Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells.

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5-20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30-40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.

Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Being a child of a parent with a diagnosis of schizophrenia or bipolar disorder: A qualitative study.

Children of people with a diagnosis of schizophrenia or bipolar disorder encounter great difficulties in coping with the symptoms of the disorders. The study was conducted to determine the feelings, opinions, life experiences, and needs of the children of parents with a diagnosis of schizophrenia or bipolar disorder. This is a descriptive study conducted using the in-depth interview design, a qualitative method. The sample consisted of 19 children who agreed to participate in the study with parental consent. Data were collected using a personal information form and a semi-structured qualitative interview form. The data were analyzed using the thematic analysis method. As a result of the thematic analysis, five main themes were obtained: Parents from children's eyes, living with parents, social pressure, coping strategies, this life with one word. The study concluded that children of parents followed up for schizophrenia or bipolar disorder struggle with many individual and social difficulties. These children have feelings of fear, embarrassment, or anger with this life experience; encounter social exclusion; and are overwhelmed with heavy responsibilities at an early age. Their coping strategies can be maladaptive, such as smoking or alcohol consumption, thinking of eloping, becoming introverted, and so on.

Validation and optimal cut-off score of the World Health Organization Well-being Index (WHO-5) as a screening tool for depression among patients with schizophrenia.

BACKGROUND: The utility of the World Health Organization Wellbeing Index (WHO-5) as rapid screening tool for depression has not yet been researched in the context of schizophrenia. The goals of this study were twofold: (1) to test the psychometric properties of the WHO-5 in a sample of Arabic-speaking patients with schizophrenia from Lebanon, with particular emphasis on validating the WHO-5 as a screening tool for wellbeing and depression in patients with schizophrenia; and (2) to determine the optimal cut-off point to identify schizophrenia patients with depression. METHODS: Chronic, remitted patients with schizophrenia took part in this cross-sectional study between August and October 2023 (n = 117; mean age of 57.86 ± 10.88 years and 63.3% males). The Calgary Depression Scale for Schizophrenia (CDSS) was included as index of validity. For the validation of the WHO-5 scale, we performed a confirmatory factor analysis (CFA) using the original structure of the scale. To assess the discriminatory validity of the Arabic version of the WHO-5 as a screening tool for depression, we conducted a Receiver operating characteristic (ROC) curve analysis, taking the WHO-5 reversed score against the dichotomized CDSS score at a cut off value of 6. RESULTS: The results of CFA supported the originally proposed unidimensional structure of the measure, with good internal consistency reliability (α = 0.80), concurrent validity, and cross-sex measurement invariance. The WHO-5 showed a sensitivity of 0.8 and a specificity of 0.7 in the detection of depression with a cut-off point of 9.5. The validity of the WHO-5 as a screening tool for depression was supported by the excellent discrimination AUC value of 0.838. Based on this WHO-5 cut-off value, 42.6% of the patients were screened as having a depression. CONCLUSION: The study contributes to the field by showing that the WHO-5 is a concise and convenient self-report measure for quickly screening and monitoring depressive symptoms in patients with schizophrenia. It is therefore highly recommended to apply this cut-off point for screening and follow-up assessments. The current findings will hopefully encourage clinicians and researchers working in Arab settings, who are often confronted with significant time and resource constraints, to start using the WHO-5 to aid their efforts in mitigating depression in this vulnerable population and fostering research in this under-researched area.

The relevance of anti-N-methyl-D-aspartate receptor encephalitis for psychiatrists.

