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Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Cognitive impairment occurs in both schizophrenia and diabetes. There is currently limited understanding whether schizophrenia with diabetes has more serious cognitive deficits than schizophrenia without diabetes or diabetes only. This study assessed cognitive performance in 190 healthy controls, 106 diabetes only, 127 schizophrenia without diabetes and 55 schizophrenia with diabetes. This study was conducted from January 2008 to December 2010. Compared to healthy controls, all patient groups had significantly decreased total and five index RBANS scores (all p<0.01–p<0.001), except for the visuospatial/constructional index. Schizophrenia with diabetes performed worse than schizophrenia without diabetes in immediate memory (p<0.01) and total RBANS scores (<0.05), and showed a trend for decreased attention (p = 0.052) and visuospatial/constructional capacity (p = 0.063). Schizophrenia with diabetes performed worse than diabetes only in immediate memory (p<0.001) and attention (p<0.05), and showed a trend for decreased total RBANS scores (p = 0.069). Regression analysis showed that the RBANS had modest correlations with schizophrenia’ PANSS scores, their duration of current antipsychotic treatment, and diagnosis of diabetes. Schizophrenia with co-morbid diabetes showed more cognitive impairment than schizophrenia without diabetes and diabetes only, especially in immediate memory and attention. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenic patients have cognitive impairments, but gender differences in these cognitive deficits have had limited study. This study assessed cognitive functioning in 471 subjects including 122 male and 78 female schizophrenic patients and 141 male and 130 female healthy controls. We found that immediate memory, language, delayed memory and total RBANS scores were significantly decreased in schizophrenia compared with healthy controls for both genders. Male patients had significant lower immediate memory, delayed memory and total RBANS scores than female patients, and healthy controls showed a similar gender difference. The RBANS showed modest correlations with PANSS scores, duration of illness and antipsychotic dose (chlorpromazine equivalents). Almost all RBANS scores in the schizophrenics and healthy controls showed significant positive correlations with education. Thus, patients of both sexes with schizophrenia experienced more deteriorated performance than healthy controls on cognitive domains of immediate memory, language and delayed memory. Furthermore, male schizophrenic patients had more serious cognitive deficits than female patients in immediate and delayed memory, but not in language, visuospatial and attention indices. [Copyright &y& Elsevier]

Abstract: Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1–ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ErbB4 knockout mice with a decreased NRG1–ErbB4 signalling, the majority post-mortem studies showed an increased NRG1–ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1–ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1–ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling. [Copyright &y& Elsevier]

Abstract: The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, using in situ quantitative autoradiography in postmortem tissue, we investigated the binding of the [3H]ketanserin to 5-HT2A receptors and [3H]mesulergine to 5-HT2C receptors in the left STG of 8 male schizophrenic patients compared to 8 control subjects. A strong [3H]ketanserin binding was observed in the STG, however there was a very weak [3H]mesulergine binding in the STG. A significant decrease in binding of [3H]ketanserin was clearly observed in schizophrenia patients in comparison with control subjects. There were no significant correlations between 5-HT2A binding density and age, postmortem intervals, or brain pH. These results suggest that the alterations of the 5-HT2A receptors contribute to the pathophysiology of the STG in schizophrenia. Furthermore, there is a clear tendency for a positive correlation between 5-HT2A and muscarinic M1 receptor bindings, and for negative correlations between 5-HT2A and GABAA receptor bindings and between muscarinic M1 and GABAA receptor bindings. This provides a possible mechanism of auditory hallucinations through interactions between 5-HT2A, acetylcholine muscarinic and GABA transmissions in the STG in schizophrenia. [Copyright &y& Elsevier]

Abstract: Perinatal phencyclidine (PCP) treatment leads to neuronal damage and causes long-term behavioural alterations in rodents. This study examined the effects of perinatal PCP treatment on behaviour of adult rats in holeboard, elevated plus maze, social interaction and forced swim tests. PCP-treated rats displayed hyperactivity in the holeboard and forced swim tests. These persistent behavioural changes are relevant to the study of psychiatric disorders such as schizophrenia. [Copyright &y& Elsevier]

Abstract: This study examined regional changes of 5-HT2A and 2C receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5mg/kg/day) and haloperidol (2.0mg/kg/day) for 36 days. 5-HT2A and 2C receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT2A receptor mRNA, predominantly in the nucleus accumbens (65%), hippocampus (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48h later. In contrast, no change in 5-HT2A receptor mRNA expression was found in the haloperidol treated groups either 2h or 48h after drug withdrawal. Clozapine also decreased 5-HT2C receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2h after the last drug administration, while rebound effects were also observed 48h later. 5-HT2C receptor mRNA was only decreased in the substantia nigra at both 2h (42%) and 48h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippocampus and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system. [Copyright &y& Elsevier]

