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Sample records for confers schizophrenia-like phenotypes

  1. Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia.

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    Perez, Stephanie M; Aguilar, David D; Neary, Jennifer L; Carless, Melanie A; Giuffrida, Andrea; Lodge, Daniel J

    2016-01-01

    Both environmental and genetic factors contribute to schizophrenia; however, the exact etiology of this disorder is not known. Animal models are utilized to better understand the mechanisms associated with neuropsychiatric diseases, including schizophrenia. One of these involves gestational administration of methylazoxymethanol acetate (MAM) to induce a developmental disruption, which in turn produces a schizophrenia-like phenotype in post-pubertal rats. The mechanisms by which MAM produces this phenotype are not clear; however, we now demonstrate that MAM induces differential DNA methylation, which may be heritable. Here we demonstrate that a subset of both second (F2) and third (F3) filial generations of MAM-treated rats displays a schizophrenia-like phenotype and hypermethylation of the transcription factor, Sp5. Specifically, ventral tegmental area of dopamine neuron activity was examined using electrophysiology as a correlate for the dopamine hyperfunction thought to underlie psychosis in patients. Interestingly, only a subset of F2 and F3 MAM rats exhibited increases in dopamine neuron population activity, indicating that this may be a unique model with a susceptibility to develop a schizophrenia-like phenotype. An increase in dopamine system function in rodent models has been previously associated with decreases in hippocampal GABAergic transmission. In line with these observations, we found a significant correlation between hippocampal parvalbumin expression and dopamine neuron activity in F2 rats. These data therefore provide evidence that offspring born from MAM-treated rats possess a susceptibility to develop aspects of a schizophrenia-like phenotype and may provide a useful tool to investigate gene-environment interactions.

  2. Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.

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    Gregory R Rompala

    Full Text Available Pharmacological and genetic studies support a role for NMDA receptor (NMDAR hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1 deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice, in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior. Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.

  3. Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.

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    Rompala, Gregory R; Zsiros, Veronika; Zhang, Shuqin; Kolata, Stefan M; Nakazawa, Kazu

    2013-01-01

    Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.

  4. GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes.

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    Zhe Yu

    Full Text Available The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1 knockout (KO mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABA(A receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.

  5. Common variants conferring risk of schizophrenia

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    Stefansson, Hreinn; Ophoff, Roel A; Steinberg, Stacy

    2009-01-01

    Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease...... conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have.......2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition....

  6. Decreased DNA Methylation in the Shati/Nat8l Promoter in Both Patients with Schizophrenia and a Methamphetamine-Induced Murine Model of Schizophrenia-Like Phenotype.

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    Kyosuke Uno

    Full Text Available The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment. The ratios of Shati/Nat8l CpG island methylation were significantly decreased in both the nucleus accumbens and the peripheral blood of model mice compared with those of control mice. We also investigated Shati/Nat8l methylation in the blood of patients with schizophrenia. We found that Shati/Nat8l CpG island methylation ratios were lower in the patients with schizophrenia than in the healthy controls, which is consistent with our findings in the mice model. To our knowledge, this is the first study to show similar alterations in methylation status of a particular genomic DNA site in both the brain and peripheral blood of mice. Furthermore, the same phenomenon was observed in corresponding human genomic sequences of the DNA extracted from the peripheral blood of patients with schizophrenia. Based on our findings, DNA methylation profiles of the CpG island of Shati/Nat8l might be a diagnostic biomarker of schizophrenia.

  7. Do mood symptoms subdivide the schizophrenia phenotype? : Association of the GMP6A gene with a depression subgroup

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    Boks, Marco P M; Hoogendoorn, Mechteld; Jungerius, Bart J; Bakker, Steven C; Sommer, Iris E; Sinke, Richard J; Ophoff, Roel A; Kahn, René S

    2008-01-01

    Genetic studies of clinically defined subgroups of schizophrenia patients may reduce the phenotypic heterogeneity of schizophrenia and thus facilitate the identification of genes that confer risk to this disorder. Several latent class analyses have provided subgroups of psychotic disorders that show

  8. The phenotypic manifestations of rare CNVs in schizophrenia.

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    Merikangas, Alison K; Segurado, Ricardo; Cormican, Paul; Heron, Elizabeth A; Anney, Richard J L; Moore, Susan; Kelleher, Eric; Hargreaves, April; Anderson-Schmidt, Heike; Gill, Michael; Gallagher, Louise; Corvin, Aiden

    2014-09-01

    There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.

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    Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

    2016-02-01

    Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.

  10. Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors' in Mice

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    Vitucci, Daniela; Di Giorgio, Annabella; Napolitano, Francesco; Pelosi, Barbara; Blasi, Giuseppe; Errico, Francesco; Attrotto, Maria Teresa; Gelao, Barbara; Fazio, Leonardo; Taurisano, Paolo; Di Maio, Anna; Marsili, Valentina; Pasqualetti, Massimo; Bertolino, Alessandro; Usiello, Alessandro

    2016-01-01

    Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia. PMID:26228524

  11. Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia.

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    Kästner, Anne; Begemann, Martin; Michel, Tanja Maria; Everts, Sarah; Stepniak, Beata; Bach, Christiane; Poustka, Luise; Becker, Joachim; Banaschewski, Tobias; Dose, Matthias; Ehrenreich, Hannelore

    2015-05-13

    Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores ≥12 obtained highest, those with scores genetic constellations modulating autistic phenotypes.

  12. Autism beyond diagnostic categories : characterization of autistic phenotypes in schizophrenia :

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    Kästner, A.; Begemann, M.; Michel, T.; Everts, S.; Stepniak, B.; Bach, C.; Poustka, L.; Becker, J.; Banaschewski, T.; Dose, M.; Ehrenreich, H.

    2015-01-01

    Abstract Background Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schi...

  13. Cigarette smoking in male patients with chronic schizophrenia in a Chinese population: prevalence and relationship to clinical phenotypes.

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    Xiang Yang Zhang

    Full Text Available The high prevalence of smoking in schizophrenia of European background may be related to smoking's reducing clinical symptoms and medication side effects. Because smoking prevalence and its associations with clinical phenotypes are less well characterized in Chinese than European patients with schizophrenia, we assessed these smoking behaviors using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND in 776 Chinese male schizophrenia and 560 control subjects. Patients also were rated on the Positive and Negative Symptom Scale (PANSS, the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES, and the Abnormal Involuntary Movement Scale (AIMS. We found that the schizophrenia patients had a higher lifetime incidence of smoking (79% vs 63%, were more likely to be heavy smokers (61% vs 31%, and had lower smoking cessation rates (4% vs 9% (all p0.05 than the non-smoking patients. These results suggest that Chinese males with schizophrenia smoke more frequently than the general population. Further, smokers with schizophrenia may display fewer negative symptoms and possibly less parkinsonism than non-smokers with schizophrenia.

  14. Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade

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    Torrisi, Sebastiano Alfio; Salomone, Salvatore; Geraci, Federica; Caraci, Filippo; Bucolo, Claudio; Drago, Filippo; Leggio, Gian Marco

    2017-01-01

    Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R-/-). Results: Buspirone (3 mg⋅kg-1, i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg-1, i.p.) in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be

  15. Drama therapy for schizophrenia or schizophrenia-like illnesses.

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    Ruddy, R A; Dent-Brown, K

    2007-01-24

    Medication is the mainstay of treatment for schizophrenia or schizophrenia-like illnesses, but many people continue to experience symptoms in spite of medication (Johnstone 1998). In addition to medication, creative therapies, such as drama therapy may prove beneficial. Drama therapy is a form of treatment that encourages spontaneity and creativity. It can promote emotional expression, but does not necessarily require the participant to have insight into their condition or psychological-mindset. To review the effects of drama therapy and related approaches as an adjunctive treatment for schizophrenia compared with standard care and other psychosocial interventions. We searched the Cochrane Schizophrenia Group's Register (October 2006), hand searched reference lists, hand searched Dramatherapy (the journal of the British Association of Dramatherapists) and Arts in Psychotherapy and contacted relevant authors. We included all randomised controlled trials that compared drama therapy, psychodrama and related approaches with standard care or other psychosocial interventions for schizophrenia. We reliably selected, quality assessed and extracted data from the studies. We excluded data where more than 50% of participants in any group were lost to follow up. For continuous outcomes we calculated a weighted mean difference and its 95% confidence interval. For binary outcomes we calculated a fixed effects risk ratio (RR), its 95% confidence interval (CI) and a number needed to treat (NNT). The search identified 183 references but only five studies (total n=210) met the inclusion criteria. All of the studies were on inpatient populations and compared the intervention with standard inpatient care. One study had drama therapy as the intervention, one had role-playing, one had a social drama group and two used psychodrama. Two of the included studies were Chinese and it is difficult to know whether psychodrama and indeed inpatient psychiatric care in China is comparable with the

  16. Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents

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    Sarnyai, Zoltán; Jashar, Cassandra; Olivier, Berend

    2015-01-01

    Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel

  17. Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice.

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    Howell, Kristy R; Pillai, Anilkumar

    2016-07-01

    Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizophrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies, we examined the long-term effects of PHX in heterozygous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6 months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor-1α (HIF-1α) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorticoid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene-environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specificity of the gene of interest.

  18. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study

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    Qin, Ping; Xu, Huylan; Laursen, Thomas Munk

    2005-01-01

    .20) in people with a history of epilepsy. The effect of epilepsy was the same in men and in women and increased with age. Family history of psychosis and a family history of epilepsy were significant risk factors for schizophrenia and schizophrenia-like psychosis, and the effect of epilepsy, both in cases......OBJECTIVES: To investigate whether age at onset of epilepsy, type of epilepsy, family history of psychosis, or family history of epilepsy affect the risk of schizophrenia or schizophrenia-like psychosis among patients with epilepsy. DESIGN: Comparison of population based data. SETTING: Danish...... and families, was greater among people with no family history of psychosis. In addition, the increased risk for schizophrenia or schizophrenia-like psychosis did not differ by type of epilepsy but increased with increasing number of admissions to hospital and, particularly, was significantly greater for people...

  19. Risk-Conferring Glutamatergic Genes and Brain Glutamate Plus Glutamine in Schizophrenia

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    Juan R. Bustillo

    2017-06-01

    Full Text Available BackgroundThe proton magnetic resonance spectroscopy (1H-MRS signals from glutamate (or the combined glutamate and glutamine signal—Glx have been found to be greater in various brain regions in people with schizophrenia. Recently, the Psychiatric Genetics Consortium reported that several common single-nucleotide polymorphisms (SNPs in glutamate-related genes confer increased risk of schizophrenia. Here, we examined the relationship between presence of these risk polymorphisms and brain Glx levels in schizophrenia.Methods1H-MRS imaging data from an axial, supraventricular tissue slab were acquired in 56 schizophrenia patients and 67 healthy subjects. Glx was measured in gray matter (GM and white matter (WM regions. The genetic data included six polymorphisms genotyped across an Illumina 5M SNP array. Only three of six glutamate as well as calcium-related SNPs were available for examination. These included three glutamate-related polymorphisms (rs10520163 in CLCN3, rs12704290 in GRM3, and rs12325245 in SLC38A7, and three calcium signaling polymorphisms (rs1339227 in RIMS1, rs7893279 in CACNB2, and rs2007044 in CACNA1C. Summary risk scores for the three glutamate and the three calcium polymorphisms were calculated.ResultsGlx levels in GM positively correlated with glutamate-related genetic risk score but only in younger (≤36 years schizophrenia patients (p = 0.01. Glx levels did not correlate with calcium risk scores. Glx was higher in the schizophrenia group compared to levels in controls in GM and WM regardless of age (p < 0.001.ConclusionElevations in brain Glx are in part, related to common allelic variants of glutamate-related genes known to increase the risk for schizophrenia. Since the glutamate risk scores did not differ between groups, some other genetic or environmental factors likely interact with the variability in glutamate-related risk SNPs to contribute to an increase in brain Glx early in the illness.

  20. Pheno-phenotypes: a holistic approach to the psychopathology of schizophrenia.

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    Stanghellini, Giovanni; Rossi, Rodolfo

    2014-05-01

    Mental disorders are mainly characterized via symptom assessment. Symptoms are state-like macroscopic anomalies of behaviour, experience, and expression that are deemed relevant for diagnostic purposes. An alternative approach is based on the concept of endophenotypes, which are physiological or behavioural measures occupying the terrain between symptoms and risk genotypes. We will critically discuss these two approaches, and later focus on the concept of pheno-phenotype as it is revealed by recent phenomenological research on schizophrenia. Several studies have been recently published on the schizophrenic pheno-phenotype mainly addressing self-disorders, as well as disorders of time and bodily experience. The mainstream approach to psychopathological phenotypes is focussed on easy-to-assess operationalizable symptoms. Thinness of phenotypes and simplification of clinical constructs are the consequences of this. Also, this approach has not been successful in investigating the biological causes of mental disorders. An integrative approach is based on the concept of 'endophenotype'. Endophenotypes were conceptualized as a supportive tool for the genetic dissection of psychiatric disorders. The underlying rationale states that disease-specific phenotypes should be the upstream phenotypic manifestation of a smaller genotype than the whole disease-related genotype. Psychopathological phenotypes can also be characterized in terms of pheno-phenotypes. This approach aims at delineating the manifold phenomena experienced by patients in all of their concrete and distinctive features, so that the features of a pathological condition emerge, while preserving their peculiar feel, meaning, and value for the patient. Systematic explorations of anomalies in the patients' experience, for example, of time, space, body, self, and otherness, may provide a useful integration to the symptom-based and endophenotype-based approaches. These abnormal phenomena can be used as pointers to the

  1. Altered Functional Subnetwork During Emotional Face Processing: A Potential Intermediate Phenotype for Schizophrenia.

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    Cao, Hengyi; Bertolino, Alessandro; Walter, Henrik; Schneider, Michael; Schäfer, Axel; Taurisano, Paolo; Blasi, Giuseppe; Haddad, Leila; Grimm, Oliver; Otto, Kristina; Dixson, Luanna; Erk, Susanne; Mohnke, Sebastian; Heinz, Andreas; Romanczuk-Seiferth, Nina; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Cichon, Sven; Noethen, Markus; Rietschel, Marcella; Tost, Heike; Meyer-Lindenberg, Andreas

    2016-06-01

    Although deficits in emotional processing are prominent in schizophrenia, it has been difficult to identify neural mechanisms related to the genetic risk for this highly heritable illness. Prior studies have not found consistent regional activation or connectivity alterations in first-degree relatives compared with healthy controls, suggesting that a more comprehensive search for connectomic biomarkers is warranted. To identify a potential systems-level intermediate phenotype linked to emotion processing in schizophrenia and to examine the psychological association, task specificity, test-retest reliability, and clinical validity of the identified phenotype. The study was performed in university research hospitals from June 1, 2008, through December 31, 2013. We examined 58 unaffected first-degree relatives of patients with schizophrenia and 94 healthy controls with an emotional face-matching functional magnetic resonance imaging paradigm. Test-retest reliability was analyzed with an independent sample of 26 healthy participants. A clinical association study was performed in 31 patients with schizophrenia and 45 healthy controls. Data analysis was performed from January 1 to September 30, 2014. Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes. Among the 152 volunteers included in the relative-control sample, 58 were unaffected first-degree relatives of patients with schizophrenia (mean [SD] age, 33.29 [12.56]; 38 were women), and 94 were healthy controls without a first-degree relative with mental illness (mean [SD] age, 32.69 [10.09] years; 55 were women). A graph-theoretical connectivity approach identified significantly decreased connectivity in a subnetwork that primarily included the limbic cortex, visual cortex, and subcortex during emotional face processing (cluster-level P corrected for familywise error =

  2. Accumulated environmental risk determining age at schizophrenia onset: a deep phenotyping-based study.

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    Stepniak, Beata; Papiol, Sergi; Hammer, Christian; Ramin, Anna; Everts, Sarah; Hennig, Lena; Begemann, Martin; Ehrenreich, Hannelore

    2014-11-01

    Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures. In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters. In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·9×10(-10)). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10(-20)). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes. These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness. German Research Foundation

  3. Duplications of the Neuropeptide Receptor VIPR2 Confer Significant Risk for Schizophrenia

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    Vacic, Vladimir; McCarthy, Shane; Malhotra, Dheeraj; Murray, Fiona; Chou, Hsun-Hua; Peoples, Aine; Makarov, Vladimir; Yoon, Seungtai; Bhandari, Abhishek; Corominas, Roser; Iakoucheva, Lilia M.; Krastoshevsky, Olga; Krause, Verena; Larach-Walters, Verónica; Welsh, David K.

    2011-01-01

    PUBLISHED PMID:21346763 Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other neuropsychiatric disorders 1 . Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at 1q21.1 2 , 3q29 3 , 15q13.3 2 and 22q11.2 4 and microduplication at 16p11.2 5 . However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant ...

  4. Common variants in the TPH2 promoter confer susceptibility to paranoid schizophrenia.

    Science.gov (United States)

    Yi, Zhenghui; Zhang, Chen; Lu, Weihong; Song, Lisheng; Liu, Dentang; Xu, Yifeng; Fang, Yiru

    2012-07-01

    Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. Our previous study suggested that promoter region of tryptophan hydroxylase 2 gene (TPH2) may confer the susceptibility to paranoid schizophrenia. In this study, we investigated whether common variants within TPH2 promoter may predispose to paranoid schizophrenia in Han Chinese. A total of 509 patients who met DSM-IV criteria for paranoid schizophrenia and 510 matched healthy controls were recruited for this study. Five polymorphisms within TPH2 promoter region were tested. No statistically significant differences were found in allele or genotype frequencies between schizophrenic patients and healthy controls. The frequency of the rs4448731T-rs6582071A-rs7963803A-rs4570625T-rs11178997A haplotype was significantly higher in cases compared to the controls (P = 0.003; OR = 1.49; 95% CI, 1.15-1.95). Our results suggest that the common variants within TPH2 promoter are associated with paranoid schizophrenia in Han Chinese. Further studies in larger samples are warranted to elucidate the role of TPH2 in the etiology of paranoid schizophrenia.

  5. Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia.

    Science.gov (United States)

    Grimm, Oliver; Heinz, Andreas; Walter, Henrik; Kirsch, Peter; Erk, Susanne; Haddad, Leila; Plichta, Michael M; Romanczuk-Seiferth, Nina; Pöhland, Lydia; Mohnke, Sebastian; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Schäfer, Axel; Cichon, Sven; Nöthen, Markus; Rietschel, Marcella; Tost, Heike; Meyer-Lindenberg, Andreas

    2014-05-01

    Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by

  6. Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study

    Science.gov (United States)

    Hill, S. Kristian; Reilly, James L.; Keefe, Richard S.E.; Gold, James M.; Bishop, Jeffrey R.; Gershon, Elliot S.; Tamminga, Carol A.; Pearlson, Godfrey D.; Keshavan, Matcheri S.; Sweeney, John A.

    2017-01-01

    Objective Familial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits. Method Participants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Results Cognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=−0.77) to schizoaffective disorder (manic z=−1.08; depressed z=−1.25) to schizophrenia (z=−1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not. Conclusions Robust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less

  7. Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

    Science.gov (United States)

    Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

    2017-08-01

    The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (pschizophrenia-related phenotype, as well as potentiated changes in the NOR (pschizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

    Directory of Open Access Journals (Sweden)

    Francesca Managò

    2016-08-01

    Full Text Available Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.

  9. Maternal care affects the phenotype of a rat model for schizophrenia

    Directory of Open Access Journals (Sweden)

    Ruben W M Van Vugt

    2014-08-01

    Full Text Available Schizophrenia is a complex mental disorder caused by an interplay between genetic and environmental factors, including early postnatal stressors. To explore this issue, we use two rat lines, apomorphine-susceptible (APO-SUS rats that display schizophrenia-relevant features and their phenotypic counterpart, apomorphine-unsusceptible (APO-UNSUS rats. These rat lines differ not only in their gnawing response to apomorphine, but also in their behavioral response to novelty (APO-SUS: high, APO-UNSUS: low. In this study, we examined the effects of early postnatal cross-fostering on maternal care and on the phenotypes of the cross-fostered APO-SUS and APO-UNSUS animals later in life. Cross-fostered APO-UNSUS animals showed decreased body weights as pups and decreased novelty-induced locomotor activity as adults (i.e., more extreme behavior, in accordance with the less appropriate maternal care provided by APO-SUS versus their own APO-UNSUS mothers (i.e., the APO-SUS mother displayed less non-arched-back nursing and more self-grooming, and was more away from its nest. In contrast, cross-fostered APO-SUS animals showed increased body weights as pups and reduced apomorphine-induced gnawing later in life (i.e., normalisation of their extreme behavior, in line with the more appropriate maternal care provided by APO-UNSUS relative to their own APO-SUS mothers (i.e., the APO-UNSUS mother displayed more non-arched-back nursing and similar self-grooming, and was not more away. Furthermore, we found that, in addition to arched-back nursing, non-arched-back nursing was an important feature of maternal care, and that cross-fostering APO-SUS mothers, but not cross-fostering APO-UNSUS mothers, displayed increased apomorphine-induced gnawing. Thus, cross-fostering not only causes early postnatal stress shaping the phenotypes of the cross-fostered animals later in life, but also affects the phenotypes of the cross-fostering mothers.

  10. The NVL gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population.

    Science.gov (United States)

    Wang, Meng; Chen, Jianhua; He, Kuanjun; Wang, Qingzhong; Li, Zhiqiang; Shen, Jiawei; Wen, Zujia; Song, Zhijian; Xu, Yifeng; Shi, Yongyong

    2015-10-01

    NVL (nuclear VCP (valosin containing protein)/p97-Like), a member of the AAA-ATPase (ATPases associated with various cellular activities) family, encodes a novel hTERT (human telomerase reverse transcriptase)-interacting protein NVL2 which is a telomerase component essential for holoenzyme assembly. Previous researches have reported the impacts of telomerase activity on mental illness and the potential association between NVL and major depressive disorder. To validate the susceptibility of NVL to major depressive disorder, and to investigate the overlapping risk conferred by NVL for both major depressive disorder and schizophrenia, we analyzed 9 tag single nucleotide polymorphisms (tag SNPs) using TaqMan® technology, in 1045 major depressive disorder patients, 1235 schizophrenia patients and 1235 normal controls of Han Chinese origin. We found that rs10916583 (P(allele) = 0.020, P(genotype) = 0.028, OR = 1.156) and rs16846649 (adjusted P(allele) = 0.014, P(genotype) = 0.007, OR = 0.718) were associated with major depressive disorder, while rs10916583 (adjusted P(allele) = 1.08E-02, OR = 1.213), rs16846649 (adjusted P(allele) = 7.40E-06, adjusted P(genotype) = 8.07E-05, OR = 0.598) and rs10799541 (adjusted P(allele) = 8.10E-03, adjusted P(genotype) = 0.049, OR= 0.826) showed statistically significant association with schizophrenia after Bonferroni correction. Furthermore, rs10916583 (adjusted P(allele) = 9.00E-03, adjusted P(genotype) = 3.15E-02, OR = 1.187) and rs16846649 (adjusted P(allele) = 8.92E-06, adjusted P(genotype) = 8.84E-05, OR = 0.653) remained strongly associated with the analysis of combined cases of major depressive disorder and schizophrenia after Bonferroni correction. Our results indicated that the NVL gene may contain overlapping common genetic risk factors for major depressive disorder and schizophrenia in the Han Chinese population. The roles of NVL in telomerase biogenesis were also highlighted in psychiatric pathogenesis. The study on

  11. THE 4th SCHIZOPHRENIA INTERNATIONAL RESEARCH SOCIETY CONFERENCE, 5–9 APRIL 2014, FLORENCE, ITALY: A summary of topics and trends

    Science.gov (United States)

    Abayomi, Olukayode; Amato, Davide; Bailey, Candace; Bitanihirwe, Byron; Bowen, Lynneice; Burshtein, Shimon; Cullen, Alexis; Fusté, Montserrat; Herrmann, Ana P; Khodaie, Babak; Kilian, Sanja; Lang, Qortni A; Manning, Elizabeth E; Massuda, Raffael; Nurjono, Milawaty; Sadiq, Sarosh; Sanchez-Gutierrez, Teresa; Sheinbaum, Tamara; Shivakumar, Venkataram; Simon, Nicholas; Spiteri-Staines, Anneliese; Sirijit, Suttajit; Toftdahl, Nanna Gilliam; Wadehra, Sunali; Wang, Yi; Wigton, Rebekah; Wright, Susan; Yagoda, Sergey; Zaytseva, Yuliya; O’Shea, Anne; DeLisi, Lynn E.

    2015-01-01

    The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5–9, 2014.and this year had as its emphasis, “Fostering Collaboration in Schizophrenia Research”. Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future. In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. PMID:25306204

  12. Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association.

    Science.gov (United States)

    Clelland, James D; Read, Laura L; Drouet, Valérie; Kaon, Angela; Kelly, Alexandra; Duff, Karen E; Nadrich, Robert H; Rajparia, Amit; Clelland, Catherine L

    2014-06-01

    25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia. We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia. 25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p=0.044, 95% CI: 1.02-4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p=0.035, 95% CI: 1.08-8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk. This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.

    Science.gov (United States)

    Rampino, Antonio; Walker, Rosie May; Torrance, Helen Scott; Anderson, Susan Maguire; Fazio, Leonardo; Di Giorgio, Annabella; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Ursini, Gianluca; Caforio, Grazia; Blasi, Giuseppe; Millar, J Kirsty; Porteous, David John; Thomson, Pippa Ann; Bertolino, Alessandro; Evans, Kathryn Louise

    2014-01-01

    Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.

  14. Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.

    Directory of Open Access Journals (Sweden)

    Antonio Rampino

    Full Text Available Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1, a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.

  15. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia.

    Science.gov (United States)

    Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

    2009-02-01

    Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

  16. [Ultrastructural changes of myelinated fibers in the brain in continuous and attack-like paranoid schizophrenia].

    Science.gov (United States)

    Uranova, N A; Kolomeets, N S; Vikhreva, O V; Zimina, I S; Rakhmanova, V I; Orlovskaya, D D

    Previously the authors have reported the ultrastructural pathology of myelinated fibers (MF) in the brain in schizophrenia. The aim of the present study was to compare the effect of disease course on ultrastructural changes of MF. Postmortem electron microscopic morphometric study of MF was performed in the prefrontal cortex, caudate nucleus and hippocampus in 19 cases of paranoid schizophrenia. Fourteen cases of continuous schizophrenia, 5 cases of attack-like schizophrenia and 25 normal matched control cases were studied. The proportion (percentage) of pathological MF was estimated in the prefrontal cortex, layer 5, CA3 area of hippocampus, pyramidal layer, and in the head of the caudate nucleus. The percentage of MF having axonal atrophy and swelling of periaxonal oligodendrocyte process was significantly higher in both continuous and attack-like schizophrenia in all brain structures studied as compared to the control group. In the hippocampus and caudate nucleus, this parameter was increased significantly in attack-like schizophrenia as compared to continuous schizophrenia. In the prefrontal cortex. The percentage of the pathological MF having signs of deformation and destruction of myelin sheaths increased significantly only in continuous schizophrenia as compared to the control group. MF pathology is similar in attack-like and continuous paranoid schizophrenia but differ by the degree of severity of pathological MF. Abnormalities in MF contribute to the disconnectivity between the prefrontal cortex, caudate nucleus and hippocampus.

  17. Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Fumagalli, Fabio; Desbonnet, Lieve; Perez-Branguli, Francesc; Moloney, Gerard; Loftus, Samim; O'Leary, Claire; Petit, Emilie; Cox, Rachel; Tighe, Orna; Clarke, Gerard; Lai, Donna; Harvey, Richard P; Cryan, John F; Mitchell, Kevin J; Dinan, Timothy G; Riva, Marco A; Waddington, John L

    2017-01-01

    Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1.

    Science.gov (United States)

    O'Leary, C; Desbonnet, L; Clarke, N; Petit, E; Tighe, O; Lai, D; Harvey, R; Waddington, J L; O'Tuathaigh, C

    2014-09-26

    Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

    Science.gov (United States)

    Zhou, Dongsheng; Lv, Dan; Wang, Zhen; Zhang, Yanhua; Chen, Zhongming; Wang, Chuang

    2018-01-01

    Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13. PMID:29695955

  20. Duplications of the Neuropeptide Receptor VIPR2 Confer Significant Risk for Schizophrenia

    Science.gov (United States)

    Vacic, Vladimir; McCarthy, Shane; Malhotra, Dheeraj; Murray, Fiona; Chou, Hsun-Hua; Peoples, Aine; Makarov, Vladimir; Yoon, Seungtai; Bhandari, Abhishek; Corominas, Roser; Iakoucheva, Lilia M.; Krastoshevsky, Olga; Krause, Verena; Larach-Walters, Verónica; Welsh, David K.; Craig, David; Kelsoe, John R.; Gershon, Elliot S.; Leal, Suzanne M.; Aquila, Marie Dell; Morris, Derek W.; Gill, Michael; Corvin, Aiden; Insel, Paul A.; McClellan, Jon; King, Mary-Claire; Karayiorgou, Maria; Levy, Deborah L.; DeLisi, Lynn E.; Sebat, Jonathan

    2012-01-01

    Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other neuropsychiatric disorders1. Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at 1q21.1 2, 3q29 3, 15q13.3 2 and 22q11.2 4 and microduplication at 16p11.2 5. However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia (P= 4.0×10-5, OR = 16.14 [3.06, ∞]). Microduplications with variable breakpoints occurred within a 362 kb region and were detected in 29 of 8,290 (0.35%) patients versus two of 7,431 (0.03%) controls in the combined sample (p-value= 5.7×10-7, odds ratio (OR) = 14.1 [3.5, 123.9]). All duplications overlapped or were located within 89 kb upstream of the vasoactive intestinal peptide receptor VIPR2. VIPR2 transcription and cyclic-AMP signaling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered VIP signaling in the pathogenesis of schizophrenia and suggest VIPR2 as a potential target for the development of novel antipsychotic drugs. PMID:21346763

  1. Brief Report: Cases for an Association between Tourette Syndrome, Autistic Disorder, and Schizophrenia-Like Disorder.

    Science.gov (United States)

    Sverd, Jeffrey; And Others

    1993-01-01

    This paper reports on two children diagnosed as having co-occurring autistic disorder, schizophrenia-like psychosis, and Tourette syndrome, and two autistic adults who had tics and episodes of schizophrenia-like psychosis. (JDD)

  2. Cognitive and Neuroplasticity Mechanisms by Which Congenital or Early Blindness May Confer a Protective Effect Against Schizophrenia

    Science.gov (United States)

    Silverstein, Steven M.; Wang, Yushi; Keane, Brian P.

    2013-01-01

    Several authors have noted that there are no reported cases of people with schizophrenia who were born blind or who developed blindness shortly after birth, suggesting that congenital or early (C/E) blindness may serve as a protective factor against schizophrenia. By what mechanisms might this effect operate? Here, we hypothesize that C/E blindness offers protection by strengthening cognitive functions whose impairment characterizes schizophrenia, and by constraining cognitive processes that exhibit excessive flexibility in schizophrenia. After briefly summarizing evidence that schizophrenia is fundamentally a cognitive disorder, we review areas of perceptual and cognitive function that are both impaired in the illness and augmented in C/E blindness, as compared to healthy sighted individuals. We next discuss: (1) the role of neuroplasticity in driving these cognitive changes in C/E blindness; (2) evidence that C/E blindness does not confer protective effects against other mental disorders; and (3) evidence that other forms of C/E sensory loss (e.g., deafness) do not reduce the risk of schizophrenia. We conclude by discussing implications of these data for designing cognitive training interventions to reduce schizophrenia-related cognitive impairment, and perhaps to reduce the likelihood of the development of the disorder itself. PMID:23349646

  3. Cognitive and Neuroplasticity Mechanisms By Which Congenital or Early Blindness May Confer a Protective Effect Against Schizophrenia

    Directory of Open Access Journals (Sweden)

    Steven eSilverstein

    2013-01-01

    Full Text Available Several authors have noted that there are no reported cases of people with schizophrenia who were born blind or who developed blindness shortly after birth, suggesting that congenital or early (C/E blindness may serve as a protective factor against schizophrenia. By what mechanisms might this effect operate? Here, we hypothesize that C/E blindness offers protection by strengthening cognitive functions whose impairment characterizes schizophrenia, and by constraining cognitive processes that exhibit excessive flexibility in schizophrenia. After briefly summarizing evidence that schizophrenia is fundamentally a cognitive disorder, we review areas of perceptual and cognitive function that are both impaired in the illness and augmented in C/E blindness, as compared to healthy sighted individuals. We next discuss: 1 the role of neuroplasticity in driving these cognitive changes in C/E blindness; 2 evidence that C/E blindness does not confer protective effects against other mental disorders; and 3 evidence that other forms of C/E sensory loss (e.g., deafness do not reduce the risk of schizophrenia. We conclude by discussing implications of these data for designing cognitive training interventions to reduce schizophrenia-related cognitive impairment, and perhaps to reduce the likelihood of the development of the disorder itself.

  4. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

    LENUS (Irish Health Repository)

    Vacic, Vladimir

    2011-03-24

    Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

  5. Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia

    Science.gov (United States)

    Matsuo, Junko; Kamio, Yoko; Takahashi, Hidetoshi; Ota, Miho; Teraishi, Toshiya; Hori, Hiroaki; Nagashima, Anna; Takei, Reiko; Higuchi, Teruhiko; Motohashi, Nobutaka; Kunugi, Hiroshi

    2015-01-01

    Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of

  6. Autistic-like traits in adult patients with mood disorders and schizophrenia.

    Science.gov (United States)

    Matsuo, Junko; Kamio, Yoko; Takahashi, Hidetoshi; Ota, Miho; Teraishi, Toshiya; Hori, Hiroaki; Nagashima, Anna; Takei, Reiko; Higuchi, Teruhiko; Motohashi, Nobutaka; Kunugi, Hiroshi

    2015-01-01

    Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of

  7. Autistic-like traits in adult patients with mood disorders and schizophrenia.

    Directory of Open Access Journals (Sweden)

    Junko Matsuo

    Full Text Available Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD, bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65. Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the

  8. The neuropsychology and neurobiology of late-onset schizophrenia and very-late-onset schizophrenia-like psychosis : a critical review

    OpenAIRE

    Assche, Van, Lies; Morrens, Manuel; Luyten, Patrick; Ven, Van de, Luc; Vandenbulcke, Mathieu

    2017-01-01

    Abstract: OBJECTIVE: The current review discusses neuropsychological profiles and the longitudinal course of cognitive dysfunction in Late Onset Schizophrenia (LOS) and Very-late-onset schizophrenia-like psychosis (VLOSLP), and attempts to clarify its neurobiological underpinnings. METHOD: A systematic literature search resulted in 29 publications describing original research on the neuropsychology of LOS/VLOSLP and 46 studies focussing on neurobiology. RESULTS: Although mildly progressive co...

  9. Genetic Markers of Human Evolution Are Enriched in Schizophrenia

    DEFF Research Database (Denmark)

    Srinivasan, Saurabh; Bettella, Francesco; Mattingsdal, Morten

    2016-01-01

    BACKGROUND: Why schizophrenia has accompanied humans throughout our history despite its negative effect on fitness remains an evolutionary enigma. It is proposed that schizophrenia is a by-product of the complex evolution of the human brain and a compromise for humans' language, creative thinking...... and ancillary information on genetic variants. We used information from the evolutionary proxy measure called the Neanderthal selective sweep (NSS) score. RESULTS: Gene loci associated with schizophrenia are significantly (p = 7.30 × 10(-9)) more prevalent in genomic regions that are likely to have undergone...... phenotypes. The false discovery rate conditional on the evolutionary proxy points to 27 candidate schizophrenia susceptibility loci, 12 of which are associated with schizophrenia and other psychiatric disorders or linked to brain development. CONCLUSIONS: Our results suggest that there is a polygenic overlap...

  10. Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia.

    Science.gov (United States)

    Perez, Stephanie M; Lodge, Daniel J

    2012-11-01

    Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

  11. No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes.

    Science.gov (United States)

    Johnson, Emma C; Border, Richard; Melroy-Greif, Whitney E; de Leeuw, Christiaan A; Ehringer, Marissa A; Keller, Matthew C

    2017-11-15

    A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not. The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia. As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes. The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis.

    Science.gov (United States)

    Blokland, Gabriëlla A M; Mesholam-Gately, Raquelle I; Toulopoulou, Timothea; Del Re, Elisabetta C; Lam, Max; DeLisi, Lynn E; Donohoe, Gary; Walters, James T R; Seidman, Larry J; Petryshen, Tracey L

    2017-07-01

    Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population. © The Author 2016. Published by Oxford University Press on behalf of

  13. Evidence for phenotypic plasticity in response to photic cues and the connection with genes of risk in schizophrenia

    Directory of Open Access Journals (Sweden)

    Christine L. Miller

    2013-07-01

    Full Text Available Numerous environmental factors have been identified as influential in the development of schizophrenia. Some are byproducts of modern life, yet others were present in our evolutionary past and persist to a lesser degree in the current era. The present study brings together published epidemiological data for schizophrenia and data on variables related to photic input for places of residence across geographical regions, using rainfall as an inverse, proxy measure for light levels. Data were gathered from the literature for two countries, the former Yugoslavia and Ireland, during a time in the early 20th century when mobility was relatively limited. The data for Yugoslavia showed a strong correlation between hospital census rates for schizophrenia (by place of birth and annual rain (r = 0.96, p= 0.008. In Ireland, the hospital census rates and first admissions for schizophrenia (by place of permanent residence showed a trend for correlation with annual rain, reaching significance for 1st admissions when the rainfall data was weighted by the underlying population distribution (r= 0.71, p= 0.047. In addition, across the years 1921-1945, birth-year variations in a spring quarter season-of-birth effect for schizophrenia in Ireland showed a trend for correlation with January-March rainfall (r= 0.80, p≤0.10. The data are discussed in terms of the effect of photoperiod on the gestation and behavior of offspring in animals, and the premise is put forth that vestigial phenotypic plasticity for such photic cues still exists in humans. Moreover, genetic polymorphisms of risk identified for psychotic disorders include genes modulated by photoperiod and sunlight intensity. Such a relationship between phenotypic plasticity in response to a particular environmental regime and subsequent natural selection for fixed changes in the environmentally responsive genes, has been well studied in animals and should not be discounted when considering human disease.

  14. CNVs conferring risk of autism or schizophrenia affect cognition in controls

    DEFF Research Database (Denmark)

    Stefansson, Hreinn; Meyer-Lindenberg, Andreas; Steinberg, Stacy

    2014-01-01

    of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV...... to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion...

  15. HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals.

    Science.gov (United States)

    Večeřa, Josef; Bártová, Eva; Krejčí, Jana; Legartová, Soňa; Komůrková, Denisa; Rudá-Kučerová, Jana; Štark, Tibor; Dražanová, Eva; Kašpárek, Tomáš; Šulcová, Alexandra; Dekker, Frank J; Szymanski, Wiktor; Seiser, Christian; Weitzer, Georg; Mechoulam, Raphael; Micale, Vincenzo; Kozubek, Stanislav

    2018-01-01

    Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype. © 2017 Wiley Periodicals, Inc.

  16. Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis.

    LENUS (Irish Health Repository)

    Kelleher, I

    2011-01-01

    Recent research shows that psychotic symptoms, or psychotic-like experiences (PLEs), are reported not only by psychosis patients but also by healthy members of the general population. Healthy individuals who report these symptoms are considered to represent a non-clinical psychosis phenotype, and have been demonstrated to be at increased risk of schizophrenia-spectrum disorder. Converging research now shows that this non-clinical psychosis phenotype is familial, heritable and covaries with familial schizophrenia-spectrum disorder. A review of the research also shows that the non-clinical phenotype is associated extensively with schizophrenia-related risk factors, including social, environmental, substance use, obstetric, developmental, anatomical, motor, cognitive, linguistic, intellectual and psychopathological risk factors. The criterion and construct validity of the non-clinical psychosis phenotype with schizophrenia demonstrates that it is a valid population in which to study the aetiology of psychosis. Furthermore, it suggests shared genetic variation between the clinical and non-clinical phenotypes. Much remains to be learned about psychosis by broadening the scope of research to include the non-clinical psychosis phenotype.

  17. BDNF rs6265 methylation and genotype interact on risk for schizophrenia.

    Science.gov (United States)

    Ursini, Gianluca; Cavalleri, Tommaso; Fazio, Leonardo; Angrisano, Tiziana; Iacovelli, Luisa; Porcelli, Annamaria; Maddalena, Giancarlo; Punzi, Giovanna; Mancini, Marina; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Calabrese, Francesca; Rampino, Antonio; Taurisano, Paolo; Di Giorgio, Annabella; Keller, Simona; Tarantini, Letizia; Sinibaldi, Lorenzo; Quarto, Tiziana; Popolizio, Teresa; Caforio, Grazia; Blasi, Giuseppe; Riva, Marco A; De Blasi, Antonio; Chiariotti, Lorenzo; Bollati, Valentina; Bertolino, Alessandro

    2016-01-01

    Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

  18. Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

    Science.gov (United States)

    Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

    2016-01-01

    The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

  19. Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

    2016-01-01

    The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy

  20. The GSK3B gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population.

    Science.gov (United States)

    Chen, Jianhua; Wang, Meng; Waheed Khan, Raja Amjad; He, Kuanjun; Wang, Qingzhong; Li, Zhiqiang; Shen, Jiawei; Song, Zhijian; Li, Wenjin; Wen, Zujia; Jiang, Yiwen; Xu, Yifeng; Shi, Yongyong; Ji, Weidong

    2015-10-01

    Glycogen synthease kinase-3B is a key gene encoding a protein kinase which is abundant in brain, and is involved in signal transduction cascades of neuronal cell development and energy metabolism. Previous researches proposed GSK3B as a potential region for schizophrenia. To validate the susceptibility of GSK3B to major depressive disorder, and to investigate the overlapping risk conferred by GSK3B for mental disorders, we performed a large-scale case-control study, analyzed 6 tag single nucleotide polymorphisms using TaqMan® technology in 1,045 major depressive disorder patients, 1,235 schizophrenia patients and 1,235 normal controls of Han Chinese origin. We found rs334535 (Pallele=2.79E-03, Pgenotype=5.00E-03, OR=1.429) and rs2199503 (Pallele=0.020, Pgenotype= 0.040, OR=1.157) showed association with major depressive disorder before Bonferroni correction. rs6771023 (adjusted Pallele=1.64E-03, adjusted Pgenotype=6.00E-03, OR=0.701) and rs2199503 (adjusted Pallele=0.001, adjusted Pgenotype=0.002, OR=1.251) showed significant association with schizophrenia after Bonferroni correction. rs2199503 (adjusted Pallele=1.70E-03, adjusted Pgenotype=0.006, OR=1.208) remained to be significant in the combined cases of major depressive disorder and schizophrenia after Bonferroni correction. Further validations of our findings in samples with larger scale are suggested, and functional genomic study is needed to elucidate the role of GSK3B in signal pathway and psychiatric disorders. Our results provide evidence that the GSK3B gene could be a promising region which contains genetic risk for both major depressive disorder and schizophrenia in the Han Chinese population. The study on variants conferring overlapping risk for multiple psychiatric disorders could be tangible pathogenesis support and clinical or diagnostic references. Copyright © 2015. Published by Elsevier B.V.

  1. Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study.

    Science.gov (United States)

    Martin, Joanna; Tilling, Kate; Hubbard, Leon; Stergiakouli, Evie; Thapar, Anita; Davey Smith, George; O'Donovan, Michael C; Zammit, Stanley

    2016-06-15

    Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991-2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1-15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

  2. Schizophrenia and chromosomal deletions

    Energy Technology Data Exchange (ETDEWEB)

    Lindsay, E.A.; Baldini, A. [Baylor College of Medicine, Houston, TX (United States); Morris, M. A. [Univ. of Geneva School of Medicine, NY (United States)] [and others

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  3. One patient with Sjogren’s syndrome presenting schizophrenia-like symptoms

    Directory of Open Access Journals (Sweden)

    Lin CE

    2016-03-01

    Full Text Available Ching-En Lin1,2 1Department of Psychiatry, Taipei Tzu-Chi Hospital, Buddhist Medical Foundation, Taiwan, Republic of China; 2School of Medicine, Tzu-Chi University, Hualien, Taiwan, Republic of China Abstract: Comorbid depression in patients with Sjogren’s syndrome has been reported frequently, while comorbid psychosis in subjects with Sjogren’s syndrome has rarely been reported. Here we report a patient with Sjogren’s syndrome who presented with schizophrenia-like symptoms such as persecutory delusions and auditory hallucinations in contrast to her previous psychiatric presentations, which only included depression and anxiety. Keywords: mental illness, psychosis, Sjogren’s syndrome, schizophrenia

  4. THE 3rd SCHIZOPHRENIA INTERNATIONAL RESEARCH SOCIETY CONFERENCE, 14-18 APRIL 2012, FLORENCE, ITALY: SUMMARIES OF ORAL SESSIONS

    Science.gov (United States)

    Abbs, Brandon; Achalia, Rashmin M; Adelufosi, Adegoke O; Aktener, Ahmet Yiğit; Beveridge, Natalie J; Bhakta, Savita G; Blackman, Rachael K; Bora, Emre; Byun, MS; Cabanis, Maurice; Carrion, Ricardo; Castellani, Christina A; Chow, Tze Jen; Dmitrzak-Weglarz, M; Gayer-Anderson, Charlotte; Gomes, Felipe V; Haut, Kristen; Hori, Hiroaki; Kantrowitz, Joshua T; Kishimoto, Taishiro; Lee, Frankie HF; Lin, Ashleigh; Palaniyappan, Lena; Quan, Meina; Rubio, Maria D; Ruiz de Azúa, Sonia; Sahoo, Saddichha; Strauss, Gregory P; Szczepankiewicz, Aleksandra; Thompson, Andrew D; Trotta, Antonella; Tully, Laura M; Uchida, Hiroyuki; Velthorst, Eva; Young, Jared W; O’Shea, Anne; DeLisi, Lynn E.

    2013-01-01

    The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012.and this year had as its emphasis, “The Globalization of Research”. Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. PMID:22910407

  5. Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

    Science.gov (United States)

    Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

    2017-11-01

    Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Online Communication about Depression and Anxiety among Twitter Users with Schizophrenia: Preliminary Findings to Inform a Digital Phenotype Using Social Media.

    Science.gov (United States)

    Hswen, Yulin; Naslund, John A; Brownstein, John S; Hawkins, Jared B

    2018-01-12

    Digital technologies hold promise for supporting the detection and management of schizophrenia. This exploratory study aimed to generate an initial understanding of whether patterns of communication about depression and anxiety on popular social media among individuals with schizophrenia are consistent with offline representations of the illness. From January to July 2016, posts on Twitter were collected from a sample of Twitter users who self-identify as having a schizophrenia spectrum disorder (n = 203) and a randomly selected sample of control users (n = 173). Frequency and timing of communication about depression and anxiety were compared between groups. In total, the groups posted n = 1,544,122 tweets and users had similar characteristics. Twitter users with schizophrenia showed significantly greater odds of tweeting about depression compared with control users (OR = 2.69; 95% CI 1.76-4.10), and significantly greater odds of tweeting about anxiety compared with control users (OR = 1.81; 95% CI 1.20-2.73). This study offers preliminary insights that Twitter users with schizophrenia may express elevated symptoms of depression and anxiety in their online posts, which is consistent with clinical characteristics of schizophrenia observed in offline settings. Social media platforms could further our understanding of schizophrenia by informing a digital phenotype and may afford new opportunities to support early illness detection.

  7. Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype

    Directory of Open Access Journals (Sweden)

    Brian E Eisinger

    2014-04-01

    Full Text Available The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for postpartum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for postpartum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC, a region implicated in both maternal behavior and psychiatric disorders. Postpartum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET, we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets and bipolar disorder (BPD, 3 of 3 sets. In contrast to previous studies of maternal lateral septum and medial preoptic area, enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets. Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7, glutamate metabotropic receptor 3 (Grm3, platelet derived growth factor, beta polypeptide (Pdgfrb, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1. RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1 and proenkephalin (Penk. Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for postpartum psychosis with aspects of schizophrenia and BPD.

  8. Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat.

    Science.gov (United States)

    Bhardwaj, S K; Forcelli, P A; Palchik, G; Gale, K; Srivastava, L K; Kondratyev, A

    2012-06-01

    Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

    Science.gov (United States)

    Bustamante, M Leonor; Herrera, Luisa; Gaspar, Pablo A; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

    2017-10-01

    Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. © 2017 Wiley Periodicals, Inc.

  10. Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Kirby, Brian P; Waddington, John L

    2011-01-01

    Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.

  11. Nardostachys jatamansi Targets BDNF-TrkB to Alleviate Ketamine-Induced Schizophrenia-Like Symptoms in Rats.

    Science.gov (United States)

    Janardhanan, Anjali; Sadanand, Anjana; Vanisree, Arambakkam Janardhanam

    2016-01-01

    Schizophrenia, a common neurological disorder appearing in the late teens or early adulthood, is characterized by disorganized thinking, behaviour, and perception of emotions. Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated synaptic plasticity is a major pathological event here due to dysfunction of dopamine and glutamate transmission at NMDA receptors. De-regulated brain-derived neurotrophic factor (BDNF), i.e., its signalling through the tropomyosin receptor kinase B (TrkB) receptor, is a major feature of schizophrenia. With recent global awareness of traditional plant medicines in reducing side effects, the aim of our study was to evaluate the efficacy of the ethanolic root extract of a herb belonging to the Valerianacea family, Nardostachys jatamansi, against ketamine-induced schizophrenia-like model in rats. The effect of the N. jatamansi drug (oral dosage of 500 mg/kg body weight for 14 days) in ketamine-administered male Wistar albino rats (30 mg/kg body weight for 5 days) on modulating behaviour and the level of neurotransmitters like dopamine and glutamate was studied in whole-brain homogenates, and its influence on BDNF and TrkB levels in 2 relevant brain regions, the hippocampus and prefrontal cortex, was assessed. We observed that N. jatamansi treatment exhibited encouraging results in the modulation of ketamine-induced schizophrenia-like behaviours, principally the positive symptoms. Our drug both significantly upregulated the glutamate level and downregulated the dopamine level in whole-brain homogenates and retained the normal levels of BDNF (in the hippocampus but not in the prefrontal cortex) and TrkB (in both hippocampus and prefrontal cortex) induced by ketamine in rats. These findings suggest a neuroprotective effect of the ethanolic root extract of N. jatamansi against ketamine-induced schizophrenia-like symptoms in rats; possibly, regarding its effect on TrkB signalling. Further research is warranted in the treatment of schizophrenic

  12. Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

    Science.gov (United States)

    Schulze-Rauschenbach, Svenja; Lennertz, Leonhard; Ruhrmann, Stephan; Petrovsky, Nadine; Ettinger, Ulrich; Pukrop, Ralf; Dreher, Jan; Klosterkötter, Joachim; Maier, Wolfgang; Wagner, Michael

    2015-12-30

    Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Schizophrenia: breaking down the barriers.

    Science.gov (United States)

    Haghighat, R

    1997-01-01

    This paper reviews the key issues presented during the Fourth International Conference on Schizophrenia, which was held in October 1996 in Vancouver, Canada. The main emphasis was placed on the problem of stigma, loneliness and work as well as on the necessity to further elucidate the physiopathology of schizophrenia. Some of the barriers discussed are unlikely to disappear from human societies in the short term with any possible cure for schizophrenia as they are part of any major long-term illness, of which there is a long and ever increasing list.

  14. Disordered Self in the Schizophrenia Spectrum

    DEFF Research Database (Denmark)

    Parnas, Josef; Henriksen, Mads Gram

    2014-01-01

    This article explores the phenomenological and empirical rediscovery of anomalous self-experience as a core feature of the schizophrenia spectrum disorders and presents the current status of research in this field. Historically, a disordered self was considered to be a constitutive phenotype...... of schizophrenia. Although the notion of a disordered self has continued to appear occasionally over the years-mainly in the phenomenologically or psychodynamically oriented literature-this notion was usually considered as a theoretical construct rather than as referring to concretely lived anomalous experiences....... Empirical research on the disorders of self-experience in schizophrenia can be traced back to the US-Denmark psychopathological collaboration in the well-known adoption and high-risk studies, which aimed at identifying trait or phenotypic vulnerability features. This research was later followed by clinical...

  15. Animal model for schizophrenia that reflects gene-environment interactions.

    Science.gov (United States)

    Nagai, Taku; Ibi, Daisuke; Yamada, Kiyofumi

    2011-01-01

    Schizophrenia is a devastating psychiatric disorder that impairs mental and social functioning and affects approximately 1% of the population worldwide. Genetic susceptibility factors for schizophrenia have recently been reported, some of which are known to play a role in neurodevelopment; these include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Moreover, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors, especially during neurodevelopment, is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidilic acid (polyI : C) is a synthetic analogue of double-stranded RNA that leads to the pronounced but time-limited production of pro-inflammatory cytokines. Maternal immune activation by polyI : C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. Recently, we have reported that neonatal injection of polyI : C in mice results in schizophrenia-like behavioral alterations in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI : C-treated DN-DISC1 mice are a well-validated animal model for schizophrenia that reflects gene-environment interactions.

  16. Self‐Disorders as schizophrenia spectrum vulnerability phenotypes

    DEFF Research Database (Denmark)

    Raballo, Andrea

    2011-01-01

    Schizophrenia spectrum disorders are characterised by manifold psychopathological expressions, which might include major symptoms (such as delusions, hallucinations or social withdrawal), psychobehavioural enduring personality patterns (e.g. schizoid/schizotypal traits), or more subtle, quasi...

