Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC-extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = -0.56, p = 0.025 uncorrected) and morning smoking severity (R = -0.59, p = 0.016 uncorrected). These results suggest that the dmPFC-extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Schizophrenia decreases guilt and increases self-disgust: Potential role of altered executive function.

Our knowledge of how the more complex self-conscious emotions (SCEs) are affected in schizophrenia is sparse. SCEs, unlike basic emotions, involve sophisticated frontal-lobe-related cognition, impairment of which characterizes the neurocognitive profile of schizophrenia. We investigated, in a cross-sectional study, whether SCEs (shame, guilt and self-disgust) are affected in schizophrenia, and the relationship between changes in SCEs and executive (dys)function. Twenty-nine Greek and thirty Arabic patients with schizophrenia were recruited alongside twenty-two Greek and thirty Arabic matched controls. Participants were administered the Self-Disgust Scale (TOSCA for shame and guilt was also administered to the Greek sample), and the Trail Making and Verbal Fluency Tests to measure executive function (EF). Trait levels of self-disgust and guilt were found to be higher and lower, respectively, in patients with schizophrenia relative to control participants; and poorer EF was related with higher trait levels of SD, but lower trait levels of guilt. The pattern of findings was largely unaffected when controlling for anxiety and depression. Given that altered levels of SCEs are closely related to poorer EF, we suggest that the link between EF and emotion regulation, widely established in basic emotions but under-studied in SCEs, may explain the current findings.

El trastorno del lenguaje de las personas con esquizofrenia y su relación con la gravedad y la funcionalidad / The language disorder of people with schizophrenia and its relationship with severity and functionality

RESUMEN: Objetivo: estudiar las características del lenguaje en pacientes que padecen esquizofrenia u otros trastornos psicóticos. Método: 55 pacientes diagnosticados de esquizofrenia (50) y trastorno esquizoafectivo (5). Se aplica la escala TLC de Andreasen, la escala EEAG para la funcionalidad, la CGI para la gravedad. Se recogen datos sociodemográficos. Resultados: Las medias son: edad: 61,47 años, internamiento: 19,47 años, CGI: 5,8, EEAG: 32,5. La subescala de desconexión de la TLC puntúa de media: 8,43, y la de Subproducción verbal: 1,2. La desconexión correlaciona negativamente con EEAG, y positivamente con CGI. La Subproducción verbal correlaciona con CGI. Conclusiones: Los participantes presentan un grado de gravedad elevado y de funcionalidad bajo. Presentan alteraciones importantes del lenguaje, particularmente de pobreza del habla, pero también de desconexión verbal. Con puntuaciones que varían de leve a moderado. Ambas subescalas correlacionan con gravedad. Además, la desconexión es mayor en los pacientes con peor funcionalidad. La alteración del lenguaje en esquizofrenia está relacionada con la gravedad y la funcionalidad, lo cual tiene importantes consecuencias en la vida de las personas que padecen esta enfermedad.

ABSTRACT Objective: to study the characteristics of language in patients suffering from schizophrenia or other psychotic disorders. Method: 55 patients diagnosed with schizophrenia (50) and schizoaffective disorder (5). The Andreasen TLC scale, the EEAG scale for functionality and the CGI for gravity are applied. Sociodemographic data are collected. Results: Mean age: 61.47 years, mean years hospitalized: 19.47 years, CGI: 5.8, EEAG: 32.5. The TLC disconnection subscale scores on average: 8.43, and the Verbal Underproduction: 1.2. Disconnection correlates negatively with EEAG, and positively with CGI. Verbal underproduction correlates with CGI. Conclusions: The participants present a high degree of severity and low functionality. They present significant language alterations, poor speech, and verbal disconnection. With scores ranging from mild to moderate. Both subscales correlate with severity. In addition, the Disconnection is greater in patients with worse functionality. Language impairment in schizophrenia is related to severity and functionality, which has important consequences in the lives of people with this disease.