Abstract: Disruption to brain development at an early stage can potentially alter chemically coded neural networks and can affect behavior in later life. During early brain development antagonism of glutamate NMDA receptors, which play an important role in neuronal outgrowth and survival, leads to neuronal damage in several brain regions and causes behavioral alterations in rodents that mimic schizophrenia symptoms and endophenotypes. There are several lines of evidence implicating involvement of a dysfunctional glutamate system in schizophrenia. In normal subjects, NMDA receptor antagonists produce behavioral and neurochemical changes that mimic schizophrenia symptoms better than any other psychotomimetic drug. Moreover, these drugs worsen symptoms in schizophrenia patients and can trigger a recrudescence of the acute psychotic state in patients with stable chronic schizophrenia. In addition, genes consistently reported as being altered in schizophrenia play roles in development, neuroplasticity and glutamate/GABAergic neurotransmission. Perinatal NMDA receptor antagonist treatment is a useful model for studying the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia because neurochemical and behavioral changes, reminiscent of those seen in schizophrenia, are present long after cessation of drug administration, which suggests that a permanent change in brain structure and organization has occurred during brain development. [Copyright &y& Elsevier]

Background: The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort. Methods: We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the Nmethyldaspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Results: Protein levels of glutamatergic receptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Furthermore, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions between these receptors in this brain region. Limitations: Investigation of these proteins in antipsychotic-naive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies. Conclusion: The present study does not provide evidence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region--dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further research into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergic-based novel therapeutics. [ABSTRACT FROM AUTHOR]

Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor - particularly the ratio of GluN2A and GluN2B subunits - in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect 'functional' NMDARs ([3H]MK-801), GluN1-coupled-GluN2A subunits ([3H]CGP-39653), and GluN1-coupled-GluN2B subunits ([3H]Ifenprodil). Quantitative RT-PCR was used to measure NMDAR subunit transcripts (GRIN1, GRIN2A and GRIN2B). The ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were calculated as an index of putative NMDAR composition. We found: 1) GluN2A binding, and 2) the ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were lower in schizophrenia cases versus controls (p < 0.05), and 3) lower GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNA ratios were exaggerated in the high inflammation/schizophrenia subgroup compared to the low inflammation/control subgroup (p < 0.05). No other NMDAR-related indices were significantly changed in the high inflammation/schizophrenia subgroup. This suggests that neuroinflammation may alter NMDAR stoichiometry rather than targeting total NMDAR levels overall, and future studies could aim to determine if anti-inflammatory treatment can alleviate this aspect of NMDAR-related pathology. [ABSTRACT FROM AUTHOR]

Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Previous studies have found dysfunction in plasma dopamine beta-hydoxylase (DBH) in schizophrenia with TD. Moreover, DBH, whose activity and levels are strongly controlled by the DBH gene, is a key enzyme in the conversion of dopamine (DA) to norepinephrine (NE) associated with excited behavior. This study examined whether the DBH5′-insertion/deletion (Ins/Del) polymorphism was associated with excited behavior in schizophrenia with TD. The presence of the DBH5′-Ins/Del polymorphism was determined in 741 schizophrenia with TD ( n = 345) and without TD ( n = 396). The Abnormal Involuntary Movement Scale and Positive and Negative Syndrome Scale were used to assess the severity of TD and psychopathology of schizophrenia. There was no significant difference in the allelic and genotypic frequencies of the DBH5′-Ins/Del polymorphism between schizophrenia with and without TD (both p > 0.05). However, the excited symptoms score was significantly different to the DBH5′-Ins/Del genotypic groups in schizophrenia with TD ( p < 0.05) but not in the two groups of non-TD and total patients (both p > 0.05). The excited symptoms score was higher in TD patients with the Del/Del genotype than those with Ins alleles ( p = 0.015). Our findings suggest that the DBH5′-Ins/Del polymorphism may not contribute directly to the development of TD in schizophrenia, but it may be involved in the excited behavior of TD patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5′-Ins/Del) and schizophrenia in a Han Chinese population. Methods: This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case-control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS). Results: We showed that the DBH5′-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first-episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05). Conclusions: The DBH5′-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl-d-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (Nrg1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and Nrg1 signaling pathways using the perinatal PCP animal model. Rats (n=5/group) were treated with PCP (10mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5weeks and 20weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/Nrg1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered Nrg1/erbB4 expression levels throughout development, including decreased Nrg1 and erbB4 at PN12 (−25–30%; p <0.05); increased erbB4 and p-erbB4 (+18–27%; p <0.01) at 5weeks; and decreased erbB4 and p-erbB4 (−16–18%; p <0.05) along with increased Nrg1 (+33%; p <0.01) at 20weeks. In the hippocampus, levels of Nrg1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20weeks (−13%; p <0.001); however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5weeks (+20–32%; p <0.05), and decreases at 20weeks (−22–29%; p <0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on Nrg1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia. [Copyright &y& Elsevier]