  17. Functional Implications of the IL-23/IL-17 Immune Axis in Schizophrenia.

    Science.gov (United States)

    Debnath, Monojit; Berk, Michael

    2017-12-01

    The aetiology of schizophrenia seems to stem from complex interactions amongst environmental, genetic, metabolic, immunologic and oxidative components. Chronic low-grade inflammation has been persistently linked to schizophrenia, and this has primarily been based on the findings derived from Th1/Th2 cytokine balance. While the IL-23/IL-17 axis plays crucial role in the pathogenesis of several immune-mediated disorders, it has remained relatively unexplored in neuropsychiatric disorders. Altered levels of cytokines related to IL-23/IL-17 axis have been observed in schizophrenia patients in a few studies. In addition, other indirect factors known to confer schizophrenia risk like complement activation and altered gut microbiota are shown to modulate the IL-23/IL-17 axis. These preliminary observations provide crucial clues about the functional implications of IL-23/IL-17 axis in schizophrenia. In this review, an attempt has been made to highlight the biology of IL-23/IL-17 axis and its relevance to schizophrenia risk and pathogenesis. Given the pathogenic potential of the IL-23/IL-17 axis, therapeutic targeting of this axis may be a promising approach to benefit patients suffering from this devastating disorder.

  18. Moving Ahead with the Schizophrenia Concept: From the Elephant to the Mouse

    Science.gov (United States)

    Keshavan, Matcheri S; Nasrallah, Henry A; Tandon, Rajiv

    2012-01-01

    The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our “facts” series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to “connect the dots” (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a “fuzzy cluster” of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families

  19. Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

    Science.gov (United States)

    Leonenko, Ganna; Richards, Alexander L; Walters, James T; Pocklington, Andrew; Chambert, Kimberly; Al Eissa, Mariam M; Sharp, Sally I; O'Brien, Niamh L; Curtis, David; Bass, Nicholas J; McQuillin, Andrew; Hultman, Christina; Moran, Jennifer L; McCarroll, Steven A; Sklar, Pamela; Neale, Benjamin M; Holmans, Peter A; Owen, Michael J; Sullivan, Patrick F; O'Donovan, Michael C

    2017-10-01

    Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies. © 2017 Wiley Periodicals, Inc.

  20. Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker

    OpenAIRE

    Brewer, Warrick J; Lin, Ashleigh; Moberg, Paul J; Smutzer, Gregory; Nelson, Barnaby; Yung, Alison R; Pantelis, Christos; McGorry, Patrick D; Turetsky, Bruce I; Wood, Stephen J.

    2012-01-01

    Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis pa...

  1. Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.

    Directory of Open Access Journals (Sweden)

    Jun Li

    Full Text Available Autism spectrum disorder (ASD is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders (for example, schizophrenia. Previous studies detected that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit and schizophrenia was detected. Furthermore, rare mutation in CACNA1C is suggested to cause Timothy syndrome, a multisystem disorder including autism-associated phenotype. However, there is no evidence for association between CACNA1C and autism in Chinese Han population. To investigate the association between single nucleotide polymorphisms (SNP in CACNA1C and autism, we first performed a family-based association study between eighteen SNPs in CACNA1C and autism in 239 trios. All SNPs were genotyped by using Sequenom genotyping platform. Two SNPs (rs1006737 and rs4765905 have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. Association analyses for SNPs and haplotype were performed by using family-based association test (FBAT and Haploview software. Permutation tests were used for multiple testing corrections of the haplotype analyses (n=10,000. The significance level for all statistical tests was two-tailed (p<0.05. The results demonstrated that G allele of rs1006737 and G allele of rs4765905 showed a preferential transmission to affected offspring in 553 trios (p=0.035. Haplotype analyses showed that two haplotypes constructed from rs1006737 and rs4765905 were significantly associated with autism (p=0.030, 0.023, respectively; Global p=0.046. These results were still significant after permutation correction (n=10,000, p=0.027. Our research suggests

  2. A Closer Look at Siblings of Patients with Schizophrenia: The Association of Depression History and Sex with Cognitive Phenotypes

    Science.gov (United States)

    Wisner, Krista M.; Elvevåg, Brita; Gold, James M.; Weinberger, Daniel R.; Dickinson, Dwight

    2010-01-01

    Background Siblings of patients with schizophrenia show impaired cognition and an increased prevalence of depression history. Although sex has been shown to moderate cognition in patients, this effect has not been examined in siblings. Here we elucidate how a history of depression and sex influences cognition in siblings unaffected by schizophrenia. Methods Unaffected siblings of patients with schizophrenia and unrelated healthy controls were evaluated neuropsychologically and completed structured clinical interviews. Participants with a depression history or no psychiatric history were selected for the sample. Cognitive performance of siblings (n = 366) and controls (n = 680) was first examined. Second, cognition of participants with a depression history and those without a psychiatric history was compared while additionally investigating the role of schizophrenia risk and sex. Results Relative to controls, siblings, with and without a psychiatric history, demonstrated significant (p siblings, but not in controls; whereas sex affected cognition in both siblings and controls. In siblings alone, sex significantly interacted with depression history to influence cognition. This interaction revealed that in male - but not female - siblings a history of depression was associated with greater cognitive impairments. Conclusion A history of depression impairs cognition in siblings, but not in controls. Moreover, depression history interacts with sex and demonstrates that only cognition in male siblings is significantly and additionally compromised by a history of depression. This interaction may be an important consideration for future phenotype and genetic association studies. PMID:21030214

  3. Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age.

    Science.gov (United States)

    Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

    2018-03-01

    A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology. We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, 42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables. This hypo-androgenic PCOS-like phenotype already exists in age stratum androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated). Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

  4. Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities.

    Science.gov (United States)

    Rocha, C F; Paiva, C L A

    2014-03-31

    Prader-Willi syndrome (PWS) is caused by the lack of expression of genes located on paternal chromosome 15q11-q13. This lack of gene expression may be due to a deletion in this chromosomal segment, to maternal uniparental disomy of chromosome 15, or to a defect in the imprinting center on 15q11-q13. PWS is characterized by hypotonia during the neonatal stage and in childhood, accompanied by a delay in neuropsychomotor development. Overeating, obesity, and mental deficiency arise later on. The syndrome has a clinical overlap with other diseases, which makes it difficult to accurately diagnose. The purpose of this article is to review the Prader-Willi-like phenotype in the scientific literature from 2000 to 2013, i.e., to review the cases of PWS caused by chromosomal abnormalities different from those found on chromosome 15. A search was carried out using the "National Center for Biotechnology Information" (www.pubmed.com) and "Scientific Electronic Library Online (www.scielo.br) databases and combinations of key words such as "Prader-Willi-like phenotype" and "Prader-Willi syndrome phenotype". Editorials, letters, reviews, and guidelines were excluded. Articles chosen contained descriptions of patients diagnosed with the PWS phenotype but who were negative for alterations on 15q11-q13. Our search found 643 articles about PWS, but only 14 of these matched with the Prader-Willi-like phenotype and with the selected years of publication (2000-2013). If two or more articles reported the same chromosomal alterations for Prader-Willi-like phenotype, the most recent was chosen. Twelve articles of 14 were case reports and 2 reported series of cases.

  5. Conferences are like swans

    OpenAIRE

    Corker, Chris

    2012-01-01

    Chris Corker was the lead on bringing the 2011 Higher Education Research Scholarship Group Conference to fruition, both in the months preceding the event and on the day. In this viewpoint, Chris shares his experiences of conference administration and delivery, and explores how conferences and swans have more in common that you would imagine.

  6. DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms.

    Science.gov (United States)

    Wang, L; Jiang, W; Lin, Q; Zhang, Y; Zhao, C

    2016-11-01

    Single nucleotide polymorphisms (SNPs) in the human type A gamma-aminobutyric acid (GABA) receptor β 2 subunit gene (GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine (MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET-induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the gabrb2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in gabrb2 promoter methylation in zebrafish. A significant increase in gabrb2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the gabrb2 promoter. Furthermore, the significant correlation between gabrb2 mRNA expression and gabrb2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that gabrb2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABA A receptor β 2 subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  7. Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia.

    Directory of Open Access Journals (Sweden)

    Baohu Ji

    Full Text Available It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67 in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.

  8. Modern representations about differential diagnosis of schizophrenia-like psychosis disorders due to psychoactive substance use

    Directory of Open Access Journals (Sweden)

    V. V. Chugunov

    2014-08-01

    Full Text Available In recent years in the world there is a tendency of quantity of persons who use drugs increase. Free availability of drugs of different groups for population is the main cause. Another trend associated with the consumption of drugs. All these factors led to the increased frequency of psychosis occurrence among consumers of psychoactive substances. In structure of such psychosis there are a variety of symptoms and syndromes. And since the number of drug users is quite broad in its structure - there are also persons with mental illness. This gives number of diagnostic difficulties. In this regard, the aim of the study was to trace the modern ideas of differential diagnosis of schizophrenia-like psychosis disorders due to the drug use. Materials and methods of research. In this work the content analysis of the modern representations of differential diagnosis of schizophrenia-like psychosis disorders as a result of the use of psychoactive substances was made. The problem of determination of primary and secondary nature of drug addiction in patients with psychotic disorders was indicated. Etiology and psychopathogenesis hypotheses of the addiction from psychoactive substances in the context of their correlation with endogenous mental pathology were defined. In the literature there is no clear diagnostic criteria that would allow distinguishing psychosis due to the use of drugs and endogenous psychosis, which is combined with the admission medicines. However, the attention of clinicians should be concentrated on the premorbid condition: the presence of hereditary family history, pathological behavior in childhood and adolescence. It was found that the majority of substances may cause one or more syndromes - delirium, dementia, and amnestic syndrome, delusional syndrome, hallucinatory syndrome, depressive syndrome, anxiety, and personality disorder, such disorders as schizophrenia-like psychosis disorders are not rare. Special attention was paid to the

  9. A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype.

    Directory of Open Access Journals (Sweden)

    Johanna Hass

    Full Text Available Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328. A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170 on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10 had p-values between 6.75×10(-6 and 8.3×10(-7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings

  10. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

    NARCIS (Netherlands)

    Franke, Barbara; Stein, Jason L.; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P.; van Hulzen, Kimm J. E.; Arias-Vasquez, Alejandro; Smoller, Jordan W.; Nichols, Thomas E.; Neale, Michael C.; McIntosh, Andrew M.; Lee, Phil; McMahon, Francis J.; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A.; Gruber, Oliver; Sachdev, Perminder S.; Roiz-Santiañez, Roberto; Saykin, Andrew J.; Ehrlich, Stefan; Mather, Karen A.; Turner, Jessica A.; Schwarz, Emanuel; Thalamuthu, Anbupalam; Yao, Yin; Ho, Yvonne Y. W.; Martin, Nicholas G.; Wright, Margaret J.; O'Donovan, Michael C.; Thompson, Paul M.; Neale, Benjamin M.; Medland, Sarah E.; Sullivan, Patrick F.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William F.; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chen, Eric Y. H.; Chen, Ronald Y. L.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; del Favero, Jurgen; DeLisi, Lynn E.; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan L.; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kähler, Anna K.; Kahn, René S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Laurent, Claudine; Lee, S. Hong; Keong, Jimmy Lee Chee; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Lönnqvist, Jouko; Loughland, Carmel M.; Lubinski, Jan; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Müller-Myhsok, Bertram; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; So, Hon-Cheong; Söderman, Erik; Spencer, Chris C. A.; Stahl, Eli A.; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Thirumalai, Srinivas; Toncheva, Draga; Tooney, Paul A.; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Wu, Jing Qin; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Visscher, Peter M.; Adolfsson, Rolf; Blackwood, Douglas H. R.; Børglum, Anders D.; Bramon, Elvira; Buxbaum, Joseph D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Nöthen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; Clair, David St; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Renteria, Miguel E.; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn; Heister, Angelien J. G. A. M.; Höhn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, David R.; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nilsson, Lars G.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Toga, Arthur W.; Traynor, Bryan; Troncoso, Juan; Hernández, Maria C. Valdés; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; Williams, Robert W.; Brunner, Han G.; Buitelaar, Jan K.; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; LeHellard, Stephanie; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Sisodiya, Sanjay M.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Luting, Xue; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Schumann, Gunter

    2016-01-01

    Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use

  11. Neuroimaging characteristics of very-late-onset schizophrenia-like psychosis

    International Nuclear Information System (INIS)

    Okuyama, Yu; Suzuki, Mitsuru; Okudera, Toshio; Matoh, Koichi

    2006-01-01

    The pathogenesis of delusion and hallucination among the elderly remains unclear. Biological markers have become required for proper diagnosis of the mental state. We aimed to identify the area and severity of both white and gray matter changes of very-late-onset schizophrenia-like psychosis (VLOSLP) by means of magnetic resonance images. Twenty-one non-demented patients who were International Statistical Classification of Disease (ICD)-10 diagnosed as schizophrenia or delusional disorder with onset after the age of 60, and those of 21 age- and gender-matched psychiatrically healthy controls were compared. Although both periventricular hyperintensites and deep and subcortical white matter hyperintensities were found both in the VLOSLP subjects and in the controls, significant difference of the white matter changes were not detected between them, except for more prominent lacuna infarctions and perivascular space at mainly bilateral frontal areas in the subjects. Regarding cortical lesions, the subjects had a significantly greater degree of bilateral frontal and temporal cortical atrophies than the controls. These structural changes suggest neuronal and vascular pathogenesis of VLOSLP. Front-temporal cortical atrophy and age-related white matter changes may be a predictive finding of VLOSLP; however, prospective and long-term follow-up neuroimaging studies are essential to integrate etiological diagnostics of VLOSLP. (author)

  12. Traditional knowledge and formulations of medicinal plants used by the traditional medical practitioners of bangladesh to treat schizophrenia like psychosis.

    Science.gov (United States)

    Ahmed, Md Nasir; Kabidul Azam, Md Nur

    2014-01-01

    Schizophrenia is a subtle disorder of brain development and plasticity; it affects the most basic human processes of perception, emotion, and judgment. In Bangladesh the traditional medical practitioners of rural and remote areas characterized the schizophrenia as an insanity or a mental problem due to possession by ghosts or evil spirits and they have used various plant species' to treat such symptoms. The aim of the present study was to conduct an ethnomedicinal plant survey and documentation of the formulations of different plant parts used by the traditional medical practitioners of Rangamati district of Bangladesh for the treatment of schizophrenia like psychosis. It was observed that the traditional medical practitioners used a total of 15 plant species to make 14 formulations. The plants were divided into 13 families, used for treatment of schizophrenia and accompanying symptoms like hallucination, depression, oversleeping or insomnia, deterioration of personal hygiene, forgetfulness, and fear due to evil spirits like genies or ghost. A search of the relevant scientific literatures showed that a number of plants used by the medicinal practitioners have been scientifically validated in their uses and traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Moreover, the antipsychotic drug reserpine, isolated from the dried root of Rauvolfia serpentina species, revolutionized the treatment of schizophrenia. So it is very much possible that formulations of the practitioner, when examined scientifically in their entireties, can form discovery of lead compounds which can be used as safe and effective antipsychotic drug to treat schizophrenia.

  13. Traditional Knowledge and Formulations of Medicinal Plants Used by the Traditional Medical Practitioners of Bangladesh to Treat Schizophrenia Like Psychosis

    Directory of Open Access Journals (Sweden)

    Md. Nasir Ahmed

    2014-01-01

    Full Text Available Schizophrenia is a subtle disorder of brain development and plasticity; it affects the most basic human processes of perception, emotion, and judgment. In Bangladesh the traditional medical practitioners of rural and remote areas characterized the schizophrenia as an insanity or a mental problem due to possession by ghosts or evil spirits and they have used various plant species’ to treat such symptoms. The aim of the present study was to conduct an ethnomedicinal plant survey and documentation of the formulations of different plant parts used by the traditional medical practitioners of Rangamati district of Bangladesh for the treatment of schizophrenia like psychosis. It was observed that the traditional medical practitioners used a total of 15 plant species to make 14 formulations. The plants were divided into 13 families, used for treatment of schizophrenia and accompanying symptoms like hallucination, depression, oversleeping or insomnia, deterioration of personal hygiene, forgetfulness, and fear due to evil spirits like genies or ghost. A search of the relevant scientific literatures showed that a number of plants used by the medicinal practitioners have been scientifically validated in their uses and traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Moreover, the antipsychotic drug reserpine, isolated from the dried root of Rauvolfia serpentina species, revolutionized the treatment of schizophrenia. So it is very much possible that formulations of the practitioner, when examined scientifically in their entireties, can form discovery of lead compounds which can be used as safe and effective antipsychotic drug to treat schizophrenia.

  14. Evidence that hippocampal-parahippocampal dysfunction is related to genetic risk for schizophrenia.

    Science.gov (United States)

    Di Giorgio, A; Gelao, B; Caforio, G; Romano, R; Andriola, I; D'Ambrosio, E; Papazacharias, A; Elifani, F; Bianco, L Lo; Taurisano, P; Fazio, L; Popolizio, T; Blasi, G; Bertolino, A

    2013-08-01

    Abnormalities in hippocampal-parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state. We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects. Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects. Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype.

  15. Large recurrent microdeletions associated with schizophrenia

    DEFF Research Database (Denmark)

    Stefansson, H.; Rujescu, D.; Cichon, S.

    2008-01-01

    Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account...... and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33......,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses...

  16. Music therapy for people with schizophrenia and schizophrenia-like disorders.

    Science.gov (United States)

    Geretsegger, Monika; Mössler, Karin A; Bieleninik, Łucja; Chen, Xi-Jing; Heldal, Tor Olav; Gold, Christian

    2017-05-29

    data were available for other outcomes. Medium-term continuous data identified good effects for music therapy on negative symptoms using the Scale for the Assessment of Negative Symptoms (3 RCTs, n = 177, SMD - 0.55 95% CI -0.87 to -0.24, low-quality evidence). General mental state endpoint scores on the Positive and Negative Symptoms Scale were better for music therapy (2 RCTs, n = 159, SMD -0.97 95% CI -1.31 to -0.63, low-quality evidence), as were average endpoint scores on the Brief Psychiatric Rating Scale (1 RCT, n = 70, SMD -1.25 95% CI -1.77 to -0.73, moderate-quality evidence). Medium-term average endpoint scores using the Global Assessment of Functioning showed no effect for music therapy on general functioning (2 RCTs, n = 118, SMD -0.19 CI -0.56 to 0.18, moderate-quality evidence). However, positive effects for music therapy were found for both social functioning (Social Disability Screening Schedule scores; 2 RCTs, n = 160, SMD -0.72 95% CI -1.04 to -0.40), and quality of life (General Well-Being Schedule scores: 1 RCT, n = 72, SMD 1.82 95% CI 1.27 to 2.38, moderate-quality evidence). There were no data available for adverse effects, service use, engagement with services, or cost. Moderate- to low-quality evidence suggests that music therapy as an addition to standard care improves the global state, mental state (including negative and general symptoms), social functioning, and quality of life of people with schizophrenia or schizophrenia-like disorders. However, effects were inconsistent across studies and depended on the number of music therapy sessions as well as the quality of the music therapy provided. Further research should especially address the long-term effects of music therapy, dose-response relationships, as well as the relevance of outcome measures in relation to music therapy.

  17. Clinical Manifestations of Self-disorders in Schizophrenia Spectrum Conditions

    Directory of Open Access Journals (Sweden)

    Henriksen Mads Gram

    2017-09-01

    Full Text Available This article explores the phenomenologically informed, theoretical and empirical research direction on self-disorders in the schizophrenia spectrum conditions. First, we describe the concept of ‘self’ that is operative in the concept of ‘self-disorders’ and we discuss how this self may be disordered or fragile in the schizophrenia spectrum. Second, we offer a detailed psychopathological presentation and discussion of 3 patients with schizophrenia. The vignettes provide paradigmatic examples of self-disorders in schizophrenia. Third, we summarize the main findings in the current empirical research on self-disorders. These findings consistently indicate that self-disorders constitute a crucial, trait phenotype of the schizophrenia spectrum.

  18. Identifying Gene-Environment Interactions in Schizophrenia

    DEFF Research Database (Denmark)

    van Os, Jim; Rutten, Bart P; Myin-Germeys, Inez

    2014-01-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual...... of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap...

  19. Crack cocaine inhalation induces schizophrenia-like symptoms and molecular alterations in mice prefrontal cortex.

    Science.gov (United States)

    Areal, Lorena Bianchine; Herlinger, Alice Laschuk; Pelição, Fabrício Souza; Martins-Silva, Cristina; Pires, Rita Gomes Wanderley

    2017-08-01

    Crack cocaine (crack) addiction represents a major social and health burden, especially seeing as users are more prone to engage in criminal and violent acts. Crack users show a higher prevalence of psychiatric comorbidities - particularly antisocial personality disorders - when compared to powder cocaine users. They also develop cognitive deficits related mainly to executive functions, including working memory. It is noteworthy that stimulant drugs can induce psychotic states, which appear to mimic some symptoms of schizophrenia among users. Social withdraw and executive function deficits are, respectively, negative and cognitive symptoms of schizophrenia mediated by reduced dopamine (DA) tone in the prefrontal cortex (PFC) of patients. That could be explained by an increased expression of D2R short isoform (D2S) in the PFC of such patients and/or by hypofunctioning NMDA receptors in this region. Reduced DA tone has already been described in the PFC of mice exposed to crack smoke. Therefore, it is possible that behavioral alterations presented by crack users result from molecular and biochemical neuronal alterations akin to schizophrenia. Accordingly, we found that upon crack inhalation mice have shown decreased social interaction and working memory deficits analogous to schizophrenia's symptoms, along with increased D2S/D2L expression ratio and decreased expression of NR1, NR2A and NR2B NMDA receptor subunits in the PFC. Herein we propose two possible mechanisms to explain the reduced DA tone in the PFC elicited by crack consumption in mice, bringing also the first direct evidence that crack use may result in schizophrenia-like neurochemical, molecular and behavioral alterations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Jinsong Tang; Fan He; Fengyu Zhang; Yin Yao Shugart; Chunyu Liu; Yanqing Tang; Raymond C.K.Chan; Chuan-Yue Wang; Yong-Gang Yao; Xiaogang Chen; Yu Fan; Hong Li; Qun Xiang; Deng-Feng Zhang; Zongchang Li; Ying He; Yanhui Liao; Ya Wang

    2017-01-01

    Schizophrenia is a common disorder with a high heritability,but its genetic architecture is still elusive.We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia.Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins,which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN,p.S2506T mutation in GCN1L1,IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis.By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes,we were able to distill genetic alterations in several schizophrenia risk genes,including GAD1,PLXNA2,RELN and FEZ1.Four inherited copy number variations (CNVs;including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families,respectively.Most of families carried both missense DNMs and inherited risk variants,which might suggest that DNMs,inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility.Our results support that schizophrenia is caused by a combination of multiple genetic factors,with each DNM/variant showing a relatively small effect size.

  1. Glucocorticoids promote a glioma stem cell-like phenotype and resistance to chemotherapy in human glioblastoma primary cells

    DEFF Research Database (Denmark)

    Kostopoulou, Ourania N; Mohammad, Abdul-Aleem; Bartek, Jiri

    2018-01-01

    Glioma stem cells (GSCs) are glioblastoma (GBM) cells that are resistant to therapy and can give rise to recurrent tumors. The identification of patient-related factors that support GSCs is thus necessary to design effective therapies for GBM patients. Glucocorticoids (GCs) are used to treat GBM......-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, which has been linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and GSCs. Here, we treated primary human GBM cells with dexamethasone and evaluated GC......-driven changes in cell morphology, proliferation, migration, gene expression, secretory activity and growth as neurospheres. Dexamethasone treatment of GBM cells appeared to promote the development of a GSC-like phenotype and conferred resistance to physiological stress and chemotherapy. We also analyzed...

  2. The TRIPS (Toll-like receptors in immuno-inflammatory pathogenesis) Hypothesis: a novel postulate to understand schizophrenia.

    Science.gov (United States)

    Venkatasubramanian, Ganesan; Debnath, Monojit

    2013-07-01

    Mounting evidence indicates that immune activation and/or immuno-inflammatory reactions during neurodevelopment apparently contribute to the pathogenesis and progression of schizophrenia. One of the important environmental factors that is known to trigger immune activation/inflammatory responses during early pregnancy is prenatal infection. Recent understanding from animal studies suggests that prenatal infection induced maternal immune activation (MIA)/inflammation in congruence with oxidative/nitrosative stress can lead to neurodevelopmental damage and behavioral abnormalities in the offspring. Although the underlying precise mechanistic processes of MIA/inflammation are yet to be completely elucidated, it is being increasingly recognized that Toll-like receptors (TLRs) that form the first line of defense against invading microorganisms could participate in the prenatal infection induced immune insults. Interestingly, some of the TLRs, especially TLR3 and TLR4 that modulate neurodevelopment, neuronal survival and neuronal plasticity by regulating the neuro-immune cross-talk in the developing and adult brain could also be affected by prenatal infection. Importantly, sustained activation of TLR3/TLR4 due to environmental factors including infection and stress has been found to generate excessive reactive oxygen species (ROS)/reactive nitrogen species (RNS) as well as pro-inflammatory mediators during embryogenesis, which result into neuronal damage by necrosis/apoptosis. In recent times, ROS/RNS and immuno-inflammatory mediators are being increasingly linked to progressive brain changes in schizophrenia. Although a significant role of TLR3/TLR4 in neurodegeneration is gaining certainty, their importance in establishing a causal link between prenatal infection and immuno-inflammatory, oxidative and nitrosative stress (IO&NS) responses and influence on adult presentation of schizophrenia is yet to be ascertained. We review here the current knowledge generated from

  3. The neuropsychology and neurobiology of late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: A critical review.

    Science.gov (United States)

    Van Assche, Lies; Morrens, Manuel; Luyten, Patrick; Van de Ven, Luc; Vandenbulcke, Mathieu

    2017-12-01

    The current review discusses neuropsychological profiles and the longitudinal course of cognitive dysfunction in Late Onset Schizophrenia (LOS) and Very-late-onset schizophrenia-like psychosis (VLOSLP), and attempts to clarify its neurobiological underpinnings. A systematic literature search resulted in 29 publications describing original research on the neuropsychology of LOS/VLOSLP and 46 studies focussing on neurobiology. Although mildly progressive cognitive impairment is usually present, only a subgroup of LOS/VLOSLP develops dementia during a 10-year follow-up succeeding the onset of psychosis. This coincides with the absence of neuropathological evidence for neurodegeneration in many cases. Cognitive deterioration is characterized by deficits in (working) memory, language, psychomotor speed and executive functioning. Underlying neurobiological changes encompass white matter pathology, increased ventricle-to-brain ratio (VBR) with coinciding atrophy and hypo-metabolism of frontal, temporal and subcortical areas. Multiple changes in neurobiology and cognition contributing to LOS/VLOSLP may reflect stress-related accelerated brain aging rather than neurodegenerative pathology. Their involvement in the onset of illness, however, might be inversely proportional to pre-existing (psychosocial and/or genetic) vulnerability to psychosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Deconstructing Bipolar Disorder and Schizophrenia: A cross-diagnostic cluster analysis of cognitive phenotypes.

    Science.gov (United States)

    Lee, Junghee; Rizzo, Shemra; Altshuler, Lori; Glahn, David C; Miklowitz, David J; Sugar, Catherine A; Wynn, Jonathan K; Green, Michael F

    2017-02-01

    Bipolar disorder (BD) and schizophrenia (SZ) show substantial overlap. It has been suggested that a subgroup of patients might contribute to these overlapping features. This study employed a cross-diagnostic cluster analysis to identify subgroups of individuals with shared cognitive phenotypes. 143 participants (68 BD patients, 39 SZ patients and 36 healthy controls) completed a battery of EEG and performance assessments on perception, nonsocial cognition and social cognition. A K-means cluster analysis was conducted with all participants across diagnostic groups. Clinical symptoms, functional capacity, and functional outcome were assessed in patients. A two-cluster solution across 3 groups was the most stable. One cluster including 44 BD patients, 31 controls and 5 SZ patients showed better cognition (High cluster) than the other cluster with 24 BD patients, 35 SZ patients and 5 controls (Low cluster). BD patients in the High cluster performed better than BD patients in the Low cluster across cognitive domains. Within each cluster, participants with different clinical diagnoses showed different profiles across cognitive domains. All patients are in the chronic phase and out of mood episode at the time of assessment and most of the assessment were behavioral measures. This study identified two clusters with shared cognitive phenotype profiles that were not proxies for clinical diagnoses. The finding of better social cognitive performance of BD patients than SZ patients in the Lowe cluster suggest that relatively preserved social cognition may be important to identify disease process distinct to each disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia.

    Science.gov (United States)

    Tang, Jinsong; Fan, Yu; Li, Hong; Xiang, Qun; Zhang, Deng-Feng; Li, Zongchang; He, Ying; Liao, Yanhui; Wang, Ya; He, Fan; Zhang, Fengyu; Shugart, Yin Yao; Liu, Chunyu; Tang, Yanqing; Chan, Raymond C K; Wang, Chuan-Yue; Yao, Yong-Gang; Chen, Xiaogang

    2017-06-20

    Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN, p.S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size. Copyright © 2017 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. All rights reserved.

  6. The estrogen hypothesis of schizophrenia implicates glucose metabolism

    DEFF Research Database (Denmark)

    Olsen, Line; Hansen, Thomas; Jakobsen, Klaus D

    2008-01-01

    expression studies have indicated an equally large set of candidate genes that only partially overlap linkage genes. A thorough assessment, beyond the resolution of current GWA studies, of the disease risk conferred by the numerous schizophrenia candidate genes is a daunting and presently not feasible task....... We undertook these challenges by using an established clinical paradigm, the estrogen hypothesis of schizophrenia, as the criterion to select candidates among the numerous genes experimentally implicated in schizophrenia. Bioinformatic tools were used to build and priorities the signaling networks...... implicated by the candidate genes resulting from the estrogen selection. We identified ten candidate genes using this approach that are all active in glucose metabolism and particularly in the glycolysis. Thus, we tested the hypothesis that variants of the glycolytic genes are associated with schizophrenia...

  7. Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure

    NARCIS (Netherlands)

    Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

    2016-01-01

    BACKGROUND: Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying

  8. Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families.

    Science.gov (United States)

    Chou, I-Jun; Kuo, Chang-Fu; Huang, Yu-Shu; Grainge, Matthew J; Valdes, Ana M; See, Lai-Chu; Yu, Kuang-Hui; Luo, Shue-Fen; Huang, Lu-Shuang; Tseng, Wen-Yi; Zhang, Weiya; Doherty, Michael

    2017-09-01

    Strong familial aggregation of schizophrenia has been reported but there is uncertainty concerning the degree of genetic contribution to the phenotypic variance of the disease. This study aimed to examine the familial aggregation and heritability of schizophrenia, and the relative risks (RRs) of other psychiatric diseases, in relatives of people with schizophrenia using the Taiwan National Health Insurance Database. The study population included individuals with affected first-degree or second-degree relatives identified from all beneficiaries (n = 23 422 955) registered in 2013. Diagnoses of schizophrenia made by psychiatrists were ascertained between January 1, 1996 and December 31, 2013. Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia. The accountability for the phenotypic variance of schizophrenia was 47.3% for genetic factors, 15.5% for shared environmental factors, and 37.2% for non-shared environmental factors. The RR (95% CI) in individuals with a first-degree relative with schizophrenia was 3.49 (3.34-3.64) for mood disorders and 3.91 (3.35-4.57) for delusional disorders. A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  9. Neuroanatomical phenotypes in mental illness: identifying convergent and divergent cortical phenotypes across autism, ADHD and schizophrenia.

    Science.gov (United States)

    Park, Min Tae M; Raznahan, Armin; Shaw, Philip; Gogtay, Nitin; Lerch, Jason P; Chakravarty, M Mallar

    2018-05-01

    There is evidence suggesting neuropsychiatric disorders share genomic, cognitive and clinical features. Here, we ask if autism-spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and schizophrenia share neuroanatomical variations. First, we used measures of cortical anatomy to estimate spatial overlap of neuroanatomical variation using univariate methods. Next, we developed a novel methodology to determine whether cortical deficits specifically target or are "enriched" within functional resting-state networks. We found cortical anomalies were preferentially enriched across functional networks rather than clustering spatially. Specifically, cortical thickness showed significant enrichment between patients with ASD and those with ADHD in the default mode network, between patients with ASD and those with schizophrenia in the frontoparietal and limbic networks, and between patients with ADHD and those with schizophrenia in the ventral attention network. Networks enriched in cortical thickness anomalies were also strongly represented in functional MRI results (Neurosynth; r = 0.64, p = 0.032). We did not account for variable symptom dimensions and severity in patient populations, and our cross-sectional design prevented longitudinal analyses of developmental trajectories. These findings suggest that common deficits across neuropsychiatric disorders cannot simply be characterized as arising out of local changes in cortical grey matter, but rather as entities of both local and systemic alterations targeting brain networks.

  10. Radiation-induced senescence-like phenotype in proliferating and plateau-phase vascular endothelial cells

    International Nuclear Information System (INIS)

    Igarashi, Kaori; Sakimoto, Ippei; Kataoka, Keiko; Ohta, Keisuke; Miura, Masahiko

    2007-01-01

    The effects of ionizing radiation (IR) on tumor angiogenesis still remain largely unknown. In this study, we found that IR (8 Gy) induces a high-frequency (80-90%) senescence-like phenotype in vascular endothelial cells (ECs) undergoing exponential growth. This finding allowed us to characterize the IR-induced senescence-like (IRSL) phenotype by examining the gene expression profiles and in vitro angiogenic activities of these ECs. The expression levels of genes associated with cell cycle progression and DNA replication were remarkably reduced in the IRSL ECs. Additionally, the in vitro invasion and migration activities of these cells through Matrigel were significantly suppressed. We also found that confluent ECs exhibited a high-frequency IRSL phenotype when they were replated immediately after irradiation, whereas incubation in plateau-phase conditions reduced the induction of this phenotype and enhanced colony formation. The kinetics of DNA double-strand break repair, which showed a faster time course in confluent ECs than in growing ECs, may contribute to the protective mechanism associated with the IRSL phenotype. These results imply that the IRSL phenotype may be important for determining the angiogenic activity of ECs following irradiation. The present study should contribute to the understanding of the effects of IR on tumor angiogenesis

  11. Pregnenolone rescues schizophrenia-like behavior in dopamine transporter knockout mice.

    Directory of Open Access Journals (Sweden)

    Peiyan Wong

    Full Text Available Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS, which has been suggested to enhance cognitive functions through GABA(A receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO. DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.

  12. Irish study of high-density Schizophrenia families: Field methods and power to detect linkage

    Energy Technology Data Exchange (ETDEWEB)

    Kendler, K.S.; Straub, R.E.; MacLean, C.J. [Virginia Commonwealth Univ., Richmond, VA (United States)] [and others

    1996-04-09

    Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. 75 refs., 6 tabs.

  13. Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits.

    Science.gov (United States)

    Chen, D C; Du, X D; Yin, G Z; Yang, K B; Nie, Y; Wang, N; Li, Y L; Xiu, M H; He, S C; Yang, F D; Cho, R Y; Kosten, T R; Soares, J C; Zhao, J P; Zhang, X Y

    2016-11-01

    Schizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia. A total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Of the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB. IGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

  14. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.

    Science.gov (United States)

    Davis, Justin; Eyre, Harris; Jacka, Felice N; Dodd, Seetal; Dean, Olivia; McEwen, Sarah; Debnath, Monojit; McGrath, John; Maes, Michael; Amminger, Paul; McGorry, Patrick D; Pantelis, Christos; Berk, Michael

    2016-06-01

    Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure.

    Science.gov (United States)

    Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

    2016-09-01

    Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development. In a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability. In total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%). Intellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  16. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics.

    Science.gov (United States)

    Plazzi, Giuseppe; Fabbri, Chiara; Pizza, Fabio; Serretti, Alessandro

    2015-01-01

    The occurrence of psychotic symptoms in narcolepsy type 1 (NT1) has been reported as responsible for delayed diagnosis due to the misdiagnosis of schizophrenia. This study aimed to identify shared and distinctive clinical characteristics between NT1 and schizophrenia, with the focus on psychotic symptoms. A total of 28 NT1 and 21 schizophrenia patients were included. Hallucination characteristics and PANSS (Positive and Negative Syndrome Scale), HRSD (Hamilton Rating Scale for Depression), DES (Dissociative Experiences Scale), and STAI (State-Trait Anxiety Inventory) scores were collected. Symptom overlap was investigated by χ(2), Fisher's or t tests and multiple logistic regression models. Hallucinations and illusions frequently occurred in both diseases. Unimodal hallucinations were more common in schizophrenia (p = 6.30e-07) and multimodal hallucinations in NT1, but no clear difference was identified in their sensory modality. Hypnagogic/hypnopompic hallucinations were typical of NT1 (p = 5.22e-07), and 25% of NT1 patients exhibited some degree of insight deficit. Hypnagogic/hypnopompic hallucinations, unimodal hallucinations and PANSS score were the most distinctive clinical characteristics. Clinical overlap was found in the dissociative and anxiety domains, while higher depressive scores were observed in schizophrenia. The overlap between NT1 and schizophrenia should be further investigated under a clinical and pathogenetic point of view to improve diagnostic and therapeutic approaches. © 2015 S. Karger AG, Basel.

  17. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

    Science.gov (United States)

    van Os, Jim; Rutten, Bart P; Myin-Germeys, Inez; Delespaul, Philippe; Viechtbauer, Wolfgang; van Zelst, Catherine; Bruggeman, Richard; Reininghaus, Ulrich; Morgan, Craig; Murray, Robin M; Di Forti, Marta; McGuire, Philip; Valmaggia, Lucia R; Kempton, Matthew J; Gayer-Anderson, Charlotte; Hubbard, Kathryn; Beards, Stephanie; Stilo, Simona A; Onyejiaka, Adanna; Bourque, Francois; Modinos, Gemma; Tognin, Stefania; Calem, Maria; O'Donovan, Michael C; Owen, Michael J; Holmans, Peter; Williams, Nigel; Craddock, Nicholas; Richards, Alexander; Humphreys, Isla; Meyer-Lindenberg, Andreas; Leweke, F Markus; Tost, Heike; Akdeniz, Ceren; Rohleder, Cathrin; Bumb, J Malte; Schwarz, Emanuel; Alptekin, Köksal; Üçok, Alp; Saka, Meram Can; Atbaşoğlu, E Cem; Gülöksüz, Sinan; Gumus-Akay, Guvem; Cihan, Burçin; Karadağ, Hasan; Soygür, Haldan; Cankurtaran, Eylem Şahin; Ulusoy, Semra; Akdede, Berna; Binbay, Tolga; Ayer, Ahmet; Noyan, Handan; Karadayı, Gülşah; Akturan, Elçin; Ulaş, Halis; Arango, Celso; Parellada, Mara; Bernardo, Miguel; Sanjuán, Julio; Bobes, Julio; Arrojo, Manuel; Santos, Jose Luis; Cuadrado, Pedro; Rodríguez Solano, José Juan; Carracedo, Angel; García Bernardo, Enrique; Roldán, Laura; López, Gonzalo; Cabrera, Bibiana; Cruz, Sabrina; Díaz Mesa, Eva Ma; Pouso, María; Jiménez, Estela; Sánchez, Teresa; Rapado, Marta; González, Emiliano; Martínez, Covadonga; Sánchez, Emilio; Olmeda, Ma Soledad; de Haan, Lieuwe; Velthorst, Eva; van der Gaag, Mark; Selten, Jean-Paul; van Dam, Daniella; van der Ven, Elsje; van der Meer, Floor; Messchaert, Elles; Kraan, Tamar; Burger, Nadine; Leboyer, Marion; Szoke, Andrei; Schürhoff, Franck; Llorca, Pierre-Michel; Jamain, Stéphane; Tortelli, Andrea; Frijda, Flora; Vilain, Jeanne; Galliot, Anne-Marie; Baudin, Grégoire; Ferchiou, Aziz; Richard, Jean-Romain; Bulzacka, Ewa; Charpeaud, Thomas; Tronche, Anne-Marie; De Hert, Marc; van Winkel, Ruud; Decoster, Jeroen; Derom, Catherine; Thiery, Evert; Stefanis, Nikos C; Sachs, Gabriele; Aschauer, Harald; Lasser, Iris; Winklbaur, Bernadette; Schlögelhofer, Monika; Riecher-Rössler, Anita; Borgwardt, Stefan; Walter, Anna; Harrisberger, Fabienne; Smieskova, Renata; Rapp, Charlotte; Ittig, Sarah; Soguel-dit-Piquard, Fabienne; Studerus, Erich; Klosterkötter, Joachim; Ruhrmann, Stephan; Paruch, Julia; Julkowski, Dominika; Hilboll, Desiree; Sham, Pak C; Cherny, Stacey S; Chen, Eric Y H; Campbell, Desmond D; Li, Miaoxin; Romeo-Casabona, Carlos María; Emaldi Cirión, Aitziber; Urruela Mora, Asier; Jones, Peter; Kirkbride, James; Cannon, Mary; Rujescu, Dan; Tarricone, Ilaria; Berardi, Domenico; Bonora, Elena; Seri, Marco; Marcacci, Thomas; Chiri, Luigi; Chierzi, Federico; Storbini, Viviana; Braca, Mauro; Minenna, Maria Gabriella; Donegani, Ivonne; Fioritti, Angelo; La Barbera, Daniele; La Cascia, Caterina Erika; Mulè, Alice; Sideli, Lucia; Sartorio, Rachele; Ferraro, Laura; Tripoli, Giada; Seminerio, Fabio; Marinaro, Anna Maria; McGorry, Patrick; Nelson, Barnaby; Amminger, G Paul; Pantelis, Christos; Menezes, Paulo R; Del-Ben, Cristina M; Gallo Tenan, Silvia H; Shuhama, Rosana; Ruggeri, Mirella; Tosato, Sarah; Lasalvia, Antonio; Bonetto, Chiara; Ira, Elisa; Nordentoft, Merete; Krebs, Marie-Odile; Barrantes-Vidal, Neus; Cristóbal, Paula; Kwapil, Thomas R; Brietzke, Elisa; Bressan, Rodrigo A; Gadelha, Ary; Maric, Nadja P; Andric, Sanja; Mihaljevic, Marina; Mirjanic, Tijana

    2014-07-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. Unipolar Depression in Paroxysmal Schizophrenia

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    Alexander S. Bobrov

    2013-12-01

    Full Text Available Based on the current study, the clinical characteristics of unipolar depression in the clinical picture of schizophrenia with the paroxysmal type of disease course are presented. Given the concomitant depression with phobic symptoms, the following clinical variants are marked: depression with generalized social phobia and/or anthropophobia and depression with generalized pathological body sensations and hypochondriacal phobias. In other words, we are talking about a necessity to allocate a special type of schizophrenia with affective structure episodes and comorbid neurosis-like symptoms. Information on the basic treatment strategy of schizophrenia with depressive structure episodes and comorbid neurosis-like symptoms in everyday psychiatric practice is also provided.

  19. NMDA receptor antagonism by repetitive MK801 administration induces schizophrenia-like structural changes in the rat brain as revealed by voxel-based morphometry and diffusion tensor imaging.

    Science.gov (United States)

    Wu, H; Wang, X; Gao, Y; Lin, F; Song, T; Zou, Y; Xu, L; Lei, H

    2016-05-13

    Animal models of N-methyl-d-aspartate receptor (NMDAR) antagonism have been widely used for schizophrenia research. Less is known whether these models are associated with macroscopic brain structural changes that resemble those in clinical schizophrenia. Magnetic resonance imaging (MRI) was used to measure brain structural changes in rats subjected to repeated administration of MK801 in a regimen (daily dose of 0.2mg/kg for 14 consecutive days) known to be able to induce schizophrenia-like cognitive impairments. Voxel-based morphometry (VBM) revealed significant gray matter (GM) atrophy in the hippocampus, ventral striatum (vStr) and cortex. Diffusion tensor imaging (DTI) demonstrated microstructural impairments in the corpus callosum (cc). Histopathological results corroborated the MRI findings. Treatment-induced behavioral abnormalities were not measured such that correlation between the brain structural changes observed and schizophrenia-like behaviors could not be established. Chronic MK801 administration induces MRI-observable brain structural changes that are comparable to those observed in schizophrenia patients, supporting the notion that NMDAR hypofunction contributes to the pathology of schizophrenia. Imaging-derived brain structural changes in animal models of NMDAR antagonism may be useful measurements for studying the effects of treatments and interventions targeting schizophrenia. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients.

    Directory of Open Access Journals (Sweden)

    Harpreet Kaur

    Full Text Available Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355 and risperidone (n = 260 treated subgroups. All associations were estimated as odds ratio (OR and 95% confidence interval (CI and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396 of PIP4K2A gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46-6.98 with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08-15.36. While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in

  1. Schizophrenia: What's Arc Got to Do with It?

    Science.gov (United States)

    Managò, Francesca; Papaleo, Francesco

    2017-01-01

    Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework. Building on this, we finally compare and evaluate several lines of evidence demonstrating that Arc genetics can alter both glutamatergic and dopaminergic systems in a very selective way, again consistent with molecular alterations characteristic of schizophrenia. Despite being only initial, accumulating and compelling data are showing that Arc might be one of the primary biological players in schizophrenia. Synaptic plasticity alterations in the genetic architecture of psychiatric disorders might be a rule, not an exception. Thus, we anticipate that additional evidence will soon emerge to clarify the Arc-dependent mechanisms involved in the psychiatric-related dysfunctional behavior.

  2. Saccade inhibition in schizophrenia : towards phenotyping based on brain function

    NARCIS (Netherlands)

    Raemaekers, M.A.H.L.L.

    2006-01-01

    Schizophrenia is a complex psychiatric illness which is caused by multiple genes and gene-environment interactions. This complex etiology has a negative impact on the power of molecular genetic studies. To improve this situation, attempts are made to define traits that are more intimately related to

  3. Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine.

    Directory of Open Access Journals (Sweden)

    Hiroko Hagiwara

    Full Text Available D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA receptor, is synthesized from L-serine by serine racemase (SRR. Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.Neonatal mice (7-9 days were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day, an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT, and prepulse inhibition (PPI were performed at juvenile (5-6 weeks old and adult (10-12 weeks old stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70 significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.

  4. Investigating causality in the association between 25(OH)D and schizophrenia.

    Science.gov (United States)

    Taylor, Amy E; Burgess, Stephen; Ware, Jennifer J; Gage, Suzanne H; Richards, J Brent; Davey Smith, George; Munafò, Marcus R

    2016-05-24

    Vitamin D deficiency is associated with increased risk of schizophrenia. However, it is not known whether this association is causal or what the direction of causality is. We performed two sample bidirectional Mendelian randomization analysis using single nucleotide polymorphisms (SNPs) robustly associated with serum 25(OH)D to investigate the causal effect of 25(OH)D on risk of schizophrenia, and SNPs robustly associated with schizophrenia to investigate the causal effect of schizophrenia on 25(OH)D. We used summary data from genome-wide association studies and meta-analyses of schizophrenia and 25(OH)D to obtain betas and standard errors for the SNP-exposure and SNP-outcome associations. These were combined using inverse variance weighted fixed effects meta-analyses. In 34,241 schizophrenia cases and 45,604 controls, there was no clear evidence for a causal effect of 25(OH)D on schizophrenia risk. The odds ratio for schizophrenia per 10% increase in 25(OH)D conferred by the four 25(OH)D increasing SNPs was 0.992 (95% CI: 0.969 to 1.015). In up to 16,125 individuals with measured serum 25(OH)D, there was no clear evidence that genetic risk for schizophrenia causally lowers serum 25(OH)D. These findings suggest that associations between schizophrenia and serum 25(OH)D may not be causal. Therefore, vitamin D supplementation may not prevent schizophrenia.

  5. [Influence of paternal age in schizophrenia].

    Science.gov (United States)

    Hubert, A; Szöke, A; Leboyer, M; Schürhoff, F

    2011-06-01

    spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA. APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA. Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  6. Neonatal stress-induced affective changes in adolescent Wistar rats: early signs of schizophrenia-like behavior

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Neves Girardi

    2014-09-01

    Full Text Available Psychiatric disorders are multifactorial diseases with etiology that may involve genetic factors, early life environment and stressful life events. The neurodevelopmental hypothesis of schizophrenia is based on a wealth of data on increased vulnerability in individuals exposed to insults during the perinatal period. Maternal deprivation disinhibits the adrenocortical response to stress in neonatal rats and has been used as an animal model of schizophrenia. To test if long-term affective consequences of early life stress were influenced by maternal presence, we submitted 10-day old rats, either deprived (for 22 h or not from their dams, to a stress challenge (i.p. saline injection. Corticosterone plasma levels were measured 2 h after the challenge, whereas another subgroup was assessed for behavior in the open field, elevated plus maze, social investigation and the negative contrast sucrose consumption test in adolescence (postnatal day 45. Maternally deprived rats exhibited increased plasma corticosterone levels which were higher in maternally deprived and stress challenged pups. Social investigation was impaired in maternally deprived rats only, while saline injection, independently of maternal deprivation, was associated with increased anxiety-like behavior in the elevated plus maze and an impaired intake decrement in the negative sucrose contrast. In the open field, center exploration was reduced in all maternally-deprived adolescents and in control rats challenged with saline injection. The most striking finding was that exposure to a stressful stimulus per se, regardless of maternal deprivation, was linked to differential emotional consequences. We therefore propose that besides being a well-known and validated model of schizophrenia in adult rats, the maternal deprivation paradigm could be extended to model early signs of psychiatric dysfunction, and would particularly be a useful tool to detect early signs that resemble schizophrenia.

  7. RasGRP1 confers the phorbol ester-sensitive phenotype to EL4 lymphoma cells.

    Science.gov (United States)

    Han, Shujie; Knoepp, Stewart M; Hallman, Mark A; Meier, Kathryn E

    2007-01-01

    The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to the tumor promoter phorbol 12-myristate 13-acetate (PMA). In sensitive EL4 cells, PMA causes robust Erk mitogen-activated protein kinase activation that results in growth arrest. In resistant cells, PMA induces minimal Erk activation, without growth arrest. PMA stimulates IL-2 production in sensitive, but not resistant, cells. The role of RasGRP1, a PMA-activated guanine nucleotide exchange factor for Ras, in EL4 phenotype was examined. Endogenous RasGRP1 protein is expressed at much higher levels in sensitive than in resistant cells. PMA-induced Ras activation is observed in sensitive cells but not in resistant cells lacking Ras-GRP1. PMA induces down-regulation of RasGRP1 protein in sensitive cells but increases RasGRP1 in resistant cells. Transfection of RasGRP1 into resistant cells enhances PMA-induced Erk activation. In the reverse experiment, introduction of small interfering RNA (siRNA) for RasGRP1 suppresses PMA-induced Ras and Erk activations in sensitive cells. Sensitive cells incubated with siRNA for RasGRP1 exhibit the PMA-resistant phenotype, in that they are able to proliferate in the presence of PMA and do not secrete IL-2 when stimulated with PMA. These studies indicate that the PMA-sensitive phenotype, as previously defined for the EL4 cell line, is conferred by endogenous expression of RasGRP1 protein.

  8. [22q11.2DS Syndrome as a Genetic Subtype of Schizophrenia].

    Science.gov (United States)

    Huertas-Rodríguez, Cindy Katherin; Payán-Gómez, César; Forero-Castro, Ruth Maribel

    2015-01-01

    The 22q11.2 deletion syndrome (22q11.2DS) is associated with the microdeletion of this chromosomal region, and represents the second most common genetic syndrome after Down's syndrome. In patients with schizophrenia, 22q11.2DS has a prevalence of 2%, and in selected groups can be increased to between 32-53%. To describe the generalities of 22q11.2DS syndrome as a genetic subtype of schizophrenia, its clinical characteristics, molecular genetic aspects, and frequency in different populations. A review was performed from 1967 to 2013 in scientific databases, compiling articles about 22q11.2DS syndrome and its association with schizophrenia. The 22q11.2 DS syndrome has a variable phenotype associated with other genetic syndromes, birth defects in many tissues and organs, and a high rate of psychiatric disorders, particularly schizophrenia. Likewise, it has been identified in clinical populations with schizophrenia selected by the presence of common syndromic characteristics. FISH, qPCR and MLPA techniques, and recently, aCGH and NGS technologies, are being used to diagnose this microdeletion. It is important in clinical practice to remember that people suffering the 22q11.2DS have a high genetic risk for developing schizophrenia, and it is considered that the simultaneous presence of this disease and 22q11.2DS represents a genetic subtype of schizophrenia. There are clear phenotypic criteria, molecular and cytogenetic methods to diagnose this group of patients, and to optimize a multidisciplinary approach in their monitoring. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  9. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zachary Freyberg

    2017-07-01

    Full Text Available For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

  10. New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens.

    Science.gov (United States)

    Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

    2017-03-01

    How anti-Müllerian hormone (AMH) and testosterone (T) interrelate in infertile women is currently largely unknown. We, therefore, in a retrospective cohort study investigated how infertile women with high-AMH (AMH ≥75th quantile; n=144) and with normal-AMH (25th-75th quantile; n=313), stratified for low-T (total testosterone ≤19.0ng/dL), normal-T (19.0-29.0ng/dL) and high-T (>29.0ng/dL) phenotypically behaved. Patient age, follicle stimulating hormone (FSH), dehyroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol (C), adrenocorticotrophic hormone (ACTH), IVF outcomes, as well as inflammatory and immune panels were then compared between groups, with AMH and T as variables. We identified a previously unknown infertile PCOS-like phenotype, characterized by high-AMH but, atypically, low-T, with predisposition toward autoimmunity. It presents with incompatible high-AMH and low-T (lean PCOS-like patients, presenting delayed for tertiary fertility services. Since also characterized by low DHEAS, low-T is likely of adrenal origina, and consequence of autoimmune adrenal insufficiency since also accompanied by low-C and evidence of autoimmunity. DHEA supplementation in such patients equalizes low- to normal-T and normalizes IVF cycle outcomes. Once recognized, this high-AMH/low-T phenotype is surprisingly common in tertiary fertility centers but, currently, goes unrecognized. Its likely adrenal autoimmune etiology offers interesting new directions for investigations of adrenals control over ovarian function via adrenal androgen production. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Auditory sensory processing deficits in sensory gating and mismatch negativity-like responses in the social isolation rat model of schizophrenia

    DEFF Research Database (Denmark)

    Witten, Louise; Oranje, Bob; Mørk, Arne

    2014-01-01

    Patients with schizophrenia exhibit disturbances in information processing. These disturbances can be investigated with different paradigms of auditory event related potentials (ERP), such as sensory gating in a double click paradigm (P50 suppression) and the mismatch negativity (MMN) component...... in an auditory oddball paradigm. The aim of the current study was to test if rats subjected to social isolation, which is believed to induce some changes that mimic features of schizophrenia, displays alterations in sensory gating and MMN-like response. Male Lister-Hooded rats were separated into two groups; one...... group socially isolated (SI) for 8 weeks and one group housed (GH). Both groups were then tested in a double click sensory gating paradigm and an auditory oddball paradigm (MMN-like) paradigm. It was observed that the SI animals showed reduced sensory gating of the cortical N1 amplitude. Furthermore...