Exploring the Relationship Between Schizophrenia and Cardiovascular Disease: A Genetic Correlation and Multivariable Mendelian Randomization Study.

Individuals with schizophrenia have a reduced life-expectancy compared to the general population, largely due to an increased risk of cardiovascular disease (CVD). Clinical and epidemiological studies have been unable to unravel the nature of this relationship. We obtained summary-data of genome-wide-association studies of schizophrenia (N = 130 644), heart failure (N = 977 323), coronary artery disease (N = 332 477), systolic and diastolic blood pressure (N = 757 601), heart rate variability (N = 46 952), QT interval (N = 103 331), early repolarization and dilated cardiomyopathy ECG patterns (N = 63 700). We computed genetic correlations and conducted bi-directional Mendelian randomization (MR) to assess causality. With multivariable MR, we investigated whether causal effects were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. Genetic correlations between schizophrenia and CVD were close to zero (-0.02-0.04). There was evidence that liability to schizophrenia causally increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization pattern, largely mediated by BMI and lipids. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting clinical studies. There was weak evidence that higher systolic blood pressure increases schizophrenia risk. Our finding that liability to schizophrenia increases heart failure is consistent with the notion that schizophrenia involves a systemic dysregulation of the body with detrimental effects on the heart. To decrease cardiovascular mortality among individuals with schizophrenia, priority should lie with optimal treatment in early stages of psychosis.

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Prevalence of tobacco dependence and associated factors among patients with schizophrenia attending their treatments at southwest Ethiopia; hospital-based cross-sectional study.

BACKGROUND: Tobacco smoking is the most typically employed in patients with mental disorders; among them, patients with schizophrenia are the very best users. The rate of smoking among patients with schizophrenia is between two and three times greater than the general population in western countries. However, there is a scarcity of studies on the magnitude and associated factors of tobacco dependence among patients with schizophrenia in Ethiopia. Therefore, we assessed the prevalence of tobacco dependence and associated factors among patients with schizophrenia at Mettu Karl referral, Bedelle, and Agaro hospitals, Southwest, Ethiopia. METHOD: Hospital-based the multistage stratified cross-sectional study design was conducted among 524 patients with schizophrenia who are on treatment. Fagerstrom Test for Nicotine Dependence (FTND) was used to screen the prevalence of tobacco dependence. Analysis of data was done using SPSS version 24. RESULT: The prevalence of tobacco dependence among study participants was 22.3% (95% CI) (18.6, 26). Concerning the severity of tobacco dependence, 3.5%, 13.8%, and 5% of the respondents report moderate, high, and very high levels of tobacco dependence respectively. The proportions of tobacco dependence among male schizophrenic patients 88 (25.8%) were higher compared to their counterparts 27 (15.5%). After controlling the effects of cofounders in the final regression analysis, male gender (AOR 2.19, 95% CI = 1.25, 3.83), being on treatment for more than 5years (AOR 4.37, 95% CI = 2.11, 9.02), having a history of admission (AOR 4.01, 95% CI = 1.99, 8.11), and family history of mental illness (AOR 1.90, 95% CI = 1.04, 3.48) were shown to have a significant positive association with tobacco dependence. CONCLUSION AND RECOMMENDATION: A study show a significant proportion of tobacco dependence among people living with schizophrenia. Factors like, being male gender, being on treatment for more than 5 years, having a history of admission, and family history of mental illness was found to have a significant positive association with tobacco dependence. Hence, there is a need for coordinated and comprehensive management clinically to manage tobacco dependence along with identified risk factors in patients with schizophrenia. Also the finding call for the clinicians, managers, ministry of health and other stakeholders on the substance use prevention strategies that target personal and environmental control.

Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal development of the brain.

BACKGROUND: Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. METHODS: In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5-p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90-92 rats were evaluated in the behavioral and biochemical tests. RESULTS: BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. CONCLUSION: The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

The prevalence, incidence, and admission rate of diagnosed schizophrenia spectrum disorders in Korea, 2008-2017: A nationwide population-based study using claims big data analysis.