Abstract: Metabotropic glutamate receptors 2 and 3 (mGluR2/3) have been shown as efficient targets for antipsychotic intervention. We therefore investigated the receptor density of mGluR2/3 in the dorsolateral prefrontal cortex (dlPFC; Brodman area 46) of schizophrenia/schizoaffective patients (n=37) and matched controls (n=37) using receptor autoradiography. No difference in mGluR2/3 density was identified in relation to schizophrenia diagnosis. Overall and in individual groups, a negative correlation of mGluR2/3 density and age at death has been found. These and previous results suggest that density of mGluR2/3 in the dlPFC is less likely to impact on the efficiency of the mGluR2/3 agonist in treating schizophrenia symptoms. [Copyright &y& Elsevier]

Abstract: This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia. [Copyright &y& Elsevier]

Previous studies suggest that long-term cannabis use causes cognitive impairment, including lack of motivation and impaired attention, conditions that also resemble core negative symptoms of schizophrenia. The anterior cingulate cortex (ACC) plays an important role in normal cognition, particularly in relation to motivation and attention. This could suggest that changes in the cannabinoid (CB) system might be present in the ACC of patients suffering schizophrenia. The present study examined the distribution and density of CB1 cannabinoid receptors in the left ACC taken postmortem from patients with schizophrenia (n=10) and matched control subjects (n=9). Radioligand binding of [3H]SR141716A, an antagonist that specifically targets CB1 receptors of the endogenous cannabinoid system, was examined on ACC sections using quantitative autoradiography. CB1 receptors had a homogenous distribution among the layers of ACC. A significant 64% increase in [3H]SR141716A specific binding to CB1 receptors was found in the schizophrenia group as compared to the control group (mean±S.E.M.: 46.15±6.22 versus 28.02±4.20 fmol/mg estimated tissue equivalents; p=0.03). The present results support the suggestion that changes in the endogenous cannabinoid system in the ACC may be involved in the pathology of schizophrenia particularly in relation to negative symptoms. [Copyright &y& Elsevier]

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [3H]MK801, [3H]L-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and [3H]kainate, which respectively label the N-methyl-D-aspartate (NMDA), AMPA, and kainate receptors of the ionotropic glutamate receptor family, in the left anterior cingulate cortex of 10 schizophrenia patients and 10 controls, matched for age, gender, and postmortem interval.AMPA receptor densities were higher in cortical layer II, whereas NMDA receptor densities were higher in cortical layers II–III in the anterior cingulate cortex of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [3H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared with the control group. Similarly, a significant 17% increase of [3H]MK801 binding was observed in layers II–III in the schizophrenia group. No statistically significant difference was observed for [3H] kainate binding between the schizophrenia and control groups.These results suggest that ionotropic glutamate receptors are differentially altered in the anterior cingulate region in schizophrenia. The increase in [3H]AMPA and [3H]MK801 binding in the superficial layers suggests a postsynaptic compensation for impaired glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia. The findings add to a growing body of literature that supports a dysfunction of excitatory activity in the anterior cingulate cortex in schizophrenia. [Copyright &y& Elsevier]

Objective: The purpose of this study was to investigate the lifetime suicide attempt rate, clinical characteristics and cognitive function of Chinese patients with chronic schizophrenia who had attempted suicide. Methods: We collected data from 908 schizophrenia inpatients about suicide attempts through interviews with the patients and their families, as well as through medical records. All patients were assessed with the Positive and Negative Syndrome Scale, the Rating Scale for Extrapyramidal Side Effects, the Abnormal Involuntary Movement Scale, and the Repeated Battery for the Assessment of Neuropsychological Status. Results: Of this sample, 97 (10.68%) had attempted suicide. Patients who had attempted suicide were younger, had longer illness duration, and more severe general psychopathology and depressive symptoms than those who had not. Logistic regression analysis confirmed that suicide attempts were correlated with age, smoking, and depression. No cognitive performance differences were observed between patients who had and had not attempted suicide. Conclusions: In China, patients with chronic schizophrenia may have a higher prevalence of lifetime suicide attempts than the general population. Some demographic and clinical variables were related to suicide attempts in patients with chronic schizophrenia. [ABSTRACT FROM AUTHOR]