  12. The genetic validation of heterogeneity in schizophrenia

    Directory of Open Access Journals (Sweden)

    Moritani Makiko

    2011-10-01

    Full Text Available Abstract Introduction Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Methods Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Results No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57 was slightly lower than among controls (6.6+/-1.39. Conclusion The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  13. Conference Support, 23rd Western Photosynthesis Conference 2014, Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Wachter, Rebekka [Arizona State Univ., Tempe, AZ (United States)

    2015-01-12

    The Western Photosynthesis Conference is a regional conference that is held on an annual basis to bring together researchers primarily from the Western United States to share their newest research advances on photosynthetic processes. The 23rd conference was focused on both fundamental and more applied research on the biological conversion of solar energy to various energy storage forms. Several particular areas of solar energy conversion were emphasized in this conference (see below). Some of these topics, such as carbon limitations on photosynthesis, biomimicry and phenotyping, have traditionally not been incorporated extensively in the Western Photosynthesis Conference. We found that these topics have substantially broadened of the scope of this meeting.

  14. Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia

    Directory of Open Access Journals (Sweden)

    Zhihong eJiang

    2013-09-01

    Full Text Available Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model of schizophrenia in which NMDARs are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010. We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the parvalbumin-positive interneurons in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al, 2013. Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of parvalbumin-positive interneurons.

  15. Diffusion tensor imaging of cingulum bundle and corpus callosum in schizophrenia vs. bipolar disorder.

    Science.gov (United States)

    Nenadić, Igor; Hoof, Anna; Dietzek, Maren; Langbein, Kerstin; Reichenbach, Jürgen R; Sauer, Heinrich; Güllmar, Daniel

    2017-08-30

    Both schizophrenia and bipolar disorder show abnormalities of white matter, as seen in diffusion tensor imaging (DTI) analyses of major brain fibre bundles. While studies in each of the two conditions have indicated possible overlap in anatomical location, there are few direct comparisons between the disorders. Also, it is unclear whether phenotypically similar subgroups (e.g. patients with bipolar disorder and psychotic features) might share white matter pathologies or be rather similar. Using region-of-interest (ROI) analysis of white matter with diffusion tensor imaging (DTI) at 3 T, we analysed fractional anisotropy (FA), radial diffusivity (RD), and apparent diffusion coefficient (ADC) of the corpus callosum and cingulum bundle in 33 schizophrenia patients, 17 euthymic (previously psychotic) bipolar disorder patients, and 36 healthy controls. ANOVA analysis showed significant main effects of group for RD and ADC (both elevated in schizophrenia). Across the corpus callosum ROIs, there was not group effect on FA, but for RD (elevated in schizophrenia, lower in bipolar disorder) and ADC (higher in schizophrenia, intermediate in bipolar disorder). Our findings show similarities and difference (some gradual) across regions of the two major fibre tracts implicated in these disorders, which would be consistent with a neurobiological overlap of similar clinical phenotypes. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  16. Regenerant arabidopsis lineages display a distinct genome-wide spectrum of mutations conferring variant phenotypes

    KAUST Repository

    Jiang, Caifu

    2011-07-28

    Multicellular organisms can be regenerated from totipotent differentiated somatic cell or nuclear founders [1-3]. Organisms regenerated from clonally related isogenic founders might a priori have been expected to be phenotypically invariant. However, clonal regenerant animals display variant phenotypes caused by defective epigenetic reprogramming of gene expression [2], and clonal regenerant plants exhibit poorly understood heritable phenotypic ("somaclonal") variation [4-7]. Here we show that somaclonal variation in regenerant Arabidopsis lineages is associated with genome-wide elevation in DNA sequence mutation rate. We also show that regenerant mutations comprise a distinctive molecular spectrum of base substitutions, insertions, and deletions that probably results from decreased DNA repair fidelity. Finally, we show that while regenerant base substitutions are a likely major genetic cause of the somaclonal variation of regenerant Arabidopsis lineages, transposon movement is unlikely to contribute substantially to that variation. We conclude that the phenotypic variation of regenerant plants, unlike that of regenerant animals, is substantially due to DNA sequence mutation. 2011 Elsevier Ltd. All rights reserved.

  17. Regenerant arabidopsis lineages display a distinct genome-wide spectrum of mutations conferring variant phenotypes

    KAUST Repository

    Jiang, Caifu; Mithani, Aziz; Gan, Xiangchao; Belfield, Eric J.; Klingler, John  P.; Zhu, Jian-Kang; Ragoussis, Jiannis; Mott, Richard; Harberd, Nicholas  P.

    2011-01-01

    Multicellular organisms can be regenerated from totipotent differentiated somatic cell or nuclear founders [1-3]. Organisms regenerated from clonally related isogenic founders might a priori have been expected to be phenotypically invariant. However, clonal regenerant animals display variant phenotypes caused by defective epigenetic reprogramming of gene expression [2], and clonal regenerant plants exhibit poorly understood heritable phenotypic ("somaclonal") variation [4-7]. Here we show that somaclonal variation in regenerant Arabidopsis lineages is associated with genome-wide elevation in DNA sequence mutation rate. We also show that regenerant mutations comprise a distinctive molecular spectrum of base substitutions, insertions, and deletions that probably results from decreased DNA repair fidelity. Finally, we show that while regenerant base substitutions are a likely major genetic cause of the somaclonal variation of regenerant Arabidopsis lineages, transposon movement is unlikely to contribute substantially to that variation. We conclude that the phenotypic variation of regenerant plants, unlike that of regenerant animals, is substantially due to DNA sequence mutation. 2011 Elsevier Ltd. All rights reserved.

  18. From risk genes to psychiatric phenotypes - Studies of fibroblast growth factor-related and genome-wide genetic variants in humans and mice

    NARCIS (Netherlands)

    Terwisscha van Scheltinga, A.F.

    2013-01-01

    Schizophrenia is a severe mental disorder with a high heritability. This thesis describes studies on the association between genetic variants and phenotypes related to schizophrenia, such as brain volume and IQ, in order to learn about which processes are affected by schizophrenia-associated genetic

  19. Desipramine rescues age-related phenotypes in depression-like rats induced by chronic mild stress.

    Science.gov (United States)

    Xie, Xiaoxian; Chen, Yangyang; Wang, Qi; Shen, Qichen; Ma, Lingyan; Huang, Liangfeng; Wu, Tao; Fu, Zhengwei

    2017-11-01

    Our previous finding demonstrates that major depressive disorder can mediate accelerated aging in rats. Desipramine is a typical tricyclic antidepressant, and can provide neuroprotection and counteract depression-like behaviors. However, whether desipramine can rescue age-related phenotypes in depressed individuals is not understood. In the present study, we investigated the physiological function of desipramine on rescuing the age-related phenotypes in these animals. The rats were induced by chronic mild stress paradigm, and the depression-like behaviors of rats were detected by sucrose intake test, open field test (OFT) and forced swimming test (FST). Then the depressed rats were treated by desipramine. Desipramine administration was effective in counteracting depression-like behaviors by increasing the sucrose solution intake, reducing the immobility time in the FST, and increasing total distance travelled and numbers of grid line crossed in the OFT. Moreover, desipramine treatment was able to reduce the oxidative damage to rat liver, and to increase the expression of telomerase reverse transcriptase (TERT), leading to correspondingly restored telomerase activity. Our findings identify that one function of desipramine may partly be to rescue age-related phenotypes in depressed individuals induced by chronic stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Cannabinoid Receptor 1 Gene Polymorphisms and Marijuana Misuse Interactions On White Matter and Cognitive Deficits in Schizophrenia

    OpenAIRE

    Ho, Beng-Choon; Wassink, Thomas H.; Ziebell, Steven; Andreasen, Nancy C.

    2011-01-01

    Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag s...

  1. Activation of c-MET induces a stem-like phenotype in human prostate cancer.

    Directory of Open Access Journals (Sweden)

    Geert J L H van Leenders

    Full Text Available Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'. We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.

  2. Understanding Stress-Related Behavioral Phenotypes: Report from the 1st International Neuroscience Summer School and the 11th International “Stress and Behavior” Conference

    Directory of Open Access Journals (Sweden)

    J. L. LaPorte

    2008-01-01

    Full Text Available The 1st International Neuroscience Summer School and the 11th International Multidisciplinary Neuroscience and Biopsychiatry Conference on Stress and Behavior were held in St. Petersburg, Russia, during May 9–20, 2008. The summer school gathered 30 talented young scientists from 15 countries worldwide, and was dedicated to different topics of behavioral neuroscience. Many interactive courses were provided on neuropharmacology, animal phenotyping, and biopsychology. The conference's excellent scientific and social program attracted almost 500 delegates from 40 countries from many areas of stress research. The eclectic interaction between medical doctors, basic scientists, psychologists, and students made for a productive and collaborative environment, which contributed greatly to the success of the school and conference.

  3. The NCAN gene: schizophrenia susceptibility and cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Wang P

    2016-11-01

    Full Text Available Peirong Wang,1 Jun Cai,2 Jianliang Ni,1 Jiangtao Zhang,1 Wei Tang,3 Chen Zhang2 1Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 2Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 3Wenzhou Kangning Hospital, Wenzhou, Zhejiang, People’s Republic of China Background: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN, is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia.Methods: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS.Results: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction.Conclusion: Our findings indicate

  4. The Diagnosis of Schizophrenia According to Kraepelin

    Directory of Open Access Journals (Sweden)

    António Gamito

    2014-10-01

    Full Text Available Kraepelin's methodology and clinical descriptions are still influential in the XXIst century psychiatry. Concerning schizophrenia, the author questions the internal cohesion and predicitve validity of the actual "phenotypes", returning to Kraepelin's concepts regarding the psychopathology and evolution of the disease. The author suggests that the validation of such concepts could influence research and clinical practice.

  5. Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies.

    Science.gov (United States)

    Arnedo, Javier; Svrakic, Dragan M; Del Val, Coral; Romero-Zaliz, Rocío; Hernández-Cuervo, Helena; Fanous, Ayman H; Pato, Michele T; Pato, Carlos N; de Erausquin, Gabriel A; Cloninger, C Robert; Zwir, Igor

    2015-02-01

    The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes. In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies. The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%). Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.

  6. Clinical manifestations of self-disorders and the Gestalt of schizophrenia

    DEFF Research Database (Denmark)

    Henriksen, Mads Gram; Parnas, Josef

    2012-01-01

    Anomalies of self-experience (self-disorders) constitute crucial phenotypes of the schizophrenia spectrum. The following qualitative study demonstrates a variety of these core experiential anomalies. From a sample of 36 first-admitted patients, all of whom underwent a comprehensive psychiatric ev...

  7. Theory of mind network activity is altered in subjects with familial liability for schizophrenia

    Science.gov (United States)

    Mohnke, Sebastian; Erk, Susanne; Schnell, Knut; Romanczuk-Seiferth, Nina; Schmierer, Phöbe; Romund, Lydia; Garbusow, Maria; Wackerhagen, Carolin; Ripke, Stephan; Grimm, Oliver; Haller, Leila; Witt, Stephanie H.; Degenhardt, Franziska; Tost, Heike; Heinz, Andreas; Meyer-Lindenberg, Andreas; Walter, Henrik

    2016-01-01

    As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. About 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk. PMID:26341902

  8. Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

    Science.gov (United States)

    Cohen, Mark; Appleby, Brian; Safar, Jiri G

    2016-01-01

    Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

  9. Contribution of nonprimate animal models in understanding the etiology of schizophrenia

    Science.gov (United States)

    Lazar, Noah L.; Neufeld, Richard W.J.; Cain, Donald P.

    2011-01-01

    Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelopmental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neurotransmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans. PMID:21247514

  10. Low calcium culture condition induces mesenchymal cell-like phenotype in normal human epidermal keratinocytes

    International Nuclear Information System (INIS)

    Takagi, Ryo; Yamato, Masayuki; Murakami, Daisuke; Sugiyama, Hiroaki; Okano, Teruo

    2011-01-01

    Highlights: → Normal human epidermal keratinocytes serially cultured under low calcium concentration were cytokeratin and vimentin double positive cells. → The human keratinocytes expressed some epithelial stem/progenitor cell makers, mesenchymal cell markers, and markers of epithelial-mesenchymal transition. → Mesenchymal cell-like phenotype in the keratinocytes was suppressed under high-calcium condition. -- Abstract: Epithelial-mesenchymal transition (EMT) is an important cellular phenomenon in organ developments, cancer invasions, and wound healing, and many types of transformed cell lines are used for investigating for molecular mechanisms of EMT. However, there are few reports for EMT in normal human epithelial cells, which are non-transformed or non-immortalized cells, in vitro. Therefore, normal human epidermal keratinocytes (NHEK) serially cultured in low-calcium concentration medium (LCM) were used for investigating relations between differentiation and proliferation and mesenchymal-like phenotype in the present study, since long-term cultivation of NHEK is achieved in LCM. Interestingly, NHEK serially cultured in LCM consisted essentially of cytokeratin-vimentin double positive cells (98%), although the NHEK exhibited differentiation under high-calcium culture condition with 3T3 feeder layer. The vimentin expression was suppressed under high-calcium condition. These results may indicate the importance of mesenchymal-like phenotype for serially cultivation of NHEK in vitro.

  11. Association analysis of 94 candidate genes and schizophrenia-related endophenotypes.

    Directory of Open Access Journals (Sweden)

    Tiffany A Greenwood

    Full Text Available While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI, P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility

  12. An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome

    OpenAIRE

    Yasutaka Tastuzawa; Kanako Sekinaka; Tetsufumi Suda; Hiroshi Matsumoto; Hiroyuki Otabe; Shigeaki Nonoyama; Aihide Yoshino

    2015-01-01

    In addition to causing polymalformative syndrome, 22q11.2 deletion can lead to various neuropsychiatric disorders including mental retardation, psychosis, and epilepsy. However, few reports regarding epilepsy-related psychosis in 22q11.2 deletion syndrome (22q11.2DS) exist. We describe the clinical characteristics and course of 22q11.2DS in a Japanese patient with comorbid mild mental retardation, childhood-onset localization-related epilepsy, and adult-onset, interictal schizophrenia-like ps...

  13. Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene × environment interaction.

    Science.gov (United States)

    Desbonnet, Lieve; O'Tuathaigh, Colm; Clarke, Gerard; O'Leary, Claire; Petit, Emilie; Clarke, Niamh; Tighe, Orna; Lai, Donna; Harvey, Richard; Cryan, John F; Dinan, Timothy G; Waddington, John L

    2012-05-01

    There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. A Mouse Model that Recapitulates Cardinal Features of the 15q13.3 Microdeletion Syndrome Including Schizophrenia- and Epilepsy-Related Alterations

    DEFF Research Database (Denmark)

    Fejgin, Kim; Nielsen, Jacob; Birknow, Michelle R.

    2014-01-01

    to develop myoclonic and absence-like seizures but decreased propensity for clonic and tonic seizures. Furthermore, they had impaired long-term spatial reference memory and a decreased theta frequency in hippocampus and prefrontal cortex. Electroencephalogram characterization revealed auditory processing......Background: Genome-wide scans have uncovered rare copy number variants conferring high risk of psychiatric disorders. The 15q13.3 microdeletion is associated with a considerably increased risk of idiopathic generalized epilepsy, intellectual disability, and schizophrenia. Methods: A 15q13.......3 microdeletion mouse model (Df[h15q13]/) was generated by hemizygous deletion of the orthologous region and characterized with focus on schizophrenia- and epilepsy-relevant parameters. Results: Df(h15q13)/ mice showed marked changes in neuronal excitability in acute seizure assays, with increased propensity...

  15. Brain structure in schizophrenia vs. psychotic bipolar I disorder: A VBM study.

    Science.gov (United States)

    Nenadic, Igor; Maitra, Raka; Langbein, Kerstin; Dietzek, Maren; Lorenz, Carsten; Smesny, Stefan; Reichenbach, Jürgen R; Sauer, Heinrich; Gaser, Christian

    2015-07-01

    While schizophrenia and bipolar disorder have been assumed to share phenotypic and genotypic features, there is also evidence for overlapping brain structural correlates, although it is unclear whether these relate to shared psychotic features. In this study, we used voxel-based morphometry (VBM8) in 34 schizophrenia patients, 17 euthymic bipolar I disorder patients (with a history of psychotic symptoms), and 34 healthy controls. Our results indicate that compared to healthy controls schizophrenia patients show grey matter deficits (pright dorsolateral prefrontal, as well as bilaterally in ventrolateral prefrontal and insular cortical areas, thalamus (bilaterally), left superior temporal cortex, and minor medial parietal and parietooccipital areas. Comparing schizophrenia vs. bipolar I patients (pleft dorsolateral prefrontal cortex, and left cerebellum. Compared to healthy controls, the deficits in bipolar I patients only reached significance at prights reserved.

  16. The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.

    Science.gov (United States)

    Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

    2013-06-01

    There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy

  17. California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS)

    OpenAIRE

    Stone, WS; Mesholam-Gately, RI; Braff, DL; Calkins, ME; Freedman, R; Green, MF; Greenwood, TA; Gur, RE; Gur, RCC; Lazzeroni, LC; Light, GA; Nuechterlein, KH; Olincy, A; Radant, AD; Siever, LJ

    2014-01-01

    © 2014. The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded “milder“ SZ phenotypes than those acquired subsequently in the COGS-2 case-control de...

  18. California verbal learning test-ii performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the consortium on the genetics of schizophrenia (COGS)

    OpenAIRE

    Stone, WS; Mesholam-Gately, RI; Braff, DL; Calkins, ME; Freedman, R; Green, MF; Greenwood, TA; Gur, RE; Gur, RC; Lazzeroni, LC; Light, GA; Nuechterlein, KH; Olincy, A; Radant, AD; Siever, LJ

    2015-01-01

    © 2014. The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control de...

  19. Phenotypic continuum between autism and schizophrenia: Evidence from the Movie for the Assessment of Social Cognition (MASC).

    Science.gov (United States)

    Martinez, Gilles; Alexandre, Charlotte; Mam-Lam-Fook, Célia; Bendjemaa, Narjes; Gaillard, Raphaël; Garel, Patricia; Dziobek, Isabel; Amado, Isabelle; Krebs, Marie-Odile

    2017-07-01

    Schizophrenic (SCZ) and autism (ASD) spectrum disorders share several features including social cognition impairments. In SCZ, the link between symptomatic dimensions and social cognition deficits remains unclear. The Movie for the Assessment of Social Cognition (MASC) test, available in several languages including English, investigates mental state attribution capabilities in complex interpersonal situations. After its translation into French, we used MASC to direct compare social cognition in 36 young participants with SCZ to 19 with ASD and 20 healthy controls (HC) matched for gender, age (18-25y.o.) and level of education. The MASC discriminated each group from the others, patients with SCZ exhibiting difficulties compared to ASD (MASC total score 28.1 (4) and 24.2 (6.6), respectively; pautism quotient, and with disorganization symptoms. Finally, in SCZ, over-mentalizing difficulties were correlated with age at disease onset. Our results demonstrate the validity of the French version of the MASC and bring direct evidence supporting the hypothesis of a phenotypic continuum between autism and schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Giant cell lesions with a Noonan-like phenotype: a case report.

    Science.gov (United States)

    Cancino, Claudia Marcela H; Gaião, Léonilson; Sant'Ana Filho, Manoel; Oliveira, Flavio Augusto Marsiaj

    2007-05-01

    The purpose of this article is to describe a case of multiple giant cell lesions of the mandible that occurred in a 14-year-old girl with phenotypic characteristics associated with Noonan Syndrome (NS). NS is a dysmorphic disorder characterized by hypertelorism, short stature, congenital heart defects, short and webbed neck, skeletal anomalies, and bleeding diathesis. A 14-year-old girl with a previous diagnosis of NS (sporadic case) presented with multiple radiolucent lesions in the body and ramus of her mandible. In terms of clinical behavior and the described radiographic characteristics, giant cells lesions with Noonan-like phenotype can be considered a form of cherubism. Therefore, surgical intervention is not necessary, but radiographic follow-up and observation is very important during the control and gradual regression of the lesions.

  1. Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

    Science.gov (United States)

    Bassett, Anne S; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W C; van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel E; Swillen, Ann; Van den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie E; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J; Scherer, Stephen W; Emanuel, Beverly S; Guo, Tingwei; Morrow, Bernice E; Marshall, Christian R

    2017-11-01

    Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

  2. Brief Report: No Association between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

    Science.gov (United States)

    Schirmbeck, Frederike; Georgi, Alexander; Strohmaier, Jana; Schmael, Christine; Boesshenz, Katja V.; Muhleisen, Thomas W.; Herms, Stefan; Hoffmann, Per; Jamra, Rami Abou; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Nothen, Markus M.; Cichon, Sven; Rietschel, Marcella; Schulze, Thomas G.

    2008-01-01

    Whereas "Dysbindin" is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. ("J Autism Dev…

  3. Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia.

    Science.gov (United States)

    Torrell, Helena; Salas, Antonio; Abasolo, Nerea; Morén, Constanza; Garrabou, Glòria; Valero, Joaquín; Alonso, Yolanda; Vilella, Elisabet; Costas, Javier; Martorell, Lourdes

    2014-10-01

    It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia. © 2014 Wiley Periodicals, Inc.

  4. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations

    NARCIS (Netherlands)

    van Os, Jim; Rutten, Bart P.; Myin-Germeys, Inez; Delespaul, Philippe; Viechtbauer, Wolfgang; van Zelst, Catherine; Bruggeman, Richard; Reininghaus, Ulrich; Morgan, Craig; Murray, Robin M.; Di Forti, Marta; McGuire, Philip; Valmaggia, Lucia R.; Kempton, Matthew J.; Gayer-Anderson, Charlotte; Hubbard, Kathryn; Beards, Stephanie; Stilo, Simona A.; Onyejiaka, Adanna; Bourque, Francois; Modinos, Gemma; Tognin, Stefania; Calem, Maria; O'Donovan, Michael C.; Owen, Michael J.; Holmans, Peter; Williams, Nigel; Craddock, Nicholas; Richards, Alexander; Humphreys, Isla; Meyer-Lindenberg, Andreas; Leweke, F. Markus; Tost, Heike; Akdeniz, Ceren; Rohleder, Cathrin; Bumb, J. Malte; Schwarz, Emanuel; Alptekin, Köksal; Üçok, Alp; Saka, Meram Can; Atbaşoğlu, E. Cem; Gülöksüz, Sinan; Gumus-Akay, Guvem; Cihan, Burçin; Karadağ, Hasan; Soygür, Haldan; Cankurtaran, Eylem Şahin; Ulusoy, Semra; Akdede, Berna; Binbay, Tolga; Ayer, Ahmet; Noyan, Handan; Karadayı, Gülşah; Akturan, Elçin; Ulaş, Halis; Arango, Celso; Parellada, Mara; Bernardo, Miguel; Sanjuán, Julio; Bobes, Julio; Arrojo, Manuel; Santos, Jose Luis; Cuadrado, Pedro; Rodríguez Solano, José Juan; Carracedo, Angel; García Bernardo, Enrique; Roldán, Laura; López, Gonzalo; Cabrera, Bibiana; Cruz, Sabrina; Díaz Mesa, Eva Ma; Pouso, María; Jiménez, Estela; Sánchez, Teresa; Rapado, Marta; González, Emiliano; Martínez, Covadonga; Sánchez, Emilio; Olmeda, Ma Soledad; de Haan, Lieuwe; Velthorst, Eva; van der Gaag, Mark; Selten, Jean-Paul; van Dam, Daniella; van der Ven, Elsje; van der Meer, Floor; Messchaert, Elles; Kraan, Tamar; Burger, Nadine; Leboyer, Marion; Szoke, Andrei; Schürhoff, Franck; Llorca, Pierre-Michel; Jamain, Stéphane; Tortelli, Andrea; Frijda, Flora; Vilain, Jeanne; Galliot, Anne-Marie; Baudin, Grégoire; Ferchiou, Aziz; Richard, Jean-Romain; Bulzacka, Ewa; Charpeaud, Thomas; Tronche, Anne-Marie; de Hert, Marc; van Winkel, Ruud; Decoster, Jeroen; Derom, Catherine; Thiery, Evert; Stefanis, Nikos C.; Sachs, Gabriele; Aschauer, Harald; Lasser, Iris; Winklbaur, Bernadette; Schlögelhofer, Monika; Riecher-Rössler, Anita; Borgwardt, Stefan; Walter, Anna; Harrisberger, Fabienne; Smieskova, Renata; Rapp, Charlotte; Ittig, Sarah; Soguel-Dit-Piquard, Fabienne; Studerus, Erich; Klosterkötter, Joachim; Ruhrmann, Stephan; Paruch, Julia; Julkowski, Dominika; Hilboll, Desiree; Sham, Pak C.; Cherny, Stacey S.; Chen, Eric Y. H.; Campbell, Desmond D.; Li, Miaoxin; Romeo-Casabona, Carlos María; Emaldi Cirión, Aitziber; Urruela Mora, Asier; Jones, Peter; Kirkbride, James; Cannon, Mary; Rujescu, Dan; Tarricone, Ilaria; Berardi, Domenico; Bonora, Elena; Seri, Marco; Marcacci, Thomas; Chiri, Luigi; Chierzi, Federico; Storbini, Viviana; Braca, Mauro; Minenna, Maria Gabriella; Donegani, Ivonne; Fioritti, Angelo; La Barbera, Daniele; La Cascia, Caterina Erika; Mulè, Alice; Sideli, Lucia; Sartorio, Rachele; Ferraro, Laura; Tripoli, Giada; Seminerio, Fabio; Marinaro, Anna Maria; McGorry, Patrick; Nelson, Barnaby; Amminger, G. Paul; Pantelis, Christos; Menezes, Paulo R.; del-Ben, Cristina M.; Gallo Tenan, Silvia H.; Shuhama, Rosana; Ruggeri, Mirella; Tosato, Sarah; Lasalvia, Antonio; Bonetto, Chiara; Ira, Elisa; Nordentoft, Merete; Krebs, Marie-Odile; Barrantes-Vidal, Neus; Cristóbal, Paula; Kwapil, Thomas R.; Brietzke, Elisa; Bressan, Rodrigo A.; Gadelha, Ary; Maric, Nadja P.; Andric, Sanja; Mihaljevic, Marina; Mirjanic, Tijana

    2014-01-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular

  5. Identifying Gene-Environment Interactions in Schizophrenia : Contemporary Challenges for Integrated, Large-scale Investigations

    NARCIS (Netherlands)

    van Os, Jim; Rutten, Bart P.; Myin-Germeys, Inez; Delespaul, Philippe; Viechtbauer, Wolfgang; van Zelst, Catherine; Bruggeman, Richard; Reininghaus, Ulrich; Morgan, Craig; Murray, Robin M.; Di Forti, Marta; McGuire, Philip; Valmaggia, Lucia R.; Kempton, Matthew J.; Gayer-Anderson, Charlotte; Hubbard, Kathryn; Beards, Stephanie; Stilo, Simona A.; Onyejiaka, Adanna; Bourque, Francois; Modinos, Gemma; Tognin, Stefania; Calem, Maria; O'Donovan, Michael C.; Owen, Michael J.; Holmans, Peter; Williams, Nigel; Craddock, Nicholas; Richards, Alexander; Humphreys, Isla; Meyer-Lindenberg, Andreas; Leweke, F. Markus; Tost, Heike; Akdeniz, Ceren; Rohleder, Cathrin; Bumb, J. Malte; Schwarz, Emanuel; Alptekin, Koksal; Ucok, Alp; Saka, Meram Can; Atbasoglu, E. Cem; Guloksuz, Sinan; Gumus-Akay, Guvem; Cihan, Burin; Karadag, Hasan; Soygur, Haldan; Cankurtaran, Eylem Sahin; Ulusoy, Semra; Akdede, Berna; Binbay, Tolga

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular

  6. Identifying Gene-Environment interactions in schizophrenia: Contemporary challenges for integrated, large-scale investigations

    NARCIS (Netherlands)

    European Network authors, o.a.; van der Gaag, M.

    2014-01-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular

  7. Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia.

    Science.gov (United States)

    Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Di Giorgio, Annabella; Caforio, Grazia; Taurisano, Paolo; Fazio, Leonardo; Gelao, Barbara; Attrotto, Maria Teresa; Colagiorgio, Lucia; Todarello, Giovanna; Piva, Francesco; Papazacharias, Apostolos; Masellis, Rita; Mancini, Marina; Porcelli, Annamaria; Romano, Raffaella; Rampino, Antonio; Quarto, Tiziana; Giulietti, Matteo; Lipska, Barbara K; Kleinman, Joel E; Popolizio, Teresa; Weinberger, Daniel R; Usiello, Alessandro; Bertolino, Alessandro

    2013-08-01

    OBJECTIVE Glycogen synthase kinase 3β (GSK-3β) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3β gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3β variation is implicated in multiple phenotypes relevant to schizophrenia.

  8. Treatment patterns for schizoaffective disorder and schizophrenia among Medicaid patients.

    Science.gov (United States)

    Olfson, Mark; Marcus, Steven C; Wan, George J

    2009-02-01

    This study compared background characteristics, pharmacologic treatment, and service use of adults treated for schizoaffective disorder and adults treated for schizophrenia. Medicaid claims data from two states were analyzed with a focus on adults treated for schizoaffective disorder or schizophrenia. Patient groups were compared regarding demographic characteristics, pharmacologic treatment, and health service use during 180 days before and after a claim for either schizophrenia or schizoaffective disorder. A larger proportion of patients were treated for schizophrenia (N=38,760; 70.1%) than for schizoaffective disorder (N=16,570; 29.9%). During the 180 days before the index diagnosis claim, significantly more patients with schizoaffective disorder than those with schizophrenia were treated for depressive disorder (19.6% versus 11.4%, pschizoaffective disorder, 87.3%; schizophrenia, 87.0%), although patients with schizoaffective disorder were significantly more likely than patients with schizophrenia to receive antidepressants (61.7% versus 44.0%, pschizoaffective disorder were also significantly more likely than patients with schizophrenia to receive psychotherapy (23.4% versus 13.0%, pSchizoaffective disorder is commonly diagnosed among Medicaid beneficiaries. These patients often receive complex pharmacologic regimens, and many also receive treatment for mood disorders. Differences in service use patterns between schizoaffective disorder and schizophrenia argue for separate consideration of their health care needs.

  9. The Protective Effect of Quince (Cydonia oblonga Miller Leaf Extract on Locomotor Activity and Anxiety-Like Behaviors in a Ketamine Model of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Akbar Hajizadeh Moghaddam

    2016-08-01

    Full Text Available Abstract Background: Schizophrenia is a chronic debilitating psychiatric disorder affecting 1% of the population worldwide. As for key role of free radicals in the development of this disease and that Quince leaf is a natural source of antioxidant substances, this study was aimed to evaluate the protective effects of Quince leaf extract on locomotor activity and anxiety-like behaviors by an intraperitoneal injection of ketamine in male mice in a ketamine model of schizophrenia. Materials and Methods: In the experimental research, male adult mice were divided into six groups including: control, Sham (received water orally and saline intraperitoneally, psychosis group (received 10 mg/kg/day ketamine i.p. for 10 days and treated psychosis groups (received 50, 100 and 150 mg/kg/day. Treated groups received hydroalcoholic Quince leaf extract orally for 3 weeks before injection of ketamine. Extract gavages continue for 5 days after the last ketamine injection. Locomotor activity and anxiety-like behavioral changes were measured in the open-field test. Results: The results showed that chronic administration of ketamine increases horizontal locomotor activity and anxiety like behaviors (p≤0.001 and pretreatment of Quince leaf extract effectively decreases horizontal locomotor activity (p<0.001 and increases duration that spends in middle area of Open field (p<0.01 and vertical ocomotor activity(p<0.001. Conclusion: The results of this research showed that chronic administration of Quince leaf extract improves locomotor disorder and induced anxiety-like behaviors by having antioxidant properties in a ketamine model of schizophrenia.

  10. Association of familial risk for schizophrenia with thalamic and medial prefrontal functional connectivity during attentional control.

    Science.gov (United States)

    Antonucci, Linda A; Taurisano, Paolo; Fazio, Leonardo; Gelao, Barbara; Romano, Raffaella; Quarto, Tiziana; Porcelli, Annamaria; Mancini, Marina; Di Giorgio, Annabella; Caforio, Grazia; Pergola, Giulio; Popolizio, Teresa; Bertolino, Alessandro; Blasi, Giuseppe

    2016-05-01

    Anomalies in behavioral correlates of attentional processing and related brain activity are crucial correlates of schizophrenia and associated with familial risk for this brain disorder. However, it is not clear how brain functional connectivity during attentional processes is key for schizophrenia and linked with trait vs. state related variables. To address this issue, we investigated patterns of functional connections during attentional control in healthy siblings of patients with schizophrenia, who share with probands genetic features but not variables related to the state of the disorder. 356 controls, 55 patients with schizophrenia on stable treatment with antipsychotics and 40 healthy siblings of patients with this brain disorder underwent the Variable Attentional Control (VAC) task during fMRI. Independent Component Analysis (ICA) is allowed to identify independent components (IC) of BOLD signal recorded during task performance. Results indicated reduced connectivity strength in patients with schizophrenia as well as in their healthy siblings in left thalamus within an attentional control component and greater connectivity in right medial prefrontal cortex (PFC) within the so-called Default Mode Network (DMN) compared to healthy individuals. These results suggest a relationship between familial risk for schizophrenia and brain functional networks during attentional control, such that this biological phenotype may be considered a useful intermediate phenotype in order to link genes effects to aspects of the pathophysiology of this brain disorder. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Family-based clusters of cognitive test performance in familial schizophrenia

    Directory of Open Access Journals (Sweden)

    Partonen Timo

    2004-07-01

    Full Text Available Abstract Background Cognitive traits derived from neuropsychological test data are considered to be potential endophenotypes of schizophrenia. Previously, these traits have been found to form a valid basis for clustering samples of schizophrenia patients into homogeneous subgroups. We set out to identify such clusters, but apart from previous studies, we included both schizophrenia patients and family members into the cluster analysis. The aim of the study was to detect family clusters with similar cognitive test performance. Methods Test scores from 54 randomly selected families comprising at least two siblings with schizophrenia spectrum disorders, and at least two unaffected family members were included in a complete-linkage cluster analysis with interactive data visualization. Results A well-performing, an impaired, and an intermediate family cluster emerged from the analysis. While the neuropsychological test scores differed significantly between the clusters, only minor differences were observed in the clinical variables. Conclusions The visually aided clustering algorithm was successful in identifying family clusters comprising both schizophrenia patients and their relatives. The present classification method may serve as a basis for selecting phenotypically more homogeneous groups of families in subsequent genetic analyses.

  12. Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: The SAFEHEART registry.

    Science.gov (United States)

    Bourbon, Mafalda; Alves, Ana Catarina; Alonso, Rodrigo; Mata, Nelva; Aguiar, Pedro; Padró, Teresa; Mata, Pedro

    2017-07-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disease of cholesterol metabolism that confers an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Therefore, early identification and treatment of these patients can improve prognosis and reduce the burden of cardiovascular mortality. The aim of this work was to perform the mutational analysis of the SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) registry. The study recruited 2938 individuals with genetic diagnosis of FH belonging to 775 families. Statistical analysis was performed using SPSS v23. A total of 194 variants have been detected in this study, 24 of them were never described before. About 88% of the patients have a pathogenic or likely pathogenic variant. Patients with null variants have a more severe phenotype than patients with defective variants, presenting with significantly higher levels of atherogenic particles (total cholesterol, LDL-cholesterol and apolipoprotein B). This study shows the molecular characteristics of the FH patients included in the SAFEHEART registry and the relationship with the phenotypic expression. The majority of the genetic variants are considered to be pathogenic or likely pathogenic, which confers a high level of confidence to the entry and follow-up data analysis performed with this registry concerning FH patients' prognosis, treatment and survival. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Dysbindin-1 Involvement in the Etiology of Schizophrenia

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    Haitao Wang

    2017-09-01

    Full Text Available Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

  14. Dysbindin-1 Involvement in the Etiology of Schizophrenia.

    Science.gov (United States)

    Wang, Haitao; Xu, Jiangping; Lazarovici, Philip; Zheng, Wenhua

    2017-09-22

    Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

  15. Core of schizophrenia: estrangement, dementia or neurocognitive disorder?

    DEFF Research Database (Denmark)

    Urfer-Parnas, Annick; Mortensen, Erik L; Parnas, Josef

    2010-01-01

    ) Is there empirical evidence pointing to a close similarity between schizophrenia and organic dementia? (3) Does empirical evidence support the view that intellectual impairment and/or more specific neuropsychological dysfunctions are core features of schizophrenia? The classic authors agreed that the intellectual......BACKGROUND: The recent literature frequently represents schizophrenia as a deteriorating neurocognitive process similar to organic degenerative dementia. METHODS: This study addresses the following questions: (1) Did the classic authors equate degenerative dementia with schizophrenia? (2...... dysfunctions were most likely a consequence rather than a primary, causal factor in the manifestation of schizophrenia despite their consensus on the assumption of its neurobiological origins. Rather, they considered impairments of intelligence and neurocognition as an expression of pseudodementia, i...

  16. Tourette syndrome and comorbid early-onset schizophrenia.

    Science.gov (United States)

    Kerbeshian, Jacob; Peng, Chun-Zi; Burd, Larry

    2009-12-01

    A study of the shared phenomenology between Tourette syndrome (TS) and schizophrenia. An illustrative case report is presented. We used a chart review of 399 clinically ascertained patients with TS to identify 10 cases meeting criteria for schizophrenia. From our 10 patients, salient clinical characteristics were then tabulated. We then extracted similar clinical characteristics from a previously published series of patients with comorbid TS and schizophrenia in order to combine cases and allow for a comparison between childhood-onset schizophrenia (COS), adolescent-onset schizophrenia (AdolOS), and adult-onset schizophrenia (AduOS) cases in these groups. We found 10 cases of schizophrenia (all were males) in the 399 TS patients for a prevalence rate of 2.5% (95% CI 0.96-4.04). Mean age of tic onset for TS diagnostic criteria ranged from 2-14 years with a mean of 8.2 years. The mean age of diagnosis for schizophrenia was 14.2 (range 9-23 years). We found six cases of schizophrenia with onset of positive psychotic symptoms by 13 years of age, two cases with onset after 13 years of age and before 18 years of age, and two cases with onset after 18 years of age. Attention deficit hyperactivity disorder was present at a higher rate (70%) than one would expect in a clinically ascertained group of patients with TS. Comparison between COS, AdolOS and AduOS in our pooled cases noted a sex bias skewed toward males. Catatonic symptoms may be more likely in child or adolescent onset cases and negative symptoms more likely in AduOS cases. The 2.5% prevalence of schizophrenia in our TS sample exceeds the 1% expected rate of schizophrenia in the general population (chi-square=9.14; P=.0025). The six cases of COS (before 13 years of age) exceeds the expected rate of 1-2 per 100,000 (chi-square=4499; P=.0001). The 752-fold increase in observed rates of comorbid TS and COS over expected rates suggests a role for unknown common underlying etiologic factors. Based on clinical features

  17. Autistic disorders and schizophrenia: related or remote? An anatomical likelihood estimation.

    Directory of Open Access Journals (Sweden)

    Charlton Cheung

    Full Text Available Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE, 313 foci were extracted from 25 voxel-based studies comprising 660 participants (308 ASD, 352 first-episode schizophrenia and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures.

  18. Electrical Differentiation of Mesenchymal Stem Cells into Schwann-Cell-Like Phenotypes Using Inkjet-Printed Graphene Circuits.

    Science.gov (United States)

    Das, Suprem R; Uz, Metin; Ding, Shaowei; Lentner, Matthew T; Hondred, John A; Cargill, Allison A; Sakaguchi, Donald S; Mallapragada, Surya; Claussen, Jonathan C

    2017-04-01

    Graphene-based materials (GBMs) have displayed tremendous promise for use as neurointerfacial substrates as they enable favorable adhesion, growth, proliferation, spreading, and migration of immobilized cells. This study reports the first case of the differentiation of mesenchymal stem cells (MSCs) into Schwann cell (SC)-like phenotypes through the application of electrical stimuli from a graphene-based electrode. Electrical differentiation of MSCs into SC-like phenotypes is carried out on a flexible, inkjet-printed graphene interdigitated electrode (IDE) circuit that is made highly conductive (sheet resistance electrically stimulated/treated (etMSCs) display significant enhanced cellular differentiation and paracrine activity above conventional chemical treatment strategies [≈85% of the etMSCs differentiated into SC-like phenotypes with ≈80 ng mL -1 of nerve growth factor (NGF) secretion vs. 75% and ≈55 ng mL -1 for chemically treated MSCs (ctMSCs)]. These results help pave the way for in vivo peripheral nerve regeneration where the flexible graphene electrodes could conform to the injury site and provide intimate electrical simulation for nerve cell regrowth. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Hospital Contacts With Infection and Risk of Schizophrenia

    DEFF Research Database (Denmark)

    Nielsen, Philip Finn Rising; Benros, Michael E; Mortensen, Preben B

    2014-01-01

    Infections and immune responses have been suggested to play an important role in the etiology of schizophrenia. Several studies have reported associations between maternal infections during pregnancy and the child's risk of schizophrenia; however, infection during childhood and adolescence...... a hospital contact with infection before their schizophrenia diagnosis (45%). Our results indicate that individuals who have had a hospital contact with infection are more likely to develop schizophrenia (relative risk [RR] = 1.41; 95% CI: 1.32-1.51) than individuals who had not had such a hospital contact....... Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82). Our study does not exclude that a certain type of infection may have a specific effect; yet, it does suggest that schizophrenia is associated with a wide range...

  20. Polymorphisms of XRCC4 are involved in reduced colorectal cancer risk in Chinese schizophrenia patients

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    Li Tao

    2010-10-01

    Full Text Available Abstract Background Genetic factors related to the regulation of apoptosis in schizophrenia patients may be involved in a reduced vulnerability to cancer. XRCC4 is one of the potential candidate genes associated with schizophrenia which might induce colorectal cancer resistance. Methods To examine the genetic association between colorectal cancer and schizophrenia, we analyzed five SNPs (rs6452526, rs2662238, rs963248, rs35268, rs2386275 covering ~205.7 kb in the region of XRCC4. Results We observed that two of the five genetic polymorphisms showed statistically significant differences between 312 colorectal cancer subjects without schizophrenia and 270 schizophrenia subjects (rs6452536, p = 0.004, OR 0.61, 95% CI 0.44-0.86; rs35268, p = 0.028, OR 1.54, 95% CI 1.05-2.26. Moreover, the haplotype which combined all five markers was the most significant, giving a global p = 0.0005. Conclusions Our data firstly indicate that XRCC4 may be a potential protective gene towards schizophrenia, conferring reduced susceptibility to colorectal cancer in the Han Chinese population.

  1. Maternal immune activation in rats produces temporal perception impairments in adult offspring analogous to those observed in schizophrenia.

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    Ashley R Deane

    Full Text Available The neurophysiology underlying temporal perception significantly overlaps with areas of dysfunction identified in schizophrenia. Patients commonly exhibit distorted temporal perception, which likely contributes to functional impairments. Thus, study of temporal perception in animal models of the disease may help to understand both cognitive and neurobiological factors involved in functional impairments in patients. As maternal immune activation (MIA has been shown to be a significant etiological risk factor in development of schizophrenia and other developmental psychiatric diseases, we tested interval timing in a rat model of MIA that has previously been shown to recapitulate several behavioural and neurophysiological impairments observed in the disease. Rats were tested on a temporal-bisection task, in which temporal duration stimuli were categorized as either "short" or "long" by responding to a corresponding lever. Data from this task were modeled to provide estimates of accuracy and sensitivity of temporal perception. Parameter estimates derived from the model fitting showed that MIA rats significantly overestimated the passage of time compared to controls. These results indicate that the MIA rat paradigm recapitulates timing distortions that are phenotypical of schizophrenia. These findings lend further support to the epidemiological validity of this MIA rat model, supporting its relevance for future research into the role of maternal immune activation in producing neurobiological and behavioural impairments in schizophrenia.

  2. Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia

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    Dimitri Hefter

    2018-03-01

    Full Text Available Intrauterine or perinatal complications constitute a major risk for psychiatric diseases. Infants who suffered from hypoxia–ischemia (HI are at twofold risk to develop schizophrenia in later life. Several animal models attempt to reproduce these complications to study the yet unknown steps between an insult in early life and outbreak of the disease decades later. However, it is very challenging to find the right type and severity of insult leading to a disease-like phenotype in the animal, but not causing necrosis and focal neurological deficits. By contrast, too mild, repetitive insults may even be protective via conditioning effects. Thus, it is not surprising that animal models of hypoxia lead to mixed results. To achieve clinically translatable findings, better protocols are urgently needed. Therefore, we compare widely used models of hypoxia and HI and propose future directions for the field.

  3. Influence of CFH gene on symptom severity of schizophrenia

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    Zhang C

    2017-03-01

    Full Text Available Chen Zhang,1 Qinyu Lv,1 Weixing Fan,2 Wei Tang,3 Zhenghui Yi1 1Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of Psychiatry, Jinhua Second Hospital, Jinhua, 3Department of Psychiatry, Wenzhou Kanging Hospital, Wenzhou, People’s Republic of China Objective: Recent advances have provided compelling evidence for the role of excessive complement activity in the pathophysiology of schizophrenia. In this study, we aimed to detect the association of the gene encoding complement factor H (CFH, a regulator in complement activation, with schizophrenia. Materials and methods: A sample of 1783 individuals with or without schizophrenia was recruited for genetic analysis. Genomic DNA samples were extracted from peripheral blood cells using multiplex polymerase chain reaction and the SNaPshot assay. A Database for Schizophrenia Genetic Research (SZDB was used to detect the association of brain CFH expression with schizophrenia. Next, we performed a genotype–phenotype analysis to identify the relationship between CFH Y402H polymorphism and clinical features of schizophrenia. Results: There was a significant association of hippocampal CFH expression with schizophrenia (P=0.017, whereas this significance did not survive after adjusting for false discovery rate (P=0.105. Comparing the genotype and allele frequencies of the genotyped single-nucleotide polymorphisms between case and control groups showed no significant difference. There were significant differences in the scores of negative symptoms and delayed memory between the patients with C allele and those without C allele (P<0.01 and P=0.04 after Bonferroni correction, respectively. Furthermore, we observed a marginally significant association between the Y402H polymorphism and CFH expression in the hippocampus (P=0.051; however, this significance was lost after multiple testing correction (P=0.51, after Bonferroni correction

  4. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties

    OpenAIRE

    St Pourcain, B.; Robinson, E.; Anttila, V.; Sullivan, B.; Maller, J.; Golding, J.; Skuse, D.; Ring, S.; Evans, D.; Zammit, S.; Fisher, S.; Neale, B.; Anney, R.; Ripke, S.; Hollegaard, M.

    2017-01-01

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and\\ud schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early\\ud childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether\\ud overlap in common genetic influences between these clinical conditions and impairments in social communication depends ...

  5. Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria

    Directory of Open Access Journals (Sweden)

    Hong Ming Huang

    2017-09-01

    Full Text Available Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host–parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1 which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845, and the other a truncated Ank-1 protein (MRI96570. Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1(MRI96570 mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845 caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host–parasite interactions, which could be the basis of future studies.

  6. The role of neurexins in schizophrenia and autistic spectrum disorder.

    Science.gov (United States)

    Reichelt, A C; Rodgers, R J; Clapcote, S J

    2012-03-01

    Schizophrenia and autistic spectrum disorder (ASD) are common, chronic mental conditions with both genetic and environmental components to their aetiology. The identification of genes influencing susceptibility to these disorders offers a rational route towards a clearer understanding of the neurobiology, and with this the prospect of treatment and prevention strategies tailored towards the remediation of the altered pathways. Copy number variants (CNVs) underlie many serious illnesses, including neurological and neurodevelopmental syndromes. Recent studies assessing copy number variation in ASD and schizophrenia have repeatedly observed heterozygous deletions eliminating exons of the neurexin-1α gene (but not the neurexin-1β gene) in patients with ASD and schizophrenia. The neurexins are synaptic adhesion proteins that are known to play a key role in synaptic formation and maintenance. The functional significance of the recurrent deletion is poorly understood, but the availability of mice with deletion of the promoter and first exon of neurexin-1α provides direct access to the biological effects of neurexin-1α disruption on phenotypes relevant to ASD and schizophrenia. We review the evidence for the role of neurexin-1α in schizophrenia and ASD, and consider how genetic disruption of neurexin-1α may underpin the neuropathology contributing to these distinct neurodevelopmental disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Entomophagy and coprophagy in undifferentiated schizophrenia.

    Science.gov (United States)

    Lingeswaran, Anand; Vijayakumar, Vinayak; Dinesh, John

    2009-01-01

    Coprophagia or the ingestion of feces, considered to be a variant of pica, has been associated with medical disorders like seizure disorders, cerebral atrophy, and tumors and with psychiatric disorders like mental retardation, alcoholism, depression, obsessive compulsive disorder, schizophrenia, schizoaffective disorder, fetishes, delirium, and dementia. But entomophagy or the practice of eating live or dead insects as food by humans has only been reported as part of eating habits by some cultures in the world and not in association with any medical or neuropsychiatric disorders. Till date, there is no report in medical literature of entomophagy as an association with any neuropsychiatric or medical illnesses. Coprophagy and entomophagy has not been together reported as well. We describe the first ever case report of a 19-year- old male patient diagnosed with undifferentiated schizophrenia and associated with both entomophagy and coprophagy. His schizophrenic symptoms, the entomophagic, coprophagic behaviors improved with olanzapine therapy. Entomophagy and coprophagy, two very unusual human behaviors, can be seen in association with schizophrenia.

  8. Changes in insulin-like growth factor signaling alter phenotypes in Fragile X Mice.

    Science.gov (United States)

    Wise, T L

    2017-02-01

    Fragile X syndrome (FXS) is an inherited form of intellectual disability that is usually caused by expansion of a polymorphic CGG repeat in the 5' untranslated region of the X-linked FMR1 gene, which leads to hypermethylation and transcriptional silencing. Two non-neurological phenotypes of FXS are enlarged testes and connective tissue dysplasia, which could be caused by alterations in a growth factor signaling pathway. FXS patients also frequently have autistic-like symptoms, suggesting that the signaling pathways affected in FXS may overlap with those affected in autism. Identifying these pathways is important for both understanding the effects of FMR1 inactivation and developing treatments for both FXS and autism. Here we show that decreasing the levels of the insulin-like growth factor (Igf) receptor 1 corrects a number of phenotypes in the mouse model of FXS, including macro-orchidism, and that increasing the levels of IGF2 exacerbates the seizure susceptibility phenotype. These results suggest that the pathways altered by the loss of the FMR1-encoded protein (FMRP) may overlap with the pathways affected by changes in Igf signaling or that one or more of the proteins that play a role in Igf signaling could interact with FMRP. They also indicate a new set of potential targets for drug treatment of FXS and autism spectrum disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  9. 'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

    Science.gov (United States)

    Hacohen, Yael; Rossor, Thomas; Mankad, Kshitij; Chong, Wk 'Kling'; Lux, Andrew; Wassmer, Evangeline; Lim, Ming; Barkhof, Frederik; Ciccarelli, Olga; Hemingway, Cheryl

    2018-04-01

    To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody-associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second-line immunotherapy. © 2017 Mac Keith Press.

  10. Family group conferencing in Dutch child welfare : Which families are most likely to organize a family group conference?

    NARCIS (Netherlands)

    Dijkstra, S.; Creemers, H.E.; Asscher, J.J.; Deković, M.; Stams, G.J.J.M.

    2017-01-01

    Aim of the present study was to identify which families involved in child welfare are willing to organize a Family Group conference (FGc; phase 1) and which are most likely to complete a conference (phase 2). Data were used of a Dutch randomized controlled trial (N =229). First, the proportion of

  11. Family group conferencing in Dutch child welfare : Which families are most likely to organize a family group conference?

    NARCIS (Netherlands)

    Dijkstra, Sharon; Creemers, Hanneke E.; Asscher, Jessica J.; Dekovic, Maja; Stams, Geert Jan J. M.

    2017-01-01

    Aim of the present study was to identify which families involved in child welfare are willing to organize a Family Group conference (FGc; phase 1) and which are most likely to complete a conference (phase 2). Data were used of a Dutch randomized controlled trial (N = 229). First, the proportion of

  12. Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

    DEFF Research Database (Denmark)

    Rohde, Palle Duun; Demontis, Ditte; Castro Dias Cuyabano, Beatriz

    2016-01-01

    was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case–control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism......Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited...... genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT...