This study estimated the prevalence and incidence rate of schizophrenia, schizotypal, and delusional disorders (SSDD) in Korea from 2008 to 2017 and analyzed the hospital admission rate, re-admission rate, and hospitalization period. It used the Korean nationwide National Health Insurance Service claims database. SSDD patients who had at least one visit to Korea's primary, secondary, or tertiary referral hospitals with a diagnosis of SSDD, according to the International Classification of Diseases, 10th Revision (ICD-10), were identified as SSDD cases if coded as F20-F29. Data were analyzed using frequency statistics. Results showed that the 12-month prevalence rate of SSDD increased steadily from 0.40% in 2008 to 0.45% in 2017. Analysis of the three-year cumulative prevalence rate of SSDD showed an increase from 0.51% in 2011 to 0.54% in 2017. In 2017, the five-year cumulative prevalence rate was 0.61%, and the 10-year cumulative prevalence rate was 0.75%. The hospital admission rate among SSDD patients decreased from 2008 (30.04%) to 2017 (28.53%). The incidence of SSDD was 0.05% and no yearly change was observed. The proportion of SSDD inpatients whose first hospital visit resulted in immediate hospitalization was 22.4% in 2017. Epidemiological indicators such as prevalence, incidence, and hospitalization rate play an important role in planning social and financial resource allocation. Therefore, efforts to produce more accurate epidemiological indicators are very important and this study's findings could have a significant social impact.

Involvement of vascular endothelial growth factor in schizophrenia.

Vascular endothelial growth factor (VEGF), which acts as an angiogenic and neurotrophic factor, is involved the regulation of cerebral blood volume and flow in Schizophrenia (SCZ). Several evidence indicates that modification of brain blood circulation due to alterations in the VEGF system affects cognitive performance and brain function in patients with SCZ. The aim of this study is: 1) To analyze the literature data concerning the role of VEGF in modulating the angiogenic response in SCZ. These data are controversial because some studies found elevated VEGF serum levels of VEGF in patients with SCZ, whereas others demonstrated no significant differences between SCZ patients and controls. 2)To analyze the role of VEGF as a predictive factor on the effects of antipsychotics agents used in the treatment of SCZ. In this context, high VEGF levels, associated to better responses to antipsychotics, might be predictive of the use of first generation antipsycotic drugs, whereas low VEGF levels, expression of resistance to therapy, might be predictive for the use of second generation antipsycotic drugs.

Use of Stereoelectroencephalography Beyond Epilepsy: A Systematic Review.

BACKGROUND: Stereoelectroencephalography (sEEG) is an increasingly popular surgical technique used clinically to study neural circuits involved in medication-refractory epilepsy, and it is concomitantly used in the scientific investigation of neural circuitry underlying behavior. METHODS: Using PRISMA guidelines, the U.S. National Library of Medicine at the National Institutes of Health PubMed database was queried for investigational or therapeutic applications of sEEG in human subjects. Abstracts were analyzed independently by 2 authors for inclusion or exclusion. RESULTS: The study search identified 752 articles, and after exclusion criteria were applied, 8 studies were selected for in-depth review. Among those 8 studies, 122 patients were included, with indications ranging from schizophrenia to Parkinson disease. All the included studies were single-institution case series representing level IV scientific evidence. CONCLUSIONS: sEEG is an important method in epilepsy surgery that could be applied to other neurologic and psychiatric diseases. Information from these studies could provide additional pathophysiologic information and lead to further development and refinement of neuromodulation therapies for such conditions.

Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register-based cohort study.