Neural cell adhesion molecule (NCAM) plays an important role in neurodevelopmental processes and regulates hippocampal plasticity. This study investigated the relationship between the serum NCAM concentrations and hippocampal volume and psychotic symptoms in first-episode drug naïve schizophrenia (FES) patients. Forty-four FES patients and forty-four healthy controls (HC) were recruited in this study. Serum concentrations of NCAM were measured by ELISA. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Brain structural images were obtained using a 3T MRI Scanner and obtained T1 images were processed in order to determine hippocampal grey matter volumes. Schizophrenia patients revealed significantly decreased serum NCAM concentrations (p = 0.017), which were positively correlated with the left (r = 0.523, p < 0.001) and right (r = 0.449, p = 0.041) hippocampal volumes, but negatively correlated with the PANSS positive symptom scores (r = −0.522 p = 0.001). However, no such correlations existed in the HC group. This is the first time to report that decreased serum NCAM concentrations were associated with hippocampal volumes and symptom severity in FES patients. Our data indicate that the low NCAM is possible neuropathology that is associated with the decreased hippocampus in FES patients. [ABSTRACT FROM AUTHOR]

The present study explored an efficient new therapy that combined repetitive transcranial magnetic stimulation (rTMS) and family intervention in addition to risperidone to improve schizophrenia. A randomized controlled trial (January 2016–September 2017) involving 200 patients, of which 188 patients completed the 12-week study, and 50 controls were conducted in the research. The patients were randomly assigned to 12 weeks of treatment with risperidone alone (risperidone group), rTMS and risperidone (rTMS group), family intervention and risperidone (family intervention group), rTMS and risperidone plus family intervention (combined group). MATRICS Consensus Cognitive Battery (MCCB) and the Positive and Negative Symptoms Scale (PANSS) were used to evaluate treatment efficacy. Repeated measures analysis of variance (RMANOVA) were performed to evaluate different treatment efficacy between four groups after 12 weeks of treatment. (1) There were no significant differences in sex, age, education, cognitive function, or PANSS scores between the four groups at baseline (p's > 0.05). (2) There was a significant decrease in the PANSS scores and an increase in the MCCB scores after 12 weeks of treatment in all groups (time effect p's < 0.001). (3) The improvements in positive symptoms and negative symptoms were more obvious in the combined group than in other groups (p's < 0.05). (4) The combined group showed the superior effect in cognition function after 12 weeks. (5) And, interestingly, a remarkable synergistic effect between rTMS and family intervention therapy was observed. There was a synergistic effect between rTMS and the family intervention as an effective combined therapy in improving schizophrenia. This study is registered with Chictr.org , number ChiCTR1900024422 (http://www.chictr.org.cn/edit.aspx?pid=34285&htm=4). [ABSTRACT FROM AUTHOR]

• The effects of CBD were examined in a female poly I:C model of schizophrenia. • CBD restored recognition memory, social withdrawal and NMDAR binding deficits. • CBD increased GAD 67 and PV levels in the hippocampus, regardless of poly I:C exposure. • CBD impaired social interaction, NMDAR and CB1R binding density in healthy rats. • CBD may be an efficacious treatment for associated deficits in female patients. Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N -methyl- d -aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbumin protein levels in the HPC. In contrast to the CBD treatment effects observed in poly I:C offspring, CBD administration to control rats reduced social interaction, cannabinoid CB1 receptor and NMDAR binding density in the PFC, suggesting that CBD administration to healthy rats may have negative consequences on social behaviour and brain maturation in adulthood. Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder with unknown etiology. Many mechanisms, including dysregulation of neurotransmitters, immune disturbance, and abnormal neurodevelopment, are proposed for the pathogenesis of schizophrenia. The significance of communication between intestinal flora and the central nervous system through the gut-brain axis is increasingly being recognized. The intestinal microbiota plays an important role in regulating neurotransmission, immune homeostasis, and brain development. We hypothesize that an imbalance in intestinal flora causes immune activation and dysfunction in the gut-brain axis, contributing to schizophrenia. In this review, we examine recent studies that explore the intestinal flora and immune-mediated neurodevelopment of schizophrenia. We conclude that an imbalance in intestinal flora may reduce protectants and increase neurotoxin and inflammatory mediators, causing neuronal and synaptic damage, which induces schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: This study was to examine the alterations in metabolic parameters, anti-oxidant superoxide dismutase (SOD), inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and microbiota after 24-week risperidone treatment in drug naïve, normal weight, first episode schizophrenia patients; the study further examined the relationship between metabolic changes and changes in microbiota.Methods: Forty-one patients completed the 24-week study and 41 controls were enrolled in this study. Metabolic parameters, SOD, hs-CRP and the copy numbers of 5 fecal bacteria were measured at baseline (both groups) and at different time points (patients only).Results: Patients had significantly lower numbers of fecal Bifidobacterium spp., Escherichia coli, Lactobacillus spp. compared with healthy controls (HC) (ps < 0.001); in contrast, the numbers of fecal Clostridium coccoides group were significantly higher in the patient group compared with HC (p < 0.001). After 24-week risperidone treatment, there were significant increases in body weight, BMI, fasting blood-glucose, triglycerides, LDL, hs-CRP, SOD and HOMA-IR (p < 0.001), significant increases in the numbers of fecal Bifidobacterium spp. and E. coli (ps < 0.001), and significant decreases in the numbers of fecal Clostridium coccoides group and Lactobacillus spp. (ps < 0.001). Hierarchical multiple linear regression analysis shows that after controlling for potential confounding variables, only the changes in fecal Bifidobacterium spp., among 4 types of fecal bacteria, entered into the model and significantly correlated with the changes in weight (unstandardized coefficient B = 4.413, R2 change = 0.167, p = 0.009) and BMI (B = 1.639, R2 change = 0.172, p = 0.008) after 24-week treatment.Conclusion: Drug naïve, first episode schizophrenia patients show abnormalities in microbiota composition. Risperidone treatment causes significant changes in certain fecal bacteria, which are likely associated with antipsychotic medication induced metabolic changes. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment.Methods: Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined.Results: Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance.Conclusion: Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs. [ABSTRACT FROM AUTHOR]

Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia; however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia. We observed significant reductions in PIAS2, FBXL21 and MDM2 in schizophrenia subjects compared to controls (p-values ranging from 0.002 to 0.004). In our developmental PCP model, MDM2 protein was significantly reduced in adult PCP-treated rats compared to controls (p = 0.034). Additionally, FBXL21 (p = 0.022) and UCHL1 (p = 0.022) were significantly decreased, whilst UBE2D1 was increased (p = 0.022), in juvenile phencyclidine-treated rats compared to controls. This is the first study reporting alterations of UPS proteins in post-mortem human schizophrenia subjects and in a neurodevelopmental model of schizophrenia. The findings from this study provide strong support for a role of these UPS proteins in the pathology and development of schizophrenia. [ABSTRACT FROM AUTHOR]

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5'-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention. [ABSTRACT FROM AUTHOR]

Rationale: An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives: We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl- d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Methods: Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results: In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions: We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment. [ABSTRACT FROM AUTHOR]

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague–Dawley rats were injected subcutaneously with PCP (10 mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n = 6/group) were sacrificed at PN12, 5 weeks, or 14 weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001 ≤ p ≤ 0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5 weeks (p > 0.05). At 14 weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014 ≤ p ≤ 0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose ( p < 0.0001) and insulin ( p = 0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls ( p = 0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects ( p = 0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed ( p = 0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n = 20/group). Protein levels of mGluR5 (total: 42%, p < 0.001; monomer: 25%, p = 0.011; dimer: 52%, p < 0.001) and mGluR5 trafficking molecules (Norbin: 47%, p < 0.001; Tamalin: 34%, p = 0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder. [ABSTRACT FROM AUTHOR]

Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects ( n = 37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22 %; dimer: +54 %; p < 0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin −37 %, p < 0.001; Tamalin −30 %, p = 0.084; Preso1 −29 %, p = 0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine; there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder. [ABSTRACT FROM AUTHOR]

Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of tardive dyskinesia (TD). We hypothesized that interleukins would have a link with TD in schizophrenia patients. In this study, the serum IL-2, IL-6 and IL-8 levels were examined by enzyme-linked immunosorbent assay (ELISA) in schizophrenia patients with TD (n = 48) and without TD (n = 45), and healthy controls (n = 44). The psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). The severity of TD was evaluated using Abnormal Involuntary Movement Scale (AIMS). The results showed that serum IL-2, IL-6 and IL-8 levels were significantly different among schizophrenia patients with TD and without TD and normal controls. Moreover, IL-2 level was significantly correlated with PANSS positive subscale and general subscale in patients with TD and without TD. In addition, IL-2 level was positively correlated with AIMS score in TD patients. The results supported that immune disturbance is related to the schizophrenia patients, especially to the patients with TD and ILs might play an important role in the pathophysiology of schizophrenia patients with TD. [ABSTRACT FROM AUTHOR]

Abstract: Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n=6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. [Copyright &y& Elsevier]

Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects. [ABSTRACT FROM AUTHOR]