  13. A False Case of Clozapine-Resistant Schizophrenia

    Directory of Open Access Journals (Sweden)

    J. P. Maia-de-Oliveira

    2010-01-01

    Full Text Available One of the subjects that most concerns physicians is treatment-resistance. About 30%–60% of schizophrenia patients do not respond adequately to antipsychotic treatment and are known as refractory schizophrenia patients. Clozapine has been the drug of choice in such cases. However, approximately 30% of them do not respond to clozapine either. Here, we describe a patient with an initial diagnosis of refractory schizophrenia who had a history of dramatic aggressiveness. However, in this case, “refractoriness” was a wrong diagnosis. A case of psychosis secondary to epilepsy had been treated as schizophrenia for almost 20 years. Reports like this one are important because they remind us of how a thorough investigation can lead to the correct diagnosis and improve the patient's prognosis.

  14. Overexpression of Rice Auxilin-Like Protein, XB21, Induces Necrotic Lesions, up-Regulates Endocytosis-Related Genes, and Confers Enhanced Resistance to Xanthomonas oryzae pv. oryzae.

    Science.gov (United States)

    Park, Chang-Jin; Wei, Tong; Sharma, Rita; Ronald, Pamela C

    2017-12-01

    The rice immune receptor XA21 confers resistance to the bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo). To elucidate the mechanism of XA21-mediated immunity, we previously performed a yeast two-hybrid screening for XA21 interactors and identified XA21 binding protein 21 (XB21). Here, we report that XB21 is an auxilin-like protein predicted to function in clathrin-mediated endocytosis. We demonstrate an XA21/XB21 in vivo interaction using co-immunoprecipitation in rice. Overexpression of XB21 in rice variety Kitaake and a Kitaake transgenic line expressing XA21 confers a necrotic lesion phenotype and enhances resistance to Xoo. RNA sequencing reveals that XB21 overexpression results in the differential expression of 8735 genes (4939 genes up- and 3846 genes down-regulated) (≥2-folds, FDR ≤0.01). The up-regulated genes include those predicted to be involved in 'cell death' and 'vesicle-mediated transport'. These results indicate that XB21 plays a role in the plant immune response and in regulation of cell death. The up-regulation of genes controlling 'vesicle-mediated transport' in XB21 overexpression lines is consistent with a functional role for XB21 as an auxilin.

  15. Nonlinkage of D6S260, a putative schizophrenia locus, to bipolar affective disorder

    Energy Technology Data Exchange (ETDEWEB)

    Adams, L.J.; Mitchell, P.B. [Univ. of South Wales (Australia); Salmon, J. [Garvan Institute of Medical Research, Sydney, New South Wales (Australia)] [and others

    1996-09-20

    To examine whether genes that predispose to schizophrenia also confer a predisposition to other psychiatric disorders such as bipolar affective disorder (BAD), we tested for linkage between the recently identified schizophrenia susceptibility locus D6S260 and the inheritance of BAD in 12 large Australian pedigrees. We found no evidence for linkage over a region of 12-27 cM from the D6S260 locus, depending on the model used. Our results therefore do not provide support for the continuum theory of psychosis. 13 refs., 2 tabs.

  16. A genetic deconstruction of neurocognitive traits in schizophrenia and bipolar disorder.

    Directory of Open Access Journals (Sweden)

    Carla P D Fernandes

    Full Text Available Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.

  17. Differential Neurodevelopmental Trajectories in Patients With Early-Onset Bipolar and Schizophrenia Disorders

    Science.gov (United States)

    Arango, Celso

    2014-01-01

    Schizophrenia and bipolar disorders share not only clinical features but also some risk factors such as genetic markers and childhood adversity, while other risk factors such as urbanicity and obstetric complications seem to be specific to schizophrenia. An intriguing question is whether the well-established abnormal neurodevelopment present in many children and adolescents who eventually develop schizophrenia is also present in bipolar patients. The literature on adult bipolar patients is controversial. We report data on a subgroup of patients with pediatric-onset psychotic bipolar disorder who seem to share some developmental trajectories with patients with early-onset schizophrenia. These early-onset psychotic bipolar patients have low intelligence quotient, more neurological signs, reduced frontal gray matter at the time of their first psychotic episode, and greater brain changes than healthy controls in a pattern similar to early-onset schizophrenia cases. However, patients with early-onset schizophrenia seem to have more social impairment, developmental abnormalities (eg, language problems), and lower academic achievement in childhood than early-onset bipolar patients. We suggest that some of these abnormal developmental trajectories are more related to the phenotypic features (eg, early-onset psychotic symptoms) of these 2 syndromes than to categorically defined Diagnostic and Statistical Manual of Mental Disorders disorders. PMID:24371326

  18. Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia.

    Science.gov (United States)

    Wolthusen, Rick P F; Hass, Johanna; Walton, Esther; Turner, Jessica A; Rössner, Veit; Sponheim, Scott R; Ho, Beng-Choon; Holt, Daphne J; Gollub, Randy L; Calhoun, Vince; Ehrlich, Stefan

    2015-08-07

    Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10 -8 ) in our GWA study, but 10 SNPs reached P-values less than 10 -6 . The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.

  19. Schizophrenia in Chinese and U.S. Online News Media: Exploring Cultural Influence on the Mediated Portrayal of Schizophrenia.

    Science.gov (United States)

    Yang, Yiyi; Parrott, Scott

    2018-05-01

    Drawing on the constructionist framing approach, this quantitative content analysis compares online news coverage of schizophrenia in China and the United States in 2015. Incorporating the concept of individualism-collectivism, this study seeks to unveil the effects of culture on the framing of causes, solutions, responsibility attribution, and discourse types. The findings reveal that the link between cultural orientation and the media's framing of schizophrenia is not simple, as both cross-cultural consistency and differences were observed. In addition, compared to U.S. online media, Chinese online news outlets were more likely to cover schizophrenia episodically, while placing more problem-solving responsibility on society. Moreover, examining stigma and challenge cues, this study also found that schizophrenia was more severely stigmatized in Chinese than in U.S. online news platforms. Theoretical and practical implications are discussed.

  20. Prevalence of schizophrenia in patients with psoriasis: a nationwide study

    Directory of Open Access Journals (Sweden)

    Hung-Pin Tu

    2017-03-01

    Conclusion: Schizophrenia is more prevalent in patients with psoriasis. Although the exact mechanisms remain to be clarified, the finding that psoriatic patients with comorbid cerebrovascular disease or chronic pulmonary disease have higher odds for schizophrenia may imply psoriatic patients with those comorbidities are likely to have higher inflammatory burden, which would contribute to the development of schizophrenia if a disruption of the blood–brain barrier is present. Further investigations are indicated to validate the hypothesis explaining the association between known comorbidies of psoriasis and schizophrenia.

  1. Schizophrenia masquerading as Dissociative Identity Disorder

    OpenAIRE

    Jegan Yogaratnam; Rajesh Jacob

    2012-01-01

    Dissociative symptoms can dominate the clinical picture in many psychiatric conditions and possess a huge challenge to the clinicians in management. We present a case report of a female with a strong family history of schizophrenia who initially presented with features suggestive of dissociative identity disorder, which is itself a rare clinical entity, was later diagnosed to have schizophrenia. Authors would like to emphasise that clinicians should have a high index of suspicion for schizoph...

  2. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

    DEFF Research Database (Denmark)

    Shi, Yongyong; Li, Zhiqiang; Xu, Qi

    2011-01-01

    Schizophrenia is a severe mental disorder affecting ~1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals...... with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort...... of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights...

  3. Mirroring the self: testing neurophysiological correlates of disturbed self-experience in schizophrenia spectrum.

    Science.gov (United States)

    Sestito, Mariateresa; Raballo, Andrea; Umiltà, Maria Alessandra; Leuci, Emanuela; Tonna, Matteo; Fortunati, Renata; De Paola, Giancarlo; Amore, Mario; Maggini, Carlo; Gallese, Vittorio

    2015-01-01

    Self-disorders (SDs) have been described as a core schizophrenia spectrum vulnerability phenotype, both in classic and contemporary psychopathological literature. However, such a core phenotype has not yet been investigated adopting a trans-domain approach that combines the phenomenological and the neurophysiological levels of analysis. The aim of this study is to investigate the relation between SDs and subtle, schizophrenia-specific impairments of emotional resonance that are supposed to reflect abnormalities in the mirror neurons mechanism. Specifically, we tested whether electromyographic response to emotional stimuli (i.e. a proxy for subtle changes in facial mimicry and related motor resonance mechanisms) would predict the occurrence of anomalous subjective experiences (i.e. SDs). Eighteen schizophrenia spectrum (SzSp) patients underwent a comprehensive psychopathological examination and were contextually tested with a multimodal paradigm, recording facial electromyographic activity of muscles in response to positive and negative emotional stimuli. Experiential anomalies were explored with the Bonn Scale for the Assessment of Basic Symptoms (BSABS) and then condensed into rational subscales mapping SzSp anomalous self-experiences. SzSp patients showed an imbalance in emotional motor resonance with a selective bias toward negative stimuli, as well as a multisensory integration impairment. Multiple regression analysis showed that electromyographic facial reactions in response to negative stimuli presented in auditory modality specifically and strongly correlated with SD subscore. The study confirms the potential of SDs as target phenotype for neurobiological research and encourages research into disturbed motor/emotional resonance as possible body-level correlate of disturbed subjective experiences in SzSp.

  4. Versican V1 Overexpression Induces a Myofibroblast-Like Phenotype in Cultured Fibroblasts.

    Directory of Open Access Journals (Sweden)

    Jon M Carthy

    Full Text Available Versican, a chondroitin sulphate proteoglycan, is one of the key components of the provisional extracellular matrix expressed after injury. The current study evaluated the hypothesis that a versican-rich matrix alters the phenotype of cultured fibroblasts.The full-length cDNA for the V1 isoform of human versican was cloned and the recombinant proteoglycan was expressed in murine fibroblasts. Versican expression induced a marked change in fibroblast phenotype. Functionally, the versican-expressing fibroblasts proliferated faster and displayed enhanced cell adhesion, but migrated slower than control cells. These changes in cell function were associated with greater N-cadherin and integrin β1 expression, along with increased FAK phosphorylation. The versican-expressing fibroblasts also displayed expression of smooth muscle α-actin, a marker of myofibroblast differentiation. Consistent with this observation, the versican fibroblasts displayed increased synthetic activity, as measured by collagen III mRNA expression, as well as a greater capacity to contract a collagen lattice. These changes appear to be mediated, at least in part, by an increase in active TGF-β signaling in the versican expressing fibroblasts, and this was measured by phosphorylation and nuclear accumulation of SMAD2.Collectively, these data indicate versican expression induces a myofibroblast-like phenotype in cultured fibroblasts.

  5. Familial and environmental influences on brain volumes in twins with schizophrenia.

    Science.gov (United States)

    Picchioni, Marco M; Rijsdijk, Fruhling; Toulopoulou, Timothea; Chaddock, Christopher; Cole, James H; Ettinger, Ulrich; Oses, Ana; Metcalfe, Hugo; Murray, Robin M; McGuire, Philip

    2017-03-01

    Reductions in whole brain and grey matter volumes are robust features of schizophrenia, yet their etiological influences are unclear. We investigated the association between the genetic and environmental risk for schizophrenia and brain volumes. Whole brain, grey matter and white matter volumes were established from structural MRIs from twins varying in their zygosity and concordance for schizophrenia. Hippocampal volumes were measured manually. We conducted between-group testing and full genetic modelling. We included 168 twins in our study. Whole brain, grey matter, white matter and right hippocampal volumes were smaller in twins with schizophrenia. Twin correlations were larger for whole brain, grey matter and white matter volumes in monozygotic than dizygotic twins and were significantly heritable, whereas hippocampal volume was the most environmentally sensitive. There was a significant phenotypic correlation between schizophrenia and reductions in all the brain volumes except for that of the left hippocampus. For whole brain, grey matter and the right hippocampus the etiological links with schizophrenia were principally associated with the shared familial environment. Lower birth weight and perinatal hypoxia were both associated with lower whole brain volume and with lower white matter and grey matter volumes, respectively. Scan data were collected across 2 sites, and some groups were modest in size. Whole brain, grey matter and right hippocampal volume reductions are linked to schizophrenia through correlated familial risk (i.e., the shared familial environment). The degree of influence of etiological factors varies between brain structures, leading to the possibility of a neuroanatomically specific etiological imprint.

  6. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice.

    Science.gov (United States)

    Iñiguez, Sergio D; Riggs, Lace M; Nieto, Steven J; Dayrit, Genesis; Zamora, Norma N; Shawhan, Kristi L; Cruz, Bryan; Warren, Brandon L

    2014-05-01

    Abstract Exposure to stress is highly correlated with the emergence of mood-related illnesses. Because major depressive disorder often emerges in adolescence, we assessed the effects of social defeat stress on responses to depressive-like behaviors in juvenile mice. To do this, postnatal day (PD) 35 male c57BL/6 mice were exposed to 10 days of social defeat stress (PD35-44), while control mice were handled daily. Twenty-four hours after the last episode of defeat (PD45), separate groups of mice were tested in the social interaction, forced swimming, sucrose preference, and elevated plus-maze behavioral assays (n = 7-12 per group). Also, we examined body weight gain across days of social defeat and levels of blood serum corticosterone 40 min after the last episode of defeat stress. Our data indicates that defeated mice exhibited a depressive-like phenotype as inferred from increased social avoidance, increased immobility in the forced swim test, and reduced sucrose preference (a measure of anhedonia), when compared to non-defeated controls. Defeated mice also displayed an anxiogenic-like phenotype when tested on the elevated plus-maze. Lastly, stressed mice displayed lower body weight gain, along with increased blood serum corticosterone levels, when compared to non-stressed controls. Overall, we show that in adolescent male c57BL/6 mice, social defeat stress induces a depression- and anxiety-like phenotype 24 h after the last episode of stress. These data suggest that the social defeat paradigm may be used to examine the etiology of stress-induced mood-related disorders during adolescence.

  7. Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia.

    Science.gov (United States)

    Winchester, Catherine L; Ohzeki, Hiromitsu; Vouyiouklis, Demetrius A; Thompson, Rhiannon; Penninger, Josef M; Yamagami, Keiji; Norrie, John D; Hunter, Robert; Pratt, Judith A; Morris, Brian J

    2012-11-15

    Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report converging evidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7-a kinase activated by glutamatergic activity. While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios: ~1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value: 3 × 10(-4)). While some caution is warranted until these association data are further replicated, these results are the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in human PFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.

  8. Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis.

    Science.gov (United States)

    Shibuya, Masako; Watanabe, Yuichiro; Nunokawa, Ayako; Egawa, Jun; Kaneko, Naoshi; Igeta, Hirofumi; Someya, Toshiyuki

    2014-01-01

    Interleukin-1 beta (IL-1β) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis. We tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations. We found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia. The present study does not support a role for IL1B in schizophrenia susceptibility.

  9. CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype.

    Science.gov (United States)

    Busquet, Perrine; Nguyen, Ngoc Khoi; Schmid, Eduard; Tanimoto, Naoyuki; Seeliger, Mathias W; Ben-Yosef, Tamar; Mizuno, Fengxia; Akopian, Abram; Striessnig, Jörg; Singewald, Nicolas

    2010-05-01

    Mounting evidence suggests that voltage-gated L-type Ca2+ channels can modulate affective behaviour. We therefore explored the role of CaV1.3 L-type Ca2+ channels in depression- and anxiety-like behaviours using CaV1.3-deficient mice (CaV1.3-/-). We showed that CaV1.3-/- mice displayed less immobility in the forced swim test as well as in the tail suspension test, indicating an antidepressant-like phenotype. Locomotor activity in the home cage or a novel open-field test was not influenced. In the elevated plus maze (EPM), CaV1.3-/- mice entered the open arms more frequently and spent more time there indicating an anxiolytic-like phenotype which was, however, not supported in the stress-induced hyperthermia test. By performing parallel experiments in Claudin 14 knockout mice (Cldn14-/-), which like CaV1.3-/- mice are congenitally deaf, an influence of deafness on the antidepressant-like phenotype could be ruled out. On the other hand, a similar EPM behaviour indicative of an anxiolytic phenotype was also found in the Cldn14-/- animals. Using electroretinography and visual behavioural tasks we demonstrated that at least in mice, CaV1.3 channels do not significantly contribute to visual function. However, marked morphological changes were revealed in synaptic ribbons in the outer plexiform layer of CaV1.3-/- retinas by immunohistochemistry suggesting a possible role of this channel type in structural plasticity at the ribbon synapse. Taken together, our findings indicate that CaV1.3 L-type Ca2+ channels modulate depression-like behaviour but are not essential for visual function. The findings raise the possibility that selective modulation of CaV1.3 channels could be a promising new therapeutic concept for the treatment of mood disorders.

  10. A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

    Science.gov (United States)

    Quinonez, Shane C; Gelehrter, Thomas D; Uhlmann, Wendy R

    2017-01-01

    Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009.

    Science.gov (United States)

    Kreyenbuhl, Julie; Buchanan, Robert W; Dickerson, Faith B; Dixon, Lisa B

    2010-01-01

    The Schizophrenia Patient Outcomes Research Team (PORT) project has played a significant role in the development and dissemination of evidence-based practices for schizophrenia. In contrast to other clinical guidelines, the Schizophrenia PORT Treatment Recommendations, initially published in 1998 and first revised in 2003, are based primarily on empirical data. Over the last 5 years, research on psychopharmacologic and psychosocial treatments for schizophrenia has continued to evolve, warranting an update of the PORT recommendations. In consultation with expert advisors, 2 Evidence Review Groups (ERGs) identified 41 treatment areas for review and conducted electronic literature searches to identify all clinical studies published since the last PORT literature review. The ERGs also reviewed studies preceding 2002 in areas not covered by previous PORT reviews, including smoking cessation, substance abuse, and weight loss. The ERGs reviewed over 600 studies and synthesized the research evidence, producing recommendations for those treatments for which the evidence was sufficiently strong to merit recommendation status. For those treatments lacking empirical support, the ERGs produced parallel summary statements. An Expert Panel consisting of 39 schizophrenia researchers, clinicians, and consumers attended a conference in November 2008 in which consensus was reached on the state of the evidence for each of the treatment areas reviewed. The methods and outcomes of the update process are presented here and resulted in recommendations for 16 psychopharmacologic and 8 psychosocial treatments for schizophrenia. Another 13 psychopharmacologic and 4 psychosocial treatments had insufficient evidence to support a recommendation, representing significant unmet needs in important treatment domains.

  12. [Evoked potentials N200/P300 disorders and clinical phenotype in Cuban families with paranoid schizophrenia: a family-based association study].

    Science.gov (United States)

    Guerra López, Seidel; Martín Reyes, Migdyrai; Pedroso Rodríguez, María de Los Ángeles; Reyes Berazain, Adnelys; Mendoza Quiñones, Raúl; Bravo Collazo, Tania Martha; Días de Villarvilla, Thais; Machado Cano, María Julia; Bobés León, María Antonieta

    2015-04-01

    N200 and P300 event-related evoked potentials provide sensitive measurements of sensory and cognitive function and have been used to study information processing in patients with schizophrenia and their unaffected first-degree relatives. Reduced amplitude and increased latency of N200 and P300 potentials have been consistently reported in schizophrenia. Thus, event-related evoked potentials abnormalities are promising possible biological markers for genetic vulnerability to schizophrenia. To assess the association of changes in latency, amplitude and topographic distribution of potentials N200 and P300 of patients with paranoid schizophrenia and their healthy first-degree relatives, in families with schizophrenia multiplex. We measured latency and amplitude of the N200 and P300 component of evoked potentials using an auditory odd-ball paradigm in 25 schizophrenic patients (probands) from 60 families multiply affected with paranoid schizophrenia, 23 of their non-schizophrenic first-degree relatives and 25 unrelated healthy controls, through a study of family association. Schizophrenic patients and their relatives showed significant latency prolongation and amplitude reduction of the N200 and P300 waves compared to controls. Left-temporal as compared to right-temporal N200 and P300 were significantly smaller in schizophrenic patients and their non-schizophrenic first-degree relatives than in controls. Our results suggest that event-related evoked potentials abnormalities may serve as markers of genetic vulnerability in schizophrenia. Confirming results of other researchers, this present study suggests that latency prolongation and amplitude reduction of the N200 and P300 waves and an altered topography at temporal sites may be a trait “marker” of paranoid schizophrenia.

  13. Proteomics as a Tool for Understanding Schizophrenia

    OpenAIRE

    Martins-de-Souza, Daniel

    2011-01-01

    Schizophrenia is likely to be a multifactorial disorder, consequence of alterations in gene and protein expression since the neurodevelopment that together to environmental factors will trigger the establishment of the disease. In the post-genomic era, proteomics has emerged as a promising strategy for revealing disease and treatment biomarkers as well as a tool for the comprehension of the mechanisms of schizophrenia pathobiology. Here, there is a discussion of the potential pathways and str...

  14. The role of social media in schizophrenia: evaluating risks, benefits, and potential.

    Science.gov (United States)

    Torous, John; Keshavan, Matcheri

    2016-05-01

    Patients with schizophrenia suffer from numerous social problems often because of negative symptoms of the illness and impairments in social cognition. Social media and social networks now offer a novel tool to engage and help patients navigate and potentially improve social functioning. In this review, we aim to explore how impaired neural networks in schizophrenia impair social functioning, examine the evidence base for social networks and social media to help in the role, consider the evidence for current risks and benefits of use, and discuss the future of social media and social networks for schizophrenia. Patients with schizophrenia are increasingly connected to and engaged with social media. There is strong evidence that they own, use, and accept digital tools like smartphones and already use social media services like Facebook at high rates, especially among those who are younger. Less is known about the clinical risks and benefits of social media use in schizophrenia, although there are increasingly more social networking platforms being designed specifically for those with mental illness. Social media tools have the potential to offer a plethora of new services to patients with schizophrenia, although the clinical evidence base for such is still nascent. It is important to ensure that both clinicians and patients are aware of and educated about the risks of using social media. Going forward, it is likely that social media will have an expanding role in care, with social media offering new pathways to address negative symptoms and impairments in social cognition in schizophrenia.

  15. Gender Identity Disorder and Schizophrenia: Neurodevelopmental Disorders with Common Causal Mechanisms?

    OpenAIRE

    Ravi Philip Rajkumar

    2014-01-01

    Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological res...

  16. Maternal genetic mutations as gestational and early life influences in producing psychiatric disease-like phenotypes in mice

    Directory of Open Access Journals (Sweden)

    Georgia eGleason

    2011-05-01

    Full Text Available Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g. maternal genetic variability and mutations. The focus of this review is maternal genotype effects that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin1A receptor (5-HT1AR and the fmr-1 gene (encoding the fragile X mental retardation protein in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Mice with 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr-1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations.

  17. Monoterpene limonene induces brown fat-like phenotype in 3T3-L1 white adipocytes.

    Science.gov (United States)

    Lone, Jameel; Yun, Jong Won

    2016-05-15

    Several dietary compounds that are able to induce the brown fat-like phenotype in white adipocytes have been considered for treatment of obesity due to their ability to increase energy expenditure. Here, we report that limonene induces the brown fat-like phenotype in 3T3-L1 adipocytes by increasing expression of brown adipocyte-specific genes and proteins. Limonene-induced browning in white adipocytes was investigated by determining expression levels of brown fat-specific genes and proteins by real-time RT-PCR, immunoblot analysis, and immunocytochemical staining. Limonene enhanced mitochondrial biogenesis, as evidenced by increased mitochondrial content and immunofluorescent intensity. Limonene also significantly elevated protein levels of HSL, PLIN, p-AMPK, p-ACC, ACO, COX4, CPT1, and CYT C, suggesting its possible role in enhancement of lipolysis and lipid catabolism. Increased expression of PRDM16, UCP1, C/EBPβ, and other brown fat-specific markers by limonene was possibly mediated by activation of β3-adnergenic receptor (β3-AR), as inhibition of β3-AR inhibited up-regulation of brown fat-specific markers. Similarly, limonene-mediated activation of ERK and up-regulation of key brown adipocyte specific markers were eliminated by treatment with ERK antagonist. Taken together, these results suggest that limonene induces browning of 3T3-L1 adipocytes via activation of β3-AR and the ERK signaling pathway. In conclusion, our findings suggest that limonene plays a dual modulatory role in induction of the brown adipocyte-like phenotype as well as promotion of lipid metabolism and thus may have potential therapeutic implications for treatment of obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

    Science.gov (United States)

    Kalueff, A V; Fox, M A; Gallagher, P S; Murphy, D L

    2007-06-01

    Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

  19. Potential impact of miR-137 and its targets in schizophrenia

    Directory of Open Access Journals (Sweden)

    Carrie eWright

    2013-04-01

    Full Text Available The significant impact of microRNAs (miRNAs on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, Ingenuity Pathway Analysis (IPA, and freely accessible bioinformatics resources. Using TargetScan and the Schizophrenia Gene Resource (SZGR database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2 and HTR2C. IPA analyses of all the potential targets identified several nervous system functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in nervous system development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function.

  20. Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first-episode schizophrenia patients

    DEFF Research Database (Denmark)

    Hammer, Trine Bjørg; Oranje, Bob; Fagerlund, Birgitte

    2011-01-01

    and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched...... not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors......Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies...

  1. CNVs conferring risk of autism or schizophrenia affect cognition in controls.

    OpenAIRE

    Stefansson, Hreinn; Meyer-Lindenberg, Andreas; Steinberg, Stacy; Magnusdottir, Brynja; Morgen, Katrin; Arnarsdottir, Sunna; Bjornsdottir, Gyda; Walters, G Bragi; Jonsdottir, Gudrun A; Doyle, Orla M; Tost, Heike; Grimm, Oliver; Kristjansdottir, Solveig; Snorrason, Heimir; Davidsdottir, Solveig R

    2014-01-01

    To access publisher's full text version of this article click on the hyperlink at the bottom of the page In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their ...

  2. Beyond diagnosis: the Core Sets for persons with schizophrenia based on the World Health Organization's International Classification of Functioning, Disability, and Health.

    Science.gov (United States)

    Gómez-Benito, Juana; Guilera, Georgina; Barrios, Maite; Rojo, Emilio; Pino, Oscar; Gorostiaga, Arantxa; Balluerka, Nekane; Hidalgo, María Dolores; Padilla, José Luis; Benítez, Isabel; Selb, Melissa

    2017-07-30

    Based on the International Classification of Functioning, Disability and Health (ICF), this paper presents the results of the process to develop the Comprehensive and Brief Core Sets for schizophrenia that allow to comprehensively describe functioning in persons with schizophrenia. Twenty health professionals from diverse backgrounds participated in a formal and iterative decision-making process during an international consensus conference to develop these Core Sets. The conference was carried out based on evidence gathered from four preparatory studies (systematic literature review, qualitative study, expert survey, and empirical study). The first step of this decision-making and consensus process comprised of discussions and voting in working groups and plenary sessions to develop the comprehensive version. The categories of the Comprehensive ICF Core Set for schizophrenia served as the basis for the second step -a ranking and cutoff procedure to decide on the brief version. Of the 184 candidate categories identified in the preparatory studies, 97 categories were included in the Comprehensive Core Set for schizophrenia. A total of 25 categories were selected to constitute the Brief Core Set. The formal decision-making and consensus process integrating evidence from four preparatory studies and expert opinion led to the first version of the Core Sets for schizophrenia. Comprehensive and Brief Core Sets for schizophrenia may provide a common language among different health professionals and researchers, and a basic international standard of what to measure, report, and assess the functioning of persons with schizophrenia. Implications for rehabilitation Schizophrenia is a chronic mental disorder that has a tremendous impact on functioning and daily life of persons living with the disorder. The International Classification of Functioning, Disability and Health (ICF) offers an internationally recognized standard for describing the functioning status of these

  3. Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia.

    Science.gov (United States)

    Hartz, Sarah M; Horton, Amy C; Oehlert, Mary; Carey, Caitlin E; Agrawal, Arpana; Bogdan, Ryan; Chen, Li-Shiun; Hancock, Dana B; Johnson, Eric O; Pato, Carlos N; Pato, Michele T; Rice, John P; Bierut, Laura J

    2017-11-15

    There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel. In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R 2 range 0.8-3.7%; minimum p = 4 × 10 -23 ). These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Staurosporine and extracellular matrix proteins mediate the conversion of small cell lung carcinoma cells into a neuron-like phenotype.

    Directory of Open Access Journals (Sweden)

    Tamara Murmann

    Full Text Available Small cell lung carcinomas (SCLCs represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions.

  5. Rethinking schizophrenia.

    Science.gov (United States)

    Insel, Thomas R

    2010-11-11

    How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades.

  6. Vitamin D in schizophrenia: a clinical review.

    Science.gov (United States)

    Chiang, Mathew; Natarajan, Radhika; Fan, Xiaoduo

    2016-02-01

    Vitamin D (vitD) is known for its essential role in calcium homeostasis and bone health. VitD is made endogenously in the skin from UVB radiation from sunlight. VitD is now considered as a potent neurosteroid hormone, critical to brain development and normal brain function, and is known for its anti-inflammatory property affecting various aspects of human health. VitD ligand-receptor, a receptor that mediates much of vitD's biological actions, has been found throughout the body including the central nervous system. VitD deficiency is common in patients with severe mental illness such as schizophrenia. Schizophrenia is a debilitating chronic mental illness characterised by positive symptoms, such as hallucinations and delusions, and negative symptoms including flat affect and lack of motivation. Several environmental risk factors for schizophrenia, such as season of birth, latitude and migration, have been linked to vitD deficiency. Recent studies have suggested a potential role of vitD in the development of schizophrenia. For example, neonatal vitD status is associated with the risk of developing schizophrenia in later life obesity, insulin resistance, diabetes, hyperlipidaemia and cardiovascular disease, which are commonly seen in patients with schizophrenia. It has been well established that vitD deficiency is related to these metabolic problems. The biological mechanism is most likely related to vitD's action on the regulation of inflammatory and immunological processes, consequently affecting the manifestation of clinical symptoms and treatment response of schizophrenia. Potential benefits of vitD supplementation to improve schizophrenia symptoms as well as physical health in patients with schizophrenia should be further explored in future studies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Epidemiological study of schizophrenia in the Chernobyl exclusion zone personnel

    International Nuclear Information System (INIS)

    Loganovsky, K.N.; Nyagu, A.I.

    1997-01-01

    Nakane and Ohta (1986) revealed very high (6 %) prevalence rate of schizophrenia in A-bomb survivors. The goal of this study was the epidemiological investigation of schizophrenia in the Chernobyl exclusion zone personnel on the base of 10-years follow up study and analysis of the psychiatric archives (1986-1996). As a result the register of schizophrenia spectrum disorders has been created, including 65 staff members. According to both ICD-9 and ICD-10 criteria there were 48 patients with schizophrenia. It has been revealed a statistically significant increase of the schizophrenia percentage amongst all psychoses in the Chernobyl exclusion zone personnel in comparison with the general Ukrainian population. It has been established that among 48 cases of schizophrenia there were 39 (81.2 %) of schizophrenia onset occurred in the zone. Since 1990 a significant increase (more than 4 times: 5.4 per 10,000 in the zone and 1.1 per 10,000 in Ukraine) in schizophrenia incidence has been taking place among the irradiated population of the exclusion zone in comparison with the general population. Our data testify to possibility of radiation-induced schizophrenia onset, which seem to be like stochastic effects of ionizing radiation. The mechanisms of these effects realization are the subject of further investigations. (author)

  8. Caregivers in schizophrenia: A cross Cultural Perspective.

    Science.gov (United States)

    Talwar, Prashant; Matheiken, Shevonne Tresa

    2010-01-01

    Schizophrenia not only influences the lives of those affected but also those around them, especially the caregivers. This study examines the different determinants that are likely to contribute to the caregivers' perception of burden of care across different countries namely Malaysia and India, using the burden assessment schedule. The goals for this study were, to study the psychosocial and demographic aspects of patients suffering from schizophrenia, to study the levels of perceived burden of the Malaysian and Indian families caring for a relative with schizophrenia, and to study the determinants that contributes to the caregivers' perception of burden of care. The study was conducted in private hospitals, both in Malaysia as well as Mangalore after obtaining the necessary approval. 50 schizophrenia patients and their caregivers in Malaysia and India were chosen using the purposive sampling technique. The inclusion criteria were a minimum of 5 years since diagnosis of schizophrenia. Although the Indian caregivers perceived difficulties in several areas such as finance, family relationship, well-being and health, they still perceived burden to be lesser compared to Malaysian counterpart. Intensified community based care can reduce burden.

  9. Clinical Decision-Making in the Treatment of Schizophrenia: Focus on Long-Acting Injectable Antipsychotics

    Directory of Open Access Journals (Sweden)

    Ludovic Samalin

    2016-11-01

    Full Text Available The purpose of this study was to identify clinician characteristics associated with higher prescription rates of long-acting injectable (LAI antipsychotics, as well as the sources that influence medical decision-making regarding the treatment of schizophrenia. We surveyed 202 psychiatrists during six regional French conferences (Bordeaux, Lyon, Marseille, Nice, Paris, and Strasbourg. Data on the characteristics of practice, prescription rates of antipsychotic, and information sources about their clinical decisions were collected. Most psychiatrists used second-generation antipsychotics (SGAs, and preferentially an oral formulation, in the treatment of schizophrenia. LAI SGAs were prescribed to 30.4% of schizophrenic patients. The duration and type of practice did not influence the class or formulation of antipsychotics used. The clinicians following the higher percentage of schizophrenic patients were associated with a higher use of LAI antipsychotics and a lower use of oral SGAs. Personal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the three main contributing factors guiding clinicians’ decision-making regarding the treatment of schizophrenia. The more clinicians follow schizophrenic patients, the more they use LAI antipsychotics. The development of specialized programs with top specialists should lead to better use of LAI antipsychotics in the treatment of schizophrenia.

  10. [Concomitant impact of organic pathology on the development of cognitive impairment in patients with attack-like paranoid schizophrenia].

    Science.gov (United States)

    Libin, L Ia; Tagil'tseva, A V; Lifanova, D E; Ganzenko, M A; Gritsevskaia, T M; Ivanov, M B

    2014-01-01

    The study included 47 patients (23 men, 24 women) with ICD-10 diagnosis of attack-like paranoid schizophrenia. Patients were divided into two groups: with- (25 patients) or without (22 patients) a concomitant organic disease. Memory, attention and thinking were assessed with psychometric tests. Inter- and intra-group differences were identified that indicated a considerable impact of a concomitant CNS organic pathology on the development of cognitive impairment in the schizophrenic process and active antipsychotic therapy. The data obtained can be used in the development of a differentiated approach to the treatment of patients with concomitant organic pathology.

  11. When should we expect microbial phenotypic traits to predict microbial abundances?

    Directory of Open Access Journals (Sweden)

    Jeremy W. Fox

    2012-08-01

    Full Text Available Species’ phenotypic traits may predict their relative abundances. Intuitively, this is because locally-abundant species have traits making them well adapted to local abiotic and biotic conditions, while locally-rare species are not as well-adapted. But this intuition may not be valid. If competing species vary in how well-adapted they are to local conditions, why doesn’t the best-adapted species simply exclude the others entirely? But conversely, if species exhibit niche differences that allow them to coexist, then by definition there is no single best adapted species. Rather, demographic rates depend on species’ relative abundances, so that phenotypic traits conferring high adaptedness do not necessarily confer high abundance. I illustrate these points using a simple theoretical model incorporating adjustable levels of "adaptedness" and "niche differences". Even very small niche differences can weaken or even reverse the expected correlation between adaptive traits and abundance. Conversely, adaptive traits confer high abundance when niche differences are very strong. Future work should be directed towards understanding the link between phenotypic traits and frequency-dependence of demographic rates.

  12. When should we expect microbial phenotypic traits to predict microbial abundances?

    Science.gov (United States)

    Fox, Jeremy W

    2012-01-01

    Species' phenotypic traits may predict their relative abundances. Intuitively, this is because locally abundant species have traits making them well-adapted to local abiotic and biotic conditions, while locally rare species are not as well-adapted. But this intuition may not be valid. If competing species vary in how well-adapted they are to local conditions, why doesn't the best-adapted species simply exclude the others entirely? But conversely, if species exhibit niche differences that allow them to coexist, then by definition there is no single best adapted species. Rather, demographic rates depend on species' relative abundances, so that phenotypic traits conferring high adaptedness do not necessarily confer high abundance. I illustrate these points using a simple theoretical model incorporating adjustable levels of "adaptedness" and "niche differences." Even very small niche differences can weaken or even reverse the expected correlation between adaptive traits and abundance. Conversely, adaptive traits confer high abundance when niche differences are very strong. Future work should be directed toward understanding the link between phenotypic traits and frequency-dependence of demographic rates.

  13. Converging models of schizophrenia - Network alterations of prefrontal cortex underlying cognitive impairments

    Science.gov (United States)

    Sakurai, Takeshi; Gamo, Nao J; Hikida, Takatoshi; Kim, Sun-Hong; Murai, Toshiya; Tomoda, Toshifumi; Sawa, Akira

    2015-01-01

    The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal. PMID:26408506

  14. Antipsychotic medication for early episode schizophrenia

    Science.gov (United States)

    Bola, John; Kao, Dennis; Soydan, Haluk; Adams, Clive E

    2014-01-01

    Background Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. Objectives To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. Search methods We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. Selection criteria Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. Data collection and analysis Working independently, we critically appraised records from 681 studies, of which five studies met inclusion criteria. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. Main results Five studies (combined total n=998) met inclusion criteria. Four studies (n=724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs n=353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT n=240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT n=236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT n=94, RR 0.96 CI 0.3 to 3.6). Two studies contributed data to assessment of adverse effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications

  15. Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

    Science.gov (United States)

    Cardno, Alastair G.

    2014-01-01

    There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant. PMID:24567502

  16. Cognitive endophenotypes, gene-environment interactions and experience-dependent plasticity in animal models of schizophrenia.

    Science.gov (United States)

    Burrows, Emma L; Hannan, Anthony J

    2016-04-01

    Schizophrenia is a devastating brain disorder caused by a complex and heterogeneous combination of genetic and environmental factors. In order to develop effective new strategies to prevent and treat schizophrenia, valid animal models are required which accurately model the disorder, and ideally provide construct, face and predictive validity. The cognitive deficits in schizophrenia represent some of the most debilitating symptoms and are also currently the most poorly treated. Therefore it is crucial that animal models are able to capture the cognitive dysfunction that characterizes schizophrenia, as well as the negative and psychotic symptoms. The genomes of mice have, prior to the recent gene-editing revolution, proven the most easily manipulable of mammalian laboratory species, and hence most genetic targeting has been performed using mouse models. Importantly, when key environmental factors of relevance to schizophrenia are experimentally manipulated, dramatic changes in the phenotypes of these animal models are often observed. We will review recent studies in rodent models which provide insight into gene-environment interactions in schizophrenia. We will focus specifically on environmental factors which modulate levels of experience-dependent plasticity, including environmental enrichment, cognitive stimulation, physical activity and stress. The insights provided by this research will not only help refine the establishment of optimally valid animal models which facilitate development of novel therapeutics, but will also provide insight into the pathogenesis of schizophrenia, thus identifying molecular and cellular targets for future preclinical and clinical investigations. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Genetic risk for schizophrenia, obstetric complications, and adolescent school outcome: evidence for gene-environment interaction.

    Science.gov (United States)

    Forsyth, Jennifer K; Ellman, Lauren M; Tanskanen, Antti; Mustonen, Ulla; Huttunen, Matti O; Suvisaari, Jaana; Cannon, Tyrone D

    2013-09-01

    Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15-16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.

  18. Clinical and epidemiological aspects of suicide in patients with schizophrenia.

    Science.gov (United States)

    Gómez-Durán, Esperanza L; Martin-Fumadó, Carles; Hurtado-Ruíz, Gemma

    2012-01-01

    Suicide is a major cause of death among patients with schizophrenia. Suicide phenomenon's characterization is the best available approach for improved prediction and prevention of suicide. Patients at high risk for suicide need a more intensive monitoring and intervention. The aim of this review is to characterize, from a clinical-epidemiological point of view, the phenomenon of completed suicide in schizophrenia. We performed a systematic review to identify the most relevant studies published between 1994 and 2009, by searching on the international database Medline and among previous reviews references. Patients with schizophrenia experience higher mortality rates than the general population, especially due to the suicide. Most patients with schizophrenia who commit suicide are likely to be young and males, with a higher risk around illness onset and hospitalization periods. Previous suicide attempts are an important risk factor for completed suicide. Suicide risk is associated to psychotic positive symptoms, affective symptoms, depression and substance abuse. Treatment adherence is as protective factor. Patients with schizophrenia are likely to commit suicide by violent means. Suicide prevention should focus on treating affective symptoms and syndromes, improving treatment compliance and providing intensive monitoring to those patients at high risk of suicide, specially around hospitalization periods. Further studies are needed to clarify differential characteristics between suicide behaviour and completed suicide.

  19. NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos

    Directory of Open Access Journals (Sweden)

    Sandra Mercier

    2013-03-01

    Holoprosencephaly (HPE is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability.

  20. Equine Mesenchymal Stromal Cells Retain a Pericyte-Like Phenotype.

    Science.gov (United States)

    Esteves, Cristina L; Sheldrake, Tara A; Dawson, Lucy; Menghini, Timothy; Rink, Burgunde Elisabeth; Amilon, Karin; Khan, Nusrat; Péault, Bruno; Donadeu, Francesc Xavier

    2017-07-01

    Mesenchymal stem/stromal cells (MSCs) have been used in human and equine regenerative medicine, and interest in exploiting their potential has increased dramatically over the years. Despite significant effort to characterize equine MSCs, the actual origin of these cells and how much of their native phenotype is maintained in culture have not been determined. In this study, we investigated the relationship between MSCs, derived from adipose tissue (AT) and bone marrow (BM), and pericytes in the horse. Both pericyte (CD146, NG2, and αSMA) and MSC (CD29, CD90, and CD73) markers were detected in equine AT and colocalized around blood vessels. Importantly, as assessed by flow cytometry, both pericyte (CD146, NG2, and αSMA) and MSC (CD29, CD44, CD90, and CD105) markers were present in a majority (≥90%) of cells in cultures of AT-MSCs and BM-MSCs; however, levels of pericyte markers were variable within each of those populations. Moreover, the expression of pericyte markers was maintained for at least eight passages in both AT-MSCs and BM-MSCs. Hematopoietic (CD45) and endothelial (CD144) markers were also detected at low levels in MSCs by quantitative polymerase chain reaction (qPCR). Finally, in coculture experiments, AT-MSCs closely associated with networks produced by endothelial cells, resembling the natural perivascular location of pericytes in vivo. Our results indicate that equine MSCs originate from perivascular cells and moreover maintain a pericyte-like phenotype in culture. Therefore, we suggest that, in addition to classical MSC markers, pericyte markers such as CD146 could be used when assessing and characterizing equine MSCs.

  1. Neural correlates of prospective memory impairments in schizophrenia.

    Science.gov (United States)

    Chen, Xing-jie; Wang, Ya; Wang, Yi; Yang, Tian-xiao; Zou, Lai-quan; Huang, Jia; Li, Feng-hua; Chen, An-tao; Wang, Wei-hong; Zheng, Han-feng; Cheung, Eric F C; Shum, David H K; Chan, Raymond C K

    2016-02-01

    Prospective memory (PM) refers to the ability to remember to carry out intended actions after a delay. PM impairments are common in schizophrenia patients and are thought to be related to their prefrontal cortex dysfunction; however, this has not yet been examined directly in the research literature. The current study aimed to examine abnormalities in brain activation during PM task performance in schizophrenia patients. Twenty-two schizophrenia patients and 25 matched healthy controls were scanned in a 3-T MRI machine while performing a PM task. The results showed that compared to the healthy controls, schizophrenia patients performed significantly worse on the PM task. Furthermore, they exhibited decreased brain activation in frontal cortex including the right superior frontal gyri (Brodmann area 10), and other related brain areas like the anterior cingulate gyrus, parietal and temporal cortex, including precuneus, and some subcortext, including parahippocampal gyrus and putamen. These findings confirm the involvement and importance of the prefrontal cortex in PM and show evidence of hypofrontality in schizophrenia patients while performing a PM task. PsycINFO Database Record (c) 2016 APA, all rights reserved.

  2. Rethinking Schizophrenia

    OpenAIRE

    Insel, Thomas R.

    2010-01-01

    How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current uns...

  3. Genes and environments in schizophrenia: The different pieces of a manifold puzzle.

    Science.gov (United States)

    Réthelyi, János M; Benkovits, Judit; Bitter, István

    2013-12-01

    Genetic research targeting schizophrenia has undergone tremendous development during recent years. Supported by recently developed high-throughput genotyping technologies, both rare and common genetic variants have been identified that show consistent association with schizophrenia. These results have been replicated by independent studies and refined in meta-analyses. The genetic variation uncovered consists of common alleles, i.e. single nucleotide polymorphisms (SNPs) conveying small effects (odds ratios below 1.1) on disease risk. The source of rare variants is copy number variations (CNVs), only detectable in a small proportion of patients (3-5% for all known CNVs) with schizophrenia, furthermore extremely rare de novo mutations captured by next generation sequencing, the most recent technological advancement in the field. Despite these findings, the search for the genetic architecture underlying schizophrenia continues since these variants explain only a small proportion of the overall phenotypic variance. Gene-environment interactions provide a compelling model for resolving this paradox and interpreting the risk factors of schizophrenia. Epidemiologically proven risk factors, such as prenatal infection, obstetric complications, urbanicity, cannabis, and trauma have been demonstrated to interact with genetic risk, giving rise to higher prevalence rates or more severe symptomatology in individuals with direct or indirect genetic predisposition for schizophrenia. Further research will have to explain how the different forms of genetic variation interact and how environmental factors modulate their effects. Moreover, the challenging question lying ahead of us is how genetic and environmental factors translate to molecular disease pathways. New approaches, including animal studies and in vitro disease modeling, as well as innovative real-world environment assessment methods, will help to understand the complex etiology of schizophrenia. Copyright © 2013

  4. Schizophrenia.

    Science.gov (United States)

    Kahn, René S; Sommer, Iris E; Murray, Robin M; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Cannon, Tyrone D; O'Donovan, Michael; Correll, Christoph U; Kane, John M; van Os, Jim; Insel, Thomas R

    2015-11-12

    Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms - such as hallucinations, delusions and disorganization - and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.

  5. Dissociation and psychosis in dissociative identity disorder and schizophrenia.

    Science.gov (United States)

    Laddis, Andreas; Dell, Paul F

    2012-01-01

    Dissociative symptoms, first-rank symptoms of schizophrenia, and delusions were assessed in 40 schizophrenia patients and 40 dissociative identity disorder (DID) patients with the Multidimensional Inventory of Dissociation (MID). Schizophrenia patients were diagnosed with the Structured Clinical Interview for the DSM-IV Axis I Disorders; DID patients were diagnosed with the Structured Clinical Interview for DSM-IV Dissociative Disorders-Revised. DID patients obtained significantly (a) higher dissociation scores; (b) higher passive-influence scores (first-rank symptoms); and (c) higher scores on scales that measure child voices, angry voices, persecutory voices, voices arguing, and voices commenting. Schizophrenia patients obtained significantly higher delusion scores than did DID patients. What is odd is that the dissociation scores of schizophrenia patients were unrelated to their reports of childhood maltreatment. Multiple regression analyses indicated that 81% of the variance in DID patients' dissociation scores was predicted by the MID's Ego-Alien Experiences Scale, whereas 92% of the variance in schizophrenia patients' dissociation scores was predicted by the MID's Voices Scale. We propose that schizophrenia patients' responses to the MID do not index the same pathology as do the responses of DID patients. We argue that neither phenomenological definitions of dissociation nor the current generation of dissociation instruments (which are uniformly phenomenological in nature) can distinguish between the dissociative phenomena of DID and what we suspect are just the dissociation-like phenomena of schizophrenia.

  6. Insight in Schizophrenia: Relationship to Positive, Negative and Neurocognitive Dimensions

    Science.gov (United States)

    Joseph, Boban; Narayanaswamy, Janardhanan C.; Venkatasubramanian, Ganesan

    2015-01-01

    Impairment of insight is considered as the hallmark of schizophrenia. Substantial proportion of patients with schizophrenia has either poor or absent insight. Insight is a multidimensional and dynamic construct which appears to have intricate links with other symptom dimensions of the psychotic illness. A better appreciation of the association that insight shares with other symptom clusters in psychosis could help us in gaining knowledge about aetiology, prognosis and treatment-related facets of the disorder. This is likely to have critical implications in the understanding and therapeutics of schizophrenia. PMID:25722504

  7. Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses.

    Science.gov (United States)

    Guilarte, Tomás R; Opler, Mark; Pletnikov, Mikhail

    2012-06-01

    Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb(2+)) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb(2+) exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb(2+) exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Is Lead Exposure in Early Life An Environmental Risk Factor for Schizophrenia? Neurobiological Connections and Testable Hypotheses

    Science.gov (United States)

    Guilarte, Tomás R.; Opler, Mark; Pletnikov, Mikhail

    2013-01-01

    Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb2+) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb2+ exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb2+ exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders. PMID:22178136

  9. [Theory of mind in schizophrenia spectrum disorders].

    Science.gov (United States)

    Bora, Emre

    2009-01-01

    To review studies that investigated theory of mind (ToM) deficits in schizophrenia spectrum disorders. After a thorough literature search, 71 studies were included in this review. Data regarding the relationship between ToM, and other cognitive skills, symptoms, and the impact of the state of illness were reviewed. ToM instruments used in schizophrenia spectrum disorders have some major psychometric limitations; however, previous research was still able to provide some important findings regarding mentalizing impairments in schizophrenia. While ToM deficits are more pronounced in the acute phase of illness, it seems to persist during periods of remission. There is also evidence of ToM deficits in the healthy relatives of schizophrenics, patients with delusional disorder and bipolar disorder (BD), and individuals with high schizotypy scores. ToM dysfunction might be secondary to other cognitive deficits in patients with schizophrenia that have a good prognosis, asymptomatic schizophrenia, delusional disorder, and BD. Other cognitive deficits do not seem to explain ToM dysfunction in patients with psychosis and severe negative symptoms. These findings support the contribution of impairment in both domain-general and domain-specific mechanisms to ToM deficits in schizophrenia spectrum disorders. ToM deficits may be important for understanding poor social functioning and poor insight in psychotic disorders. While ToM is influenced by state variables, it might be an endophenotype of schizophrenia; however, ToM is likely to be an indicator of other frontal lobe-related endophenotypes. Longitudinal studies conducted with high-risk individuals are particularly important.

  10. Sensitization, Epileptic-Like Symptoms and Local Synchronization in Patients with Paranoid Schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Bob, P.; Paluš, Milan; Šusta, M.; Glaslová, K.

    2010-01-01

    Roč. 34, č. 1 (2010), s. 143-146 ISSN 0278-5846 Grant - others:GA MŠk(CZ) 1M06039 Institutional research plan: CEZ:AV0Z10300504 Keywords : coarse-grained information rate * EEG * limbic irritability * schizophrenia * synchronization Subject RIV: FH - Neurology Impact factor: 2.877, year: 2010

  11. [Schizophrenia and informed consent to research].

    Science.gov (United States)

    Fovet, T; Amad, A; Thomas, P; Jardri, R

    2015-10-01

    Informed consent to research remains a complex issue, while sometimes staying difficult to obtain, even in the general population. This problem may be maximized with patients suffering from schizophrenia. This paper summarizes available data in the literature about informed consent for research involving patients suffering from schizophrenia. Medline and Google Scholar searches were conducted using the following MESH terms: schizophrenia, informed consent and research. Studies using dedicated standardized scales (e.g. MacCAT-CR) revealed a decrease in the capacity to consent of patients with schizophrenia when compared with healthy individuals. Keeping in mind that schizophrenia is an heterogeneous disorder, patients with the lowest insight as well as those with the most severe cognitive symptoms appeared more impaired in their capacity to consent. Such a poor capacity to understand and consent to trials was shown linked with alterations in decision-making. For these specific patients, interventions may be set up to increase their capacity to consent. Various strategies were proposed: enhanced consent forms, extended discussion, test/feedback method or multimedia interventions. Among them, interventions relying on communication and the growing field of information technologies (e.g. web-based tools) seem promising. Finally, associations grouping families and patients (like the French Association UNAFAM) may facilitate the involvement of patients in research programs with safer conditions. Patients suffering from schizophrenia appear able to consent to research programs when suitable interventions are proposed. Further studies are now needed to optimize and individualize such interventions. Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  12. Risk factors of schizophrenia development in patients with amphetamines dependence and psychosis (amphetamine-induced psychosis and schizophrenia), and without psychosis [Czynniki ryzyka rozwoju schizofrenii u pacjentów uzależnionych od amfetaminy i jej pochodnych z psychozą (pointoksykacyjną lub schizofrenią) oraz bez psychozy

    OpenAIRE

    Rabe-Jabłońska, Jolanta; Mirek, Marta; Pawełczyk, Tomasz

    2012-01-01

    Aim. Amphetamine and its derivates can induce, usually after many intoxications, schizophrenia-like psychosis. These disorders appeared only in part patients with amphetamine dependence. Aim of the study was to establish prevalence of selective risk factors of schizophrenia development in amphetamine users: 1) with amphetamine – induced schizophrenialike psychosis, 2) with schizophrenia, and 2) without psychotic symptoms. Material. In the study 3 groups of subjects were included: 30 amphet...

