice (SRT) and Choice Reaction Time (CRT) evaluated psychomotor speed. Drop-out rate was 15% per group, attrition rate was 4.9%. Most IVR-assigned participants (77.8%) reported willingness to continue. IVR did not worsen overall or positive psychotic symptoms. A significant IVR between-group improvement emerged for negative symptoms (p < 0.01), psychomotor speed (SRT p = 0.01, CRT p = 0.01), DSST (p = 0.02), and ANT (p = 0.04). GAF and TMT-A changes were nonsignificant. Adverse effects were mostly mild and transient, decreasing over repeated sessions. IVR-based cognitive rehabilitation appears feasible and tolerated in stable outpatients with schizophrenia. Our findings suggest improvement in psychomotor speed and modest improvement in negative symptoms. Larger and longer trials are warranted to confirm clinical relevance.
We investigated differences in cognitive and social functioning between patients with schizophrenia who met criteria for recovery or remission and healthy controls. This cross-sectional study included 55 patients with schizophrenia who met recovery or remission criteria and 20 healthy controls. Cognitive function was assessed using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J), and social function was assessed using the Japanese version of the Social Functioning Scale. Executive function scores did not differ significantly among the three groups; however, the other primary and composite scores of the BACS-J differed significantly among the three groups. In the post hoc analysis, verbal fluency (VF) and attention and processing speed (AP) were higher in the recovery group compared with the remission group (VF: p = 0.043; AP: p = 0.045). All domains of social functioning differed significantly among the three groups. In the post hoc analysis, significant differences between the recovery and remission groups were observed in interpersonal communication (p = 0.002), prosocial activity (p = 0.005), employment/occupation (p < 0.001), and total score (p = 0.005). These results indicate that VF and AP may be important cognitive domains related to clinical recovery in patients with schizophrenia. Furthermore, social functioning domains that require interaction with others may be more important for recovery than daily living skills.