Rationale: Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl- d-aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. Methods: DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. Results: DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. Conclusions: These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Objective: The rate-corrected electrocardiographic QT (QTc) interval may significantly increase in patients with schizophrenia taking antipsychotics. The objective of this naturalistic study was to assess the prevalence of prolonged QTc interval in a large population of inpatients with chronic schizophrenia and to explore QTc relationship with demographic variables and prescribed treatments. Materials and methods: Electrocardiograms were obtained from age- and sex-matched 456 controls and 1,006 inpatients with schizophrenia (male/female = 689/317) taking antipsychotics. QTc prolongation was defined as a mean value of two standard deviations above the controls. The adjusted relative risk was calculated using logistic regression analysis. Results: QTc prolongation was present in 45 (4.5%) of 1,006 patients overall. Fewer men (3.2%, 22 of 689) than women (7.3%, 23 of 317) displayed QTc prolongation ( p < 0.004). Moreover, QTc intervals were shorter in male (391 ± 31 ms) than female subjects (400 ± 37 ms) ( p < 0.001). Clozapine was found to produce a longer QTc intervals compared to risperidone and typical antipsychotics. Furthermore, multiple regression analysis showed that significant predictors for QTc prolongation were comorbid cardiovascular disease, antipsychotic types, sex, and age (all p < 0.01). Conclusion: Our present findings suggest that there are sex differences in the prevalence of QTc prolongation and QTc lengthening in schizophrenia. Antipsychotic types are risk factors for QTc prolongation, and risks are substantially higher for clozapine. [ABSTRACT FROM AUTHOR]

Abstract: N-methyl-d-aspartate (NMDA) receptor blockade in rodents induces behavioural and neurochemical changes reminiscent of schizophrenia symptoms and pathology. To examine how NMDA receptor blockade affects glutamatergic and GABAergic pathways when administered during early brain development, [3H]MK-801 and [3H]muscimol binding to NMDA and GABAA receptors was examined at four time-points following injections of phencyclidine (PCP) or saline on postnatal days (PN)7, 9 and 11. [3H]MK-801 binding was significantly increased in PCP-treated rats in the thalamus from PN18 to PN96, in the prefrontal and anterior cingulate cortices at PN32, and in the hippocampus at PN96. In a similar manner, [3H]muscimol binding was increased in PCP-treated rats in the thalamus and hippocampus from PN18 to PN96, and in the prefrontal and anterior cingulate cortices at PN32. Glutamatergic and GABAergic transmission is therefore chronically altered by this treatment, which has relevance to disease processes that may be involved in schizophrenia. [Copyright &y& Elsevier]

Abstract: Statins are widely being used for the treatment of a variety of conditions beyond their original indication for lowering cholesterol. We have previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate locomotor and anxiety effects along with the regional changes of N-methyl-d-aspartate (NMDA) receptors in the rat brain after 4-week administration of simvastatin. Hyperlocomotive and anxiolytic-like activities in the rat were observed after chronic administration of high dose simvastatin (10 mg/kg/day). Distributions and alterations of NMDA receptors in the post-mortem rat brain were detected by [3H] MK-801 binding autoradiography. Simvastatin increased [3H] MK-801 binding, predominantly in the prefrontal cortex (20%, p =0.003), primary motor cortex (20%, p <0.001), cingulate cortex (28%, p <0.001), hippocampus (41%, p <0.001), caudate putamen (30%, p =0.029), nucleus accumbens (27%, p =0.035) and amygdala (45%, p <0.001) compared to controls. Significant positive correlations were identified between hyperlocomotive as well as anxiolytic-like activities and the upregulation of NMDA receptors in different brain regions. Our results also provide strong evidence that chronic high dose simvastatin administration is to exhibit NMDA antagonist-like effects, which would partially explain the anxiolytic and hyperlocomotor activities. These findings contribute to a better understanding of the critical roles of simvastatin in modulating psycho-neurodegenerative disorders, via NMDA receptors. [Copyright &y& Elsevier]

Abstract: Perinatal phencyclidine (PCP) treatment has been used to model brain pathological processes that may be present in schizophrenia such as increased apoptosis during early brain development, and long-term alterations in expression of parvalbumin-containing interneurons and glutamatergic N-methyl-d-aspartate (NMDA) receptors. We report that this treatment also affects receptor expression of another excitatory neurotransmitter receptor, the muscarinic receptor. Female rat pups received injections of the NMDA receptor antagonist PCP (10 mg/kg, s.c.) or saline on postnatal days (PN)7, 9 and 11. [3H]Pirenzepine binding to M1/4 receptors was examined at four time-points (PN12, 18, 32 and 96) following treatment cessation. Significant effects of treatment on [3H]pirenzepine binding were evident immediately after treatment cessation with a decrease in PCP-treated rats at PN12 in the prefrontal cortex (−24%, p <0.05) and hippocampus (−19%, p <0.05). After this initial decrease, binding subsequently increased to 47% above control levels in the prefrontal cortex of adolescent animals, which remained elevated in adulthood (+10%, p <0.05), while in the hippocampus there was a trend towards increased binding in adolescent animals and no change thereafter. This work adds to findings demonstrating that perinatal PCP exposure leads to long-term imbalance of excitatory and inhibitory neurotransmitter systems, supporting its relevance as a developmental model of schizophrenia pathology. Alterations in muscarinic receptor expression may contribute specifically to the cognitive impairments reported to occur after perinatal NMDA receptor antagonist treatment. [Copyright &y& Elsevier]