Psychiatrists are often the first to be consulted in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. While this disease is rare, psychiatrists need to be aware of its relevant fundamental, clinical and therapeutic aspects. We begin by reviewing the connection between anti-NMDAR encephalitis and the glutamate hypothesis of schizophrenia. Next, we focus on the profile of the patient typically afflicted with this disease. Then, we tackle the limited utility of current diagnostic criteria during the early stage of the disease. After reviewing the psychiatric features, we debate the quest for finding specific psychiatric phenotypes that could facilitate early-stage diagnosis. We conclude by discussing the treatment of psychiatric symptoms and disease outcomes. As follows, this paper presents the relevance of anti-NMDAR encephalitis for psychiatrists.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an essential differential diagnosis in Psychiatry, particularly when dealing with first-episode psychosis.Psychiatrists are often the first to be consulted in patients with NMDAR encephalitis, so they need to be aware of the relevant fundamental, clinical and therapeutic aspects of this disease.

Association Between Clozapine Exposure and Risk of Hematologic Malignancies in Veterans With Schizophrenia.

Objective: The objective of this study was to examine the relationship between clozapine use and hematologic malignancies, using national administrative data from the United States Veterans Health Administration (VHA).Methods: This case-control study of veterans with schizophrenia matched cases with incident hematologic malignancy to 10 controls without hematologic malignancy by gender, age, and time since first schizophrenia diagnosis from October 1999, the beginning of VHA data archives, to June 2022. Schizophrenia diagnoses were identified using International Classification of Diseases, Ninth Revision, code 295.x and International Statistical Classification of Diseases, Tenth Revision, codes F20.x and F25.x from inpatient hospitalization and outpatient encounter data. Additional inclusion criteria were age 18-85 years, no prior history of malignancy, and at least 1 year of antipsychotic exposure. Clozapine exposure was assessed using 3 metrics: any exposure, years of exposure, and cumulative defined daily doses (DDD). Conditional multivariable logistic regression was used to adjust for nonmatched confounding variables.Results: A total of 2,306 veterans with schizophrenia were identified with an incident diagnosis of hematologic malignancy and matched to 23,043 controls. Any prior clozapine exposure was more commonly observed among cases (5.3%) than controls (4.1%) and was significantly different after adjustment (odds ratio [OR], 1.31; 95% CI, 1.08-1.60). Risk was dose-dependent, where cumulative clozapine exposures from 3,000 to 4,999 DDD (OR, 1.78; 95% CI, 1.13-2.79) and ≥5,000 DDD (OR, 1.81; 95% CI, 1.24-2.64) were significantly associated with malignancy risk. Similarly, clozapine exposure of 5 or more years was associated with malignancy risk (OR, 1.88; 95% CI, 1.43-2.47).Conclusion: Consistent with prior report, this study observed an increased risk of hematologic malignancy associated with clozapine exposure. These findings suggest patients receiving clozapine use, particularly those with long-term use, should be closely monitored for hematologic malignancy.

Systematic Review on the Relationship between Toxoplasmosis and Mental Disorders.

BACKGROUND: Toxoplasmosis is a worldwide parasitic zoonosis caused by the protozoan Toxoplasma gondii. In cases of vertical infection, and in immunosuppressed people by the human immunodeficiency virus (HIV) serious clinical conditions may appear, while immunocompetent people do not present symptoms. However, T. gondii infection has been linked to several mental disorders for decades. OBJECTIVE: To substantiate the possible relationship between T. gondii and mental disorders and suggest control and prevention strategies. MATERIAL AND METHODS: A systematic review has been carried out to analyze the relationship between T. gondii exposure (presence of IgG) and the onset of mental disorders in minors and adults. The etiopathogenic mechanisms described by the authors have also been included and the systems of surveillance, prevention and control of infection have been evaluated. RESULTS: Several processes linked to the presence of cysts and the reactivation of the parasite in certain situations produce an immune and inflammatory response. Also, direct and indirect actions on different neurotransmitters. These mechanisms, together with other environmental and genetic factors, would predispose to different psychiatric pathologies. CONCLUSIONS: Due to the limits of the study, no conclusions can be drawn in childhood and adolescence. However, the results of this systematic review show a possible association of schizophrenia, bipolar disorder and compulsive disorder with T. gondii infection in adults. There is a need to improve control, integrated surveillance and extend prevention measures to the entire population.

Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data.

INTRODUCTION: Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. METHODS: Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. RESULTS: Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). CONCLUSION: LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

Circulating miR-30e-3p induces disruption of neurite development in SH-SY5Y cells by targeting ABI1, a novel biomarker for schizophrenia.

Schizophrenia (SCZ) represents a set of enduring mental illnesses whose underlying etiology remains elusive, posing a significant challenge to public health. Previous studies have shown that the neurodevelopmental process involving small molecules such as miRNA and mRNA is one of the etiological hypotheses of SCZ. We identified and verified that miR-30e-3p and ABI1 can be used as biomarkers in peripheral blood transcriptome sequencing data of patients with SCZ, and confirmed the regulatory relationship between them. To further explore their involvement, we employed retinoic acid (RA)-treated SH-SY5Y differentiated cells as a model system. Our findings indicate that in RA-induced SH-SY5Y cells, ABI1 expression is up-regulated, while miR-30e-3p expression is down-regulated. Functionally, both miR-30e-3p down-regulation and ABI1 up-regulation promote apoptosis and inhibit the proliferation of SH-SY5Y cells. Subsequently, the immunofluorescence assay detected the expression location and abundance of the neuron-specific protein ß-tubulinIII. The expression levels of neuronal marker genes MAPT, TUBB3 and SYP were detected by RT-qPCR. We observed that these changes of miR-30e-3p and ABI1 inhibit the neurite growth of SH-SY5Y cells. Rescue experiments further support that ABI1 silencing can correct miR-30e-3p down-regulation-induced SH-SY5Y neurodevelopmental defects. Collectively, our results establish that miR-30e-3p's regulation of neurite development in SH-SY5Y cells is mediated through ABI1, highlighting a potential mechanism in SCZ pathogenesis.

Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables.

Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.

Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

Tannic acid coated nanosuspension for oral delivery of chrysin intended for anti-schizophrenic effect in mice.

Chrysin is a flavonoid drug with numerous therapeutic activities. It suffers from low intestinal absorption owing to its hydrophobicity. Therefore, the aim of this study is to exploit the efficient technique of nanosuspension (NSP) to formulate chrysin-NSP coated with tannic acid (TA) to improve the solubility and anti-schizophrenic activity of chrysin. A 23 full factorial design was constructed where the independent factors were type of polymer, surfactant concentration (0.5 or 1 %) and the aqueous phase volume (5 or 15 mL), while the dependent responses were the particle size (PS) of the obtained formulation as well as the % chrysin dissolved after 2 h (Q2h). The optimum formulation (NSP-4) composed of 1 % PEG 400 and 1 % Cremophor RH40 in 15 mL aqueous phase. It achieved a PS and Q2h values of 108.00 nm and 38.77 %, respectively. NSP-4 was then coated with TA (TA-coated NSP-4) for further enhancement of chrysin solubility. TA-coated NSP-4 revealed PS and zeta potential values of 150 ± 14 nm and -32.54 ± 2.45 mV, respectively. After 6 h, chrysin dissolved % were 53.97 and 80.22 for uncoated NSP-4 and TA-coated NSP-4, respectively, compared with only 9.47 for free chrysin. The developed formulations and free chrysin were assessed regarding their effect on schizophrenia induced in mice by cuprizone (CPZ). Treatment with the developed formulations and free chrysin ameliorated demyelination and behavioral deficit induced by CPZ via elevating MBP and PI3K/PKC activities as well as reducing GFAP expression levels. The developed formulations and free chrysin inhibited Galactin-3 and TGF-ß expressions and stimulated GST antioxidant enzyme. Furthermore, they maintained the balances in glutamatergic and dopaminergic neurotransmission via modulation on neuregulin-1 and alleviated nuclear pyknosis and degeneration in the neurons. The order of activity was: TA-coated NSP-4 > NSP-4 > free chrysin.