The aim of this study was to assess the risks of psychiatric disorders in a large cohort of 905 individuals with NF1 and 7614 population comparisons matched on sex and year of birth. The cohort was linked to the Danish Psychiatric Central Research Register to ascertain information on hospital contacts for psychiatric disorders based on the International Classification of Diseases version 8 and 10. The hazard ratio (HR) for a first psychiatric hospital contact was higher in girls (4.19, 95% confidence interval [CI] 1.81-9.69) and boys with NF1 (5.02, 95% CI 3.27-7.69) <7 years of age than in the population comparisons. Both sexes had increased HRs for developmental disorders, including attention deficit/hyperactivity disorders, autism spectrum disorders, and intellectual disabilities in childhood. Females with NF1 had also increased HRs for unipolar depression, other emotional and behavioral disorders, and severe stress reaction and adjustment disorders in early adulthood. The HRs for psychoses, schizophrenia, bipolar disorders, and substance abuse were similar in individuals with NF1 and the population comparisons. Finally, the cumulative incidence of a first hospital contact due to any psychiatric disorder by age 30 years was 35% (95% CI 29-41) in females and 28% (95% CI 19-37) in males with NF1. Thus, screening for psychiatric disorders may be important for early diagnosis and facilitation of appropriate and effective treatment in individuals with NF1.

Mini-review: Brain energy metabolism and its role in animal models of depression, bipolar disorder, schizophrenia and autism.

Mitochondria are cellular organelles essential for energy metabolism and antioxidant defense. Mitochondrial impairment is implicated in many psychiatric disorders, including depression, bipolar disorder, schizophrenia, and autism. To characterize and eventually find effective treatments of bioenergetic impairment in psychiatric disease, researchers find animal models indispensable. The present review focuses on brain energetics in several environmental, genetic, drug-induced, and surgery-induced animal models of depression, bipolar disorder, schizophrenia, and autism. Most reported deficits included decreased activity in the electron transport chain, increased oxidative damage, decreased antioxidant defense, decreased ATP levels, and decreased mitochondrial potential. Models of depression, bipolar disorder, schizophrenia, and autism shared many bioenergetic deficits. This is in concordance with the absence of a disease-specific brain energy phenotype in human patients. Unfortunately, due to the absence of null results in examined literature, indicative of reporting bias, we refrain from making generalized conclusions. Present review can be a valuable tool for comparing current findings, generating more targeted hypotheses, and selecting fitting models for further preclinical research.

Sex differences in P50 inhibition defects with psychopathology and cognition in patients with first-episode schizophrenia.

BACKGROUND: A large number of studies have shown that the pathophysiology of schizophrenia may be involved in sensory gating that appears to be P50 inhibition. However, few studies have investigated the relationship between clinical symptoms, cognitive impairment and sensory gating disorders in patients with first-episode schizophrenia. The purpose of this study was to explore the sex differences in the relationship between clinical symptoms, cognitive impairment and P50 inhibition defects in patients with first-episode schizophrenia, which has not been reported. METHODS: 130 patients with first-episode schizophrenia (53 males and 77 females) and 189 healthy controls (87 males and 102 females) participated in the study. Positive and Negative Syndrome Scale (PANSS) was used to evaluate the patients' psychopathological symptoms, and the 64-channel electroencephalogram (EEG) system was used to record the P50 inhibition. RESULTS: Male patients had higher PANSS negative symptom, general psychopathology, cognitive factor and total scores than female patients (all p < 0.01). The S1 amplitude was smaller in male than female patients (all p < 0.05). Multiple regression analysis showed that in male patients, S1 latency was contributor to negative symptoms, while S1 latency, S2 latency, age, and smoking status were contributors to cognitive factor (all p < 0.05). In female patients, no P50 component was found to be an independent contributor to PANSS scores (all p > 0.05). CONCLUSIONS: Our results indicate that there is a sex difference in the relationship between clinical symptoms, cognitive impairment and P50 inhibition defects in Chinese Han patients with first-episode schizophrenia.

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks.

The neuregulin 1 (NRG1) ErbB4 module is at the core of an "at risk" signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of "brain-wide" vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia.

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal's lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders.

PURPOSE OF REVIEW: Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders. RECENT FINDINGS: Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ. SUMMARY: Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition.

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.

Using iPSC Models to Understand the Role of Estrogen in Neuron-Glia Interactions in Schizophrenia and Bipolar Disorder.

Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron-glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron-glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron-glia interactions.