  13. Emotional intelligence in non-psychotic first-degree relatives of people with schizophrenia.

    Science.gov (United States)

    Albacete, Auria; Bosque, Clara; Custal, Nuria; Crespo, José M; Gilabert, Ester; Albiach, Angela; Menchón, José M; Contreras, Fernando

    2016-08-01

    Subtle social cognitive deficits in unaffected relatives of schizophrenia patients have received increasing attention over the last few years, supporting their potential endophenotypic role for this disorder. The current study assessed non-psychotic first-degree relatives' performance on a multidimensional measure of emotional intelligence (EI): the Mayer-Salovey-Caruso Emotional Intelligence Test 2.0 (MSCEIT). Endorsed by the National Institute of Mental Health, the MSCEIT is a valid and reliable instrument for detecting emotion-processing deficits among schizophrenia patients and people high in schizotypy. Thirty-seven first-degree relatives, 37 schizophrenia outpatients and 37 healthy controls completed the MSCEIT, which comprises eight subscales aimed to assess the four branches of EI: Identifying, Facilitating, Understanding and Managing Emotions. Potential associations with cognitive function and schizotypy levels, measured with the Schizotypal Personality Questionnaire-Brief, were further evaluated. Relatives had significantly lower MSCEIT total scores than controls and also significantly lower scores on the Identifying emotions branch. Nevertheless, schizophrenia patients still had the poorest global EI performance. The strongest positive correlations were found in relatives and controls with measures of executive function, processing speed and general intelligence. A higher level of schizotypy correlated significantly with lower MSCEIT scores among controls, but not among relatives. Contrary to expectations in the general population, the current study observed subtle EI impairment in non-psychotic first-degree relatives of schizophrenia patients. These findings support the hypothesis that these EI deficiencies may be potential endophenotypes located between the clinical phenotype and the genetic predisposition for schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Does Neonatal Brain Ischemia Induce Schizophrenia-Like Behavior in Young Adult Rats?

    Czech Academy of Sciences Publication Activity Database

    Tejkalová, H.; Kaiser, M.; Klaschka, Jan; Šťastný, František

    2007-01-01

    Roč. 56, č. 6 (2007), s. 815-823 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NR8797 Institutional research plan: CEZ:AV0Z10300504; CEZ:AV0Z50110509 Keywords : neonatal ischemia * schizophrenia * rat * prepulse inhibition Subject RIV: FL - Psychiatry, Sexuology Impact factor: 1.505, year: 2007

  15. Study of a possible role of the monoamine oxidase A (MAOA) gene in paranoid schizophrenia among a Chinese population.

    Science.gov (United States)

    Sun, Yuhui; Zhang, Jiexu; Yuan, Yanbo; Yu, Xin; Shen, Yan; Xu, Qi

    2012-01-01

    Monoamine oxidase A (MAOA) is the enzyme responsible for degradation of several monoamines, such as dopamine and serotonin that are considered as being two of the most important neurotransmitters involved in the pathophysiology of schizophrenia. To study a possible role of the MAOA gene in conferring susceptibility to schizophrenia, the present study genotyped the variable number of tandem repeat (VNTR) polymorphism and 41 SNPs across this gene among 555 unrelated patients with paranoid schizophrenia and 567 unrelated healthy controls. Quantitative real-time PCR analysis was employed to quantify expression of MAOA mRNA in 73 drug-free patients. While none of these genotyped DNA markers showed allelic association with paranoid schizophrenia, haplotypic association was found for the VNTR-rs6323, VNTR-rs1137070, and VNTR-rs6323-rs1137070 haplotypes in female subjects. Nevertheless, no significant change of the expression of MAOA mRNA was detected in either female or male patients with paranoid schizophrenia. Our study suggests that the interaction between genetic variants within the MAOA gene may contribute to an increased risk of paranoid schizophrenia, but the precise mechanism needs further investigation. Copyright © 2011 Wiley Periodicals, Inc.

  16. MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

    NARCIS (Netherlands)

    E. Walton (Esther); J. Liu (Jingyu); J. Hass (Johanna); T.J.H. White (Tonya); M. Scholz (Markus); V. Rœssner (Veit); R.L. Gollub (Randy); V.D. Calhoun (Vince); S.M. Ehrlich (Stefan)

    2014-01-01

    textabstractMany genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of

  17. Overexpression of Reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder.

    Science.gov (United States)

    Teixeira, Cátia M; Martín, Eduardo D; Sahún, Ignasi; Masachs, Nuria; Pujadas, Lluís; Corvelo, André; Bosch, Carles; Rossi, Daniela; Martinez, Albert; Maldonado, Rafael; Dierssen, Mara; Soriano, Eduardo

    2011-11-01

    Despite the impact of schizophrenia and mood disorders, which in extreme cases can lead to death, recent decades have brought little progress in the development of new treatments. Recent studies have shown that Reelin, an extracellular protein that is critical for neuronal development, is reduced in schizophrenia and bipolar disorder patients. However, data on a causal or protective role of Reelin in psychiatric diseases is scarce. In order to study the direct influence of Reelin's levels on behavior, we subjected two mouse lines, in which Reelin levels are either reduced (Reelin heterozygous mice) or increased (Reelin overexpressing mice), to a battery of behavioral tests: open-field, black-white box, novelty-suppressed-feeding, forced-swim-test, chronic corticosterone treatment followed by forced-swim-test, cocaine sensitization and pre-pulse inhibition (PPI) deficits induced by N-methyl-D-aspartate (NMDA) antagonists. These tests were designed to model some aspects of psychiatric disorders such as schizophrenia, mood, and anxiety disorders. We found no differences between Reeler heterozygous mice and their wild-type littermates. However, Reelin overexpression in the mouse forebrain reduced the time spent floating in the forced-swim-test in mice subjected to chronic corticosterone treatment, reduced behavioral sensitization to cocaine, and reduced PPI deficits induced by a NMDA antagonist. In addition, we demonstrate that while stress increased NMDA NR2B-mediated synaptic transmission, known to be implicated in depression, Reelin overexpression significantly reduced it. Together, these results point to the Reelin signaling pathway as a relevant drug target for the treatment of a range of psychiatric disorders.

  18. Transduction of Oct6 or Oct9 gene concomitant with Myc family gene induced osteoblast-like phenotypic conversion in normal human fibroblasts

    International Nuclear Information System (INIS)

    Mizoshiri, N.; Kishida, T.; Yamamoto, K.; Shirai, T.; Terauchi, R.; Tsuchida, S.; Mori, Y.; Ejima, A.; Sato, Y.; Arai, Y.; Fujiwara, H.; Yamamoto, T.; Kanamura, N.; Mazda, O.; Kubo, T.

    2015-01-01

    Introduction: Osteoblasts play essential roles in bone formation and regeneration, while they have low proliferation potential. Recently we established a procedure to directly convert human fibroblasts into osteoblasts (dOBs). Transduction of Runx2 (R), Osterix (X), Oct3/4 (O) and L-myc (L) genes followed by culturing under osteogenic conditions induced normal human fibroblasts to express osteoblast-specific genes and produce calcified bone matrix both in vitro and in vivo Intriguingly, a combination of only two factors, Oct3/4 and L-myc, significantly induced osteoblast-like phenotype in fibroblasts, but the mechanisms underlying the direct conversion remains to be unveiled. Materials and Methods: We examined which Oct family genes and Myc family genes are capable of inducing osteoblast-like phenotypic conversion. Results: As result Oct3/4, Oct6 and Oct9, among other Oct family members, had the capability, while N-myc was the most effective Myc family gene. The Oct9 plus N-myc was the best combination to induce direct conversion of human fibroblasts into osteoblast-like cells. Discussion: The present findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases. - Highlights: • Introducing L-myc in a combination with either Oct3/4, Oct6 or Oct9 enables the conversion of fibroblasts to osteoblasts. • A combination of L-myc with Oct3/4 or Oct9 can induce the cells to a phenotype closer to normal osteoblasts. • N-myc was considered the most appropriate Myc family gene for induction of osteoblast-like phenotype in fibroblasts. • The combination of Oct9 plus N-myc has the strongest capability of inducing osteoblast-like phenotype.

  19. Transduction of Oct6 or Oct9 gene concomitant with Myc family gene induced osteoblast-like phenotypic conversion in normal human fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Mizoshiri, N. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto (Japan); Kishida, T. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Yamamoto, K. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Dental Medicine, Kyoto Prefectural University of Medicine, Kyoto (Japan); Shirai, T.; Terauchi, R.; Tsuchida, S. [Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto (Japan); Mori, Y. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto (Japan); Ejima, A. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Sato, Y. [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Dental Medicine, Kyoto Prefectural University of Medicine, Kyoto (Japan); Arai, Y.; Fujiwara, H. [Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto (Japan); Yamamoto, T.; Kanamura, N. [Department of Dental Medicine, Kyoto Prefectural University of Medicine, Kyoto (Japan); Mazda, O., E-mail: mazda@koto.kpu-m.ac.jp [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Kubo, T. [Department of Orthopaedics, Kyoto Prefectural University of Medicine, Kyoto (Japan)

    2015-11-27

    Introduction: Osteoblasts play essential roles in bone formation and regeneration, while they have low proliferation potential. Recently we established a procedure to directly convert human fibroblasts into osteoblasts (dOBs). Transduction of Runx2 (R), Osterix (X), Oct3/4 (O) and L-myc (L) genes followed by culturing under osteogenic conditions induced normal human fibroblasts to express osteoblast-specific genes and produce calcified bone matrix both in vitro and in vivo Intriguingly, a combination of only two factors, Oct3/4 and L-myc, significantly induced osteoblast-like phenotype in fibroblasts, but the mechanisms underlying the direct conversion remains to be unveiled. Materials and Methods: We examined which Oct family genes and Myc family genes are capable of inducing osteoblast-like phenotypic conversion. Results: As result Oct3/4, Oct6 and Oct9, among other Oct family members, had the capability, while N-myc was the most effective Myc family gene. The Oct9 plus N-myc was the best combination to induce direct conversion of human fibroblasts into osteoblast-like cells. Discussion: The present findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases. - Highlights: • Introducing L-myc in a combination with either Oct3/4, Oct6 or Oct9 enables the conversion of fibroblasts to osteoblasts. • A combination of L-myc with Oct3/4 or Oct9 can induce the cells to a phenotype closer to normal osteoblasts. • N-myc was considered the most appropriate Myc family gene for induction of osteoblast-like phenotype in fibroblasts. • The combination of Oct9 plus N-myc has the strongest capability of inducing osteoblast-like phenotype.

  20. Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment.

    Science.gov (United States)

    Mouri, Akihiro; Noda, Yukihiro; Enomoto, Takeshi; Nabeshima, Toshitaka

    2007-01-01

    In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.

  1. Fundamental role of Methylenetetrahydrofolate Reductase 677 C->T genotype and Flavin compounds in biochemical phenotypes for schizophrenia and schizoaffective psychosis.

    Directory of Open Access Journals (Sweden)

    Stephanie Fryar-Williams

    2016-11-01

    different biochemical phenotypes govern findings in relationship to case-identification, illness severity, duration of illness and functional disability in schizophrenia and schizoaffective psychosis and establish a basis for gene variation guided precision treatment for the management of psychosis.

  2. Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies.

    Science.gov (United States)

    Radant, Allen D; Millard, Steven P; Braff, David L; Calkins, Monica E; Dobie, Dorcas J; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Meichle, Sean P; Nuechterlein, Keith H; Olincy, Ann; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Swerdlow, Neal R; Sugar, Catherine A; Tsuang, Ming T; Turetsky, Bruce I; Tsuang, Debby W

    2015-04-01

    The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors. Published by Elsevier B.V.

  3. Central N-acetyl aspartylglutamate deficit: a possible pathogenesis of schizophrenia.

    Science.gov (United States)

    Tsai, Shih-Jen

    2005-09-01

    The "glutamate hypothesis" of schizophrenia has emerged from the finding that phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate (NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells, including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA) and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to have some neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3 metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release. In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increase glutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate at NMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increase glutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. In this report, it is suggested that the central NAAG deficit, possibly through decreased synthesis or increased degradation of NAAG, may play a role in the pathogenesis of schizophrenia. Evidence is presented and discussed from magnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The central NAAG deficit model of schizophrenia could explain the disease process, from the perspectives of both neurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia.

  4. Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

    Science.gov (United States)

    Hijazi, H; Salih, M A; Hamad, M H A; Hassan, H H; Salih, S B M; Mohamed, K A; Mukhtar, M M; Karrar, Z A; Ansari, S; Ibrahim, N; Alkuraya, F S

    2015-01-01

    An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Strategies for Advancing Disease Definition Using Biomarkers and Genetics: The Bipolar and Schizophrenia Network for Intermediate Phenotypes.

    Science.gov (United States)

    Tamminga, Carol A; Pearlson, Godfrey D; Stan, Ana D; Gibbons, Robert D; Padmanabhan, Jaya; Keshavan, Matcheri; Clementz, Brett A

    2017-01-01

    It is critical for psychiatry as a field to develop approaches to define the molecular, cellular, and circuit basis of its brain diseases, especially for serious mental illnesses, and then to use these definitions to generate biologically based disease categories, as well as to explore disease mechanisms and illness etiologies. Our current reliance on phenomenology is inadequate to support exploration of molecular treatment targets and disease formulations, and the leap directly from phenomenology to disease biology has been limiting because of broad heterogeneity within conventional diagnoses. The questions addressed in this review are formulated around how we can use brain biomarkers to achieve disease categories that are biologically based. We have grouped together a series of vignettes as examples of early approaches, all using the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) biomarker database and collaborators, starting off with describing the foundational statistical methods for these goals. We use primarily criterion-free statistics to identify pertinent groups of involved genes related to psychosis as well as symptoms, and finally, to create new biologically based disease cohorts within the psychopathological dimension of psychosis. Although we do not put these results forward as final formulations, they represent a novel effort to rely minimally on phenomenology as a diagnostic tool and to fully embrace brain characteristics of structure, as well as molecular and cellular characteristics and function, to support disease definition in psychosis. Copyright © 2016. Published by Elsevier Inc.

  6. Catechol-O-methyltransferase Val(158)Met association with parahippocampal physiology during memory encoding in schizophrenia.

    Science.gov (United States)

    Di Giorgio, A; Caforio, G; Blasi, G; Taurisano, P; Fazio, L; Romano, R; Ursini, G; Gelao, B; Bianco, L Lo; Papazacharias, A; Sinibaldi, L; Popolizio, T; Bellomo, A; Bertolino, A

    2011-08-01

    Catechol-O-methyltransferase (COMT) Val158Met has been associated with activity of the mesial temporal lobe during episodic memory and it may weakly increase risk for schizophrenia. However, how this variant affects parahippocampal and hippocampal physiology when dopamine transmission is perturbed is unclear. The aim of the present study was to compare the effects of the COMT Val158Met genotype on parahippocampal and hippocampal physiology during encoding of recognition memory in patients with schizophrenia and in healthy subjects. Using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we studied 28 patients with schizophrenia and 33 healthy subjects matched for a series of sociodemographic and genetic variables while they performed a recognition memory task. We found that healthy subjects had greater parahippocampal and hippocampal activity during memory encoding compared to patients with schizophrenia. We also found different activity of the parahippocampal region between healthy subjects and patients with schizophrenia as a function of the COMT genotype, in that the predicted COMT Met allele dose effect had an opposite direction in controls and patients. Our results demonstrate a COMT Val158Met genotype by diagnosis interaction in parahippocampal activity during memory encoding and may suggest that modulation of dopamine signaling interacts with other disease-related processes in determining the phenotype of parahippocampal physiology in schizophrenia. © Cambridge University Press 2010

  7. An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Yasutaka Tastuzawa

    2015-01-01

    Full Text Available In addition to causing polymalformative syndrome, 22q11.2 deletion can lead to various neuropsychiatric disorders including mental retardation, psychosis, and epilepsy. However, few reports regarding epilepsy-related psychosis in 22q11.2 deletion syndrome (22q11.2DS exist. We describe the clinical characteristics and course of 22q11.2DS in a Japanese patient with comorbid mild mental retardation, childhood-onset localization-related epilepsy, and adult-onset, interictal schizophrenia-like psychosis. From a diagnostic viewpoint, early detection of impaired intellectual functioning and hyperprolinemia in patients with epilepsy with 22q11.2DS may be helpful in predicting the developmental timing of interictal psychosis. From a therapeutic viewpoint, special attention needs to be paid to phenytoin-induced hypocalcemia in this syndrome.

  8. Animal models of gene-environment interactions in schizophrenia.

    Science.gov (United States)

    Ayhan, Yavuz; Sawa, Akira; Ross, Christopher A; Pletnikov, Mikhail V

    2009-12-07

    The pathogenesis of schizophrenia and related mental illnesses likely involves multiple interactions between susceptibility genes of small effects and environmental factors. Gene-environment interactions occur across different stages of neurodevelopment to produce heterogeneous clinical and pathological manifestations of the disease. The main obstacle for mechanistic studies of gene-environment interplay has been the paucity of appropriate experimental systems for elucidating the molecular pathways that mediate gene-environment interactions relevant to schizophrenia. Recent advances in psychiatric genetics and a plethora of experimental data from animal studies allow us to suggest a new approach to gene-environment interactions in schizophrenia. We propose that animal models based on identified genetic mutations and measurable environment factors will help advance studies of the molecular mechanisms of gene-environment interplay.

  9. Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia.

    Science.gov (United States)

    Rubin, Leah H; Carter, C Sue; Drogos, Lauren; Jamadar, Rhoda; Pournajafi-Nazarloo, Hossein; Sweeney, John A; Maki, Pauline M

    2011-08-01

    We previously reported that higher levels of peripheral oxytocin are associated with lower levels of positive, general, and overall symptoms in women but not in men with schizophrenia. Here we investigate the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on emotional processing in men and women with schizophrenia. Twenty-two women with schizophrenia and 31 female controls completed the Penn Emotion Acuity Test (PEAT), a facial emotion recognition and perception task, during two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-six males with schizophrenia and 26 male controls completed testing at comparable intervals. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. No sex differences were noted on the PEAT. Plasma oxytocin levels did not fluctuate across phases of the menstrual cycle. However, female patients and controls more accurately identified facial emotions during the early follicular versus midluteal phase (pmen. Like healthy women, women with schizophrenia demonstrate menstrual-cycle dependent fluctuations in recognizing emotional cues. Like healthy women, female patients with higher levels of oxytocin perceived faces as happier. Future studies need to address whether this sex-specific relationship is associated with trust and other positive emotions, and whether exogenous oxytocin might enhance mood states and social interaction in female or all schizophrenia patients. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Alanine aminotransferase variants conferring diverse NUE phenotypes in Arabidopsis thaliana.

    Science.gov (United States)

    McAllister, Chandra H; Good, Allen G

    2015-01-01

    Alanine aminotransferase (AlaAT, E.C. 2.6.1.2), is a pyridoxal-5'-phosphate-dependent (PLP) enzyme that catalyzes the reversible transfer of an amino group from alanine to 2-oxoglutarate to produce glutamate and pyruvate, or vice versa. It has been well documented in both greenhouse and field studies that tissue-specific over-expression of AlaAT from barley (Hordeum vulgare, HvAlaAT) results in a significant increase in plant NUE in both canola and rice. While the physical phenotypes associated with over-expression of HvAlaAT have been well characterized, the role this enzyme plays in vivo to create a more N efficient plant remains unknown. Furthermore, the importance of HvAlaAT, in contrast to other AlaAT enzyme homologues in creating this phenotype has not yet been explored. To address the role of AlaAT in NUE, AlaAT variants from diverse sources and different subcellular locations, were expressed in the wild-type Arabidopsis thaliana Col-0 background and alaat1;2 (alaat1-1;alaat2-1) knockout background in various N environments. The analysis and comparison of both the physical and physiological properties of AlaAT over-expressing transgenic plants demonstrated significant differences between plants expressing the different AlaAT enzymes under different external conditions. This analysis indicates that the over-expression of AlaAT variants other than HvAlaAT in crop plants could further increase the NUE phenotype(s) previously observed.

  11. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.

    Science.gov (United States)

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-20

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies.

  12. Gamma synchrony: towards a translational biomarker for the treatment resistant symptoms of schizophrenia

    Science.gov (United States)

    Gandal, Michael J.; Edgar, J. Christopher; Klook, Kerstin; Siegel, Steven J.

    2011-01-01

    The lack of efficacy for antipsychotics with respect to negative symptoms and cognitive deficits is a significant obstacle for the treatment of schizophrenia. Developing new drugs to target these symptoms requires appropriate neural biomarkers that can be investigated in model organisms, be used to track treatment response, and provide insight into pathophysiological disease mechanisms. A growing body of evidence indicates that neural oscillations in the gamma frequency range (30–80 Hz) are disturbed in schizophrenia. Gamma synchrony has been shown to mediate a host of sensory and cognitive functions, including perceptual encoding, selective attention, salience, and working memory – neurocognitive processes that are dysfunctional in schizophrenia and largely refractory to treatment. This review summarizes the current state of clinical literature with respect to gamma band responses (GBRs) in schizophrenia, focusing on resting and auditory paradigms. Next, preclinical studies of schizophrenia that have investigated gamma band activity are reviewed to gain insight into neural mechanisms associated with these deficits. We conclude that abnormalities in gamma synchrony are ubiquitous in schizophrenia and likely reflect an elevation in baseline cortical gamma synchrony (‘noise’) coupled with reduced stimulus-evoked GBRs (‘signal’). Such a model likely reflects hippocampal and cortical dysfunction, as well as reduced glutamatergic signaling with downstream GABAergic deficits, but is probably less influenced by dopaminergic abnormalities implicated in schizophrenia. Finally, we propose that analogous signal-to-noise deficits in the flow of cortical information in preclinical models are useful targets for the development of new drugs that target the treatment-resistant symptoms of schizophrenia. PMID:21349276

  13. Refining clinical phenotypes by contrasting ethnically different populations with schizophrenia from Australia, India and Sarawak.

    Science.gov (United States)

    McLean, Duncan; John, Sujit; Barrett, Robert; McGrath, John; Loa, Peter; Thara, Rangaswamy; Mowry, Bryan

    2012-04-30

    We contrasted demographic and clinical characteristics in transethnic schizophrenia populations from Australia (n=821), India (n=520) and Sarawak, Malaysia (n=298) and proposed cultural explanations for identified site differences. From these we aimed to identify candidate variables free from significant cultural confounding that are hence suitable for inclusion in genetic analyses. We observed five phenomena: (1) more individuals were living alone in Australia than India or Sarawak; (2) drug use was lower in India than Australia or Sarawak; (3) duration of untreated psychosis (DUP) was longer in India than Australia or Sarawak; (4) the rate of schizoaffective disorder was lower in India than Australia or Sarawak; and (5) age at psychosis onset (AAO) was older in Sarawak than Australia or India. We suggest that site differences for living arrangements, drug use and DUP are culturally confounded. The schizoaffective site difference likely results from measurement bias. The AAO site difference, however, has no obvious cultural or measurement bias explanation. Therefore, this may be an ideal candidate for use in genetic studies, given that genetic variants affecting AAO have already been proposed. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function.

    Science.gov (United States)

    Smeland, Olav B; Frei, Oleksandr; Kauppi, Karolina; Hill, W David; Li, Wen; Wang, Yunpeng; Krull, Florian; Bettella, Francesco; Eriksen, Jon A; Witoelar, Aree; Davies, Gail; Fan, Chun C; Thompson, Wesley K; Lam, Max; Lencz, Todd; Chen, Chi-Hua; Ueland, Torill; Jönsson, Erik G; Djurovic, Srdjan; Deary, Ian J; Dale, Anders M; Andreassen, Ole A

    2017-10-01

    Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and

  15. Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1

    DEFF Research Database (Denmark)

    Holm-hansen, S.; Low, J. K.; Zieba, J.

    2016-01-01

    on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex....

  16. Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants.

    Science.gov (United States)

    Hauberg, Mads Engel; Roussos, Panos; Grove, Jakob; Børglum, Anders Dupont; Mattheisen, Manuel

    2016-04-01

    The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes. To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation. The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes. Results from association tests for miRNA targetomes and related analyses. In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.

  17. Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

    Science.gov (United States)

    Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

    2016-08-01

    Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

  18. Decreased left middle temporal gyrus volume in antipsychotic drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings.

    Science.gov (United States)

    Hu, Maorong; Li, Jun; Eyler, Lisa; Guo, Xiaofeng; Wei, Qingling; Tang, Jingsong; Liu, Feng; He, Zhong; Li, Lihua; Jin, Hua; Liu, Zhening; Wang, Juan; Liu, Fang; Chen, Huafu; Zhao, Jingping

    2013-03-01

    The shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover gray matter volume differences in patients with schizophrenia and their unaffected siblings with voxel-based morphometry (VBM). We recruited antipsychotic drug-naive, first-episode schizophrenia (FES) patients, their unaffected siblings and age-, sex- and handedness-matched healthy controls. We used VBM to investigate differences in gray matter volume among the 3 groups. There were significant gray matter volumetric differences among the 3 groups in bilateral hippocampal and parahippocampal gyri, bilateral middle temporal gyri, and superior temporal gyri (FDR ptemporal gyrus, and volume of this region was not different between siblings and patients. Our findings confirm and extend previous VBM analyses in schizophrenia and it indicate that schizophrenia may be characterized by an abnormal development of cerebral lateralization. Furthermore, these data argue that patients and their unaffected siblings might share decreases in the gray matter volume of the left middle temporal gyrus, and this regional reduction might be a potential endophenotype for schizophrenia. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study.

    Science.gov (United States)

    Howell, Kristy R; Pillai, Anilkumar

    2014-08-01

    Both genetic and environmental factors play important roles in the pathophysiology of schizophrenia. Although prenatal hypoxia is a potential environmental factor implicated in schizophrenia, very little is known about the consequences of combining models of genetic risk factor with prenatal hypoxia. Heterozygous reeler (haploinsufficient for reelin; HRM) and wild-type (WT) mice were exposed to prenatal hypoxia (9% oxygen for two hour) or normoxia at embryonic day 17 (E17). Behavioral (Prepulse inhibition, Y-maze and Open field) and functional (regional volume in frontal cortex and hippocampus as well as hippocampal blood flow) tests were performed at 3 months of age. The levels of hypoxia and stress-related molecules such as hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial factor (VEGF), VEGF receptor-2 (VEGFR2/Flk1) and glucocorticoid receptor (GR) were examined in frontal cortex and hippocampus at E18, 1 month and 3 months of age. In addition, serum VEGF and corticosterone levels were also examined. Prenatal hypoxia induced anxiety-like behavior in both HRM and WT mice. A significant reduction in hippocampal blood flow, but no change in brain regional volume was observed following prenatal hypoxia. Significant age and region-dependent changes in HIF-1α, VEGF, Flk1 and GR were found following prenatal hypoxia. Serum VEGF and corticosterone levels were found decreased following prenatal hypoxia. None of the above prenatal hypoxia-induced changes were either diminished or exacerbated due to reelin deficiency. These results argue against any gene-environment interaction between hypoxia and reelin deficiency. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  20. WORKING MEMORY IMPAIRMENT AS AN ENDOPHENOTYPIC MARKER OF A SCHIZOPHRENIA DIATHESIS.

    Science.gov (United States)

    Park, Sohee; Gooding, Diane C

    2014-09-01

    This chapter focuses on the viability of working memory impairment as an endophenotypic marker of a schizophrenia diathesis. It begins with an introduction of the construct of working memory. It follows with a review of the operational criteria for defining an endophenotype. Research findings regarding the working memory performance of schizophrenia and schizophrenia-spectrum patients, first-degree relatives of schizophrenia patients and healthy controls, are reviewed in terms of the criteria for being considered an endophenotypic marker. Special attention is paid to specific components of the working memory deficit (namely, encoding, maintenance, and manipulation), in terms of which aspects are likely to be the best candidates for endophenotypes. We consider the extant literature regarding working memory performance in bipolar disorder and major depression in order to address the issue of relative specificity to schizophrenia. Despite some unresolved issues, it appears that working memory impairment is a very promising candidate for an endophenotypic marker of a schizophrenia diathesis but not for mood disorders. Throughout this chapter, we identify future directions for research in this exciting and dynamic area of research and evaluate the contribution of working memory research to our understanding of schizophrenia.

  1. Working memory impairment as an endophenotypic marker of a schizophrenia diathesis

    Directory of Open Access Journals (Sweden)

    Sohee Park

    2014-09-01

    Full Text Available This review focuses on the viability of working memory impairment as an endophenotypic marker of a schizophrenia diathesis. It begins with an introduction of the construct of working memory. It follows with a consideration of the operational criteria for defining an endophenotype. Research findings regarding the working memory performance of schizophrenia and schizophrenia-spectrum patients, first-degree relatives of schizophrenia patients and healthy controls, are reviewed in terms of the criteria for being considered an endophenotypic marker. Special attention is paid to specific components of the working memory deficit (namely, encoding, maintenance, and manipulation, in terms of which aspects are likely to be the best candidates for endophenotypes. We examine the extant literature regarding working memory performance in bipolar disorder and major depression in order to address the issue of relative specificity to schizophrenia. Despite some unresolved issues, it appears that working memory impairment is a very promising candidate for an endophenotypic marker of a schizophrenia diathesis but not for mood disorders. Throughout this review, we identify future directions for research in this exciting and dynamic area of research and evaluate the contribution of working memory research to our understanding of schizophrenia.

  2. The 4-Item Negative Symptom Assessment (NSA-4) Instrument: A Simple Tool for Evaluating Negative Symptoms in Schizophrenia Following Brief Training.

    Science.gov (United States)

    Alphs, Larry; Morlock, Robert; Coon, Cheryl; van Willigenburg, Arjen; Panagides, John

    2010-07-01

    Objective. To assess the ability of mental health professionals to use the 4-item Negative Symptom Assessment instrument, derived from the Negative Symptom Assessment-16, to rapidly determine the severity of negative symptoms of schizophrenia.Design. Open participation.Setting. Medical education conferences.Participants. Attendees at two international psychiatry conferences.Measurements. Participants read a brief set of the 4-item Negative Symptom Assessment instructions and viewed a videotape of a patient with schizophrenia. Using the 1 to 6 4-item Negative Symptom Assessment severity rating scale, they rated four negative symptom items and the overall global negative symptoms. These ratings were compared with a consensus rating determination using frequency distributions and Chi-square tests for the proportion of participant ratings that were within one point of the expert rating.Results. More than 400 medical professionals (293 physicians, 50% with a European practice, and 55% who reported past utilization of schizophrenia ratings scales) participated. Between 82.1 and 91.1 percent of the 4-items and the global rating determinations by the participants were within one rating point of the consensus expert ratings. The differences between the percentage of participant rating scores that were within one point versus the percentage that were greater than one point different from those by the consensus experts was significant (pnegative symptoms using the 4-item Negative Symptom Assessment did not generally differ among the geographic regions of practice, the professional credentialing, or their familiarity with the use of schizophrenia symptom rating instruments.Conclusion. These findings suggest that clinicians from a variety of geographic practices can, after brief training, use the 4-item Negative Symptom Assessment effectively to rapidly assess negative symptoms in patients with schizophrenia.

  3. Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register

    DEFF Research Database (Denmark)

    Hilker, Rikke; Helenius, Dorte; Fagerlund, Birgitte

    2018-01-01

    sample. The estimated 79% heritability of SZ is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of SZ spectrum disorders. The low concordance rate of 33% in monozygotic twins demonstrates that illness vulnerability......BACKGROUND: Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data...... the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%). CONCLUSIONS: The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin...

  4. More Pronounced Deficits in Facial Emotion Recognition for Schizophrenia than Bipolar Disorder

    Science.gov (United States)

    Goghari, Vina M; Sponheim, Scott R

    2012-01-01

    Schizophrenia and bipolar disorder are typically separated in diagnostic systems. Behavioural, cognitive, and brain abnormalities associated with each disorder nonetheless overlap. We evaluated the diagnostic specificity of facial emotion recognition deficits in schizophrenia and bipolar disorder to determine whether select aspects of emotion recognition differed for the two disorders. The investigation used an experimental task that included the same facial images in an emotion recognition condition and an age recognition condition (to control for processes associated with general face recognition) in 27 schizophrenia patients, 16 bipolar I patients, and 30 controls. Schizophrenia and bipolar patients exhibited both shared and distinct aspects of facial emotion recognition deficits. Schizophrenia patients had deficits in recognizing angry facial expressions compared to healthy controls and bipolar patients. Compared to control participants, both schizophrenia and bipolar patients were more likely to mislabel facial expressions of anger as fear. Given that schizophrenia patients exhibited a deficit in emotion recognition for angry faces, which did not appear due to generalized perceptual and cognitive dysfunction, improving recognition of threat-related expression may be an important intervention target to improve social functioning in schizophrenia. PMID:23218816

  5. SCHIZOPHRENIA: A REVIEW

    OpenAIRE

    Parle Milind; Sharma Kailash

    2013-01-01

    Schizophrenia continues to be a mysterious disease fascinating the minds of psychiatrists, pharmacologists and neuroscientists all over the world for more than a century. The crucial welfare of the millions afflicted with schizophrenia is at stake. The cause of schizophrenia is not yet identified. However, it appears from the available reports that schizophrenia results from genetic, occupational and environmental risk factors, which act independently or combine synergistically to develop sch...

  6. Accuracy of body image perception and preferred weight loss strategies in schizophrenia: a controlled pilot study.

    Science.gov (United States)

    Loh, C; Meyer, J M; Leckband, S G

    2008-02-01

    Obesity in severely mentally ill (SMI) populations is an increasing problem, but there is no controlled data regarding the relationship between SMI and weight perception. Fifty patients with schizophrenia and 50 demographically matched control participants were recruited. Weight, height, and body image accuracy were assessed for all participants, and assessments of mood, psychotic symptom severity and anxiety, and preferred modes of weight loss were assessed for the schizophrenia sample. Patients with schizophrenia were significantly more likely to be obese than controls (46% vs. 18%, P < 0.005), and most patients expressed an interest in losing weight. Obese participants with schizophrenia underestimated their body size (11.0%) more than controls (4.9%) (P < 0.05). Patients with schizophrenia are more likely to underestimate their body size, independent of the effects of obesity. However, they also express concern about weight issues and willingness to participate in psychoeducational groups targeted at weight loss.

  7. Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks.

    Science.gov (United States)

    Dawson, Neil; Xiao, Xiaolin; McDonald, Martin; Higham, Desmond J; Morris, Brian J; Pratt, Judith A

    2014-02-01

    Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.

  8. Comparison of depression symptoms between primary depression and secondary-to-schizophrenia depression.

    Science.gov (United States)

    Rahim, Twana; Rashid, Roshe

    2017-11-01

    This study exclusively aimed to clinically assess which symptom pattern discriminates primary depression from depression-secondary to-schizophrenia. A total of 98 patients with primary depression and 71 patients with secondary-to-schizophrenia depression were assessed for identifying the clinical phenomena of depression. Diagnosis of schizophrenia was confirmed by Mini International Neuropsychiatric Interview. Each participant was, however, assessed by Patient Health Questionnaire-9 as well as Calgary Depression Scale for Schizophrenia (CDSS) for possible concurrent depressive symptoms. Depressed mood, loss of interest, reduced energy and pathological guilt were more common in primary depression, whereas sleep disturbance and guilty ideas of reference were more amounting towards the diagnosis of depression secondary-to-schizophrenia. It is clinically hard to differentiate primary from secondary-to-schizophrenia depression, especially in the absence of obvious psychotic symptoms. However, the classical symptoms of depression like subjective depressed mood, anhedonia, reduced energy and pathological guilt are more prominent in the primary depression.

  9. Attention in schizophrenia and in epileptic psychosis

    Directory of Open Access Journals (Sweden)

    I.C.J Kairalla

    2008-01-01

    Full Text Available The adaptive behavior of human beings is usually supported by rapid monitoring of outstanding events in the environment. Some investigators have suggested that a primary attention deficit might trigger symptoms of schizophrenia. In addition, researchers have long discussed the relationship between schizophrenia and the schizophrenia-like psychosis of epilepsy (SLPE. On the basis of these considerations, the objective of the present study was to investigate attention performance of patients with both disorders. Patient age was 18 to 60 years, and all patients had received formal schooling for at least four years. Patients were excluded if they had any systemic disease with neurologic or psychiatric comorbidity, or a history of brain surgery. The computer-assisted TAVIS-2R test was applied to all patients and to a control group to evaluate and discriminate between selective, alternating and sustained attention. The TAVIS-2R test is divided into three parts: one for selective attention (5 min, the second for alternating attention (5 min, and the third for the evaluation of vigilance or sustained attention (10 min. The same computer software was used for statistical analysis of reaction time, omission errors, and commission errors. The sample consisted of 36 patients with schizophrenia, 28 with interictal SLPE, and 47 healthy controls. The results of the selective attention tests for both patient groups were significantly lower than that for controls. The patients with schizophrenia and SLPE performed differently in the alternating and sustained attention tests: patients with SLPE had alternating attention deficits, whereas patients with schizophrenia showed deficits in sustained attention. These quantitative results confirmed the qualitative clinical observations for both patient groups, that is, that patients with schizophrenia had difficulties in focusing attention, whereas those with epilepsy showed perseveration in attention focus.

  10. Unlocking the treasure trove: from genes to schizophrenia biology.

    Science.gov (United States)

    McCarthy, Shane E; McCombie, W Richard; Corvin, Aiden

    2014-05-01

    Significant progress is being made in defining the genetic etiology of schizophrenia. As the list of implicated genes grows, parallel developments in gene editing technology provide new methods to investigate gene function in model systems. The confluence of these two research fields--gene discovery and functional biology--may offer novel insights into schizophrenia etiology. We review recent advances in these fields, consider the likely obstacles to progress, and consider strategies as to how these can be overcome.

  11. Molindone for schizophrenia and severe mental illness.

    Science.gov (United States)

    Bagnall, A; Fenton, M; Kleijnen, J; Lewis, R

    2007-01-24

    Antipsychotic therapy is the mainstay of treatment for people with schizophrenia. In recent years new or atypical antipsychotics have been introduced. These are less likely to produce movement disorders and raise serum prolactin. Researchers have suggested that molindone should be classified as an atypical antipsychotic. To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. For the original search we searched the following databases: Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999). We also searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog and the references of all identified studies for further trials. Finally, we contacted the manufacturer of molindone and the authors of any relevant trials. For the update of this review, we searched The Cochrane Schizophrenia Group's Trials Register (August 2005). We included all randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses. We extracted data independently and analysed on an intention to treat basis calculating, for binary data, the fixed effect relative risk (RR), their 95% confidence intervals (CI), and the number needed to treat or harm (NNT or NNH). We excluded data if loss to follow up was greater than 50%. We included fourteen studies. Duration ranged from very short (10 days) studies of the intramuscular preparation, to trials lasting over three months. For measures of global assessment, available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics we found no evidence of a difference in effectiveness (doctors' 4 RCTs n=150

  12. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.

    Science.gov (United States)

    Bramswig, Nuria C; Caluseriu, O; Lüdecke, H-J; Bolduc, F V; Noel, N C L; Wieland, T; Surowy, H M; Christen, H-J; Engels, H; Strom, T M; Wieczorek, D

    2017-03-01

    Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.

  13. Comorbid Obsessive-Compulsive Symptoms in Schizophrenia: Insight into Pathomechanisms Facilitates Treatment

    Directory of Open Access Journals (Sweden)

    Mathias Zink

    2014-01-01

    Full Text Available Insight into the biological pathomechanism of a clinical syndrome facilitates the development of effective interventions. This paper applies this perspective to the important clinical problem of obsessive-compulsive symptoms (OCS occurring during the lifetime diagnosis of schizophrenia. Up to 25% of schizophrenia patients suffer from OCS and about 12% fulfil the diagnostic criteria of obsessive-compulsive disorder (OCD. This is accompanied by marked subjective burden of disease, high levels of anxiety, depression and suicidality, increased neurocognitive impairment, less favourable levels of social and vocational functioning, and greater service utilization. Comorbid patients can be assigned to heterogeneous subgroups. It is assumed that second generation antipsychotics (SGAs, most importantly clozapine, might aggravate or even induce second-onset OCS. Several epidemiological and pharmacological arguments support this assumption. Specific genetic risk factors seem to dispose patients with schizophrenia to develop OCS and risk-conferring polymorphisms has been defined in SLC1A1, BDNF, DLGAP3, and GRIN2B and in interactions between these individual genes. Further research is needed with detailed characterization of large samples. In particular interactions between genetic risk constellations, pharmacological and psychosocial factors should be analysed. Results will further define homogeneous subgroups, which are in need for differential causative interventions. In clinical practise, schizophrenia patients should be carefully monitored for OCS, starting with at-risk mental states of psychosis and longitudinal follow-ups, hopefully leading to the development of multimodal therapeutic interventions.

  14. Paternal age related schizophrenia (PARS): Latent subgroups detected by k-means clustering analysis.

    Science.gov (United States)

    Lee, Hyejoo; Malaspina, Dolores; Ahn, Hongshik; Perrin, Mary; Opler, Mark G; Kleinhaus, Karine; Harlap, Susan; Goetz, Raymond; Antonius, Daniel

    2011-05-01

    Paternal age related schizophrenia (PARS) has been proposed as a subgroup of schizophrenia with distinct etiology, pathophysiology and symptoms. This study uses a k-means clustering analysis approach to generate hypotheses about differences between PARS and other cases of schizophrenia. We studied PARS (operationally defined as not having any family history of schizophrenia among first and second-degree relatives and fathers' age at birth ≥ 35 years) in a series of schizophrenia cases recruited from a research unit. Data were available on demographic variables, symptoms (Positive and Negative Syndrome Scale; PANSS), cognitive tests (Wechsler Adult Intelligence Scale-Revised; WAIS-R) and olfaction (University of Pennsylvania Smell Identification Test; UPSIT). We conducted a series of k-means clustering analyses to identify clusters of cases containing high concentrations of PARS. Two analyses generated clusters with high concentrations of PARS cases. The first analysis (N=136; PARS=34) revealed a cluster containing 83% PARS cases, in which the patients showed a significant discrepancy between verbal and performance intelligence. The mean paternal and maternal ages were 41 and 33, respectively. The second analysis (N=123; PARS=30) revealed a cluster containing 71% PARS cases, of which 93% were females; the mean age of onset of psychosis, at 17.2, was significantly early. These results strengthen the evidence that PARS cases differ from other patients with schizophrenia. Hypothesis-generating findings suggest that features of PARS may include a discrepancy between verbal and performance intelligence, and in females, an early age of onset. These findings provide a rationale for separating these phenotypes from others in future clinical, genetic and pathophysiologic studies of schizophrenia and in considering responses to treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Updating the mild encephalitis hypothesis of schizophrenia.

    Science.gov (United States)

    Bechter, K

    2013-04-05

    reactivation related to persistent infection) may be involved and other pathomechanisms including dysfunction of the blood-brain barrier or the blood-CSF barrier, CNS-endogenous immunity and the volume transmission mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity, and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Assessment of relatedness between neurocan gene as bipolar disorder susceptibility locus and schizophrenia

    Directory of Open Access Journals (Sweden)

    Lilijana Oruč

    2012-11-01

    Full Text Available Large scale genetic association meta-analyses showed that neurocan (NCAN gene polymorphism rs1064395 is susceptibility locus for bipolar disorder. These studies also included patients with bipolar disorder originated from Bosnia and Herzegovina. Followed by theory of shared genetic elements between bipolar disorder and schizophrenia susceptibility, other studies explored several genetic factors with schizophrenia vulnerability as well. In this work, authors investigated the association between previously confirmed bipolar disorder genetic risk factor-neurocan with schizophrenia in a population sample of Bosnia and Herzegovina.Ethical aspects of this research were assessed by Ethics Committee of Clinical Center University of Sarajevo. Blood samples for DNA extraction were taken from the total of 86 patients and healthy individuals who previously signed informed consent. Genotyping for rs 1064395 was done using direct sequencing method. A case-control analysis of common genetic polymorphism within neurocan gene and schizophrenia status in a consecutively sampled patient cohort have been done using Fisher-exact test with odds-ratio calculation. No statistically significant allele and genotype association with disease status was found (p>0.05.Our finding supports the fact that large-scale genetic association studies approach need to be employed when detecting the variants with small additive effect in phenotypes with complex ethiology.

  17. [Decision-making and schizophrenia].

    Science.gov (United States)

    Adida, M; Maurel, M; Kaladjian, A; Fakra, E; Lazerges, P; Da Fonseca, D; Belzeaux, R; Cermolacce, M; Azorin, J-M

    2011-12-01

    Abnormalities involving the prefrontal cortex (PFC) have long been postulated to underpin the pathophysiology of schizophrenia. Investigations of PFC integrity have focused mainly on the dorsolateral PFC (DLPFC) and abnormalities in this region have been extensively documented. However, defects in schizophrenia may extend to other prefrontal regions, including the ventromedial PFC (VMPFC), and evidence of VMPFC abnormalities comes from neuropathological, structural and functional studies. Patients with acquired brain injury to the VMPFC display profound disruption of social behaviour and poor judgment in their personal lives. The Iowa Gambling Task (IGT) was developed to assess decision-making in these neurological cases : it presents a series of 100 choices from four card decks that differ in the distribution of rewarding and punishing outcomes. Whilst healthy volunteers gradually develop a preference for the two "safe" decks over the course of the task, patients with VMPFC lesions maintain a preference for the two "risky" decks which are associated with high reinforcement in the short term, but significant long-term debt. Interestingly, damage to VMPFC may cause both poor performance on the IGT and lack of insight concerning the acquired personality modification. Recently, our group reported a trait-related decisionmaking impairment in the three phases of bipolar disorder. In a PET study, VMPFC dysfunction was shown in bipolar manic patients impaired on a decision-making task and an association between decision-making cognition and lack of insight was described in mania. A quantitative association between grey matter volume of VMPFC and memory impairment was previously reported in schizophrenia. Research suggests that lack of insight is a prevalent feature in schizophrenia patients, like auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. Because schizophrenia is associated with significant social or occupational

  18. Self-stigma by people diagnosed with schizophrenia, depression and anxiety: Cross-sectional survey design.

    Science.gov (United States)

    Hasan, Abd Al-Hadi; Musleh, Mahmoud

    2018-04-01

    This study investigated self-attitudes towards schizophrenia, depression and anxiety. A survey was conducted with 564 people with a schizophrenia, depression and anxiety who are currently being treated at a psychiatric clinic in Amman, Jordan. The research found that stigma towards schizophrenia, depression and anxiety was based around three factors: preconceived stereotypes, personal responsibility/blame and the perceived inability of a patient to recover. Schizophrenia, in particular, was linked more strongly to negative stereotypes and an inability to recover and less associated to personal responsibility/blame in comparison to depression and anxiety. Three identical stigma factors emerged for each diagnosis which reflected themes identified in previous literature. People with schizophrenia are seen as more dangerous and less likely to recover than those suffering from other mental illness. Anxiety was seen most favourably by the self; it was associated with less negative stereotypes and seen as more likely to cure. Interestingly, anxiety and depression were seen almost identically. The self-perception of mental health conditions, such as schizophrenia, depression and anxiety, have important implications for the planning of anti-stigma and awareness raising programmes. By gaining a thorough understanding of these perceptions and the rationale behind them, it may be possible to develop effective, tailor-made interventions. © 2017 Wiley Periodicals, Inc.

  19. First episode schizophrenia

    African Journals Online (AJOL)

    with schizophrenia present clinically with psychotic, negative and cognitive ... changes in their emotions, cognition or behaviour which may indicate a ... contribute 80% to the risk of schizophrenia developing. A number of .... Positive symptoms ... Depression ... treatment of first episode schizophrenia is of critical importance.

  20. Do patients think cannabis causes schizophrenia? - A qualitative study on the causal beliefs of cannabis using patients with schizophrenia

    Directory of Open Access Journals (Sweden)

    Schaub Michael

    2010-09-01

    Full Text Available Abstract Background There has been a considerable amount of debate among the research community whether cannabis use may cause schizophrenia and whether cannabis use of patients with schizophrenia is associated with earlier and more frequent relapses. Considering that studies exploring patients' view on controversial topics have contributed to our understanding of important clinical issues, it is surprising how little these views have been explored to add to our understanding of the link between cannabis and psychosis. The present study was designed to elucidate whether patients with schizophrenia who use cannabis believe that its use has caused their schizophrenia and to explore these patients other beliefs and perceptions about the effects of the drug. Methods We recruited ten consecutive patients fulfilling criteria for paranoid schizophrenia and for a harmful use of/dependence from cannabis (ICD-10 F20.0 + F12.1 or F12.2 from the in- and outpatient clinic of the Psychiatric University Hospital Zurich. They were interviewed using qualitative methodology. Furthermore, information on amount, frequency, and effects of use was obtained. A grounded theory approach to data analysis was taken to evaluate findings. Results None of the patients described a causal link between the use of cannabis and their schizophrenia. Disease models included upbringing under difficult circumstances (5 or use of substances other than cannabis (e. g. hallucinogens, 3. Two patients gave other reasons. Four patients considered cannabis a therapeutic aid and reported that positive effects (reduction of anxiety and tension prevailed over its possible disadvantages (exacerbation of positive symptoms. Conclusions Patients with schizophrenia did not establish a causal link between schizophrenia and the use of cannabis. We suggest that clinicians consider our findings in their work with patients suffering from these co-occurring disorders. Withholding treatment or excluding

  1. Causes of schizophrenia reported by urban African American lay community members.

    Science.gov (United States)

    Compton, Michael T; Esterberg, Michelle L; Broussard, Beth

    2008-01-01

    Although mental health professionals' "etiologic beliefs" concerning schizophrenia have evolved in accordance with diathesis-stress and neurodevelopmental models, little is known about etiologic attributions in nonclinical general population samples in the United States. Yet, course and outcome for people with the illness may be indirectly influenced by beliefs about causes in the larger community. Because of very limited research in this area, especially among African Americans in particular, this descriptive study investigated the causes of schizophrenia reported by 127 urban African Americans from the general population. The aim of this study was to assess the most commonly reported causes of schizophrenia, as well as the frequency of endorsing items from a list of 30 factors, some of which are congruent with current psychiatric conceptualizations of schizophrenia, whereas others are not. Results of this report complement previously reported findings from the same setting involving family members of patients with schizophrenia [Esterberg ML, Compton MT. Causes of schizophrenia reported by family members of urban African American hospitalized patients with schizophrenia. Compr Psychiatry 2006;47:221-226]. The 5 most commonly reported causes were disturbance of brain biochemistry (49.6%), drug/alcohol abuse (42.5%), hereditary factors (40.9%), brain injury (40.2%), and avoidance of problems in life (37.8%). The mean number of likely or very likely causes endorsed by participants was 7.5 +/- 5.7. Some 47.9% reported one or more esoteric factors as a cause. Of the 6 esoteric factors, possession by evil spirits (28.3%), radiation (20.2%), and punishment by God (19.7%) were most common. Esoteric causes were more commonly chosen by male participants, those with 12 years of education or less, and participants who reported never having known someone with schizophrenia. Future research should seek to better understand how esoteric beliefs about causation affect attitudes

  2. Entomophagy and coprophagy in undifferentiated schizophrenia

    OpenAIRE

    Lingeswaran Anand; Vijayakumar Vinayak; Dinesh John

    2009-01-01

    Coprophagia or the ingestion of feces, considered to be a variant of pica, has been associated with medical disorders like seizure disorders, cerebral atrophy, and tumors and with psychiatric disorders like mental retardation, alcoholism, depression, obsessive compulsive disorder, schizophrenia, schizoaffective disorder, fetishes, delirium, and dementia. But entomophagy or the practice of eating live or dead insects as food by humans has only been reported as part of eating habits by some cul...

  3. Influence of contact with schizophrenia on implicit attitudes towards schizophrenia patients held by clinical residents

    Directory of Open Access Journals (Sweden)

    Omori Ataru

    2012-11-01

    Full Text Available Abstract Background Patients with schizophrenia and their families have suffered greatly from stigmatizing effects. Although many efforts have been made to eradicate both prejudice and stigma, they still prevail even among medical professionals, and little is known about how contact with schizophrenia patients affects their attitudes towards schizophrenia. Methods We assessed the impact of the renaming of the Japanese term for schizophrenia on clinical residents and also evaluated the influence of contact with schizophrenia patients on attitudes toward schizophrenia by comparing the attitudes toward schizophrenia before and after a one-month clinical training period in psychiatry. Fifty-one clinical residents participated. Their attitudes toward schizophrenia were assessed twice, before and one month after clinical training in psychiatry using the Implicit Association Test (IAT as well as Link’s devaluation-discrimination scale. Results The old term for schizophrenia, “Seishin-Bunretsu-Byo”, was more congruent with criminal than the new term for schizophrenia, “Togo-Shitcho-Sho”, before clinical training. However, quite opposite to our expectation, after clinical training the new term had become even more congruent with criminal than the old term. There was no significant correlation between Link's scale and IAT effect. Conclusions Renaming the Japanese term for schizophrenia still reduced the negative images of schizophrenia among clinical residents. However, contact with schizophrenia patients unexpectedly changed clinical residents’ attitudes towards schizophrenia negatively. Our results might contribute to an understanding of the formation of negative attitudes about schizophrenia and assist in developing appropriate clinical training in psychiatry that could reduce prejudice and stigma concerning schizophrenia.

  4. Improving Functional Outcomes in College and University Students with Schizophrenia in the Western World

    Science.gov (United States)

    Christianson, Laura

    2018-01-01

    Retrospective research from patients with schizophrenia suggests that remission becomes increasingly less likely the longer psychosis goes untreated. Yet symptoms of schizophrenia are insidious and disease evolution varies between patients, requiring an ongoing diagnostic process. One way of justifying early treatment is by focusing on…

  5. Epigenetic mechanisms in schizophrenia.

    Science.gov (United States)

    Akbarian, Schahram

    2014-09-01

    Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.