Multimorbidity and the Etiology of Schizophrenia.

PURPOSE OF REVIEW: A global study of multimorbidity in schizophrenia, especially of the association with physical conditions, might offer much needed etiological insights. RECENT FINDINGS: Our review suggests that life-style factors and medication related to schizophrenia are only part of the explanation of the increase in risk for cardiovascular, metabolic, pulmonary disorders, and some cancers. Positive associations with autoimmune disorders (with the exception of rheumatoid arthritis) and epilepsy are promising avenues of research but to date have not been fully exploited. The same holds for the negative comorbidity seen for rheumatoid arthritis and some cancers (e.g., prostate). As a whole, our review suggests that most of the explored conditions have a different prevalence in schizophrenia than in the general population. Several hypotheses emerged from this review such as the role of immune and genetic factors, of sex hormones, and of more general variability factors.

Function and mechanism exploring of icariin in schizophrenia through network pharmacology.

This study aims to explore the therapeutic effect and possible mechanisms of icariin in schizophrenia. SD rats were divided into five groups, a control group, a MK801-induced schizophrenia model group, and three icariin treatment groups, with twelve rats in each group. Morris water maze and open field were used to observe the spatial learning and memory ability of rats. Compared with the control group, rats in the MK801-induced model group showed an increase in stereotypic behavior score, distance of spontaneous activities, escape latency, malondialdehyde (MDA) content, and IL-6, IL-1ß, TNF-α expression, but a decrease in platform crossing times and superoxide dismutase (SOD) activity (P < 0.05). Furthermore, all the above changes of the model group were reversed after icariin treatment in a dose-dependent manner (P < 0.05). Network pharmacology found that icariin can exert anti-schizophrenic effects through some signaling pathways, such as relaxin, estrogen, and TNF signaling pathways. MAPK1, MAPK3, FOS, RELA, TNF, and JUN were the key targets of icariin on schizophrenia, and their expression was detected in animal models, which was consistent with the predicted results of network pharmacology. Icariin treatment may improve the spatial learning and memory ability of schizophrenic rats through TNF signaling pathway.

HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

Genetic correlation and causal associations between psychiatric disorders and lung cancer risk.

BACKGROUND: Patients with certain psychiatric disorders have increased lung cancer incidence. However, establishing a causal relationship through traditional epidemiological methods poses challenges. METHODS: Available summary statistics of genome-wide association studies of cigarette smoking, lung cancer, and eight psychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), autism, depression, major depressive disorder, bipolar disorder, insomnia, neuroticism, and schizophrenia (range N: 46,350-1,331,010) were leveraged to estimate genetic correlations using Linkage Disequilibrium Score Regression and assess causal effect of each psychiatric disorder on lung cancer using two-sample Mendelian randomization (MR) models, comprising inverse-variance weighted (IVW), weighted median, MR-Egger, pleiotropy residual sum and outlier testing (MR-PRESSO), and a constrained maximum likelihood approach (cML-MR). RESULTS: Significant positive correlations were observed between each psychiatric disorder and both smoking and lung cancer (all FDR < 0.05), except for the correlation between autism and lung cancer. Both univariable and the cML-MA MR analyses demonstrated that liability to schizophrenia, depression, ADHD, or insomnia was associated with an increased risk of overall lung cancer. Genetic liability to insomnia was linked specifically to squamous cell carcinoma (SCC), while genetic liability to ADHD was associated with an elevated risk of both SCC and small cell lung cancer (all P < 0.05). The later was further supported by multivariable MR analyses, which accounted for smoking. LIMITATIONS: Participants were constrained to European ancestry populations. Causal estimates from binary psychiatric disorders may be biased. CONCLUSION: Our findings suggest appropriate management of several psychiatric disorders, particularly ADHD, may potentially reduce the risk of developing lung cancer.