Abstract: Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4h after a single injection of PCP. We used receptor autoradiography and [3H]MK801, [3H]AMPA, [3H]pirenzepine and [3H]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F =14.5, d.f.=1, p <0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (−16%), hippocampus CA2 (−25%), dentate gyrus (−27%), parietal cortex layers III–VI (−19%), central nucleus of the amygdala (−40%), and basolateral amygdala (−19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions. [Copyright &y& Elsevier]

Abstract: The posterior cingulate cortex (PCC), a key component of the limbic system, has been implicated in the pathology of schizophrenia because of its sensitivity to NMDA receptor antagonists. Recent studies have shown that the PCC is dysfunctional in schizophrenia, and it is now suspected to be critically involved in the pathogenesis of schizophrenia. Studies also suggest that there are abnormalities in muscarinic and GABAergic neurotransmission in schizophrenia. Therefore, in the present study we used quantitative autoradiography to investigate the binding of [3H]pirenzepine, [3H]AF-DX 384 and [3H]muscimol, which respectively label M1/4 and M2/4 muscarinic and GABAA receptors, in the PCC of schizophrenia and control subjects matched for age and post-mortem interval. The present study found that [3H]pirenzepine binding was significantly decreased in the superficial (−24%, p =0.002) and deep (−35%, p <0.001) layers of the PCC in the schizophrenia group as compared with the control group. In contrast, a dramatic increase in [3H]muscimol binding was observed in the superficial (+112%, p =0.001) and deep layers (+100%, p =0.017) of the PCC in the schizophrenia group. No difference was observed for [3H]AF-DX 384 binding between the schizophrenia and control groups. The authors found a significant inverse correlation between [3H]pirenzepine binding in the deep cortical layers and [3H]muscimol binding in the superficial layers (rho=−0.732, p =0.003). In addition, negative correlations were also found between age and [3H]pirenzepine binding in both superficial and deep cortical layers (rho=−0.669 p =0.049 and rho=−0.778, p =0.014), and between age of schizophrenia onset and [3H]AF-DX 384 binding (rho=−0.798, p =0.018). These results for the first time demonstrated the status of M1/M4, M2/M4 and GABAA receptors in the PCC in schizophrenia. Whilst the exact mechanism causing these alterations is not yet known, a possible increased acetylcholine and down regulated GABA stimulation in the PCC of schizophrenia is suggested. [Copyright &y& Elsevier]

Abstract: The amygdala has a role in the modulation of moods and emotion, processes that are known to be affected in people with psychiatric disorders such as schizophrenia and depression. The tachykinin NK1 receptor is known to be expressed in the amygdala. However to date, there is limited knowledge of the distribution of the NK1 receptor in this region. This study used immunohistochemistry to analyse the distribution of the NK1 receptor in fixed human amygdala tissue in control subjects with no history of psychiatric illness and matched subjects with a diagnosis of schizophrenia (n =4 pairs). The NK1 receptor was observed sparsely distributed in cell bodies in all amygdaloid nuclei with the basolateral and lateral having a greater relative density of NK1 receptor-immunoreactive cell bodies than the other nuclei. Double labelling with antibodies to microtubule associated protein and the NK1 receptor revealed that the NK1 receptor is expressed by large pyramidal, small stellate and large bipolar neurons. Interestingly, the basal nucleus of Meynert, which is just dorsal to the amygdala, was observed to have a significantly higher relative density of NK1 receptor-immunoreactive cell bodies compared to any of the amygdaloid nuclei. Preliminary analysis of the density of NK1 receptor-immunoreactive cell bodies in the major amygdaloid nuclei and the basal nucleus of Meynert revealed no significant differences between schizophrenia and control subjects. Real-time PCR showed that the mRNA for both the short and long isoforms of the NK1 receptor was expressed at low levels in fresh frozen human amygdala tissue from control subjects and that this was not different in matched subjects with schizophrenia (n =11 pairs). In conclusion, this study has demonstrated that the NK1 receptor is widely distributed in the amygdala, and has shown for the first time a high relative density of NK1 receptor-immunoreactive cell bodies in the basal nucleus of Meynert. [Copyright &y& Elsevier]