  6. Community pharmacy loyalty among individuals with schizophrenia.

    Science.gov (United States)

    Lauzier, Sophie; Grégoire, Jean-Pierre; Lesage, Alain; Moisan, Jocelyne

    2013-01-01

    Community pharmacists can use medication records to assist individuals who are loyal to their pharmacy in better managing their pharmacotherapy. However, the extent of community pharmacy loyalty among individuals with severe mental illness such as schizophrenia remains unknown. To assess the extent of community pharmacy loyalty among individuals with schizophrenia and identify factors associated with loyalty. Using the Quebec Health Insurance Board databases, a cohort study of individuals with schizophrenia who claimed an antipsychotic drug for the first time between January 1, 2001 and December 31, 2005 was conducted. Such individuals were considered loyal to their community pharmacy if they filled all their prescriptions for any drug at the same community pharmacy during the second year after antipsychotics initiation. Logistic regression models were used to identify factors associated with community pharmacy loyalty (measured in the first year after antipsychotics initiation). Of the 6159 individuals in the study, 57.8% were loyal to one pharmacy. Men were more likely to be loyal (Adjusted OR = 1.29; 95% CI = 1.16-1.44), as were individuals aged 30-64 years and those aged ≥65 years, when compared to individuals 20-29 years (1.70; 1.48-1.95 and 2.39; 1.97-2.90, respectively). Individuals who filled their antipsychotics on a weekly basis were also more likely to be loyal (1.39; 1.18-1.63). Factors associated with non-loyalty were welfare beneficiary status (0.79; 0.70-0.89), having substance-use disorder (0.69; 0.60-0.80), a greater number of different types of drugs (5-8 types = 0.76; 0.66-0.87; 9-51 = 0.59; 0.50-0.69), and emergency department visits (0.71; 0.60-0.82). Results suggest that medication records in community pharmacies are incomplete for 42.2% of individuals with schizophrenia. Individuals more likely to experience more severe illness were also those less likely to be loyal. Given the potentially severe consequences of medication-related problems

  7. Hypothesis: grandiosity and guilt cause paranoia; paranoid schizophrenia is a psychotic mood disorder; a review.

    Science.gov (United States)

    Lake, Charles Raymond

    2008-11-01

    Delusional paranoia has been associated with severe mental illness for over a century. Kraepelin introduced a disorder called "paranoid depression," but "paranoid" became linked to schizophrenia, not to mood disorders. Paranoid remains the most common subtype of schizophrenia, but some of these cases, as Kraepelin initially implied, may be unrecognized psychotic mood disorders, so the relationship of paranoid schizophrenia to psychotic bipolar disorder warrants reevaluation. To address whether paranoia associates more with schizophrenia or mood disorders, a selected literature is reviewed and 11 cases are summarized. Comparative clinical and recent molecular genetic data find phenotypic and genotypic commonalities between patients diagnosed with schizophrenia and psychotic bipolar disorder lending support to the idea that paranoid schizophrenia could be the same disorder as psychotic bipolar disorder. A selected clinical literature finds no symptom, course, or characteristic traditionally considered diagnostic of schizophrenia that cannot be accounted for by psychotic bipolar disorder patients. For example, it is hypothesized here that 2 common mood-based symptoms, grandiosity and guilt, may underlie functional paranoia. Mania explains paranoia when there are grandiose delusions that one's possessions are so valuable that others will kill for them. Similarly, depression explains paranoia when delusional guilt convinces patients that they deserve punishment. In both cases, fear becomes the overwhelming emotion but patient and physician focus on the paranoia rather than on underlying mood symptoms can cause misdiagnoses. This study uses a clinical, case-based, hypothesis generation approach that warrants follow-up with a larger representative sample of psychotic patients followed prospectively to determine the degree to which the clinical course observed herein is typical of all such patients. Differential diagnoses, nomenclature, and treatment implications are

  8. Randomization and resilience of brain functional networks as systems-level endophenotypes of schizophrenia.

    Science.gov (United States)

    Lo, Chun-Yi Zac; Su, Tsung-Wei; Huang, Chu-Chung; Hung, Chia-Chun; Chen, Wei-Ling; Lan, Tsuo-Hung; Lin, Ching-Po; Bullmore, Edward T

    2015-07-21

    Schizophrenia is increasingly conceived as a disorder of brain network organization or dysconnectivity syndrome. Functional MRI (fMRI) networks in schizophrenia have been characterized by abnormally random topology. We tested the hypothesis that network randomization is an endophenotype of schizophrenia and therefore evident also in nonpsychotic relatives of patients. Head movement-corrected, resting-state fMRI data were acquired from 25 patients with schizophrenia, 25 first-degree relatives of patients, and 29 healthy volunteers. Graphs were used to model functional connectivity as a set of edges between regional nodes. We estimated the topological efficiency, clustering, degree distribution, resilience, and connection distance (in millimeters) of each functional network. The schizophrenic group demonstrated significant randomization of global network metrics (reduced clustering, greater efficiency), a shift in the degree distribution to a more homogeneous form (fewer hubs), a shift in the distance distribution (proportionally more long-distance edges), and greater resilience to targeted attack on network hubs. The networks of the relatives also demonstrated abnormal randomization and resilience compared with healthy volunteers, but they were typically less topologically abnormal than the patients' networks and did not have abnormal connection distances. We conclude that schizophrenia is associated with replicable and convergent evidence for functional network randomization, and a similar topological profile was evident also in nonpsychotic relatives, suggesting that this is a systems-level endophenotype or marker of familial risk. We speculate that the greater resilience of brain networks may confer some fitness advantages on nonpsychotic relatives that could explain persistence of this endophenotype in the population.

  9. DNA methyl transferase (DNMT gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia.

    Directory of Open Access Journals (Sweden)

    Koramannil Radha Saradalekshmi

    Full Text Available DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022 and rs2228611 (genotype P = 0.004, allele P = 0.022 were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023 and allele (P = 0.0063 increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033 was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009. DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026 confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.

  10. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    Energy Technology Data Exchange (ETDEWEB)

    Barbieri, Federica; Wurth, Roberto [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy); Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina [Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D' Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Piazza Borgo Pila, 16129, Genova (Italy); Thellung, Stefano [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy); Daga, Antonio [Laboratory of Translational Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino - IST- Istituto Nazionale Ricerca sul Cancro, L.go R. Benzi, 10, 16132 Genova Italy (Italy); Cilli, Michele [Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino - IST- Istituto Nazionale Ricerca sul Cancro, L.go R. Benzi, 10, 16132 Genova Italy (Italy); Ferrari, Angelo [Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D' Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Piazza Borgo Pila, 16129, Genova (Italy); Florio, Tullio, E-mail: tullio.florio@unige.it [Section of Pharmacology, Dept. of Internal Medicine Di.M.I., and Center of Excellence for Biomedical Research - University of Genova, Viale Benedetto XV, 2, 16132 Genova (Italy)

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  11. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    International Nuclear Information System (INIS)

    Barbieri, Federica; Wurth, Roberto; Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina; Thellung, Stefano; Daga, Antonio; Cilli, Michele; Ferrari, Angelo; Florio, Tullio

    2012-01-01

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell–like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-α and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: ► Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 ► These grow as spheres in serum-free medium and self-renew ► Isolated stem-like cancer cells initiate tumor in immunodeficient mice ► Xenografted tumors are phenotypically similar to the original tumor ► Upon differentiation, cells grow as monolayers, loosing the tumorigenic potential

  12. Canadian Practice Guidelines for Comprehensive Community Treatment for Schizophrenia and Schizophrenia Spectrum Disorders.

    Science.gov (United States)

    Addington, Donald; Anderson, Elizabeth; Kelly, Martina; Lesage, Alain; Summerville, Chris

    2017-09-01

    The objective of this review is to identify the features and components of a comprehensive system of services for people living with schizophrenia. A comprehensive system was conceived as one that served the full range of people with schizophrenia and was designed with consideration of the incidence and prevalence of schizophrenia. The system should provide access to the full range of evidence-based services, should be recovery oriented, and should provide patient-centred care. A systematic search was conducted for published guidelines for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted were primarily drawn from the National Institute for Clinical Excellence (2014) Guideline on Psychosis and Schizophrenia in adults and the Scottish Intercollegiate Guidelines Network guidelines on management of schizophrenia. The recommendations adapted for Canada cover the range of services required to provide comprehensive services. Comprehensive services for people with schizophrenia can be organized and delivered to improve the quality of life of people with schizophrenia and their carers. The services need to be organized in a system that provides access to those who need them.

  13. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

    Science.gov (United States)

    Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

    2015-02-15

    The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

  14. Dreaming and Schizophrenia.

    Science.gov (United States)

    Stickney, Jeffrey L.

    Parallels between dream states and schizophrenia suggest that the study of dreams may offer some information about schizophrenia. A major theoretical assumption of the research on dreaming and schizophrenia is that, in schizophrenics, the dream state intrudes on the awake state creating a dreamlike symptomatology. This theory, called the REM…

  15. Brain neurodevelopmental markers related to the deficit subtype of schizophrenia.

    Science.gov (United States)

    Takahashi, Tsutomu; Takayanagi, Yoichiro; Nishikawa, Yumiko; Nakamura, Mihoko; Komori, Yuko; Furuichi, Atsushi; Kido, Mikio; Sasabayashi, Daiki; Noguchi, Kyo; Suzuki, Michio

    2017-08-30

    Deficit schizophrenia is a homogeneous subtype characterized by a trait-like feature of primary and prominent negative symptoms, but the etiologic factors related to this specific subtype remain largely unknown. This magnetic resonance imaging study aimed to examine gross brain morphology that probably reflects early neurodevelopment in 38 patients with deficit schizophrenia, 37 patients with non-deficit schizophrenia, and 59 healthy controls. Potential brain neurodevelopmental markers investigated in this study were the adhesio interthalamica (AI), cavum septi pellucidi (CSP), and surface morphology (i.e., olfactory sulcus depth, sulcogyral pattern, and number of orbital sulci) of the orbitofrontal cortex (OFC). The subtype classification of schizophrenia patients was based on the score of Proxy for the Deficit Syndrome. The deficit schizophrenia group had a significantly shorter AI compared with the non-deficit group and controls. The deficit group, but not the non-deficit group, was also characterized by an altered distribution of the OFC sulcogyral pattern, as well as fewer posterior orbital sulcus compared with controls. Other neurodevelopmental markers did not differentiate the deficit and non-deficit subgroups. These results suggest that the deficit subtype of schizophrenia and its clinical manifestation may be at least partly related to prominent neurodevelopmental pathology. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  16. Modifiable risk factors for schizophrenia and autism--shared risk factors impacting on brain development.

    Science.gov (United States)

    Hamlyn, Jess; Duhig, Michael; McGrath, John; Scott, James

    2013-05-01

    Schizophrenia and autism are two poorly understood clinical syndromes that differ in age of onset and clinical profile. However, recent genetic and epidemiological research suggests that these two neurodevelopmental disorders share certain risk factors. The aims of this review are to describe modifiable risk factors that have been identified in both disorders, and, where available, collate salient systematic reviews and meta-analyses that have examined shared risk factors. Based on searches of Medline, Embase and PsycINFO, inspection of review articles and expert opinion, we first compiled a set of candidate modifiable risk factors associated with autism. Where available, we next collated systematic-reviews (with or without meta-analyses) related to modifiable risk factors associated with both autism and schizophrenia. We identified three modifiable risk factors that have been examined in systematic reviews for both autism and schizophrenia. Advanced paternal age was reported as a risk factor for schizophrenia in a single meta-analysis and as a risk factor in two meta-analyses for autism. With respect to pregnancy and birth complications, for autism one meta-analysis identified maternal diabetes and bleeding during pregnancy as risks factors for autism whilst a meta-analysis of eight studies identified obstetric complications as a risk factor for schizophrenia. Migrant status was identified as a risk factor for both autism and schizophrenia. Two separate meta-analyses were identified for each disorder. Despite distinct clinical phenotypes, the evidence suggests that at least some non-genetic risk factors are shared between these two syndromes. In particular, exposure to drugs, nutritional excesses or deficiencies and infectious agents lend themselves to public health interventions. Studies are now needed to quantify any increase in risk of either autism or schizophrenia that is associated with these modifiable environmental factors. Copyright © 2012 Elsevier Inc

  17. Beliefs about the cause of schizophrenia among caregivers in Midwestern Nigeria

    Directory of Open Access Journals (Sweden)

    Osayi Igberase

    2017-07-01

    Full Text Available Schizophrenia is a devastating illness with a chronic and relapsing course. While Western countries may endorse, biological and psychosocial causes more commonly than supernatural causes, non-western cultures like Nigeria in contrast, tend to endorse supernatural causes. Belief in supernatural causes has been reported to have consequences for treatment seeking behavior. This study aimed to examine the causes of schizophrenia reported by family members of outpatients with schizophrenia in a neuropsychiatric hospital in Midwestern Nigeria. In this study, we recruited a convenient sample of 200 consecutive caregivers of patients visiting the outpatient department of the Psychiatric Hospital, Benin City, Nigeria. These primary caregivers were unpaid relatives who provided support to patients. The patients were service users who fulfilled the diagnostic criteria of the International Classification of Disease [ICD-10; World Health Organization 1993] for schizophrenia and had been on treatment for at least two years. Majority (72.0% of caregivers endorsed supernatural causes as most important in the etiology of schizophrenia, while 28.0% endorsed natural causes. Every participant without formal education endorsed supernatural attribution. In our study, it was evident that participants embraced multiple causal attributions for schizophrenia.

  18. Odontoblast-Like Cells Differentiated from Dental Pulp Stem Cells Retain Their Phenotype after Subcultivation

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    Paula A. Baldión

    2018-01-01

    Full Text Available Odontoblasts, the main cell type in teeth pulp tissue, are not cultivable and they are responsible for the first line of response after dental restauration. Studies on dental materials cytotoxicity and odontoblast cells physiology require large quantity of homogenous cells retaining most of the phenotype characteristics. Odontoblast-like cells (OLC were differentiated from human dental pulp stem cells using differentiation medium (containing TGF-β1, and OLC expanded after trypsinization (EXP-21 were evaluated and compared. Despite a slower cell growth curve, EXP-21 cells express similarly the odontoblast markers dentinal sialophosphoprotein and dentin matrix protein-1 concomitantly with RUNX2 transcripts and low alkaline phosphatase activity as expected. Both OLC and EXP-21 cells showed similar mineral deposition activity evidenced by alizarin red and von Kossa staining. These results pointed out minor changes in phenotype of subcultured EXP-21 regarding the primarily differentiated OLC, making the subcultivation of these cells a useful strategy to obtain odontoblasts for biocompatibility or cell physiology studies in dentistry.

  19. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia.

    Science.gov (United States)

    Salisbury, Dean F; Shenton, Martha E; Griggs, Carlye B; Bonner-Jackson, Aaron; McCarley, Robert W

    2002-08-01

    Mismatch negativity (MMN) is an event-related brain potential that is sensitive to stimulus deviation from a repetitive pattern. The MMN is thought primarily to reflect the activity of sensory memory, with, at most, moderate influences of higher-level cognitive processes, such as attention. The MMN is reported to be reduced in patients with chronic schizophrenia. However, it is unknown whether MMN is reduced in patients with first-episode schizophrenia (at first hospitalization). Subject groups comprised patients with chronic schizophrenia (n = 16) and older control subjects (n = 13), and patients with first-episode schizophrenia (n = 21) and younger control subjects (n = 27). The MMN was visualized by subtracting the averaged event-related brain potential to standard tones (1 kHz [95% of all tones]) from the event-related brain potential to pitch-deviant tones (1.2 kHz [5% of all tones]). The MMN voltage was the mean voltage from 100 to 200 milliseconds. Pitch-deviant MMN was reduced by approximately 47% in patients with chronic illness along the sagittal midline relative to controls. The MMN was not reduced in patients with first-episode schizophrenia. All 4 groups showed approximately 64% larger MMN to pitch-deviant tones over the right hemisphere compared with the left hemisphere. The pitch-deviant MMN reductions present in patients with chronic schizophrenia are not present at first hospitalization. The sensory, echoic memory functions indexed by MMN seem unaffected early in the schizophrenia disease process. Reductions in MMN amplitude may develop over time and index the progression of the disorder, although that can only be definitively determined by longitudinal assessments.

  20. Phenotypic characterization, genetic mapping and candidate gene analysis of a source conferring reduced plant height in sunflower.

    Science.gov (United States)

    Ramos, María Laura; Altieri, Emiliano; Bulos, Mariano; Sala, Carlos A

    2013-01-01

    Reduced height germplasm has the potential to increase stem strength, standability, and also yields potential of the sunflower crop (Helianthus annuus L. var. macrocarpus Ckll.). In this study, we report on the inheritance, mapping, phenotypic and molecular characterization of a reduced plant height trait in inbred lines derived from the source DDR. This trait is controlled by a semidominant allele, Rht1, which maps on linkage group 12 of the sunflower public consensus map. Phenotypic effects of this allele include shorter height and internode length, insensibility to exogenous gibberellin application, normal skotomorphogenetic response, and reduced seed set under self-pollination conditions. This later effect presumably is related to the reduced pollen viability observed in all DDR-derived lines studied. Rht1 completely cosegregated with a haplotype of the HaDella1 gene sequence. This haplotype consists of a point mutation converting a leucine residue in a proline within the conserved DELLA domain. Taken together, the phenotypic, genetic, and molecular results reported here indicate that Rht1 in sunflower likely encodes an altered DELLA protein. If the DELPA motif of the HaDELLA1 sequence in the Rht1-encoded protein determines by itself the observed reduction in height is a matter that remains to be investigated.

  1. [Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia].

    Science.gov (United States)

    Zeng, Li-ping; Hu, Zheng-mao; Mu, Li-li; Mei, Gui-sen; Lu, Xiu-ling; Zheng, Yong-jun; Li, Pei-jian; Zhang, Ying-xue; Pan, Qian; Long, Zhi-gao; Dai, He-ping; Zhang, Zhuo-hua; Xia, Jia-hui; Zhao, Jing-ping; Xia, Kun

    2011-06-01

    inheritance mode the maximum single-point HLOD score was 1.26 (α = 0.40) and the multi-point HLOD was 1.12 (α = 0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P= 0.0402) and the multi-point NPL score was 1.92 (P= 0.0206) at D6S289. Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.

  2. Altered cortical processing of motor inhibition in schizophrenia.

    Science.gov (United States)

    Lindberg, Påvel G; Térémetz, Maxime; Charron, Sylvain; Kebir, Oussama; Saby, Agathe; Bendjemaa, Narjes; Lion, Stéphanie; Crépon, Benoît; Gaillard, Raphaël; Oppenheim, Catherine; Krebs, Marie-Odile; Amado, Isabelle

    2016-12-01

    Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. A family affair: brain abnormalities in siblings of patients with schizophrenia

    Science.gov (United States)

    Hulshoff Pol, Hilleke; Gogtay, Nitin

    2013-01-01

    Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development. PMID:23698280

  4. BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zhengrong Zhang

    2017-09-01

    Full Text Available Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of about 1% in the general population. Recent studies have shown that Neuregulin-1 (Nrg1 is a candidate gene for schizophrenia. At least 15 alternative splicing of NRG1 isoforms all contain an extracellular epidermal growth factor (EGF-like domain, which is sufficient for Nrg1 biological activity including the formation of myelin sheaths and the regulation of synaptic plasticity. It is known that Nrg1 can be cleaved by β-secretase (BACE1 and the resulting N-terminal fragment (Nrg1-ntf binds to receptor tyrosine kinase ErbB4, which activates Nrg1/ErbB4 signaling. While changes in Nrg1 expression levels in schizophrenia still remain controversial, understanding the BACE1-cleaved Nrg1-ntf and Nrg1/ErbB4 signaling in schizophrenia neuropathogenesis is essential and important. In this review paper, we included three major parts: (1 Nrg1 structure and cleavage pattern by BACE1; (2 BACE1-dependent Nrg1 cleavage associated with schizophrenia in human studies; and (3 Animal studies of Nrg1 and BACE1 mutations with behavioral observations. Our review will provide a better understanding of Nrg1 in schizophrenia and a potential strategy for using BACE1 cleavage of Nrg1 as a unique biomarker for diagnosis, as well as a new therapeutic target, of schizophrenia.

  5. Fundamental Role of Methylenetetrahydrofolate Reductase 677 C → T Genotype and Flavin Compounds in Biochemical Phenotypes for Schizophrenia and Schizoaffective Psychosis

    Science.gov (United States)

    Fryar-Williams, Stephanie

    2016-01-01

    two gene variants and their different biochemical phenotypes govern findings in relationship to case-identification, illness severity, duration of illness, and functional disability in schizophrenia and schizoaffective psychosis, and establish a basis for trials of gene-guided precision treatment for the management of psychosis. PMID:27881965

  6. Decoding emotion of the other differs among schizophrenia patients and schizoaffective patients: A pilot study.

    Science.gov (United States)

    Tadmor, Hagar; Levin, Maya; Dadon, Tzameret; Meiman, Meital E; Ajameeh, Alaa; Mazzawi, Hosam; Rigbi, Amihai; Kremer, Ilana; Golani, Idit; Shamir, Alon

    2016-09-01

    The deficit in ability to attribute mental states such as thoughts, beliefs, and intentions of another person is a key component in the functional impairment of social cognition in schizophrenia. In the current study, we compared the ability of persons with first episode schizophrenia (FE-SZ) and individuals with schizophrenia displaying symptomatic remission (SZ-CR) to decode the mental state of others with healthy individuals and schizoaffective patients. In addition, we analyzed the effect of dopamine-related genes polymorphism on the ability to decode the mental state of another, and searched for different genetic signatures. Our results show that overall, individuals with schizophrenia performed worse in the "Reading the Mind in the Eyes" (eyes) test, a simple well-defined task to infer the mental state of others than healthy individuals. Within the schizophrenia group, schizoaffective scored significantly higher than FE-SZ, SZ-CR, and healthy individuals. No difference was observed in performance between FE-SZ and SZ-CR subjects. Interestingly, FE-SZ and SZ-CR, but not schizoaffective individuals, performed worse in decoding negative and neutral emotional valance than the healthy control group. At the genetic level, we observed a significant effect of the DAT genotype, but not D4R genotype, on the eyes test performance. Our data suggest that understanding the mental state of another person is a trait marker of the illness, and might serve as an intermediate phenotype in the diagnostic process of schizophrenia disorders, and raise the possibility that DA-related DAT gene might have a role in decoding the mental state of another person.

  7. Anomalous subjective experience among first-admitted schizophrenia spectrum patients: empirical investigation

    DEFF Research Database (Denmark)

    Parnas, Josef; Handest, Peter; Jansson, Lennart Bertil

    2005-01-01

    , the vulnerability markers to Sz--indicators that are intrinsic to this disorder and which were historically considered as constituting the phenotypic anchor of the very concept and the diagnostic validity of Sz spectrum disorders. In a more pragmatic clinical context, these indicators, considered here as symptoms......Our research group has for several years conducted philosophically informed, phenomenological-empirical studies of morbid alterations of conscious experience (subjectivity) in schizophrenia (Sz) and its spectrum of disorders. Some of these experiential alterations constitute, in our view...

  8. Sertindole versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schwarz, Sandra; Schmid, Franziska; Lewis, Ruth; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (atypical) antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether and, if so, how much the effects of the various second generation antipsychotics differ is a matter of debate. Objectives To evaluate the effects of sertindole compared with other second generation antipsychotics for people with schizophrenia and schizophrenia-like psychosis. Search methods We searched the Cochrane Schizophrenia Group Trials Register (April 2007) and ClinicalTrials.gov (February 2009). Selection criteria We included all randomised trials comparing oral sertindole with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychosis. Data collection and analysis We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model. Main results The review currently includes two short-term low-quality randomised trials (total n=508) both comparing sertindole with risperidone. One third of participants left the studies early (2 RCTs, n=504, RR 1.23 CI 0.94 to 1.60). There was no difference in efficacy (2 RCTs, n=493, WMD PANSS total change from baseline 1.98 CI −8.24 to 12.20). Compared with relatively high doses of risperidone (between 4 and 12 mg/day), sertindole produced significantly less akathisia and parkinsonism (1 RCT, n=321, RR 0.24 CI 0.09 to 0.69, NNT 14, CI 8 to 100). Sertindole produced more cardiac effects (2 RCTs, n=508, RR QTc prolongation 4.86 CI 1.94 to 12.18), weight change (2 RCTs, n=328, WMD 0.99 CI 0.12 to 1.86) and male sexual dysfunction (2 RCTs, n=437, RR 2.90 CI 1.32 to 6.35, NNH 13 CI 8 to 33

  9. Genetics Home Reference: schizophrenia

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions Schizophrenia Schizophrenia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Schizophrenia is a brain disorder classified as a psychosis, ...

  10. Neurodevelopmental risk factors in schizophrenia

    Directory of Open Access Journals (Sweden)

    Lobato M.I.

    2001-01-01

    Full Text Available The authors review environmental and neurodevelopmental risk factors for schizophrenic disorders, with emphasis on minor physical anomalies, particularly craniofacial anomalies and dermatoglyphic variations. The high prevalence of these anomalies among schizophrenic subjects supports the neurodevelopmental theory of the etiology of schizophrenia, since they suggest either genetically or epigenetically controlled faulty embryonic development of structures of ectodermal origin like brain and skin. This may disturb neurodevelopment that in turn may cause these subjects to be at increased risk for the development of schizophrenia and related disorders. The precise confirmation of this theory, at least in some cases, will provide further understanding of these illnesses, allowing easy and inexpensive identification of subjects at risk and providing guidelines for the development of new pharmacological interventions for early treatment and even for primary prevention of the illness.

  11. Effect of GLP-1 Receptor Agonist Treatment on Body weight in Obese Antipsychotic-treated Patients with Schizophrenia

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2017-01-01

    AIMS: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects like obesity...... and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. MATERIAL AND METHODS......: Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for three months. The primary outcome was body weight loss after treatment and repeated measures...

  12. Schizophrenia and Suicide

    Directory of Open Access Journals (Sweden)

    Ozlem Cetin

    2011-12-01

    Full Text Available Suicide is one of the major causes of premature death among patients with schizophrenia. Follow-up studies have estimated that 4-5% of these patients die by suicide. Reducing the high rates of suicide in schizophrenia is possible with understanding of predictive risk factors. Various studies have identified risk factors for suicide in schizophrenia patients. Clinical risk factors include previous suicide attempts, comorbid depression, feelings of hopelessness, concept of insight and substance abuse. Biopsychosocial factors, such as a high intelligence quotient and high level of premorbid functioning, have also been associated with an increased risk of suicide in patients with schizophrenia. The risk of suicide is considered to be highest in the early course of illness. Antipsychotic drugs, in particular clozapine and antidepressants may be helpful in reducing the risk of suicide in schizophrenia.

  13. Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

    Science.gov (United States)

    Kesby, James P; Burne, Thomas H J; McGrath, John J; Eyles, Darryl W

    2006-09-15

    Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

  14. [Epigenetics of schizophrenia: a review].

    Science.gov (United States)

    Rivollier, F; Lotersztajn, L; Chaumette, B; Krebs, M-O; Kebir, O

    2014-10-01

    Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post

  15. African American males diagnosed with schizophrenia: a phenomenological study.

    Science.gov (United States)

    Anderson, Lorraine Ballard

    2014-08-01

    Little is known about how African American men with schizophrenia experience their every day existence. Through applying interpretive phenomenology and using a methodological structure designed by van Manen (1990, 1997), this research aimed to enrich the current understanding of what it is like for these African American males to live with schizophrenia. In this study, five men ranging in age from 21 to 57 described their lives within the context of existing with the diagnosis of schizophrenia. The lived experiences across the interviews revealed four overarching themes: They know that they are mentally ill; they make a special effort to test reality; they assert their autonomy and; they experience reality differently, which they see as a gift. To provide appropriate treatment support to African American males diagnosed with schizophrenia, it is important to recognize the clients' ability to assert their autonomy and appreciate each man's view of himself as unique and special. Moreover, in terms of symptom management, it is pivotal to understand that although the client may not be free of hallucinations and delusions, he nevertheless may be at his optimum state of wellness. The realization that these men have transcended their diagnosis of schizophrenia rather than being crushed by their condition is evident in their stories.

  16. Occipital bending in schizophrenia.

    Science.gov (United States)

    Maller, Jerome J; Anderson, Rodney J; Thomson, Richard H; Daskalakis, Zafiris J; Rosenfeld, Jeffrey V; Fitzgerald, Paul B

    2017-01-01

    To investigate the prevalence of occipital bending (an occipital lobe crossing or twisting across the midline) in subjects with schizophrenia and matched healthy controls. Occipital bending prevalence was investigated in 37 patients with schizophrenia and 44 healthy controls. Ratings showed that prevalence was nearly three times higher among schizophrenia patients (13/37 [35.1%]) than in control subjects (6/44 [13.6%]). Furthermore, those with schizophrenia had greater normalized gray matter volume but less white matter volume and had larger brain-to-cranial ratio. The results suggest that occipital bending is more prevalent among schizophrenia patients than healthy subjects and that schizophrenia patients have different gray matter-white matter proportions. Although the cause and clinical ramifications of occipital bending are unclear, the results infer that occipital bending may be a marker of psychiatric illness.

  17. Genome-wide association study of schizophrenia in Japanese population.

    Directory of Open Access Journals (Sweden)

    Kazuo Yamada

    Full Text Available Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions. The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila-like 2] gene located on 9p21.3 (p = 0.00087. In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026. The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.

  18. A cross-cultural comparison of British and Pakistani medical students' understanding of schizophrenia.

    Science.gov (United States)

    Furnham, Adrian; Raja, Nazia; Khan, Umar Ali

    2008-06-30

    This study aimed to compare British, British Pakistani and Native Pakistani (from Pakistan) medical students' beliefs about the manifestation, causes and cures of schizophrenia, prior to any psychiatric training. A total of 305 participants completed a questionnaire on general beliefs about people with schizophrenia, causal explanations concerning the aetiology of schizophrenia and the role of hospitals and society in treating people with schizophrenia. It was predicted that compared with the British and British Pakistanis, the Pakistanis would have more negative beliefs and attitudes, considering people with schizophrenia to be more dangerous and unpredictable; they were also expected to use more superstitious beliefs to explain the cause of schizophrenia and its symptoms; as well as believe more in seeking help from God and faith healers. There was strong evidence to suggest that Pakistanis possessed more negative beliefs and attitudes about people with schizophrenia, but there was no evidence to indicate that Pakistanis believed more in superstitious causal explanations. Pakistanis were more likely to consider seeking help from faith healers, but not God, compared with British Pakistanis and the British. Results confirm previous European-Asian difference in the understanding of the cause, manifestation and cure of schizophrenia. The impact of traditional and Western cultural influences on British Pakistanis is considered.

  19. Thyroid gland and cerebella lesions: New risk factors for sudden cardiac death in schizophrenia?

    Science.gov (United States)

    Scorza, Fulvio A; Cavalheiro, Esper A; de Albuquerque, Marly; de Albuquerque, Juliana; Cysneiros, Roberta M; Terra, Vera C; Arida, Ricardo M

    2011-02-01

    People with schizophrenia show a two to threefold increased risk to die prematurely than those without schizophrenia. Patients' life style, suicide, premature development of cardiovascular disease, high prevalence of metabolic syndrome and sudden cardiac death are well-known causes of the excess mortality. The exact pathophysiological cause of sudden death in schizophrenia is unknown, but it is likely that cardiac arrhythmia and respiratory abnormalities play potential role. Some antipsychotics may be associated with cardiovascular adverse events (e.g., QT interval prolongation) and lesions in specific brain regions, such as cerebella may be associated with respiratory abnormalities, suggesting that metabolic and brain dysfunction could lead to sudden cardiac death in patients with schizophrenia. However, exact knowledge regarding the association of these findings and schizophrenia is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease and cerebella progressive atrophy has been observed in patients with schizophrenia, we propose in this paper that subclinical thyroid dysfunction and cerebella volume loss could be considered as new risk factor for sudden cardiac death in schizophrenia. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Phenotype development in TgHD minipigs

    Czech Academy of Sciences Publication Activity Database

    Ellederová, Zdeňka; Vidinská, Daniela; Mačáková, Monika; Kučerová, S.; Bohuslavová, Božena; Sedláčková, M.; Lišková, Irena; Valeková, Ivona; Baxa, Monika; Ardan, Taras; Juhás, Štefan; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 11-11 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : phenotype * minipig model of Huntington ´s disease * reproductive failure Subject RIV: EB - Genetics ; Molecular Biology

  1. Ovarian Aging-Like Phenotype in the Hyperandrogenism-Induced Murine Model of Polycystic Ovary

    Directory of Open Access Journals (Sweden)

    Mohammad Amin Rezvanfar

    2014-01-01

    Full Text Available There are prominently similar symptoms, effectors, and commonalities in the majority of characteristics between ovarian aging and polycystic ovarian syndrome (PCOS. Despite the approved role of oxidative stress in the pathogenesis of PCOS and aging, to our knowledge, the link between the PCO(S and aging has not been investigated yet. In this study we investigated the possible exhibition of ovarian aging phenotype in murine model of PCO induced by daily oral administration of letrozole (1 mg/kg body weight for 21 consecutive days in the female Wistar rats. Hyperandrogenization showed irregular cycles and histopathological characteristics of PCO which was associated with a significant increase in lipid peroxidation (LPO and reactive oxygen species (ROS and decrease in total antioxidant capacity (TAC in serum and ovary. Moreover, serum testosterone, insulin and tumor necrosis factor-alpha (TNF-α levels, and ovarian matrix metalloproteinase-2 (MMP-2 were increased in PCO rats compared with healthy controls, while estradiol and progesterone diminished. Almost all of these findings are interestingly found to be common with the characteristics identified with (ovarian aging showing that hyperandrogenism-induced PCO in rat is associated with ovarian aging-like phenotypes. To our knowledge, this is the first report that provides evidence regarding the phenomenon of aging in PCO.

  2. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

    Science.gov (United States)

    Jentsch, J D; Roth, R H

    1999-03-01

    Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

  3. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder.

    LENUS (Irish Health Repository)

    Williams, H J

    2011-04-01

    A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia\\/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

  4. Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study.

    Science.gov (United States)

    Rajkumar, Anto P; Horsdal, Henriette Thisted; Wimberley, Theresa; Cohen, Dan; Mors, Ole; Børglum, Anders D; Gasse, Christiane

    2017-07-01

    Diabetes mellitus contributes to excessive cardiovascular deaths and reduced life expectancy in schizophrenia. This population-based cohort study investigated the endogenous risk for diabetes in antipsychotic-naive schizophrenia and evaluated the risks added by starting antipsychotic treatment in people with schizophrenia. The study followed all people born in Denmark on or after Jan. 1, 1977, until Jan. 1, 2013 (N=2,736,510). The Danish Psychiatric Central Research Register ascertained schizophrenia diagnoses. The Danish National Prescription Registry provided data on prescriptions of antipsychotics. Diabetes was ascertained from the Danish National Patient Register and Danish National Prescription Registry. The authors estimated the endogenous and antipsychotic-related risks for diabetes by using Cox proportional hazards regression models, while accounting for potential confounders. Of the cohort members, 14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person-years). The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71-5.41) in antipsychotic-naive schizophrenia compared with the general population. The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95-6.82) than the risk in antipsychotic-naive schizophrenia, after adjustment for family history of diabetes and other potential confounders. First-line treatment with either first-generation antipsychotics (adjusted hazard ratio, 3.06; 95% CI, 1.32-7.05) or second-generation antipsychotics (adjusted hazard ratio, 3.44; 95% CI, 1.73-6.83) increased the risk for diabetes without a statistically significant difference. Appropriate sensitivity analyses limited to type 2 diabetes corroborated these results. Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics

  5. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder.

    Science.gov (United States)

    Arion, D; Corradi, J P; Tang, S; Datta, D; Boothe, F; He, A; Cacace, A M; Zaczek, R; Albright, C F; Tseng, G; Lewis, D A

    2015-11-01

    Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, Pschizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

  6. Towards a new classification of stable phase schizophrenia into major and simple neuro-cognitive psychosis: Results of unsupervised machine learning analysis.

    Science.gov (United States)

    Kanchanatawan, Buranee; Sriswasdi, Sira; Thika, Supaksorn; Stoyanov, Drozdstoy; Sirivichayakul, Sunee; Carvalho, André F; Geffard, Michel; Maes, Michael

    2018-05-23

    Deficit schizophrenia, as defined by the Schedule for Deficit Syndrome, may represent a distinct diagnostic class defined by neurocognitive impairments coupled with changes in IgA/IgM responses to tryptophan catabolites (TRYCATs). Adequate classifications should be based on supervised and unsupervised learning rather than on consensus criteria. This study used machine learning as means to provide a more accurate classification of patients with stable phase schizophrenia. We found that using negative symptoms as discriminatory variables, schizophrenia patients may be divided into two distinct classes modelled by (A) impairments in IgA/IgM responses to noxious and generally more protective tryptophan catabolites, (B) impairments in episodic and semantic memory, paired associative learning and false memory creation, and (C) psychotic, excitation, hostility, mannerism, negative, and affective symptoms. The first cluster shows increased negative, psychotic, excitation, hostility, mannerism, depression and anxiety symptoms, and more neuroimmune and cognitive disorders and is therefore called "major neurocognitive psychosis" (MNP). The second cluster, called "simple neurocognitive psychosis" (SNP) is discriminated from normal controls by the same features although the impairments are less well developed than in MNP. The latter is additionally externally validated by lowered quality of life, body mass (reflecting a leptosome body type), and education (reflecting lower cognitive reserve). Previous distinctions including "type 1" (positive)/"type 2" (negative) and DSM-IV-TR (eg, paranoid) schizophrenia could not be validated using machine learning techniques. Previous names of the illness, including schizophrenia, are not very adequate because they do not describe the features of the illness, namely, interrelated neuroimmune, cognitive, and clinical features. Stable-phase schizophrenia consists of 2 relevant qualitatively distinct categories or nosological entities with SNP

  7. The prevention of diabetes and cardiovascular disease in people with schizophrenia.

    Science.gov (United States)

    Holt, R I G

    2015-08-01

    Primary prevention of diabetes and cardiovascular disease is an important priority for people with schizophrenia. This review aims to identify lifestyle and pharmacological interventions that reduce diabetes and cardiovascular disease in people with schizophrenia. PubMed and other electronic databases were searched to identify relevant articles. Lifestyle interventions that focus on diet and physical activity reduce the incidence of diabetes. Similar programmes in people with schizophrenia have led to significant weight loss and may reasonably be expected to reduce diabetes in the long-term. Metformin may be considered when lifestyle change is not feasible or effective. Lifestyle interventions, particularly smoking cessation, are likely to be effective in reducing cardiovascular disease in people with schizophrenia. Although cardiovascular prevention trials with statins have not been performed in people with schizophrenia, similar reductions in cholesterol has been seen as in the general population and statins should be considered for those at high risk. Traditional cardiovascular risk prediction models perform well in identifying those at high cardiovascular risk, but bespoke prediction models using data from people with schizophrenia perform better. Reducing diabetes and cardiovascular disease requires a coordinated and concerted effort from mental and physical health teams working across primary and secondary care. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Use of clozapine in older Asian patients with schizophrenia between 2001 and 2009.

    Directory of Open Access Journals (Sweden)

    Yu-Tao Xiang

    Full Text Available BACKGROUND: To date there has been no large-scale international study that examined the use of clozapine in older patients with schizophrenia. This study examined the use of clozapine and its demographic and clinical correlates in older patients with schizophrenia in East Asia during the period between 2001 and 2009. METHOD: Information on 1,157 hospitalized patients with schizophrenia aged 50 or older in five East Asian countries and territories (China, Hong Kong, Korea, Singapore and Taiwan was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP project. Socio-demographic and clinical characteristics and prescription of psychotropic medications were recorded. RESULTS: Clozapine was prescribed for 20.6% of the pooled sample; 19.0% in 2001, 19.4% in 2004 and 22.9% in 2009. Multiple logistic regression analysis of the whole sample revealed that patients taking clozapine had a longer duration of illness, more negative symptoms and were less likely to receive first generation antipsychotic and anticholinergic drugs, but more likely to report weight gain compared to those not receiving clozapine. Compared to those in other sites, older patients in China were more likely to receive clozapine. CONCLUSIONS: The prescription of clozapine for older Asian schizophrenia inpatients has remained at a stable level during the past decade. The appropriateness of use of clozapine in China needs to be further explored.

  9. Pathological Imitative Behavior and Response Preparation in Schizophrenia.

    Science.gov (United States)

    Dankinas, Denisas; Melynyte, Sigita; Siurkute, Aldona; Dapsys, Kastytis

    2017-08-01

    Pathological imitative behavior (ehopraxia) is occasionally observed in schizophrenia patients. However, only a severe form of echopraxia can be detected with the help of a direct observation. Therefore, our goal was to study a latent form of pathological imitative behavior in this disorder, which is indicated by an increase of imitative tendencies. In our study, 14 schizophrenia patients and 15 healthy subjects were employed in two tasks: (a) in an imitative task they had to copy a hand action seen on a screen; (b) in a counter-imitative task they had to make a different movement (which involves an inhibition of prepotent imitative tendency that is impaired in case of pathological imitative behavior). Imitative tendencies were assessed by an interference score - a difference between counter-imitative and imitative response parameters. We also studied a response preparation in both groups by employing precueing probabilistic information. Our results revealed that schizophrenia patients were able to employ probabilistic information to prepare properly not only the imitative, but also the counter-imitative responses, the same as the healthy subjects did. Nevertheless, we detected increased prepotent imitative tendencies in schizophrenia patients, what indicates the latent pathological imitative behavior in case of this disorder. The obtained results suggest that in the case of schizophrenia problems with pathological imitative behavior more likely occurred in executive rather than in the preparatory stage of response. Our findings can help to detect a latent echopraxia in schizophrenia patients that cannot be revealed by direct observation. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Effort-Based Reinforcement Processing and Functional Connectivity Underlying Amotivation in Medicated Patients with Depression and Schizophrenia.

    Science.gov (United States)

    Park, Il Ho; Lee, Boung Chul; Kim, Jae-Jin; Kim, Joong Il; Koo, Min-Seung

    2017-04-19

    Amotivation is a common phenotype of major depressive disorder and schizophrenia, which are clinically distinct disorders. Effective treatment targets and strategies can be discovered by examining the dopaminergic reward network function underlying amotivation between these disorders. We conducted an fMRI study in healthy human participants and medicated patients with depression and schizophrenia using an effort-based reinforcement task. We examined regional activations related to reward type (positive and negative reinforcement), effort level, and their composite value, as well as resting-state functional connectivities within the meso-striatal-prefrontal pathway. We found that integrated reward and effort values of low effort-positive reinforcement and high effort-negative reinforcement were behaviorally anticipated and represented in the putamen and medial orbitofrontal cortex activities. Patients with schizophrenia and depression did not show anticipation-related and work-related reaction time reductions, respectively. Greater amotivation severity correlated with smaller work-related putamen activity changes according to reward type in schizophrenia and effort level in depression. Patients with schizophrenia showed feedback-related putamen hyperactivity of low effort compared with healthy controls and depressed patients. The strength of medial orbitofrontal-striatal functional connectivity predicted work-related reaction time reduction of high effort negative reinforcement in healthy controls and amotivation severity in both patients with schizophrenia and those with depression. Patients with depression showed deficient medial orbitofrontal-striatal functional connectivity compared with healthy controls and patients with schizophrenia. These results indicate that amotivation in depression and schizophrenia involves different pathophysiology in the prefrontal-striatal circuitry. SIGNIFICANCE STATEMENT Amotivation is present in both depression and schizophrenia

  11. Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats

    Directory of Open Access Journals (Sweden)

    Uta Waterhouse

    2016-10-01

    Full Text Available Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg at one of three neurodevelopmental time periods [gestation days (GD 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND 60] and included: prepulse inhibition (PPI, latent inhibition (LI and delayed non-matching to sample (DNMTS. Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously were administered, and animals were re-tested in the same tasks (PND 110. Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11 resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI and selective (LI improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI and induced a global enhancement of sensorimotor gating (PPI.

  12. Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.

    Science.gov (United States)

    Chabry, Joëlle; Nicolas, Sarah; Cazareth, Julie; Murris, Emilie; Guyon, Alice; Glaichenhaus, Nicolas; Heurteaux, Catherine; Petit-Paitel, Agnès

    2015-11-01

    Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. A human DAZ transgene confers partial rescue of the mouse Dazl null phenotype

    Science.gov (United States)

    Slee, R.; Grimes, B.; Speed, R. M.; Taggart, M.; Maguire, S. M.; Ross, A.; McGill, N. I.; Saunders, P. T. K.; Cooke, H. J.

    1999-01-01

    In a subset of infertile men, a spectrum of spermatogenic defects ranging from a complete absence of germ cells (sertoli cell only) to oligozoospermia is associated with microdeletions of the DAZ (deleted in azoospermia) gene cluster on human distal Yq. DAZ encodes a testis-specific protein with RNA-binding potential recently derived from a single-copy gene DAZL1 (DAZ-like) on chromosome 3. Y chromosomal DAZ homologues are confined to humans and higher primates. It remains unclear which function unique to higher primate spermatogenesis DAZ may serve, and the functional status of the gene recently has been questioned. To assess the extent of functional conservation we have tested the capacity of a human DAZ gene contained in a 225-kb yeast artificial chromosome to complement the sterile phenotype of the Dazl null mouse (Dazl−/−), which is characterized by severe germ-cell depletion and meiotic failure. Although Dazl−/− mice remained infertile when the DAZ transgene was introduced, histological examination revealed a partial and variable rescue of the mutant phenotype, manifest as a pronounced increase in the germ cell population of the seminiferous tubules and survival to the pachytene stage of meiosis. As well as constituting definitive proof of the spermatogenic role of the DAZ gene product, these findings confirm the high degree of functional conservation between the DAZ and DAZL1 genes, suggesting they may constitute a single target for contraceptive intervention and raising the possibility of therapeutic up-regulation of the DAZL1 gene in infertile men. PMID:10393944

  14. The environment and susceptibility to schizophrenia.

    Science.gov (United States)

    Brown, Alan S

    2011-01-01

    In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban-rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections [e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2)], nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures [e.g. lead, rhesus (Rh) incompatibility, maternal stress]. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and

  15. Exploring rationality in schizophrenia

    DEFF Research Database (Denmark)

    Revsbech, Rasmus; Mortensen, Erik Lykke; Owen, Gareth

    2015-01-01

    Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Meth...... differences became non-significant. Conclusions When taking intelligence and neuropsychological performance into account, patients with schizophrenia and controls perform similarly on syllogism tests of rationality.......Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Method...... Thirty-eight first-admitted patients with schizophrenia and 38 healthy controls solved 29 syllogisms that varied in presentation content (ordinary v. unusual) and validity (valid v. invalid). Statistical tests were made of unadjusted and adjusted group differences in models adjusting for intelligence...

  16. Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome.

    Science.gov (United States)

    Green, Isobel W; Glausier, Jill R

    2016-05-01

    Schizophrenia is a clinically heterogeneous disorder that is perhaps more accurately characterized as "the schizophrenia syndrome." This clinical heterogeneity is reflected in the heterogeneous neurobiological presentations associated with the illness. Moreover, even highly specific neural aberrations that are associated with distinct symptoms of schizophrenia are linked to a wide range of risk factors. As such, any individual with schizophrenia likely has a particular set of risk factors that interact and converge to cross the disease threshold, forming a particular etiology that ultimately generates a core pathophysiology. This core pathophysiology may then produce 1 or more symptoms of schizophrenia, leading to common symptoms across individuals in spite of disparate etiologies. As such, the schizophrenia syndrome can be considered as anequifinalentity: a state of dysfunction that can arise from different upstream etiologies. Moreover, schizophrenia etiologies are multifactorial and can involve the interactive effects of a broad range of genetic, environmental, and developmental risk factors. Through a consideration of how disparate etiologies, caused by different sets of risk factors, converge on the same net dysfunction, this paper aims to model the equifinal nature of schizophrenia symptoms. To demonstrate the equifinal model, we discuss how maternal infection and adolescent cannabis use, 2 recognized schizophrenia risk factors, may interact with other genetic, environmental, and/or developmental risk factors to cause the conserved clinical presentation of impaired working memory. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

    Science.gov (United States)

    Blokland, Gabriëlla A M; Del Re, Elisabetta C; Mesholam-Gately, Raquelle I; Jovicich, Jorge; Trampush, Joey W; Keshavan, Matcheri S; DeLisi, Lynn E; Walters, James T R; Turner, Jessica A; Malhotra, Anil K; Lencz, Todd; Shenton, Martha E; Voineskos, Aristotle N; Rujescu, Dan; Giegling, Ina; Kahn, René S; Roffman, Joshua L; Holt, Daphne J; Ehrlich, Stefan; Kikinis, Zora; Dazzan, Paola; Murray, Robin M; Di Forti, Marta; Lee, Jimmy; Sim, Kang; Lam, Max; Wolthusen, Rick P F; de Zwarte, Sonja M C; Walton, Esther; Cosgrove, Donna; Kelly, Sinead; Maleki, Nasim; Osiecki, Lisa; Picchioni, Marco M; Bramon, Elvira; Russo, Manuela; David, Anthony S; Mondelli, Valeria; Reinders, Antje A T S; Falcone, M Aurora; Hartmann, Annette M; Konte, Bettina; Morris, Derek W; Gill, Michael; Corvin, Aiden P; Cahn, Wiepke; Ho, New Fei; Liu, Jian Jun; Keefe, Richard S E; Gollub, Randy L; Manoach, Dara S; Calhoun, Vince D; Schulz, S Charles; Sponheim, Scott R; Goff, Donald C; Buka, Stephen L; Cherkerzian, Sara; Thermenos, Heidi W; Kubicki, Marek; Nestor, Paul G; Dickie, Erin W; Vassos, Evangelos; Ciufolini, Simone; Reis Marques, Tiago; Crossley, Nicolas A; Purcell, Shaun M; Smoller, Jordan W; van Haren, Neeltje E M; Toulopoulou, Timothea; Donohoe, Gary; Goldstein, Jill M; Seidman, Larry J; McCarley, Robert W; Petryshen, Tracey L

    2018-05-01

    Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both pneuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Schizophrenia on YouTube.

    Science.gov (United States)

    Nour, Matthew M; Nour, Murraih H; Tsatalou, Olga-Maria; Barrera, Alvaro

    2017-01-01

    YouTube ( www.youtube.com ) is the most popular video-sharing Web site on the Internet and is used by medical students as a source of information regarding mental health conditions, including schizophrenia. The accuracy and educational utility of schizophrenia presentations on YouTube are unknown. The purpose of this study was to analyze the accuracy of depictions of psychosis in the context of a diagnosis of schizophrenia (referred to in this article as "acute schizophrenia") on YouTube and to assess the utility of these videos as educational tools for teaching medical students to recognize the clinical features of acute schizophrenia. YouTube was searched for videos purporting to show acute schizophrenia. Eligible videos were independently rated by two consultant psychiatrists on two separate occasions 22 days apart for diagnostic accuracy, psychopathology, and educational utility. Videos (N=4,200) were assessed against predefined inclusion and exclusion criteria. The majority were not eligible for further analysis, mostly because they did not claim to show a patient with schizophrenia (74%) or contained duplicated content (11%). Of 35 videos that met the eligibility and adequacy criteria, only 12 accurately depicted acute schizophrenia. Accurate videos were characterized by persecutory delusions (83%), inappropriate affect (75%), and negative symptoms (83%). Despite the fact that 83% of accurate videos were deemed to have good educational utility compared with 15% of inaccurate videos, accurate and inaccurate videos had similar view counts (290,048 versus 186,124). Schizophrenia presentations on YouTube offer a distorted picture of the condition.

  19. GABAergic Mechanisms in Schizophrenia

    DEFF Research Database (Denmark)

    de Jonge, Jeroen C; Vinkers, Christiaan H; Hulshoff Pol, Hilleke E

    2017-01-01

    Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features...... of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations...... in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology...

  20. Ovarian cancer plasticity and epigenomics in the acquisition of a stem-like phenotype

    Directory of Open Access Journals (Sweden)

    Berry Nicholas B

    2008-11-01

    Full Text Available Abstract Aggressive epithelial ovarian cancer (EOC is genetically and epigenetically distinct from normal ovarian surface epithelial cells (OSE and early neoplasia. Co-expression of epithelial and mesenchymal markers in EOC suggests an involvement of epithelial-mesenchymal transition (EMT in cancer initiation and progression. This phenomenon is often associated with acquisition of a stem cell-like phenotype and chemoresistance that correlate with the specific gene expression patterns accompanying transformation, revealing a plasticity of the ovarian cancer cell genome during disease progression. Differential gene expressions between normal and transformed cells reflect the varying mechanisms of regulation including genetic changes like rearrangements within the genome, as well as epigenetic changes such as global genomic hypomethylation with localized promoter CpG island hypermethylation. The similarity of gene expression between ovarian cancer cells and the stem-like ovarian cancer initiating cells (OCIC are surprisingly also correlated with epigenetic mechanisms of gene regulation in normal stem cells. Both normal and cancer stem cells maintain genetic flexibility by co-placement of activating and/or repressive epigenetic modifications on histone H3. The co-occupancy of such opposing histone marks is believed to maintain gene flexibility and such bivalent histones have been described as being poised for transcriptional activation or epigenetic silencing. The involvement of both-microRNA (miRNA mediated epigenetic regulation, as well as epigenetic-induced changes in miRNA expression further highlight an additional complexity in cancer stem cell epigenomics. Recent advances in array-based whole-genome/epigenome analyses will continue to further unravel the genomes and epigenomes of cancer and cancer stem cells. In order to illuminate phenotypic signatures that delineate ovarian cancer from their associated cancer stem cells, a priority must lie

  1. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

    Science.gov (United States)

    Allou, Lila; Lambert, Laetitia; Amsallem, Daniel; Bieth, Eric; Edery, Patrick; Destrée, Anne; Rivier, François; Amor, David; Thompson, Elizabeth; Nicholl, Julian; Harbord, Michael; Nemos, Christophe; Saunier, Aline; Moustaïne, Aissa; Vigouroux, Adeline; Jonveaux, Philippe; Philippe, Christophe

    2012-01-01

    The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (−4 to−6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype. PMID:22739344

  2. Psychoeducation for schizophrenia

    Science.gov (United States)

    Xia, Jun; Merinder, Lars Bertil; Belgamwar, Madhvi R

    2014-01-01

    .89, NNT 5 CI 4 to 13). Scale-derived data also suggested that psychoeducation promotes better social and global functioning. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. Evidence suggests that participants receiving psychoeducation are more likely to be satisfied with mental health services (n = 236, RR 0.24 CI 0.12 to 0.50, NNT 5 CI 5 to 8) and have improved quality of life. Authors’ conclusions Psychoeducation does seem to reduce relapse, readmission and encourage medication compliance, as well as reduce the length of hospital stay in these hospital-based studies of limited quality. The true size of effect is likely to be less than demonstrated in this review - but, nevertheless, some sort of psychoeducation could be clinically effective and potentially cost beneficial. It is not difficult to justify better, more applicable, research in this area aimed at fully investigating the effects of this promising approach. Note: the 27 new citations in the awaiting classification section of the review may alter the conclusions of the review once assessed. PMID:21678337

  3. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia

    Directory of Open Access Journals (Sweden)

    Wen-Jun eGao

    2013-03-01

    Full Text Available Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR, a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.