TNF receptor 2 knockout mouse had reduced lung cancer growth and schizophrenia-like behavior through a decrease in TrkB-dependent BDNF level.

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 µg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels.

Serum brain-derived neurotrophic factor level and its relation with cannabis use disorder and schizophrenia: A cross-sectional exploratory study in patients at a tertiary care hospital.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has considerable relevance in neural growth and differentiation. It has been evaluated as a biomarker for individuals with various psychiatric disorders such as substance-related disorders and psychotic disorders. OBJECTIVE: The present study explored differences in the levels of BDNF (in serum) among subjects using cannabis (with and without schizophrenia). METHODS: This cross-sectional observational study compared the serum BDNF level in male subjects aged 18-45 years. Four groups of 20 subjects each were included: individuals with tobacco use disorder only, patients having schizophrenia, patients with cannabis use disorder, and finally patients with comorbid cannabis use disorder and schizophrenia. RESULTS: The BDNF levels were found to be significantly different across the four groups. The BDNF levels in subjects with concurrent schizophrenia and cannabis use disorder were higher than each of the other three groups (cannabis use disorder, schizophrenia, and tobacco use disorder only). CONCLUSION: We find that BDNF may be higher when cannabis use disorder and schizophrenia co-occur, as compared to either of the conditions alone. The findings should be interpreted with caution due to the low sample size and potential confounders.

Sex-specific associations of plasma neutrophil gelatinase-associated lipocalin (NGAL) with cognition in patients with drug-naïve schizophrenia.

This present study aimed to investigate the sex-specific association of plasma neutrophil gelatinase-associated lipocalin (NGAL) with cognition in drug-naïve schizophrenia patients for the first time. A total of 204 participants in this study, including 137 drug-naïve schizophrenia (DNS) patients and 67 healthy controls (HCs). All participants completed the Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), and were collected fasting venous blood for NGAL measurement. DNS patients also complete the Positive and Negative Syndrome Scale (PANSS). Partial correlation analysis and multiple linear regression were used to explore sex-specific associations between NGAL and cognition. All dimensions of MCCB scores were significantly lower in both male and female DNS patients than HCs. Sex differences were significant in cognitive performance in both DNS patients and HCs. Female DNS patients experienced poorer working memory and reason& problem solving than male patients. Female HCs performed a better attention/vigilance and visual learning, a poorer reason& problem solving than male HCs. In patients with DNS, NGAL levels were negatively associated with positive subscale of PANSS and positively associated with working memory and visual learning only in female. However, there was no significant correlation between NGAL levels and all cognitive tests in both male and female HCs. Regression model showed that higher level of NGAL was an independent protective factor for cognitive performance in female patients with DNS, whereas there was no such role in male patients. Our findings suggest sex specificity between NGAL levels and cognitive performance in DNS patients.

EGR3 Polymorphism Is a Potential Susceptibility Factor of Schizophrenia Risk in a Chinese Population.

Objective: The purpose of this study was to evaluate the association between the single nucleotide polymorphisms (SNPs) (EGR3 rs1996147; EGR4 rs3813226, rs6747506; ERBB3 rs2292238; and ERBB4 rs707284, rs7560730) and the risk of schizophrenia (SZ) in a Chinese population. Materials and Methods: We conducted a case-control study, including 248 patients with SZ and 236 healthy controls matched for age and sex. The Mass-array platform was used to detect all the genotypes of the SNPs. Results: The results revealed that the EGR3 rs1996147 AA genotype was associated with borderline decreased SZ risk (AA vs. GG: adjusted OR = 0.43, 95% CI: 0.18-1.02, p = 0.06). However, no significant correlation was found between the other SNPs and overall SZ risk. Subgroup analysis also failed to show any significant association between all SNPs and the risk of SZ. Conclusion: In summary, this study revealed that the EGR3 rs1996147 AA genotype was associated with a borderline risk for SZ.