Abstract: We have previously shown a decrease in [3H]pirenzepine binding to M1/M4 muscarinic receptors in the anterior cingulate cortex in schizophrenia but not in major depression or bipolar disorder. The present study aimed to extend these findings by examining the binding of [3H]AF-DX 384 to M2/M4 receptors in the same cohort of subjects. Using quantitative autoradiography we measured [3H]AF-DX 384 binding in the anterior cingulate cortex of 15 schizophrenia, 15 bipolar, 15 major depression and 15 control cases. Post-mortem tissue was obtained from the Stanley Foundation Brain Bank. [3H]AF-DX 384 binding had a homogenous distribution amongst the layers of the anterior cingulate cortex, was higher in males than in females and declined with prolonged storage of tissue. An inverse correlation between [3H]AF-DX384 binding and age of onset of the disease was observed in the schizophrenia group suggesting that the earlier the age at onset the higher the binding was. In the depression group, there was a significant effect of gender on [3H]AF-DX 384 binding with females having lower binding in comparison to males. In the bipolar group, there was a significant inverse correlation between antipsychotic medication and [3H]AF-DX 384 binding, suggesting that the higher the dose of medication the lower the binding was. No differences in [3H]AF-DX 384 binding were seen between the four groups. The present results provide no evidence of M2/M4 receptor alterations in the anterior cingulate cortex in schizophrenia and affective disorders and extend the body of evidence implicating cortical M1 but not M2 involvement in the pathology and pharmacotherapy of schizophrenia. [Copyright &y& Elsevier]

Abnormal cholinergic neurotransmission has been suggested to occur in psychiatric illness. Therefore, this study investigated cholinergic muscarinic receptors in the anterior cingulate cortex (ACC) of schizophrenia, bipolar disorder and major depression disorder (n = 15 per group). We used quantitative autoradiography to measure [³H]pirenzepine binding to M1 and M4 receptors. Brain tissue was obtained from the Stanley Foundation Neuropathology Consortium. [³H]pirenzepine binding was higher in superficial laminae (I-II) than in deep laminae (Ill-VI) of the ACC. There was a significant 24% reduction in the density of [³H]pirenzepine in the deep laminae and a significant 19% reduction in the upper laminae of the ACC in the schizophrenia group compared to the control group. There were no differences in [³H]pirenzepine binding in any laminae of the ACC in the bipolar or major depression groups compared with the control group, except for a trend towards decreased [³H]pirenzepine binding in subjects with major depression relative to control subjects. We also detected a significant effect of suicide on [³H]pirenzepine binding in the ACC in subjects who died as a result of suicide relative to those who did not, which was more evident in patients with schizophrenia. A significant effect of the onset of the disease was also observed that was more evident in patients with bipolar disorder. The study provides evidence of decreased muscarinic receptor density in the ACC in schizophrenia but no evidence for significant changes in these receptors in the bipolar and major depression groups. The changes observed in schizophrenia may contribute to dysfunctional ACC neural circuits. [ABSTRACT FROM AUTHOR]

Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2–) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2−, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume. [ABSTRACT FROM AUTHOR]

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl- d -aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model. [ABSTRACT FROM AUTHOR]

Background: Neural cell adhesion molecule (NCAM) is a glycoprotein and plays an important role in cell-cell adhesion, neural migration, neurite outgrowth, synaptic plasticity and brain development. We investigated the relationship between the serum NCAM concentration and cognitive deficit in first episode drug naïve schizophrenia (FES) patients.Methods: Thirty FES patients and thirty healthy controls were recruited for this study. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Cognitive functions were assessed by measurement and treatment research to improve cognition in schizophrenia (MATRICS) and consensus cognitive battery (MCCB). Serum levels of NCAM were determined by ELISA.Results: Schizophrenia patients had decreased serum NCAM concentrations than controls (-30%, p<0.001). Cognitive scores were significantly lower in FES patients than healthy controls (-34%, p<0.001). The NCAM concentrations were positively correlated with the total scores of MCCB (r=0.438, p=0.003). Multiple regression analysis confirmed that serum NCAM concentration was an independent contributor to MCCB total Scores.Conclusions: There were a close relationship between the serum NCAM concentrations and cognitive deficits in FES patients. Since NCAM has an important role in neurodevelopmental processes, these results support the neurodevelopmental dysfunction hypothesis of schizophrenia and suggest that an altered NCAM may be one of the risk factors for schizophrenia including cognitive deficits. [ABSTRACT FROM AUTHOR]