  4. Ablation of Mrds1/Ofcc1 Induces Hyper-γ-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice

    Science.gov (United States)

    Ohnishi, Tetsuo; Yamada, Kazuo; Watanabe, Akiko; Ohba, Hisako; Sakaguchi, Toru; Honma, Yota; Iwayama, Yoshimi; Toyota, Tomoko; Maekawa, Motoko; Watanabe, Kazutada; Detera-Wadleigh, Sevilla D.; Wakana, Shigeharu; Yoshikawa, Takeo

    2011-01-01

    Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia. PMID:22242126

  5. Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.

    Directory of Open Access Journals (Sweden)

    Tetsuo Ohnishi

    Full Text Available Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT, a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia.

  6. Decoding emotion of the other differs among schizophrenia patients and schizoaffective patients: A pilot study

    Directory of Open Access Journals (Sweden)

    Hagar Tadmor

    2016-09-01

    Full Text Available The deficit in ability to attribute mental states such as thoughts, beliefs, and intentions of another person is a key component in the functional impairment of social cognition in schizophrenia. In the current study, we compared the ability of persons with first episode schizophrenia (FE-SZ and individuals with schizophrenia displaying symptomatic remission (SZ-CR to decode the mental state of others with healthy individuals and schizoaffective patients. In addition, we analyzed the effect of dopamine-related genes polymorphism on the ability to decode the mental state of another, and searched for different genetic signatures. Our results show that overall, individuals with schizophrenia performed worse in the “Reading the Mind in the Eyes” (eyes test, a simple well-defined task to infer the mental state of others than healthy individuals. Within the schizophrenia group, schizoaffective scored significantly higher than FE-SZ, SZ-CR, and healthy individuals. No difference was observed in performance between FE-SZ and SZ-CR subjects. Interestingly, FE-SZ and SZ-CR, but not schizoaffective individuals, performed worse in decoding negative and neutral emotional valance than the healthy control group. At the genetic level, we observed a significant effect of the DAT genotype, but not D4R genotype, on the eyes test performance. Our data suggest that understanding the mental state of another person is a trait marker of the illness, and might serve as an intermediate phenotype in the diagnostic process of schizophrenia disorders, and raise the possibility that DA-related DAT gene might have a role in decoding the mental state of another person.

  7. Comparison of suicide attempts in schizophrenia and major depressive disorder: an exploratory study.

    Science.gov (United States)

    Banwari, Girish H; Vankar, Ganpat K; Parikh, Minakshi N

    2013-12-01

    Schizophrenia and major depressive disorder (MDD) are among the most common psychiatric diagnoses associated with suicide. There is a dearth of published research systematically comparing suicidal behavior in schizophrenia and MDD. The present study aimed to compare suicide attempts in schizophrenia and MDD. In this hospital-based, cross-sectional study, 50 outpatients each of schizophrenia and MDD were evaluated for their sociodemographic characteristics. In subjects with a history of suicide attempt(s), additional information related to the attempt(s) was obtained. Suicide Intent Scale (SIS) was used to assess the suicidal intent and Mini International Neuropsychiatric Interview (MINI) was used to measure the current suicidal risk. Thirty-four percent and 44% of patients with schizophrenia and MDD, respectively, attempted suicide. The attempters in schizophrenia compared to those in MDD were younger and more likely to be single (unmarried, separated or divorced). Suicidal intent was stronger in schizophrenia, while the attempters with MDD were more often preoccupied with a death wish and reported that stressful life events influenced the attempt. There were no differences in the attempt methods of the two groups. Current suicidal risk was higher in attempters compared to the non-attempters in schizophrenia as well as MDD. Suicide attempts in schizophrenia and MDD have similar features, with quite a few notable differences, which have been discussed at length in the present paper. Copyright © 2012 Wiley Publishing Asia Pty Ltd.

  8. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

    NARCIS (Netherlands)

    Williams, H.J.; Norton, N.; Dwyer, S.; Moskvina, V.; Nikolov, I.; Carroll, L.; Georgieva, L.; Williams, N.M.; Morris, D.W.; Quinn, E.M.; Giegling, I.; Ikeda, M.; Wood, J.; Lencz, T.; Hultman, C.; Lichtenstein, P.; Thiselton, D.; Maher, B.S.; Malhotra, A.K.; Riley, B.; Kendler, K.S.; Gill, M.; Sullivan, P.; Sklar, P.; Purcell, S.; Nimgaonkar, V.L.; Kirov, G.; Holmans, P.; Corvin, A.; Rujescu, D.; Craddock, N.; Owen, M.J.; O'Donovan, M.C.; GROUP investigators, [No Value

    2011-01-01

    A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P = 1.61 x 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P = 9.96 x 10(-9)). In this

  9. A schizophrenia rat model induced by early postnatal phencyclidine treatment and characterized by Magnetic Resonance Imaging

    DEFF Research Database (Denmark)

    Broberg, Brian V; Madsen, Kristoffer H; Plath, Niels

    2013-01-01

    administration of phencyclidine (PCP) induces schizophrenia-like symptoms in healthy volunteers and exacerbates symptoms in patients with schizophrenia. In this study, pharmacological Magnetic Resonance Imaging (phMRI) was used to evaluate if rats treated with 20mg/kg PCP on postnatal days 7, 9, and 11 (neo...

  10. Hamburg Accelerator Conference (2)

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Edmund J.N. [CERN Accelerator School (Switzerland)

    1992-11-15

    From 20-24 July, Hamburg welcomed the Fifteenth International Conference on High Energy Accelerators (HEACC). The HEACC Conference traditionally reviews the status of all major accelerator projects whether they are already running like clockwork, still in the construction phase, or waiting impatiently for financial approval.

  11. Hamburg Accelerator Conference (2)

    International Nuclear Information System (INIS)

    Wilson, Edmund J.N.

    1992-01-01

    From 20-24 July, Hamburg welcomed the Fifteenth International Conference on High Energy Accelerators (HEACC). The HEACC Conference traditionally reviews the status of all major accelerator projects whether they are already running like clockwork, still in the construction phase, or waiting impatiently for financial approval

  12. The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype.

    Science.gov (United States)

    Bertola, Débora; Yamamoto, Guilherme; Buscarilli, Michelle; Jorge, Alexander; Passos-Bueno, Maria Rita; Kim, Chong

    2017-03-01

    We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Attitudes towards schizophrenia on YouTube: A content analysis of Finnish and Greek videos.

    Science.gov (United States)

    Athanasopoulou, Christina; Suni, Sanna; Hätönen, Heli; Apostolakis, Ioannis; Lionis, Christos; Välimäki, Maritta

    2016-01-01

    To investigate attitudes towards schizophrenia and people with schizophrenia presented in YouTube videos. We searched YouTube using the search terms "schizophrenia" and "psychosis" in Finnish and Greek language on April 3rd, 2013. The first 20 videos from each search (N = 80) were retrieved. Deductive content analysis was first applied for coding and data interpretation and it was followed by descriptive statistical analysis. A total of 52 videos were analyzed (65%). The majority of the videos were in the "Music" category (50%, n = 26). Most of the videos (83%, n = 43) tended to present schizophrenia in a negative way, while less than a fifth (17%, n = 9) presented schizophrenia in a positive or neutral way. Specifically, the most common negative attitude towards schizophrenia was dangerousness (29%, n = 15), while the most often identified positive attitude was objective, medically appropriate beliefs (21%, n = 11). All attitudes identified were similarly present in the Finnish and Greek videos, without any statistically significant difference. Negative presentations of schizophrenia are most likely to be accessed when searching YouTube for schizophrenia in Finnish and Greek language. More research is needed to investigate to what extent, if any, YouTube viewers' attitudes are affected by the videos they watch.

  14. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

    DEFF Research Database (Denmark)

    Santini, Martin A; Ratner, Cecilia Friis; Aznar, Susana

    2013-01-01

    Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia...

  15. Executive function needs to be targeted to improve social functioning with Cognitive Remediation Therapy (CRT) in schizophrenia.

    Science.gov (United States)

    Penadés, Rafael; Catalán, Rosa; Puig, Olga; Masana, Guillem; Pujol, Núria; Navarro, Víctor; Guarch, Joana; Gastó, Cristóbal

    2010-05-15

    While the role of impaired cognition in accounting for functional outcome in schizophrenia is generally established, the relationship between cognitive and functional change in the context of treatments is far from clear. The current paper tries to identify which cognitive changes lead to improvements in daily functioning among persons with chronic schizophrenia who had current negative symptoms and evidenced neuropsychological impairments. In a previous work, Cognitive Remediation Therapy (CRT) was compared with a control therapy, involving similar length of therapist contact but different targets. At the end of treatment, CRT conferred a benefit to people with schizophrenia in cognition and functioning [Schizophrenia Research, 87 (2006) 323-331]. Subsequently, analyses of covariance (ANCOVA) were conducted with baseline and cognitive change scores as covariates to test whether cognitive change predicted change in functioning. Additionally, statistical tests to establish the mediation path with significant variables were performed. Although verbal memory, but not executive functioning, was associated with functioning at baseline, it was the improvement in executive functioning that predicted improved daily functioning. Verbal memory played a mediator role in the change process. Consequently, in order to improve daily functioning with CRT, executive function still needs to be targeted in despite of multiple cognitive impairments being present. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  16. GABA(B) receptors, schizophrenia and sleep dysfunction: a review of the relationship and its potential clinical and therapeutic implications.

    Science.gov (United States)

    Kantrowitz, Joshua; Citrome, Leslie; Javitt, Daniel

    2009-08-01

    Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of

  17. Women and schizophrenia

    OpenAIRE

    Thara, R.; Kamath, Shantha

    2015-01-01

    Women's mental health is closely linked to their status in society. This paper outlines the clinical features of women with schizophrenia and highlights the interpersonal and social ramifications on their lives. There is no significant gender difference in the incidence and prevalence of schizophrenia. There is no clear trend in mortality, although suicides seem to be more in women with schizophrenia. In India, women face a lot of problems, especially in relation to marriage, pregnancy, child...

  18. The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders.

    Science.gov (United States)

    Barrantes-Vidal, Neus; Grant, Phillip; Kwapil, Thomas R

    2015-03-01

    Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease-specific characteristics. Finally, schizotypy's promise for studying gene-environment interactions is considered. © The Author 2015. Published by Oxford University

  19. Induction of adipocyte-like phenotype in human mesenchymal stem cells by hypoxia

    DEFF Research Database (Denmark)

    Fink, Trine; Abildtrup, Lisbeth Ann; Fogd, Kirsten

    2004-01-01

    Human mesenchymal stem cells (hMSCs) have the capacity to differentiate along several pathways to form bone, cartilage, tendon, muscle, and adipose tissues. The adult hMSCs reside in vivo in the bone marrow in niches where oxygen concentration is far below the ambient air, which is the most...... commonly encountered laboratory condition. The study reported here was designed to determine whether oxygen has a role in the differentiation of hMSCs into adipocytes. Indeed, when exposed to atmosphere containing only 1% of oxygen, the formation of adipocyte-like phenotype with cytoplasmic lipid....... High level of induction, however, was observed with the PPAR-gamma-induced angiopoietin-related gene, PGAR. The lack of an adipocyte-specific transcription pattern thus indicates that despite accumulation of the lipid, true adipogenic differentiation did not take place. In conclusion, hypoxia appears...

  20. Aripiprazole versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Schmid, Franziska; Hunger, Heike; Schwarz, Sandra; El-Sayeh, Hany George G; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (atypical) antipsychotics have become first line drug treatments for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of other second generation antipsychotics. Objectives To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Group Trials Register (March 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. Selection criteria We included all randomised trials comparing oral aripiprazole with oral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychoses. Data collection and analysis We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. Main results The review currently includes four trials with 1404 participants on two out of eight possible comparisons - aripiprazole versus olanzapine and aripiprazole versus risperidone. The overall number of participants leaving the studies early was considerable (38.5%), limiting the validity of the findings, but with no significant differences between groups. Aripiprazole was less efficacious than olanzapine in terms of the general mental state (PANSS total score: n=794, 2 RCTs, MD 4.96 CI 1.85 to 8.06), but it was associated with fewer side

  1. Steeper discounting of delayed rewards in schizophrenia but not first-degree relatives.

    Science.gov (United States)

    Yu, Linda Q; Lee, Sangil; Katchmar, Natalie; Satterthwaite, Theodore D; Kable, Joseph W; Wolf, Daniel H

    2017-06-01

    Excessive discounting of future rewards has been related to a variety of risky behaviors and adverse clinical conditions. Prior work examining delay discounting in schizophrenia suggests an elevated discount rate. However, it remains uncertain whether this reflects the disease process itself or an underlying genetic vulnerability, whether it is selective for delay discounting or reflects pervasive changes in decision-making, and whether it is driven by specific clinical dimensions such as cognitive impairment. Here we investigated delay discounting, as well as loss aversion and risk aversion, in three groups: schizophrenia (SZ), unaffected first-degree family members (FM), and controls without a family history of psychosis (NC). SZ had elevated discounting, without changes in loss aversion or risk aversion. Contrary to expectations, the FM group did not show an intermediate phenotype in discounting. Higher discount rates correlated with lower cognitive performance on verbal reasoning, but this did not explain elevated discount rates in SZ. Group differences were driven primarily by the non-smoking majority of the sample. This study provides further evidence for elevated discounting in schizophrenia, and demonstrates that steeper discounting is not necessarily associated with familial risk, cannot be wholly accounted for by cognitive deficits, and is not attributable to smoking-related impulsivity. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  2. Family structure and risk factors for schizophrenia: case-sibling study

    Directory of Open Access Journals (Sweden)

    Lönnqvist Jouko

    2004-11-01

    Full Text Available Abstract Background Several family structure-related factors, such as birth order, family size, parental age, and age differences to siblings, have been suggested as risk factors for schizophrenia. We examined how family-structure-related variables modified the risk of schizophrenia in Finnish families with at least one child with schizophrenia born from 1950 to 1976. Methods We used case-sibling design, a variant of the matched case-control design in the analysis. Patients hospitalized for schizophrenia between 1969 and 1996 were identified from the Finnish Hospital Discharge Register, and their families from the Population Register Center. Only families with at least two children (7914 sibships and 21059 individuals were included in the analysis. Conditional logistic regression with sex, birth cohort, maternal schizophrenia status, and several family-related variables as explanatory variables was used in the case-sibling design. The effect of variables with the same value in each sibship was analyzed using ordinary logistic regression. Results Having a sibling who was less than five years older (OR 1.46, 95% CI 1.29–1.66, or being the firstborn (first born vs. second born 1.62, 1.87–1.4 predicted an elevated risk, but having siblings who were more than ten years older predicted a lower risk (0.66, 0.56–0.79. Conclusions Several family-structure-related variables were identified as risk factors for schizophrenia. The underlying causative mechanisms are likely to be variable.

  3. Peripubertal exposure to environmental enrichment prevents schizophrenia-like behaviors in the SHR strain animal model.

    Science.gov (United States)

    Santos, Camila Mauricio; Peres, Fernanda Fiel; Diana, Mariana Cepollaro; Justi, Veronica; Suiama, Mayra Akimi; Santana, Marcela Gonçalves; Abílio, Vanessa Costhek

    2016-10-01

    Schizophrenia is a highly disabling mental disorder, in which genetics and environmental factors interact culminating in the disease. The treatment of negative symptoms and cognitive deficits with antipsychotics is currently inefficient and is an important field of research. Environmental enrichment (EE) has been suggested to improve some cognitive deficits in animal models of various psychiatric disorders. In this study, we aimed to evaluate a possible beneficial effect of early and long-term exposure to EE on an animal model of schizophrenia, the SHR strain. Young male Wistar rats (control strain) and SHRs (21 post-natal days) were housed for 6weeks in two different conditions: in large cages (10 animals per cage) containing objects of different textures, forms, colors and materials that were changed 3 times/week (EE condition) or in standard cages (5 animals per cage - Control condition). Behavioral evaluations - social interaction (SI), locomotion, prepulse inhibition of startle (PPI) and spontaneous alternation (SA) - were performed 6weeks after the end of EE. SHRs presented deficits in PPI (a sensorimotor impairment), SI (mimicking the negative symptoms) and SA (a working memory deficit), and also hyperlocomotion (modeling the positive symptoms). EE was able to reduce locomotion and increase PPI in both strains, and to prevent the working memory deficit in SHRs. EE also increased the number of neurons in the CA1 and CA3 of the hippocampus. In conclusion, EE can be a potential nonpharmacological strategy to prevent some behavioral deficits associated with schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. The Danish Schizophrenia Registry

    DEFF Research Database (Denmark)

    Baandrup, Lone; Cerqueira, Charlotte; Haller, Lea

    2016-01-01

    Aim of database: To systematically monitor and improve the quality of treatment and care of patients with schizophrenia in Denmark. In addition, the database is accessible as a resource for research. Study population: Patients diagnosed with schizophrenia and receiving mental health care...... to the data for use in specific research projects by applying to the steering committee. Conclusion: The Danish Schizophrenia Registry represents a valuable source of informative data to monitor and improve the quality of care of patients with schizophrenia in Denmark. However, continuous resources and time...

  5. Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats.

    Science.gov (United States)

    Barbarich-Marsteller, Nicole C; Underwood, Mark D; Foltin, Richard W; Myers, Michael M; Walsh, B Timothy; Barrett, Jeffrey S; Marsteller, Douglas A

    2013-11-01

    Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30-35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. Copyright © 2013 Wiley Periodicals, Inc.

  6. Vehicular Networking Conference (VNC)

    NARCIS (Netherlands)

    Altintas, O.; Chen, W.; Heijenk, Geert; Dressler, F.; Ekici, E.; Kargl, Frank; Shigeno, H.; Dietzel, Stefan

    2011-01-01

    On behalf of the Organizing Committee, we would like to welcome you to the third edition of the IEEE Vehicular Networking Conference (IEEE VNC 2011) in Amsterdam, the Netherlands. IEEE VNC is a unique conference sponsored by both the IEEE Communications Society and the IEEE Intelligent

  7. SOCIODEMOGRAPHIC PROFILE OF SCHIZOPHRENIA WITH AND WITHOUT OBSESSIVE COMPULSIVE SYMPTOMS

    Directory of Open Access Journals (Sweden)

    Adavalath Druhin

    2017-12-01

    Full Text Available BACKGROUND Schizophrenia is a complex neurobehavioural disorder affecting about 1% of the general population. Schizophrenia is characterised by disordered cognition including a “gain of function” in psychotic symptoms and “loss of function” in specific cognitive functions such as working and declarative memory, but without the progressive dementia that characterises classical neurodegenerative disorder. The primary aim of the study was to compare the profile of patients diagnosed with schizophrenia with and without obsessive compulsive symptoms. MATERIALS AND METHODS This was a cross-sectional study. Consecutive patients in the age group of 18-59 years diagnosed to have schizophrenia with at least 2 years of duration of illness consulting in outpatient department of psychiatry and inpatients admitted in psychiatry ward at a tertiary care centre at northern Kerala were included. Clinical status of the patient was assessed using Structured Clinical Interview for DSM - IV - TR (SCID I, the Positive and Negative Symptom Scale (PANSS and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS severity and symptom checklist. YBOCS ≥16 was labelled as OCD. Sociodemographic profile of the patients will be collected using specially designed pro forma. Data analysis was done using software “R” (Chi-square and t test. RESULTS A total of 73 participants formed the study sample. The schizophrenia with OCS were better educated were more likely to come from a semi-urban background had alcohol dependence and longer duration of untreated illness than the group with schizophrenia alone. Though, there was increased frequency of paranoid subtype in the study sample, schizophrenia patients with OCD/OCS had majority of undifferentiated subtype. There is no difference in gender, family type, marital status, occupation, religion or socioeconomic status. CONCLUSION Schizophrenia patients with OCS/OCD and without OCS/OCD have comparable clinical profile with few

  8. Association between variations in the disrupted in schizophrenia 1 gene and schizophrenia: A meta-analysis.

    Science.gov (United States)

    Xu, Yiliang; Ren, Jun; Ye, Haihong

    2018-04-20

    Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Income inequality and schizophrenia: increased schizophrenia incidence in countries with high levels of income inequality.

    Science.gov (United States)

    Burns, Jonathan K; Tomita, Andrew; Kapadia, Amy S

    2014-03-01

    Income inequality is associated with numerous negative health outcomes. There is evidence that ecological-level socio-environmental factors may increase risk for schizophrenia. The aim was to investigate whether measures of income inequality are associated with incidence of schizophrenia at the country level. We conducted a systematic review of incidence rates for schizophrenia, reported between 1975 and 2011. For each country, national measures of income inequality (Gini coefficient) along with covariate risk factors for schizophrenia were obtained. Multi-level mixed-effects Poisson regression was performed to investigate the relationship between Gini coefficients and incidence rates of schizophrenia controlling for covariates. One hundred and seven incidence rates (from 26 countries) were included. Mean incidence of schizophrenia was 18.50 per 100,000 (SD = 11.9; range = 1.7-67). There was a significant positive relationship between incidence rate of schizophrenia and Gini coefficient (β = 1.02; Z = 2.28; p = .02; 95% CI = 1.00, 1.03). Countries characterized by a large rich-poor gap may be at increased risk of schizophrenia. We suggest that income inequality impacts negatively on social cohesion, eroding social capital, and that chronic stress associated with living in highly disparate societies places individuals at risk of schizophrenia.

  10. Non-adherence to pharmacological treatment in schizophrenia and schizophrenia spectrum disorders

    DEFF Research Database (Denmark)

    Ljungdalh, P. M.

    2017-01-01

    Background and objectives The primary treatment for schizophrenia and schizophrenia-spectrum disorders is antipsychotic medication. One of the many public health challenges in mental illness, is to identify contributing factors to non-adherence to pharmacological treatment. The objective...... of this study was to perform an updated systematic review of risk factors for non-adherence to pharmacological treatment in schizophrenia in a European and American context. Methods The study was a systematic literature review of studies that included at least two measurements of pharmacological adherence...... of illness, alcohol or drug abuse and unspecified younger age. Conclusions The findings in this systematic literature review are consistent with previous reviews on non-adherence and schizophrenia. It stresses the methodological challenges in psychiatric adherence research and establishes the need for more...

  11. The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.

    Science.gov (United States)

    Nimgaonkar, V L; Prasad, K M; Chowdari, K V; Severance, E G; Yolken, R H

    2017-11-01

    The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

  12. STUDY OF FACTORS AFFECTING SUICIDE ATTEMPTS IN PERSONS WITH SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    Ottilingam Somasundaram Ravindran

    2016-09-01

    Full Text Available BACKGROUND Schizophrenia has been called a ‘Life-shortening disease’, because many sufferers die early than general population and suicide accounts for a significant proportion of those dying prematurely. Suicide attempts in schizophrenia has been an intriguing area of research work for mental health professionals. Indian research on suicide attempts in schizophrenia have been few. OBJECTIVES The objectives were to study the suicidal behaviour in schizophrenia, to compare and study the positive and negative symptoms, depressive symptoms, hopelessness and suicide intent in schizophrenic population with suicide attempt compared to nonattempters, along with socio-demographic parameters. METHODS A sample of 60 consecutive patients attending OPD of a Private tertiary care Hospital in Chennai were selected. Those who had a diagnosis of schizophrenia were screened for the presence of past suicide attempts. They were divided into two groups as suicide attempters and non-attempters, and analysed using the Positive and Negative Syndrome Scale (PANSS, Calgary Depression Scale for Schizophrenia (CDSS, Beck’s hopelessness scale (BHS, and Suicide intent scale (SIS. RESULTS Among the disorders schizophrenia is rated the second most common reason for suicide attempts (53.3%, especially when associated with positive symptoms, depressive features and significant hopelessness. Demographic parameters like age, sex, educational status, occupation, economic status, and marital status were not found to be significant factors linked to the suicide attempts, however family history of suicide had a significant association in schizophrenic suicide attempts. Suicidal intent severity was medium to high among most of the attempters; poisoning was the commonest method; and were found to be due to positive symptoms and depressive symptoms in the schizophrenic illness course.

  13. Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM Model

    Science.gov (United States)

    Gomes, Felipe V.; Rincón-Cortés, Millie; Grace, Anthony A.

    2016-01-01

    Adolescence is a time of extensive neuroanatomical, functional and chemical reorganization of the brain, which parallels substantial maturational changes in behavior and cognition. Environmental factors that impinge on the timing of these developmental factors, including stress and drug exposure, increase the risk for psychiatric disorders. Indeed, antecedents to affective and psychotic disorders, which have clinical and pathophysiological overlap, are commonly associated with risk factors during adolescence that predispose to these disorders. In the context of schizophrenia, psychosis typically begins in late adolescence/early adulthood, which has been replicated by animal models. Rats exposed during gestational day (GD) 17 to the mitotoxin methylazoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. Here we provide an overview of adolescent changes within the dopamine system and the PFC and review recent findings regarding the effects of stress and cannabis exposure during the peripubertal period as risk factors for the emergence of schizophrenia-like deficits. Finally, we discuss peripubertal interventions appearing to circumvent the emergence of adult schizophrenia-like deficits. PMID:27235082

  14. Socio-demographic and clinical profiles of paranoid and nonparanoid schizophrenia: a prospective, multicenter study in China.

    Science.gov (United States)

    Xiang, Yu-Tao; Wang, Chuan-Yue; Chiu, Helen F K; Weng, Yong-Zhen; Bo, Qi-Jing; Chan, Sandra S M; Lee, Edwin H M; Ungvari, Gabor S

    2011-07-01

    This study aimed to explore the socio-demographic and clinical characteristics of paranoid and nonparanoid subtypes of schizophrenia. In a multicenter, randomized, controlled, longitudinal study, 374 clinically stable schizophrenia patients were interviewed at entry with standardized assessment instruments and followed for 12-26 months. In the multivariate analysis, male sex, married marital status, urban abode, and more frequent relapse over the study period were independently associated with paranoid schizophrenia. The socio-demographic and clinical characteristics of Chinese patients with the paranoid subtype of schizophrenia are different from those of their Caucasian counterparts who are more likely to be women and have a better outcome. © 2010 Wiley Periodicals, Inc.

  15. Systematic Prioritization and Integrative Analysis of Copy Number Variations in Schizophrenia Reveal Key Schizophrenia Susceptibility Genes

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-01-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  16. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Hamada, Shin; Masamune, Atsushi; Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa; Hamada, Hirofumi; Kobune, Masayoshi; Satoh, Kennichi; Shimosegawa, Tooru

    2012-01-01

    Highlights: ► Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. ► Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. ► Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. ► Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. ► This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called “cancer stem cells”, within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the “stemness” of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.

  17. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.

    Science.gov (United States)

    Allou, L; Julia, S; Amsallem, D; El Chehadeh, S; Lambert, L; Thevenon, J; Duffourd, Y; Saunier, A; Bouquet, P; Pere, S; Moustaïne, A; Ruaud, L; Roth, V; Jonveaux, P; Philippe, C

    2017-03-01

    Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) study: the moderating role of smoking status and antipsychotic medications.

    Science.gov (United States)

    Lee, Junghee; Green, Michael F; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Nuechterlein, Keith H; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

    2015-04-01

    Working memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. From 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter-number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. Schizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. Results confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

    Science.gov (United States)

    Clelland, C L; Drouet, V; Rilett, K C; Smeed, J A; Nadrich, R H; Rajparia, A; Read, L L; Clelland, J D

    2016-09-13

    Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (PScale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.

  20. Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia.

    Directory of Open Access Journals (Sweden)

    Jing Qin Wu

    Full Text Available While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22 from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05. Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1 gene.This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.

  1. Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells

    International Nuclear Information System (INIS)

    Yang, Min; Ma, Bo; Shao, Hanshuang; Clark, Amanda M.; Wells, Alan

    2016-01-01

    Metastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment. Here we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages. We found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells. Our findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due

  2. Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype

    International Nuclear Information System (INIS)

    Martínez-Méndez, David; Rivera-Toledo, Evelyn; Ortega, Enrique; Licona-Limón, Ileana; Huerta, Leonor

    2017-01-01

    Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4"+ T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling. - Highlights: • Jurkat T cells expressing the HIV-1 envelope fuse with THP-1 monocytes. • Heterokaryons display a dominant myeloid phenotype and monocyte function. • Heterokaryons exhibit activation features in the absence of activation agents. • Activation is not due to cell-cell interaction but requires cell-cell fusion. • The

  3. Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Martínez-Méndez, David; Rivera-Toledo, Evelyn; Ortega, Enrique; Licona-Limón, Ileana; Huerta, Leonor, E-mail: leonorhh@biomedicas.unam.mx

    2017-03-01

    Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4{sup +} T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling. - Highlights: • Jurkat T cells expressing the HIV-1 envelope fuse with THP-1 monocytes. • Heterokaryons display a dominant myeloid phenotype and monocyte function. • Heterokaryons exhibit activation features in the absence of activation agents. • Activation is not due to cell-cell interaction but requires cell-cell fusion. • The

  4. Family intervention for schizophrenia.

    Science.gov (United States)

    Pharoah, F M; Mari, J J; Streiner, D

    2000-01-01

    It has been showed that people with schizophrenia from families that express high levels of criticism, hostility, or over involvement, have more frequent relapses than people with similar problems from families that tend to be less expressive of their emotions. Psychosocial interventions designed to reduce these levels of expressed emotions within families now exist for mental health workers. These interventions are proposed as adjuncts rather than alternatives to drug treatments, and their main purpose is to decrease the stress within the family and also the rate of relapse. To estimate the effects of family psychosocial interventions in community settings for the care of those with schizophrenia or schizophrenia-like conditions compared to standard care. Electronic searches of the Cochrane Library (Issue 2, 1998), the Cochrane Schizophrenia Group's Register (June 1998), EMBASE (1981-1995) and MEDLINE (1966-1995) were undertaken and supplemented with reference searching of the identified literature. Randomised or quasi-randomised studies were selected if they focused on families of people with schizophrenia or schizoaffective disorder and compared community-orientated family-based psychosocial intervention of more than five sessions to standard care. Data were reliably extracted, and, where appropriate and possible, summated. Peto odds ratios (OR), their 95% confidence intervals (CI) and number needed to treat (NNT) were estimated. The reviewers assume that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Family intervention may decrease the frequency of relapse (one year OR 0.57 CI 0.4-0.8, NNT 6.5 CI 4-14). The trend over time of this main finding is towards the null and some small but negative studies may not have been identified by the search. Family intervention may decrease hospitalisation and encourage compliance with medication but data are few and equivocal. Family intervention does not

  5. Some new approaches for prevention of schizophrenia spectrum disorders in patients exposed to exogenous stressors

    Directory of Open Access Journals (Sweden)

    Nataliya Dzeruzhinska

    2017-08-01

    Full Text Available Background. Environment factors affect to the clinical phenotype of schizophrenia spectrum disorders. Aim. To develop recommendations for the prevention schizophrenia spectrum disorders considering the influence of environmental factors on the clinical pathomorphosis of the disease. Methods. It was conducted the psychopathological and psychodiagnostic survey of 186 patients with schizophrenia spectrum disorders with an assessment of clinical features and level of social functioning. It was identified factors that have the most significant pathological effects on the course of disorders on the basis of the received data: the using of a cannabinoid in a family history, mother`s infectious and somatic diseases during pregnancy, mother's using alcohol during pregnancy, consumption of alcohol in adolescent patients, fetal hypoxia or perinatal trauma of the patient at birth, problems with the group of primary support in the family of a child in childhood, maternal toxicosis, crisis relationships in the family, migration to different cultural environment. Results. Clinical pathomorphism of disorders of the spectrum of schizophrenia under the influence of environmental factors determines the features of psychotherapeutic interventions. In people with cannabinoids, it is important to eliminate the symptoms of anxiety through emotion-supportive measures, as well as to create a motivation to ask help in case of symptoms of schizophrenia spectrum disorders. In a group with perinatal complications, the emphasis should be put on cognitive methods in order to correct mental disorders and overcome hypochondria. Early measures to form a positive attitude towards themselves and the environment, supporting family relationships, overcoming depressive symptoms, and developing social activity are targets of psychotherapeutic interventions in people with schizophrenic spectrum disorders and psychological traumatic events. Conclusion. Minimization of environmental

  6. Glutaminase-Deficient Mice Display Hippocampal Hypoactivity, Insensitivity to Pro-Psychotic Drugs and Potentiated Latent Inhibition: Relevance to Schizophrenia

    Science.gov (United States)

    Gaisler-Salomon, Inna; Miller, Gretchen M; Chuhma, Nao; Lee, Sooyeon; Zhang, Hong; Ghoddoussi, Farhad; Lewandowski, Nicole; Fairhurst, Stephen; Wang, Yvonne; Conjard-Duplany, Agnès; Masson, Justine; Balsam, Peter; Hen, René; Arancio, Ottavio; Galloway, Matthew P; Moore, Holly M; Small, Scott A; Rayport, Stephen

    2009-01-01

    Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathophysiology of schizophrenia (SCZ). Recently, presynaptic modulation of glutamate transmission has been shown to have therapeutic promise. We asked whether genetic knockdown of glutaminase (gene GLS1) to reduce glutamatergic transmission presynaptically by slowing the recycling of glutamine to glutamate, would produce a phenotype relevant to SCZ and its treatment. GLS1 heterozygous (GLS1 het) mice showed about a 50% global reduction in glutaminase activity, and a modest reduction in glutamate levels in brain regions relevant to SCZ pathophysiology, but displayed neither general behavioral abnormalities nor SCZ-associated phenotypes. Functional imaging, measuring regional cerebral blood volume, showed hippocampal hypometabolism mainly in the CA1 subregion and subiculum, the inverse of recent clinical imaging findings in prodromal and SCZ patients. GLS1 het mice were less sensitive to the behavioral stimulating effects of amphetamine, showed a reduction in amphetamine-induced striatal dopamine release and in ketamine-induced frontal cortical activation, suggesting that GLS1 het mice are resistant to the effects of these pro-psychotic challenges. Moreover, GLS1 het mice showed clozapine-like potentiation of latent inhibition, suggesting that reduction in glutaminase has antipsychotic-like properties. These observations provide further support for the pivotal role of altered glutamatergic synaptic transmission in the pathophysiology of SCZ, and suggest that presynaptic modulation of the glutamine–glutamate pathway through glutaminase inhibition may provide a new direction for the pharmacotherapy of SCZ. PMID:19516252

  7. Social cognition and neurocognitive deficits in first-episode schizophrenia

    DEFF Research Database (Denmark)

    Bliksted, Vibeke Fuglsang; Fagerlund, Birgitte; Weed, Ethan

    2014-01-01

    BACKGROUND: Recent research has shown a significant impact of social cognitive domains on real world functioning and prognosis in schizophrenia. However, the correlations between specific aspects of social cognition, neurocognition, IQ and clinical symptoms remain unclear in first-episode schizop...... are comparable to the implicit and explicit mentalising discussed in the developmental literature. The two forms of social cognitive deficits are likely to require quite different social cognitive interventions.......BACKGROUND: Recent research has shown a significant impact of social cognitive domains on real world functioning and prognosis in schizophrenia. However, the correlations between specific aspects of social cognition, neurocognition, IQ and clinical symptoms remain unclear in first...

  8. Attentional dysfunction in abstinent long-term cannabis users with and without schizophrenia.

    Science.gov (United States)

    Rentzsch, Johannes; Stadtmann, Ada; Montag, Christiane; Kunte, Hagen; Plöckl, Doris; Hellweg, Rainer; Gallinat, Jürgen; Kronenberg, Golo; Jockers-Scherübl, Maria Christiane

    2016-08-01

    Long-term cannabis use may confer cognitive deficits and increased risk of psychosis. However, the relationship between cannabis use and schizophrenia is complex. In particular, little is known about the effects of chronic cannabis use on the attention-related electric brain response in schizophrenia. We investigated auditory novelty and oddball P300 evoked potentials in a mixed sample of first-episode and chronic schizophrenic patients and healthy controls with (SZCA, n = 20; COCA, n = 20, abstinence ≥28 days) or without (SZ, n = 20; CO, n = 20) chronic cannabis use. Duration of regular cannabis use was 8.3 ± 5.6 (SZCA) and 9.1 ± 7.1 (COCA) years. In general, schizophrenic patients showed reduced P300 amplitudes. Cannabis use was associated with both a reduced early and late left-hemispheric novelty P300. There was a significant 'diagnosis × cannabis' interaction for the left-hemispheric late novelty P300 in that cannabis use was associated with a reduced amplitude in the otherwise healthy but not in the schizophrenic group compared with their relative control groups (corrected p  0.9, respectively). The left-hemispheric late novelty P300 in the otherwise healthy cannabis group correlated inversely with amount and duration of cannabis use (r = -0.50, p = 0.024; r = -0.57, p = 0.009, respectively). Our study confirms attentional deficits with chronic cannabis use. However, cannabis use may lead to different cognitive sequelae in patients with schizophrenia and in healthy controls, possibly reflecting preexisting alterations in the endocannabinoid system in schizophrenia.

  9. A review of structural neuroimaging in schizophrenia: from connectivity to connectomics

    Directory of Open Access Journals (Sweden)

    Anne L Wheeler

    2014-08-01

    Full Text Available In patients with schizophrenia neuroimaging studies have revealed global differences with some brain regions showing focal abnormalities. Examining neurocircuitry, diffusion-weighted imaging studies have identified altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi and corpus callosum associated with the illness. Furthermore, structural co-variance analyses have revealed altered structural relationships among regional morphology in the thalamus, frontal, temporal and parietal cortices in schizophrenia patients. The distributed nature of these abnormalities in schizophrenia suggests that multiple brain circuits are impaired, a neural feature that may be better addressed with network level analyses. However, even with the advent of these newer analyses, a large amount of variability in findings remains, likely partially due to the considerable heterogeneity of this disorder.

  10. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia.

    Science.gov (United States)

    Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Taurisano, Paolo; Romano, Raffaella; Caforio, Grazia; Fazio, Leonardo; Gelao, Barbara; Di Giorgio, Annabella; Iacovelli, Luisa; Sinibaldi, Lorenzo; Popolizio, Teresa; Usiello, Alessandro; Bertolino, Alessandro

    2011-01-18

    The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.

  11. Horticultural therapy for schizophrenia.

    Science.gov (United States)

    Liu, Yan; Bo, Li; Sampson, Stephanie; Roberts, Samantha; Zhang, Guoyou; Wu, Weiping

    2014-05-19

    Horticultural therapy is defined as the process of utilising fruits, vegetables, flowers and plants facilitated by a trained therapist or healthcare provider, to achieve specific treatment goals or to simply improve a person's well-being. It can be used for therapy or rehabilitation programs for cognitive, physical, social, emotional, and recreational benefits, thus improving the person's body, mind and spirit. Between 5% to 15% of people with schizophrenia continue to experience symptoms in spite of medication, and may also develop undesirable adverse effects, horticultural therapy may be of value for these people. To evaluate the effects of horticultural therapy for people with schizophrenia or schizophrenia-like illnesses compared with standard care or other additional psychosocial interventions. We searched the Cochrane Schizophrenia Group Trials Register (Janurary 2013) and supplemented this by contacting relevant study authors, and manually searching reference lists. We included one randomised controlled trial (RCT) comparing horticultural therapy plus standard care with standard care alone for people with schizophrenia. We reliably selected, quality assessed and extracted data. For continuous outcomes, we calculated a mean difference (MD) and for binary outcomes we calculated risk ratio (RR), both with 95% confidence intervals (CI). We assessed risk of bias and created a 'Summary of findings' table using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. We included one single blind study (total n = 24). The overall risk of bias in the study was considered to be unclear although the randomisation was adequate. It compared a package of horticultural therapy which consisted of one hour per day of horticultural activity plus standard care with standard care alone over two weeks (10 consecutive days) with no long-term follow-up. Only two people were lost to follow-up in the study, both in the horticultural therapy group (1 RCT

  12. A recombination hotspot in a schizophrenia-associated region of GABRB2.

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    Siu-Kin Ng

    Full Text Available BACKGROUND: Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2 subunit of GABA(A receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs and containing schizophrenia-associated SNPs and haplotypes. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d over mutation rate (theta, was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. CONCLUSIONS/SIGNIFICANCE: The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and

  13. Gigantol Suppresses Cancer Stem Cell-Like Phenotypes in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Narumol Bhummaphan

    2015-01-01

    Full Text Available As cancer stem cells (CSCs contribute to malignancy, metastasis, and relapse of cancers, potential of compound in inhibition of CSCs has garnered most attention in the cancer research as well as drug development fields recently. Herein, we have demonstrated for the first time that gigantol, a pure compound isolated from Dendrobium draconis, dramatically suppressed stem-like phenotypes of human lung cancer cells. Gigantol at nontoxic concentrations significantly reduced anchorage-independent growth and survival of the cancer cells. Importantly, gigantol significantly reduced the ability of the cancer cells to form tumor spheroids, a critical hallmark of CSCs. Concomitantly, the treatment of the compound was shown to reduce well-known lung CSCs markers, including CD133 and ALDH1A1. Moreover, we revealed that gigantol decreased stemness in the cancer cells by suppressing the activation of protein kinase B (Akt signal which in turn decreased the cellular levels of pluripotency and self-renewal factors Oct4 and Nanog. In conclusion, gigantol possesses CSCs suppressing activity which may facilitate the development of this compound for therapeutic approaches by targeting CSCs.

  14. The beneficial influence of inattention on visual interference in schizophrenia.

    Science.gov (United States)

    Brodeur, Mathieu B; Kiang, Michael; Christensen, Bruce K

    2016-09-01

    Schizophrenia is associated with poor spatial attention. However, although this deficit undermines the perception of target information, it may be helpful for ignoring irrelevant inputs. The present study examined whether event-related brain potential (ERP) indices of visual spatial attention predicted the magnitude of the brain response to interference in schizophrenia. ERPs were recorded in 16 schizophrenia patients and 20 healthy control participants who had to indicate whether the target E was global or local in compound letter stimuli. The nontarget could be either highly similar to the target (i.e., a global E composed of local Ss and vice versa) and thus produce more interference, or it could be dissimilar (i.e., a global E composed of local Hs and vice versa) and generate less interference. Both groups' responses were slowed by interference. Voltage amplitudes of the P1, and of ERP interference effects from 300-500 ms after stimulus onset, were significantly smaller in schizophrenia patients than in healthy participants when the target was global. In patients, larger P1 amplitudes were correlated with larger interference effects and with more severe symptoms of attentional deficits and conceptual disorganization. Schizophrenia participants thus exhibited abnormal ERPs to interference despite normal behavioral performance. Schizophrenia patients likely pay less attention to stimuli in general; however, the impact of this impairment on target detection is compensated by relatively greater inattention to irrelevant components of the stimuli, and this explains why they are not more influenced by interference than healthy participants at the behavioral level. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  15. From linkage studies to epigenetics: what we know and what we need to know in the neurobiology of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Ariel eCariaga-Martinez

    2016-05-01

    Full Text Available Schizophrenia is a complex psychiatric disorder characterized by the presence of positive, negative and cognitive symptoms that lacks a unifying neuropathology. In the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including genetic and epigenetic studies. In relation to the latter, basic research suggests that normal cognition is regulated by epigenetic mechanisms and its dysfunction occurs upon epigenetic misregulation, providing new insights into missing heritability of complex psychiatric diseases, referring to the discrepancy between epidemiological heritability and the proportion of phenotypic variation explained by DNA sequence difference. In schizophrenia the absence of consistently replicated genetic effects together with evidence for lasting changes in gene expression after environmental exposures suggest a role of epigenetic mechanisms. In this review we will focus on epigenetic modifications as a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychotic conditions throughout life.

  16. Biological study in schizophrenia

    International Nuclear Information System (INIS)

    Kasai, Kiyoto; Yoshikawa, Akane; Natsubori, Takanobu; Koike, Shinsuke; Nagai, Tatsuya; Araki, Tsuyoshi; Nishimura, Yukika; Iwamoto, Kazuya

    2012-01-01

    Schizophrenia is associated with enormous morbidity, mortality, personal disability, and social cost. Although considerable research on schizophrenia has been performed, the etiology of this disease has not been fully elucidated. In recent years, imaging and genetic technologies have been developed dramatically. Disturbances in glutamate and gamma-aminobutyric acid (GABA)ergic neurotransmission may underlie the pathophysiology of schizophrenia. We attempted an integrative review, of studies pertaining to recent advances of schizophrenia research with a focus on neuroimaging and genetic studies. Additionally, we present the preliminary findings of the clinical research in our outpatient unit, specialized for early intervention, at the University of Tokyo Hospital. (author)

  17. The Role of Catechol-O-Methyltransferase (COMT Gene in the Etiopathogenesis of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Ceren Acar

    2014-09-01

    Full Text Available Genetic factors in the risk of developing schizophrenia is of great importance. With the help of the advances in the field of genetics in recent years by using linkage analysis several genes have been identified that may be a risk factor in schizophrenia. Several association studies have been performed in many different populations on the candidate susceptibility genes that were defined in previous studies. However, these studies give controversial results in different countries with different populations, and there are problems in obtaining replicable results. In this review we aimed to focus on the genetic basis of schizophrenia and the relationship between schizophrenia and catechol-O-methyltransferase (COMT gene. COMT encodes an enzyme molecule which has an important function in dopamine pathways. It has great importance in catecholamine metabolism and pharmacology and genetic mechanism of catechol metabolism variations and their clinical consequences. COMT transfers the methyl group from S-adenosyl-methionine to the hydroxyl group of catechol nucleus (such as dopamine, norepinephrine or catechol estrogen. Genetic variations found in COMT gene are associated with a broad spectrum of clinical phenotype including psychiatric disorders or estrogen related cancers. Several groups have performed studies on the relationship between schizophrenia and COMT. The most commonly studied polymorphism in COMT gene is rs4680 and it causes a valine methionine conversion at codon 158. The association studies on this polymorphism in different populations gave both positive and negative results. Schizoprenia is a complex disease caused by the interaction of environmental and genetic factors, while interpreting the genetic data, this fact and the possibility of the presence of different gene products should be taken into account. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(3.000: 217-226

  18. Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia.

    Science.gov (United States)

    Mueller, Toni M; Yates, Stefani D; Haroutunian, Vahram; Meador-Woodruff, James H

    2017-04-01

    Glycosylation is a post-translational modification that is an essential element in cell signaling and neurodevelopmental pathway regulation. Glycan attachment can influence the tertiary structure and molecular interactions of glycosylated substrates, adding an additional layer of regulatory complexity to functional mechanisms underlying central cell biological processes. One type of enzyme-mediated glycan attachment, fucosylation, can mediate glycoprotein and glycolipid cell surface expression, trafficking, secretion, and quality control to modulate a variety of inter- and intracellular signaling cascades. Building on prior reports of glycosylation abnormalities and evidence of dysregulated glycosylation enzyme expression in schizophrenia, we examined the protein expression of 5 key fucose-modifying enzymes: GDP-fucose:protein O-fucosyltransferase 1 (POFUT1), GDP-fucose:protein O-fucosyltransferase 2 (POFUT2), fucosyltransferase 8 (FUT8), fucosyltransferase 11 (FUT11), and plasma α-l-fucosidase (FUCA2) in postmortem superior temporal gyrus of schizophrenia (N=16) and comparison (N=14) subjects. We also used the fucose binding protein, Aleuria aurantia lectin (AAL), to assess α-1,6-fucosylated N-glycoprotein abundance in the same subjects. In schizophrenia, we found increased expression of POFUT2, a fucosyltransferase uniquely responsible for O-fucosylation of thrombospondin-like repeat domains that is involved in a non-canonical endoplasmic reticulum quality control pathway. We also found decreased expression of FUT8 in schizophrenia. Given that FUT8 is the only α-1,6-fucosyltransferase expressed in mammals, the concurrent decrease in AAL binding in schizophrenia, particularly evident for N-glycoproteins in the ~52-58kDa and ~60-70kDa molecular mass ranges, likely reflects a consequence of abnormal FUT8 expression in the disorder. Dysregulated FUT8 and POFUT2 expression could potentially explain a variety of molecular abnormalities in schizophrenia. Copyright

  19. The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

    OpenAIRE

    Mössner, R; Schumacher, A; Wagner, M; Lennertz, L; Steinbrecher, A; Quednow, Boris B; Rujescu, D; Rietschel, M; Maier, W

    2012-01-01

    Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive sympto...

  20. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype

    Science.gov (United States)

    Paschall, Amy V.; Yang, Dafeng; Lu, Chunwan; Redd, Priscilla S.; Choi, Jeong-Hyeon; Heaton, Christopher M.; Lee, Jeffrey R.; Nayak-Kapoor, Asha; Liu, Kebin

    2016-01-01

    The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells. PMID:27659530

  1. Association study between the Taq1A (rs1800497 polymorphism and schizophrenia in a Brazilian sample

    Directory of Open Access Journals (Sweden)

    Quirino Cordeiro

    2014-08-01

    Full Text Available Schizophrenia is a severe psychotic disorder with recurrent relapse and functional impairment. It results from a poorly understood gene-environment interaction. The Taq1A polymorphism (located in the gene cluster NTAD is a likely candidate for schizophrenia. Its rs1800497 polymorphism was shown to be associated with DRD2 gene expression. Therefore the present work aims to investigate a possible association between schizophrenia and such polymorphism. The compared distribution of the alleles and genotypes of the studied polymorphism was investigated in a Brazilian sample of 235 patients and 834 controls. Genotypic frequencies were in Hardy-Weinberg equilibrium. There was a trend of allelic association between the Taq1A polymorphism (rs1800497 with schizophrenia in the studied sample. However no statistically differences were found between cases and controls when analyzed by gender or schizophrenia subtypes.

  2. Self-disorders in schizophrenia-spectrum disorders

    DEFF Research Database (Denmark)

    Nordgaard, Julie; Nilsson, Lars Siersbæk; Sæbye, Ditte

    2017-01-01

    Self-disorders have been hypothesized to be an underlying and trait-like core feature of schizophrenia-spectrum disorders and a certain degree of temporal stability of self-disorders would therefore be expected. The aim of the study was to examine the persistence of self-disorders measured...... by the Examination of Anomalous Self Experiences over a time span of 5 years. 48 patients with schizophrenia-spectrum disorders were thoroughly assessed for psychopathology at baseline and 5 years later. Self-disorders were assessed by the Examination of Anomalous Self Experiences. The level of self-disorders...... was same at the two occasions for the full Examination of Anomalous Self Disorders and for four out of the five domains. For one domain, the level of self-disorders increased slightly from baseline to follow-up. The correlations between baseline and follow-up were moderate. 9 out of the 13 most...

  3. Language Disorder In Schizophrenia Patient: A Case Study Of Five Schizophrenia Paranoid Patients In Simeulue District Hospital

    OpenAIRE

    Kurnia, Beby Febri

    2015-01-01

    Language disorder in schizophrenia patients is an acquired language disorder due to thought disorder. This analysis analyzed language disorder in schizophrenia paranoid patients in Simeulue District Hospital. The objective of this analysis were: (1) to find out the types of schizophrenic speech found in schizophrenia paranoid patients, (2) to find out the most dominant type of schizophrenia speech found in schizophrenia paranoid patients, and (3) to find out which patient has most severe lang...

  4. Irradiation in adulthood as a new model of schizophrenia.

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    Yasuhide Iwata

    Full Text Available BACKGROUND: Epidemiological studies suggest that radiation exposure may be a potential risk factor for schizophrenia in adult humans. Here, we investigated whether adult irradiation in rats caused behavioral abnormalities relevant to schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: A total dose of 15-Gy irradiation in six fractionations during 3 weeks was exposed to the forebrain including the subventricular zone (SVZ and subgranular zone (SGZ with male rats in the prone position. Behavioral, immunohistochemical, and neurochemical studies were performed three months after fractionated ionizing irradiation. Three months after fractionated ionizing irradiation, the total numbers of BrdU-positive cells in both the SVZ and SGZ zones of irradiated rats were significantly lower than those of control (sham-irradiated rats. Hyperactivity after administration of the dopaminergic agonist methamphetamine, but not the N-methyl-D-aspartate (NMDA receptor antagonist dizocilpine, was significantly enhanced in the irradiated rats although spontaneous locomotion in the irradiated rats was significantly lower than that of controls. Behavioral abnormalities including auditory sensory gating deficits, social interaction deficits, and working memory deficits were observed in the irradiated rats. CONCLUSION/SIGNIFICANCE: The present study suggests that irradiation in adulthood caused behavioral abnormalities relevant to schizophrenia, and that reduction of adult neurogenesis by irradiation may be associated with schizophrenia-like behaviors in rats.

  5. Simulating real world functioning in schizophrenia using a naturalistic city environment and single-trial, goal-directed navigation

    Directory of Open Access Journals (Sweden)

    John A Zawadzki

    2013-11-01

    Full Text Available Objective: To develop a virtual reality platform that would serve as a functionally meaningful measure of cognition in schizophrenia that would complement standard batteries of cognitive tests during clinical trials for cognitive treatments in schizophrenia, be amenable to human neuroimaging research, yet lend itself to neurobiological comparison with rodent analogues.Method: Thirty-three patients with schizophrenia and 33 healthy controls matched for age, sex, video gaming experience and education completed eight rapid, single-trial virtual navigation tasks within a naturalistic virtual city. Four trials tested their ability to find different targets seen during the passive viewing of a closed path that led them around different city blocks. Four subsequent trials tested their ability to return to four different starting points after viewing a path that took them several blocks away from the starting position. Results: Individuals with schizophrenia had difficulties in way-finding, measured as distance travelled to find targets previously encountered within the virtual city. They were also more likely not to notice the target during passive viewing, less likely to find novel shortcuts to targets and more likely to become lost and fail completely in finding the target. Total travel distances across all eight trials strongly correlated (negatively with neurocognitive measures and, for 49 participants who completed the Quality of Life Scale, psychosocial functioning. Conclusion: Single-trial, goal-directed navigation in a naturalistic virtual environment is a functionally meaningful measure of cognitive functioning in schizophrenia.

  6. California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS).

    Science.gov (United States)

    Stone, William S; Mesholam-Gately, Raquelle I; Braff, David L; Calkins, Monica E; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Seidman, Larry J

    2015-04-01

    The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ. Copyright © 2014. Published by Elsevier B.V.

  7. Resting EEG deficits in accused murderers with schizophrenia.

    Science.gov (United States)

    Schug, Robert A; Yang, Yaling; Raine, Adrian; Han, Chenbo; Liu, Jianghong; Li, Liejia

    2011-10-31

    Empirical evidence continues to suggest a biologically distinct violent subtype of schizophrenia. The present study examined whether murderers with schizophrenia would demonstrate resting EEG deficits distinguishing them from both non-violent schizophrenia patients and murderers without schizophrenia. Resting EEG data were collected from five diagnostic groups (normal controls, non-murderers with schizophrenia, murderers with schizophrenia, murderers without schizophrenia, and murderers with psychiatric conditions other than schizophrenia) at a brain hospital in Nanjing, China. Murderers with schizophrenia were characterized by increased left-hemispheric fast-wave EEG activity relative to non-violent schizophrenia patients, while non-violent schizophrenia patients instead demonstrated increased diffuse slow-wave activity compared to all other groups. Results are discussed within the framework of a proposed left-hemispheric over-processing hypothesis specific to violent individuals with schizophrenia, involving left hemispheric hyperarousal deficits, which may lead to a homicidally violent schizophrenia outcome. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Schizophrenia : Current concepts in aetiology

    Directory of Open Access Journals (Sweden)

    P S Bhat

    2014-01-01

    Full Text Available Schizophrenia is perhaps the most devastating neuropsychiatric illness. Worldwide, its prevalence rate is about 1%. Schizophrenia is considered a neurodevelopmental disorder involving the interplay of susceptibility genes and environmental factors. There is a wide range of pathologic findings, but there is no specific or diagnostic laboratory abnormality. Till date, the aetiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Over the last forty years, the dopaminergic model has been the leading neurochemical hypothesis of schizophrenia. Yet it remains unlikely that dopaminergic dysfunction, on its own. Glutamatergic models provide an alternate approach for conceptualizing the brain abnormalities associated with schizophrenia. New pharmacological and behavioral approaches aimed at potentiating glutamatergic neurotransmission, offer new hopeforfuture clinical development

  9. Pharmacotherapy of Schizophrenia: Ploypharmacy Approaches

    Directory of Open Access Journals (Sweden)

    Fatemeh Rahiminejad

    2010-07-01

    Full Text Available "nSchizophrenia is a debilitating illness, rating as one of the leading causes of lost years of quality of life. The illness imposes a disproportionate burden on patients and their families, healthcare systems and society. Pharmacological management is the cornerstone of treatment of schizophrenia, and antipsychotics, both first generation of antipsychotics and second generation of antipsychotics, are efficacious in reducing levels of psychopathology in acute episodes of schizophrenia. Clearly a need for innovative treatment strategies in schizophrenia that will ensure increased effectiveness against negative symptoms and cognitive dysfunction dysfunction. Therefore, in majority of cases polypharmacy is one of the effective approaches. This review focused on polypharmacy in the treatment of schizophrenia and in particular negative symptoms.

  10. Cognitive Remediation in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Joana Vieira

    2014-06-01

    Full Text Available Several reviews of the literature support the idea that cognitive deficits observed in a large percentage of patients with schizophrenia are responsible for the cognitive performance deficit and functional disability associated with the disease. The grow- ing importance of neurocognition in Psychiatry, especially with regard to planning strategies and rehabilitative therapies to improve the prognosis of patients contrib- utes to the interest of achieving this literature review on cognitive rehabilitation in schizophrenia. In this work, drawn from research in the areas of schizophrenia, cog- nition, cognitive rehabilitation and cognitive remediation (2000-2012 through PubMed and The Cochrane Collaboration, it is intended, to describe the types of psychological and behavioral therapies recommended in the treatment of cognitive disabilities in patients diagnosed with schizophrenia. This review will also highlight the clinical and scientific evidence of each of these therapies, as their effect on cognitive performance, symptoms and functionality in patients with schizophrenia.

  11. Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation

    Directory of Open Access Journals (Sweden)

    Marangoni Sérgio

    2009-04-01

    Full Text Available Abstract Background Schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. Methods We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area – BA22p identifying by mass spectrometry several protein expression alterations that could be related to the disease. Results Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6 and glial fibrillary acidic protein (GFAP were confirmed by western blot in schizophrenia prefrontal cortex. Conclusion Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease.

  12. Toxoplasma gondii and schizophrenia

    OpenAIRE

    Mokhtari Mohammadreza; Mokhtari Mojgan

    2006-01-01

    Recent epidemiologic studies indicate that infectious agents may contribute to some cases of schizophrenia. In animals, infection with Toxoplasma gondii can alter behavior and neurotransmitter function. In humans, acute infection with T. gondii can produce psychotic symptoms similar to those displayed by persons with schizophrenia. Since 1953, a total of 19 studies of T. gondii antibodies in persons with schizophrenia and other severe psychiatric disorders and in controls have been reported; ...

  13. Differential sensory fMRI signatures in autism and schizophrenia: Analysis of amplitude and trial-to-trial variability.

    Science.gov (United States)

    Haigh, Sarah M; Gupta, Akshat; Barb, Scott M; Glass, Summer A F; Minshew, Nancy J; Dinstein, Ilan; Heeger, David J; Eack, Shaun M; Behrmann, Marlene

    2016-08-01

    Autism and schizophrenia share multiple phenotypic and genotypic markers, and there is ongoing debate regarding the relationship of these two disorders. To examine whether cortical dynamics are similar across these disorders, we directly compared fMRI responses to visual, somatosensory and auditory stimuli in adults with autism (N=15), with schizophrenia (N=15), and matched controls (N=15). All participants completed a one-back letter detection task presented at fixation (to control attention) while task-irrelevant sensory stimulation was delivered to the different modalities. We focused specifically on the response amplitudes and the variability in sensory fMRI responses of the two groups, given the evidence of greater trial-to-trial variability in adults with autism. Both autism and schizophrenia individuals showed weaker signal-to-noise ratios (SNR) in sensory-evoked responses compared to controls (d>0.42), but for different reasons. For the autism group, the fMRI response amplitudes were indistinguishable from controls but were more variable trial-to-trial (d=0.47). For the schizophrenia group, response amplitudes were smaller compared to autism (d=0.44) and control groups (d=0.74), but were not significantly more variable (dautism and is not a defining characteristic of schizophrenia, and (2) that blunted response amplitudes may be characteristic of schizophrenia. The relationship between the amplitude and the variability of cortical activity might serve as a specific signature differentiating these neurodevelopmental disorders. Identifying the neural basis of these responses and their relationship to the underlying genetic bases may substantially enlighten the understanding of both disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.

    Science.gov (United States)

    St Pourcain, B; Robinson, E B; Anttila, V; Sullivan, B B; Maller, J; Golding, J; Skuse, D; Ring, S; Evans, D M; Zammit, S; Fisher, S E; Neale, B M; Anney, R J L; Ripke, S; Hollegaard, M V; Werge, T; Ronald, A; Grove, J; Hougaard, D M; Børglum, A D; Mortensen, P B; Daly, M J; Davey Smith, G

    2018-02-01

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.

  15. Theory of mind and context processing in schizophrenia: the role of cognitive flexibility.

    Science.gov (United States)

    Champagne-Lavau, Maud; Charest, Anick; Anselmo, Karyne; Rodriguez, Jean-Pierre; Blouin, Guy

    2012-12-30

    The present study sought to identify whether cognitive flexibility and context processing may impact theory of mind (ToM) ability in schizophrenia. Thirty two patients with schizophrenia and 29 matched healthy participants were tested individually on their ToM ability using a task involving attribution and comprehension of a speaker's ironic intent. This task made it possible to determine whether the degree of incongruity between contextual information and a target sentence has an impact on the attribution of ironic intent to the protagonists of a story. Participants were also assessed on their cognitive flexibility and working memory. The main results revealed that participants with schizophrenia correctly perceived contextual information cueing attribution of ironic intent to the protagonist of the stimulus, but they showed difficulty to correctly integrate this information, performing significantly worse than healthy participants when they attributed mental states. However, some participants with schizophrenia performed like healthy control participants on the ToM task while others did not. A lack of flexibility seems to differentiate the two schizophrenia subgroups thereby obtained, suggesting that cognitive flexibility has an impact on ToM performances in schizophrenia. These difficulties were not associated with clinical symptoms. Such results will have an impact on cognitive remediation. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Low IQ scores in schizophrenia : primary or secondary deficit?

    NARCIS (Netherlands)

    van Beilen, M; Withaar, F; van Zomeren, AH; van den Bosch, R

    Background: Schizophrenia is consistently associated with lower IQ compared to the IQ of control groups, or estimated premorbid IQ. It is not likely that the IQ scores deteriorate during the prodromal phase or first psychotic episode; they are already present before the onset of the prodromal phase

  17. Uncoupling proteins (UCP) in unicellular eukaryotes: true UCPs or UCP1-like acting proteins?

    Science.gov (United States)

    Luévano-Martínez, Luis Alberto

    2012-04-05

    Uncoupling proteins belong to the superfamily of mitochondrial anion carriers. They are apparently present throughout the Eukarya domain in which only some members have an established physiological function, i.e. UCP1 from brown adipose tissue is involved in non-shivering thermogenesis. However, the proteins responsible for the phenotype observed in unicellular organisms have not been characterized. In this report we analyzed functional evidence concerning unicellular UCPs and found that true UCPs are restricted to some taxonomical groups while proteins conferring a UCP1-like phenotype to fungi and most protists are the result of a promiscuous activity exerted by other mitochondrial anion carriers. We describe a possible evolutionary route followed by these proteins by which they acquire this promiscuous mechanism. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. Visual masking & schizophrenia

    Directory of Open Access Journals (Sweden)

    Michael H. Herzog

    2015-06-01

    Full Text Available Visual masking is a frequently used tool in schizophrenia research. Visual masking has a very high sensitivity and specificity and masking paradigms have been proven to be endophenotypes. Whereas masking is a powerful technique to study schizophrenia, the underlying mechanisms are discussed controversially. For example, for more than 25 years, masking deficits of schizophrenia patients were mainly attributed to a deficient magno-cellular system (M-system. Here, we show that there is very little evidence that masking deficits are magno-cellular deficits. We will discuss the magno-cellular and other approaches in detail and highlight their pros and cons.

  19. Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.

    Science.gov (United States)

    Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

    2016-06-01

    Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

  20. Loss aversion in schizophrenia.

    Science.gov (United States)

    Trémeau, Fabien; Brady, Melissa; Saccente, Erica; Moreno, Alexis; Epstein, Henry; Citrome, Leslie; Malaspina, Dolores; Javitt, Daniel

    2008-08-01

    Loss aversion in decision-making refers to a higher sensitivity to losses than to gains. Loss aversion is conceived as an affective interference in cognitive processes such as judgment and decision-making. Loss aversion in non-risky choices has not been studied in schizophrenia. Forty-two individuals with schizophrenia and 42 non-patient control subjects, matched by gender and age, were randomized to two different scenarios (a buying scenario and a selling scenario). Subjects were asked to evaluate the price of a decorated mug. Schizophrenia subjects were re-tested four weeks later with the other scenario. Contrary to non-patient controls, schizophrenia subjects did not show loss aversion. In the schizophrenia group, absence of loss aversion was correlated with age, duration of illness, number of months in State hospitals, and poorer performance in the Wisconsin Card Sorting Test, but not with current psychopathology and two domains of emotional experience. Absence of loss aversion in schizophrenia represents a deficit in the processing of emotional information during decision-making. It can be interpreted as a lack of integration between the emotional and the cognitive systems, or to a more diffuse and de-differentiated impact of emotional information on decision-making. Future studies should bring more clarity to this question.

  1. Attention/vigilance in schizophrenia: performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS).

    Science.gov (United States)

    Nuechterlein, Keith H; Green, Michael F; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

    2015-04-01

    Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Inflammation and elevation of interleukin-12p40 in patients with schizophrenia

    Directory of Open Access Journals (Sweden)

    Nora eBedrossian

    2016-03-01

    Full Text Available Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning, which suggests that it likely has neurodegenerative characteristics. Inflammatory markers such as pro-inflammatory cytokines are well-known etiological contributors for psychiatric disorders, including schizophrenia. Although the role of inflammation in schizophrenia is becoming evident, the number of studies in this area is relatively scarce, especially in Lebanon, and increased procedural thoroughness is needed. Cytokines play a key role in the activation of the immune system and strongly influence neurotransmission. Previous investigation of plasma levels showed dysregulation of interleukin (IL-12. However, genotypical variations of this interleukin have not been investigated for patients with schizophrenia yet. Thus, in this paper, we aimed to compute and assess IL-12p40 levels in the sera of individuals with schizophrenia from different provinces in Lebanon and compare it to controls. Healthy subjects comprised 60 individuals with a male/female (M/F ratio of 31/29, whereas patients with schizophrenia consisted of 63 subjects with an M/F ratio of 30/33. The mean age for healthy controls was 30 years, whereas that for patients with schizophrenia was 35 years. A standardized ELISA technique was used to measure the concentration of IL-12p40 in all collected sera (n=123. The mean IL-12p40 levels in patients with schizophrenia were significantly higher than in healthy controls (p=0.002. Healthy females had a significantly higher concentration of IL-12p40 than healthy males (p=0.009. Female patients with schizophrenia had significantly higher concentrations of IL-12p40 than their male counterparts (p<0.001, healthy females (p=0.018 and healthy males (p<0.001, respectively. Male patients with schizophrenia had significantly higher concentrations of IL-12p40 than healthy males (p=0.023. The study’s results suggest that IL-12p40

  3. Gender identity disorder and schizophrenia: neurodevelopmental disorders with common causal mechanisms?

    Science.gov (United States)

    Rajkumar, Ravi Philip

    2014-01-01

    Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF), early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed.

  4. Gender Identity Disorder and Schizophrenia: Neurodevelopmental Disorders with Common Causal Mechanisms?

    Directory of Open Access Journals (Sweden)

    Ravi Philip Rajkumar

    2014-01-01

    Full Text Available Gender identity disorder (GID, recently renamed gender dysphoria (GD, is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF, early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed.

  5. Role of CACNA1C gene polymorphisms and protein expressions in the pathogenesis of schizophrenia: a case-control study in a Chinese population.

    Science.gov (United States)

    Zhang, Sheng-Yu; Hu, Qiang; Tang, Tao; Liu, Chao; Li, Cheng-Chong; Yang, Xiao-Guang; Zang, Yin-Yin; Cai, Wei-Xiong

    2017-08-01

    The study aimed to investigate the correlations of CACNA1C genetic polymorphisms and protein expression with the pathogenesis of schizophrenia in a Chinese population. This research included 139 patients diagnosed with schizophrenia (case group) and 141 healthy volunteers (control group). Case and control samples were genotyped using denaturing high-performance liquid chromatography (DHPLC). Haplotypes of rs10848683, rs2238032, and rs2299661 were analyzed using the Shesis software. A mouse model of schizophrenia was established and assigned to test and blank groups. Western blotting was used to detect CACNA1C protein expression. The genotype and allele distribution of rs2238032 and rs2299661 differed between the case and control groups. TT genotype of rs2238032 and G allele of rs2299661 could potentially reduce the risk of schizophrenia. The distribution of rs2238032 genotype has a close connection with cognitive disturbance and the results of the general psychopathology classification exam. The distribution of rs2299661 genotypes was closely related to sensory and perceptual disorders, negative symptom subscales, and the results of the general psychopathology classification exam. CTC haplotype increased and CTG decreased the risk of schizophrenia in healthy people. In the brain tissues of mice with schizophrenia, the CACNA1C protein expression was higher in the test group than in the blank group. Our study demonstrated that CACNA1C gene polymorphisms and CACNA1C protein expression were associated with schizophrenia and its clinical phenotypes.

  6. The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis.

    Science.gov (United States)

    Silva, Everton F; Medeiros, Marco A; McBride, Alan J A; Matsunaga, Jim; Esteves, Gabriela S; Ramos, João G R; Santos, Cleiton S; Croda, Júlio; Homma, Akira; Dellagostin, Odir A; Haake, David A; Reis, Mitermayer G; Ko, Albert I

    2007-08-14

    Subunit vaccines are a potential intervention strategy against leptospirosis, which is a major public health problem in developing countries and a veterinary disease in livestock and companion animals worldwide. Leptospiral immunoglobulin-like (Lig) proteins are a family of surface-exposed determinants that have Ig-like repeat domains found in virulence factors such as intimin and invasin. We expressed fragments of the repeat domain regions of LigA and LigB from Leptospira interrogans serovar Copenhageni. Immunization of Golden Syrian hamsters with Lig fragments in Freund's adjuvant induced robust antibody responses against recombinant protein and native protein, as detected by ELISA and immunoblot, respectively. A single fragment, LigANI, which corresponds to the six carboxy-terminal Ig-like repeat domains of the LigA molecule, conferred immunoprotection against mortality (67-100%, P<0.05) in hamsters which received a lethal inoculum of L. interrogans serovar Copenhageni. However, immunization with this fragment did not confer sterilizing immunity. These findings indicate that the carboxy-terminal portion of LigA is an immunoprotective domain and may serve as a vaccine candidate for human and veterinary leptospirosis.

  7. Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

    OpenAIRE

    Paparelli, Alessandra; Di Forti, Marta; Morrison, Paul D.; Murray, Robin M.

    2011-01-01

    The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the re...

  8. Relationship between toxoplasmosis and schizophrenia: A review.

    Science.gov (United States)

    Fuglewicz, Aleksander J; Piotrowski, Patryk; Stodolak, Anna

    2017-09-01

    A growing body of evidence suggests a correlation between schizophrenia and exposure to infectious agents. The majority of studied cases concerns the infection caused by T. gondii, an obligatory intracellular parasite that infects about 1/3 of the entire human population, according to the available data. The acute stage of the disease, predominantly short-lived and transient, transforms into the latent and chronic phase in which the parasite localizes within tissue cysts, mainly in the central nervous system. The chronic toxoplasmosis, primarily regarded as benign and asymptomatic, might be responsible, in light of current scientific evidence, for a vast array of neuropsychiatric symptoms. Numerous epidemiological case-control studies show a higher prevalence of T. gondii infestation in individuals with various psychiatric and behavior disorders, including schizophrenia. This paper tends to review the relevant studies that demonstrate links between schizophrenia and T. gondii infestation, of which the latter may be acquired in different developmental phases. Apart from epidemiological correlation studies, some papers on other associations were also presented, describing putative patophysiological mechanisms that might be at least partly responsible for chronic infection-induced neuromediator disturbances, together with morphological and functional alterations, e.g., low-grade neuroinflammation, which are likely to induce psychopathological symptoms. Toxoplasmosis is only one of the putative infectious agents that derange correct brain growth and differentiation, alongside genetic and environmental factors. All of them may lead eventually to schizophrenia. A better knowledge of infection mechanisms and its influence on neurobiochemical and neuropathological pathways may enable more efficient therapy and the prevention of this devastating disease.

  9. Psychopathology of Lived Time: Abnormal Time Experience in Persons With Schizophrenia.

    Science.gov (United States)

    Stanghellini, Giovanni; Ballerini, Massimo; Presenza, Simona; Mancini, Milena; Raballo, Andrea; Blasi, Stefano; Cutting, John

    2016-01-01

    Abnormal time experience (ATE) in schizophrenia is a long-standing theme of phenomenological psychopathology. This is because temporality constitutes the bedrock of any experience and its integrity is fundamental for the sense of coherence and continuity of selfhood and personal identity. To characterize ATE in schizophrenia patients as compared to major depressives we interviewed, in a clinical setting over a period of 15 years, 550 consecutive patients affected by schizophrenic and affective disorders. Clinical files were analyzed by means of Consensual Qualitative Research (CQR), an inductive method suited to research that requires rich descriptions of inner experiences. Of the whole sample, 109 persons affected by schizophrenic (n = 95 acute, n = 14 chronic) and 37 by major depression reported at least 1 ATE. ATE are more represented in acute (N = 109 out of 198; 55%) than in chronic schizophrenic patients (N = 14 out of 103; 13%). The main feature of ATE in people with schizophrenia is the fragmentation of time experience (71 out of 109 patients), an impairment of the automatic and prereflexive synthesis of primal impression-retention-protention. This includes 4 subcategories: disruption of time flowing, déjà vu/vecu, premonitions about oneself and the external world. We contrasted ATE in schizophrenia and in major depression, finding relevant differences: in major depressives there is no disarticulation of time experience, rather timelessness because time lacks duration, not articulation. These core features of the schizophrenic pheno-phenotype may be related to self-disorders and to the manifold of characteristic schizophrenic symptoms, including so called bizarre delusions and verbal-acoustic hallucinations. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  10. Predictors of admission to a high-security hospital of people with intellectual disability with and without schizophrenia.

    Science.gov (United States)

    Doody, G A; Thomson, L D; Miller, P; Johnstone, E C

    2000-04-01

    Admission to secure hospital facilities is a rare outcome for people with intellectual disability with or without concomitant psychosis. The present study compares people with mild intellectual disability with and without schizophrenia resident in the Scottish and Northern Irish State Hospital, Carstairs, to matched mild intellectual disability controls, also with and without schizophrenia, in the community. It is hoped that this study may identify socio-demographic, clinical or historical predictors which may lead to admission to secure hospital facilities for people with mild intellectual disability. One hundred and eight subjects were identified from two previous studies which concerned State Hospital patients and patients with intellectual disability with and without schizophrenia. Four experimental groups were derived: (1) 14 individuals with comorbid intellectual disability and schizophrenia who had been resident in the State Hospital; (2) 34 comorbid community control subjects; (3) 33 individuals with intellectual disability and no psychosis who had been resident in the State Hospital; and (4) 27 community control subjects with mild intellectual disability. The four groups were compared on a range of socio-demographic, historical and clinical variables obtained from case records and subject interviews. Relative to community controls, people with intellectual disability and no psychosis in the State Hospital are likely to be single, to have a later age of first psychiatric hospital admission, and to have a history of previous suicide attempts, alcohol abuse or drug misuse. Subjects with comorbid intellectual disability and schizophrenia in the State Hospital are more likely to be male, to have an early age of first psychiatric admission, and to have no family history of either schizophrenia or intellectual disability. Strategies aimed at addressing suicidal behaviour, alcohol and drug misuse amongst people with intellectual disability may facilitate a

  11. Schizophrenia, depression, and sleep disorders: Their traditional oriental medicine equivalents

    NARCIS (Netherlands)

    Bosch, M.P.C.; Rover, P. de; Staudte, H.; Lim, S.; Noort, M.W.M.L. van den

    2015-01-01

    Psychiatric disorders can be described and treated from both a Western (allopathic) and an Eastern perspective, which should be taken into account when conducting research. Patients with schizophrenia or depression are likely to be undergoing Western treatment when they are referred to an

  12. cis-3-Hexenol and trans-2-hexenal mixture prevents development of PTSD-like phenotype in rats.

    Science.gov (United States)

    Nikaido, Yoshikazu; Yamada, Junko; Migita, Keisuke; Shiba, Yuko; Furukawa, Tomonori; Nakashima, Toshihiro; Ueno, Shinya

    2016-01-15

    Several green leaf volatiles have anxiolytic/antidepressant properties and attenuate adrenocortical stress response in rodents. However, it remains unknown whether a mixture of cis-3-hexenol and trans-2-hexenal so-called 'green odor (GO)' affects fear-associated post-traumatic stress disorder (PTSD)-like behavior. In the present study, fear memory of the initial conditioning stimulus was stably maintained by weekly presentation of conditioned tone. Examination of open field behavior, acoustic startle response, prepulse inhibition, and immobility in the forced swim test for 2 weeks after initial conditioning revealed that conditioned rats sustained anxiety, enhanced startle response, hypervigilance, depression-like behavior, and hypocortisolism, which is consistent with PTSD symptoms. Daily, not acute, GO presentation facilitated fear extinction and reduced PTSD-like behavioral and endocrinal responses. To further investigate the mechanism of effect of GO, we examined the effect of paroxetine (a selective serotonin reuptake inhibitor), p-chlorophenylalanine (PCPA, an irreversible serotonin synthesis inhibitor), alone or in combination of GO on PTSD-like phenotype. The alleviative effects of GO were masked by simultaneous paroxetine administration. PCPA-induced serotonin depletion abolished the effects of GO. Our results suggest that daily GO presentation facilitates fear extinction and prevents development of PTSD-like symptoms. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Bleuler and the neurobiology of schizophrenia.

    Science.gov (United States)

    Heckers, Stephan

    2011-11-01

    Schizophrenia remains a major challenge for psychiatry. One hundred years after the publication of Eugen Bleuler's monograph, we are still debating the nosology and mechanisms of schizophrenia. We have stalled in the development of more effective treatments, after success with the introduction of antipsychotic medication. Cure and prevention remain in the distance. This article reviews the importance of Bleuler's monograph for the neuroscientific exploration of schizophrenia. While Bleuler assumed that schizophrenia has a neural basis, he remained agnostic on possible mechanisms and skeptical about the value of pathological diagnosis. He preferred psychological understanding over neural explanation. He gave hope by making schizophrenia dimensional and less predictive of course and outcome. To make progress now, we need to redefine schizophrenia at the level of the brain.

  14. Interventions to reduce weight gain in schizophrenia.

    Science.gov (United States)

    Faulkner, G; Cohn, T; Remington, G

    2007-01-24

    Weight gain is common for people with schizophrenia and this has serious implications for health and well being. To determine the effects of both pharmacological (excluding medication switching) and non pharmacological strategies for reducing or preventing weight gain in people with schizophrenia. We searched key databases and the Cochrane Schizophrenia Group's trials register (April 2006), reference sections within relevant papers, hand searched key journals, and contacted the first author of each relevant study and other experts to collect further information. We included all clinical randomised controlled trials comparing any pharmacological or non pharmacological intervention for weight gain (diet and exercise counselling) with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. We reliably selected, quality assessed and extracted data from studies. As weight is a continuous outcome measurement, weighted mean differences (WMD) of the change from baseline were calculated. The primary outcome measure was weight loss. Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size

  15. GENE X ENVIRONMENT INTERACTIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER:EVIDENCE FROM NEUROIMAGING

    Directory of Open Access Journals (Sweden)

    Pierre Alexis Geoffroy

    2013-10-01

    Full Text Available Introduction: Schizophrenia (SZ and Bipolar disorder (BD are considered as severe multifactorial diseases, stemming from genetic and environmental influences. Growing evidence supports gene x environment (GxE interactions in these disorders and neuroimaging studies can help us to understand how those factors mechanistically interact. No reviews synthesized the existing data of neuroimaging studies in these issues.Methods: We conduct a systematic review on the neuroimaging studies exploring GxE interactions relative to SZ or BD in PubMed.Results: First results of the influence of genetic and environmental risks on brain structures came from monozygotic twin pairs concordant and discordant for SZ or BD. Few structural magnetic resonance imaging (sMRI studies have explored the GxE interactions. No other imaging methods were found. Two main GxE interactions on brain volumes have arisen. First, an interaction between genetic liability to SZ and obstetric complications on gray matter, cerebrospinal fluid and hippocampal volumes. Second, cannabis use and genetic liability interaction effects on cortical thickness and white matter volumes.Conclusion: Combining GxE interactions and neuroimaging domains is a promising approach. Genetic risk and environmental exposures such as cannabis or obstetrical complications seem to interact leading to specific neuroimaging cerebral alterations in SZ. They are suggestive of GxE interactions that confer phenotypic abnormalities in SZ and possibly BD. We need further, larger neuroimaging studies of GxE interactions for which we may propose a framework focusing on GxE interactions data already known to have a clinical effect such as infections, early stress, urbanicity and substance abuse.

  16. Dominant negative mutations of Caenorhabditis elegans daf-7 confer a novel developmental phenotype.

    Science.gov (United States)

    Crook, Matt; Grant, Warwick N

    2013-06-01

    TGF-β signaling pathways are involved in the control of development in every member of the animal kingdom. As such, TGF-β ligands are widely divergent yet retain a set of core conserved features, specifically, a pre-protein cleavage site and several conserved ligand domain residues, the disruption of which produces a dominant negative phenotype. We have extended these observations into an invertebrate system by creating a series of loss-of-function Caenorhabditis elegans daf-7 transgenes. When we tested these mutant transgenes in a daf-7/+ background, we saw a molting and excretory canal phenotype. Members of both pathways downstream of daf-4 were required for this phenotype. Our results show that the basic mechanisms of TGF-β function are conserved across the animal kingdom. A subset of our daf-7 mutations also produced an unexpected and novel phenotype. Epistasis experiments demonstrated that both daf-3/-5 and sma-4/-9 were downstream of our mutant daf-7 transgenes, which suggests not only a role for DAF-7 in the control of molting and the development of the excretory system but also that daf-7 and dbl-1 signaling may converge downstream of their shared Type II receptor, daf-4. Our approach may unveil new roles in development for other invertebrate TGF-β ligands. Copyright © 2013 Wiley Periodicals, Inc.

  17. Schizophrenia and city life.

    Science.gov (United States)

    Lewis, G; David, A; Andréasson, S; Allebeck, P

    1992-07-18

    Prevalence of schizophrenia and rates of first admission to hospital for this disorder are higher in most modern industrialised cities, and in urban compared with rural areas. The "geographical drift" hypothesis (ie, most schizophrenics tend to drift into city areas because of their illness or its prodrome) has remained largely unchallenged. We have investigated the association between place of upbringing and the incidence of schizophrenia with data from a cohort of 49,191 male Swedish conscripts linked to the Swedish National Register of Psychiatric Care. The incidence of schizophrenia was 1.65 times higher (95% confidence interval 1.19-2.28) among men brought up in cities than in those who had had a rural upbringing. The association persisted despite adjustment for other factors associated with city life such as cannabis use, parental divorce, and family history of psychiatric disorder. This finding cannot be explained by the widely held notion that people with schizophrenia drift into cities at the beginning of their illness. We conclude that undetermined environmental factors found in cities increase the risk of schizophrenia.

  18. The relationship between default mode network connectivity and social functioning in individuals at familial high-risk for schizophrenia

    OpenAIRE

    Dodell-Feder, David; DeLisi, Lynn E.; Hooker, Christine I.

    2014-01-01

    Unaffected first-degree relatives of individuals with schizophrenia (i.e., those at familial high-risk [FHR]), demonstrate social dysfunction qualitatively similar though less severe than that of their affected relatives. These social difficulties may be the consequence of genetically conferred disruption to aspects of the default mode network (DMN), such as the dMPFC subsystem, which overlaps with the network of brain regions recruited during social cognitive processes. In the present study,...

  19. Association of obesity and treated hypertension and diabetes with cognitive ability in bipolar disorder and schizophrenia.

    Science.gov (United States)

    Depp, Colin A; Strassnig, Martin; Mausbach, Brent T; Bowie, Christopher R; Wolyniec, Paula; Thornquist, Mary H; Luke, James R; McGrath, John A; Pulver, Ann E; Patterson, Thomas L; Harvey, Philip D

    2014-06-01

    People with bipolar disorder or schizophrenia are at greater risk for obesity and other cardio-metabolic risk factors, and several prior studies have linked these risk factors to poorer cognitive ability. In a large ethnically homogenous outpatient sample, we examined associations among variables related to obesity, treated hypertension and/or diabetes and cognitive abilities in these two patient populations. In a study cohort of outpatients with either bipolar disorder (n = 341) or schizophrenia (n = 417), we investigated the association of self-reported body mass index and current use of medications for hypertension or diabetes with performance on a comprehensive neurocognitive battery. We examined sociodemographic and clinical factors as potential covariates. Patients with bipolar disorder were less likely to be overweight or obese than patients with schizophrenia, and also less likely to be prescribed medication for hypertension or diabetes. However, obesity and treated hypertension were associated with worse global cognitive ability in bipolar disorder (as well as with poorer performance on individual tests of processing speed, reasoning/problem-solving, and sustained attention), with no such relationships observed in schizophrenia. Obesity was not associated with symptom severity in either group. Although less prevalent in bipolar disorder compared to schizophrenia, obesity was associated with substantially worse cognitive performance in bipolar disorder. This association was independent of symptom severity and not present in schizophrenia. Better understanding of the mechanisms and management of obesity may aid in efforts to preserve cognitive health in bipolar disorder. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. "We're Not Just Sitting on the Periphery": A Staff Perspective of Physical Activity in Older Adults with Schizophrenia

    Science.gov (United States)

    Leutwyler, Heather; Hubbard, Erin M.; Jeste, Dilip V.; Vinogradov, Sophia

    2013-01-01

    Targeted physical activity interventions to improve the poor physical function of older adults with schizophrenia are necessary but currently not available. Given disordered thought processes and institutionalization, it is likely that older adults with schizophrenia have unique barriers and facilitators to physical activity. It is necessary to…

  1. Structural brain abnormalities in first episode schizophrenia. Is it just illness?

    NARCIS (Netherlands)

    Rais, M.

    2011-01-01

    Although neuroimaging studies consistently demonstrated brain volume alterations in patients with schizophrenia, confounding factors like age, IQ, duration of the illness, use of antipsychotic medication and drug (ab-)use might partly explain these results. Therefore, the relation between

  2. Criterion and construct validity of the CogState Schizophrenia Battery in Japanese patients with schizophrenia.

    Directory of Open Access Journals (Sweden)

    Taisuke Yoshida

    Full Text Available BACKGROUND: The CogState Schizophrenia Battery (CSB, a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J in Japanese patients with schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. CONCLUSIONS/SIGNIFICANCE: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.

  3. Levels-of-processing effects in first-degree relatives of individuals with schizophrenia.

    Science.gov (United States)

    Bonner-Jackson, Aaron; Csernansky, John G; Barch, Deanna M

    2007-05-15

    First-degree relatives of individuals with schizophrenia show cognitive impairments that are similar to but less severe than their ill relatives. We have shown that memory impairments can be improved and prefrontal cortical (PFC) activity increased in individuals with schizophrenia by providing beneficial encoding strategies. The current study used a similar paradigm to determine whether siblings of individuals with schizophrenia (SIBs) also show increases in brain activity when presented with beneficial encoding strategies. Twenty-one SIBs and 38 siblings of healthy comparison subjects underwent functional magnetic resonance imaging scans while engaged in deep (abstract/concrete judgments) and shallow (orthographic judgments) encoding. Subjects were then given a recognition memory test. The groups did not differ on encoding or recognition accuracy, and the SIBs benefited from deep encoding to a similar degree as control subjects. The SIBs showed deep encoding-related activity in a number of PFC regions typically activated during semantic processing. However, SIBs showed more activity than control subjects in three subregions of PFC (left BA 44 & BA 47 bilaterally). Siblings of individuals with schizophrenia benefit from supportive verbal encoding conditions. Like individuals with schizophrenia, SIBs also show increased task-related activity in a larger number of PFC subregions than control subjects during deep verbal encoding.

  4. Mosaic Turner syndrome associated with schizophrenia.

    Science.gov (United States)

    Jung, Sook Young; Park, Joo Won; Kim, Dong Hyun; Jun, Yong Hoon; Lee, Jeong Seop; Lee, Ji Eun

    2014-03-01

    Turner syndrome is a sex-chromosome disorder; occurring in 1 in 2,500 female births. There are sporadic few case reports of concomitant Turner syndrome with schizophrenia worldwide. Most Turner females had a 45,X monosomy, whereas the majority of comorbidity between Turner syndrome and schizophrenia had a mosaic karyotype (45,X/46,XX). We present a case of a 21-year-old woman with Turner syndrome, mosaic karyotype (45,X/46,XX), showing mental retardation, hypothyroidism, and schizophrenia. HOPA gene within Xq13 is related to mental retardation, hypothyroidism, and schizophrenia. Our case may be a potential clue which supports the hypothesis for involvement of genes on X chromosome in development of schizophrenia. Further studies including comorbid cases reports are need in order to discern the cause of schizophrenia in patients having Turner syndrome.

  5. Neurocognitive performance, psychopathology and social functioning in individuals at high risk for schizophrenia or psychotic bipolar disorder.

    Science.gov (United States)

    Gkintoni, Evgenia; Pallis, Eleftherios G; Bitsios, Panos; Giakoumaki, Stella G

    2017-01-15

    Although cognitive deficits are consistent endophenotypes of schizophrenia and bipolar disorder, findings in psychotic bipolar disorder (BDP) are inconsistent. In this study we compared adult unaffected first-degree relatives of schizophrenia and BDP patients on cognition, psychopathology, social functioning and quality of life. Sixty-six unaffected first-degree relatives of schizophrenia patients (SUnR), 36 unaffected first-degree relatives of BDP patients (BDPUnR) and 102 controls participated in the study. Between-group differences were examined and Discriminant Function Analysis (DFA) predicted group membership. Visual memory, control inhibition, working memory, cognitive flexibility and abstract reasoning were linearly impaired in the relatives' groups. Poorer verbal fluency and processing speed were evident only in the SUnR group. The SUnR group had higher depressive and somatization symptoms while the BDPUnR group had higher anxiety and lower social functioning compared with the controls. Individuals with superior cognition were more likely to be classified as controls; those with higher social functioning, prolonged processing speed and lower anxiety were more likely to be classified as SUnR. The relatives' sample is quite heterogeneous; the effects of genetic or environmental risk-factors were not examined. Cognitive functions mediated by a fronto-parietal network, show linear impairments in unaffected relatives of BDP and schizophrenia patients; processing speed and verbal fluency impairments were evident only in schizophrenia relatives. Self-perceived symptomatology and social functioning also differ between schizophrenia and BDP relatives. The continuum seen in patients in several indices was also seen in the cognitive impairments in unaffected relatives of schizophrenia and BDP patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. [Cognitive remediation and cognitive assistive technologies in schizophrenia].

    Science.gov (United States)

    Sablier, J; Stip, E; Franck, N

    2009-04-01

    . Finally, we present a review of recent studies testing innovative devices developed to assist schizophrenia patients. First, we found several cognitive programs proven to be effective with schizophrenia patients, but only three were validated in French. It could be useful to adapt other programs for French-speaking populations. Unfortunately, we found that very few of the existing cognitive assistive technologies are proposed to be used with schizophrenia patients. In fact, most of the available cognitive orthoses were tested primarily in people with neurological injuries (for example, various memory impairments caused by traumas), and in elderly illnesses (like Alzheimer disease). Devices for patients with mental deficits (e.g., mental retardation) were developed later, and only very recently explored for use in schizophrenia. As a result of an international collaboration between France and Canada, currently a tool called MOBUS is being tested. This technology aims at improving the autonomy of schizophrenia patients, by helping them plan and remember their daily activities. Furthermore, it encourages patient-caregiver communication, and permits monitoring patients' subjective reports of their symptoms. The use of cognitive assistive technologies is not meant to isolate patients by replacing the human element of relatives and caregivers by a machine. On the contrary, they offer a sense of security and they improve interpersonal relationships by permitting enhanced autonomy and greater self-confidence. Finally, a literature review of cognitive remediation in schizophrenia emphasizes the importance of a structured application of the technique in order for it to succeed. First, it is crucial to detect the impairments that will be targeted in each patient presenting a specific pattern of impairments. For this purpose, validated and customised neuropsychological tests are required. Then, cognitive remediation programs must be customised to each patient's needs in order to

  7. Suicide risk in schizophrenia: learning from the past to change the future.

    Science.gov (United States)

    Pompili, Maurizio; Amador, Xavier F; Girardi, Paolo; Harkavy-Friedman, Jill; Harrow, Martin; Kaplan, Kalman; Krausz, Michael; Lester, David; Meltzer, Herbert Y; Modestin, Jiri; Montross, Lori P; Mortensen, Preben Bo; Munk-Jørgensen, Povl; Nielsen, Jimmi; Nordentoft, Merete; Saarinen, Pirjo Irmeli; Zisook, Sidney; Wilson, Scott T; Tatarelli, Roberto

    2007-03-16

    Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5-13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures. This review paper is the result of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophrenia

  8. Role of 108 schizophrenia-associated loci in modulating psychopathological dimensions in schizophrenia and bipolar disorder.

    Science.gov (United States)

    Fabbri, Chiara; Serretti, Alessandro

    2017-10-01

    The Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) identified 108 loci associated with schizophrenia, but their role in modulating specific psychopathological dimensions of the disease is unknown. This study investigated which symptom dimensions may be affected by these loci in schizophrenia, and bipolar disorder. Positive, negative and depressive symptoms, suicidal ideation, cognition, violent behaviors, quality of life, and early onset were investigated in schizophrenia and bipolar disorder using the clinical antipsychotic trials of intervention effectiveness (CATIE) and systematic treatment enhancement program for bipolar disorder (STEP-BD) studies. Individual loci were investigated, then genes within 50 Kbp from polymorphisms with p schizophrenia-associated variant (rs75059851) may modulate negative symptoms. Multi-locus models may provide interesting insights about the biological mechanisms that mediate psychopathological dimensions. © 2017 Wiley Periodicals, Inc.

  9. The role of ethnicity in treatment refractory schizophrenia.

    Science.gov (United States)

    Teo, Celine; Borlido, Carol; Kennedy, James L; De Luca, Vincenzo

    2013-02-01

    The goal of this research was to describe the relationship between treatment resistant schizophrenia, defined using the APA criteria and ethnic background in patients with schizophrenia spectrum disorders in a Canadian sample. A secondary goal was to analyze the number of antipsychotics failed due to side effects and number of antipsychotics failed due to non-response. We included 497 patients diagnosed with schizophrenia spectrum disorders using the SCID. The medication history was extracted from the electronic health records. Data collection included demographics (sex, age, ethnicity), principal diagnosis according to SCID (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), duration of mental illness, number of psychiatric admissions and treatment information. If patients were on clozapine or polypharmacy treatment, this was recorded at the time of the SCID interview. Additional data, including prior antipsychotic history, were collected from the health records. Thirty per cent of the patients were classified as resistant according to the APA criteria. There were significantly more white European subjects in the treatment resistant group (p=0.031). The duration of illness was significantly higher in the resistant group then in the non-resistant group (21.0 vs 15.1 years; p<0.001). Patients who were treatment resistant were more likely to be on polypharmacy compared with non-resistant patients (p=0.001; OR=2.424; 95%CI=1.446-4.065). When we considered the number of drug trials failed due to non response and drug trial failed because of side effects, we found a strong negative correlation in both white Europeans and non-white Europeans. White European ethnicity is associated with treatment resistant schizophrenia. In addition, patients with treatment-resistant schizophrenia were on polypharmacy at higher rate than non resistant patients. Copyright © 2013. Published by Elsevier Inc.

  10. Associations of common copy number variants in glutathione S-transferase mu 1 and D-dopachrome tautomerase-like protein genes with risk of schizophrenia in a Japanese population.

    Science.gov (United States)

    Nakamura, Toru; Ohnuma, Tohru; Hanzawa, Ryo; Takebayashi, Yuto; Takeda, Mayu; Nishimon, Shohei; Sannohe, Takahiro; Katsuta, Narimasa; Higashiyama, Ryoko; Shibata, Nobuto; Arai, Heii

    2015-10-01

    Oxidative-stress, genetic regions of interest (1p13 and 22q11), and common copy number variations (CNVs) may play roles in the pathophysiology of schizophrenia. In the present study, we confirmed associations between schizophrenia and the common CNVs in the glutathione (GSH)-related genes GSTT1, DDTL, and GSTM1 using quantitative real-time polymerase chain reaction analyses of 620 patients with schizophrenia and in 622 controls. No significant differences in GSTT1 copy number distributions were found between patient groups. However, frequencies of characterized CNVs and assumed gain alleles of DDTL and GSTM1 were significantly higher in patients with schizophrenia. In agreement with a previous report, the present data indicate that gains in the CNV alleles DDTL and GSTM1 are genetic risk factors in Japanese patients with schizophrenia, and suggest involvement of micro-inflammation and oxidative stress in the pathophysiology of schizophrenia. © 2015 Wiley Periodicals, Inc.

  11. Genetics, Cognition and Neurobiology of Schizotypal Personality: A Review of the Overlap with Schizophrenia

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    Ulrich eEttinger

    2014-02-01

    Full Text Available Schizotypy refers to a set of temporally stable traits that are observed in the general population and that resemble the signs and symptoms of schizophrenia. Here, we review evidence from studies on genetics, cognition, perception, motor and oculomotor control, brain structure, brain function and psychopharmacology in schizotypy. We specifically focused on identifying areas of overlap between schizotypy and schizophrenia. Evidence was corroborated that significant overlap exists between the two, covering the behavioural, brain structural and functional as well molecular levels. In particular, several studies showed that individuals with high levels of schizotypal traits exhibit alterations in neurocognitive task performance and underlying brain function similar to the deficits seen in patients with schizophrenia. Studies of brain structure have shown both volume reductions and increases in schizotypy, pointing to schizophrenia-like deficits as well as possible protective or compensatory mechanisms. Experimental pharmacological studies have shown that high levels of schizotypy are associated with (i enhanced dopaminergic response in striatum following administration of amphetamine and (ii improvement of cognitive performance following administration of antipsychotic compounds. Together, this body of work suggests that schizotypy shows overlap with schizophrenia across multiple behavioural and neurobiological domains, suggesting that the study of schizotypal traits may be useful in improving our understanding of the aetiology of schizophrenia.

  12. LORETA current source density for duration mismatch negativity and neuropsychological assessment in early schizophrenia.

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    Tomohiro Miyanishi

    Full Text Available INTRODUCTION: Patients with schizophrenia elicit cognitive decline from the early phase of the illness. Mismatch negativity (MMN has been shown to be associated with cognitive function. We investigated the current source density of duration mismatch negativity (dMMN, by using low-resolution brain electromagnetic tomography (LORETA, and neuropsychological performance in subjects with early schizophrenia. METHODS: Data were obtained from 20 patients meeting DSM-IV criteria for schizophrenia or schizophreniform disorder, and 20 healthy control (HC subjects. An auditory odd-ball paradigm was used to measure dMMN. Neuropsychological performance was evaluated by the brief assessment of cognition in schizophrenia Japanese version (BACS-J. RESULTS: Patients showed smaller dMMN amplitudes than those in the HC subjects. LORETA current density for dMMN was significantly lower in patients compared to HC subjects, especially in the temporal lobes. dMMN current density in the frontal lobe was positively correlated with working memory performance in patients. CONCLUSIONS: This is the first study to identify brain regions showing smaller dMMN current density in early schizophrenia. Further, poor working memory was associated with decreased dMMN current density in patients. These results are likely to help understand the neural basis for cognitive impairment of schizophrenia.

  13. Face recognition in schizophrenia: do individual and average ROCs tell the same story?

    Science.gov (United States)

    Tiberghien, Guy; Martin, Clara; Baudouin, Jean-Yves; Franck, Nicolas; Guillaume, Fabrice; Huron, Caroline

    2015-01-01

    Many studies have shown that recollection process is impaired in patients with schizophrenia, whereas familiarity is generally spared. However, in these studies, the Receiver Operating Characteristic (ROC) presented is average ROC likely to mask individual differences. In the present study using a face-recognition task, we computed the individual ROC of patients with schizophrenia and control participants. Each group was divided into two subgroups on the basis of the type of recognition processes implemented: recognition based on familiarity only and recognition based on familiarity and recollection. The recognition performance of the schizophrenia patients was below that of the control participants only when recognition was based solely on familiarity. For the familiarity-alone patients, the score obtained on the Scale for the Assessment of Positive Symptoms (SAPS) was correlated with the variance of the old-face familiarity. For the familiarity-recollection patients, the score obtained on the Scale for the Assessment of Negative Symptoms (SANS) was correlated with the decision criterion and with the old-face recollection probability. These results show that one cannot ascribe the impaired recognition observed in patients with schizophrenia to a recollection deficit alone. These results show that individual ROC can be used to distinguish between subtypes of schizophrenia and could serve as a basis for setting up specific cognitive remediation therapy for individuals with schizophrenia.

  14. Spouse with schizophrenia and risk of dementia.

    Science.gov (United States)

    Rohde, Christopher; Agerbo, Esben; Nielsen, Philip Rising

    2016-12-01

    Increased prevalence of lifestyle risk factors or shared etiology may underlie the association between schizophrenia and the subsequent risk of dementia. We explored the association between having a spouse with schizophrenia and the risk of dementia. We found a positive relationship between having a spouse with schizophrenia and vascular dementia in individuals without a mental disorder themselves but no association between having a spouse with schizophrenia and Alzheimer's dementia. As spouses share environmental risk factors and lifestyle, this might suggest that the excess risk of dementia in probands with schizophrenia could be ascribed to the unhealthy living environment among individuals with schizophrenia.

  15. Heterogeneity of schizophrenia: Genetic and symptomatic factors.

    Science.gov (United States)

    Takahashi, Sakae

    2013-10-01

    Schizophrenia may have etiological heterogeneity, and may reflect common symptomatology caused by many genetic and environmental factors. In this review, we show the potential existence of heterogeneity in schizophrenia based on the results of our previous studies. In our study of the NOTCH4 gene, there were no significant associations between any single nucleotide polymorphisms (SNPs) of NOTCH4 and schizophrenia. However, exploratory analyses suggested that the SNP, rs3134928 may be associated with early-onset schizophrenia, and that rs387071 may be associated with schizophrenia characterized by negative symptoms. In our highly familial schizophrenia study, the African-American cohort without environmental exposure showed a possible linkage at marker 8p23.1 in the dominant model and in the European-American cohort, a marker at 22q13.32 showed a probable linkage in the recessive model. In the less familial schizophrenia families, these linkages were not shown. Based on our eye movement study, a putative subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization may be associated with chromosome 22q11. We consider that a sample stratification approach may clarify the heterogeneity of schizophrenia. Therefore, this approach may lead to a more straightforward way of identifying susceptibility genes of schizophrenia. © 2013 Wiley Periodicals, Inc.

  16. Environmental risk factors and their impact on the age of onset of schizophrenia: Comparing familial to non-familial schizophrenia.

    Science.gov (United States)

    Scherr, Martin; Hamann, Melanie; Schwerthöffer, Dirk; Froböse, Teresa; Vukovich, Ruth; Pitschel-Walz, Gabriele; Bäuml, Josef

    2012-04-01

    Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder). Aside from the age of onset of psychosis, we examined the risk factors for schizophrenia including obstetric complications, birth during winter or spring, behavioral deviances or delayed motor and speech development, exposure to adverse life events and exposure to substance use within a group of 100 patients (45 female, 55 male) with a mean age (± standard deviation) of 35.15 ± 13.21. Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified. Certain environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, they do not seem to have an impact on familial schizophrenia.

  17. The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy.

    Science.gov (United States)

    Choi, Chang Soon; Gonzales, Edson Luck; Kim, Ki Chan; Yang, Sung Min; Kim, Ji-Woon; Mabunga, Darine Froy; Cheong, Jae Hoon; Han, Seol-Heui; Bahn, Geon Ho; Shin, Chan Young

    2016-11-07

    Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.

  18. A series of drawings of a patient with schizophrenia-like psychosis associated with epilepsy: Captured illustration of multifaced selfexpression

    Directory of Open Access Journals (Sweden)

    Mandić-Gajić Gordana

    2016-01-01

    Full Text Available Introduction. Drawings may give an insight into the complex mental process, however they have been underutilized in patients with psychosis associated with epilepsy. Case report. A 33-year-old, right handed female, diagnosed with schizophrenia- like psychosis associated with epilepsy, was treated in the Day Unit due to psychosocial rehabilitation. Besides other treatments, the patient underwent group analysis of drawings once a week. Qualitative analysis of the form and content of drawings made by free associations were performed. The varying of size and motives with vivid colours and the curve of perspective were documentated in three figures, followed by the last drawing which was without such elements. Conclusion. A series of drawings of patients with psychosis associated with epilepsy is needed to record a possible variations and disturbance of the immediate mental process. Group sessions may additionally contribute to diminish stigma and enhance psychosocial reintegration.

  19. Avoidant personality disorder symptoms in first-degree relatives of schizophrenia patients predict performance on neurocognitive measures: the UCLA family study.

    Science.gov (United States)

    Fogelson, D L; Asarnow, R A; Sugar, C A; Subotnik, K L; Jacobson, K C; Neale, M C; Kendler, K S; Kuppinger, H; Nuechterlein, K H

    2010-07-01

    Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia. 367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models. Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3-7 Continuous Performance Test (3-7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent. Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype. (c) 2009 Elsevier B.V. All rights reserved.

  20. Cannabis use and cognition in schizophrenia

    Directory of Open Access Journals (Sweden)

    Else-Marie Løberg

    2009-11-01

    Full Text Available People with schizophrenia frequently report cannabis use, and cannabis may be a risk factor for schizophrenia, mediated through effects on brain function and biochemistry. Thus, it is conceivable that cannabis may also influence cognitive functioning in this patients group. We report data from our own laboratory on the use of cannabis by schizophrenia patients, and review the existing literature on the effects of cannabis on cognition in schizophrenia and related psychosis. Of the 23 studies that were found, 14 reported that the cannabis users had better cognitive performance than the schizophrenia non-users. Eight studies reported no or minimal differences in cognitive performance in the two groups, but only one study reported better cognitive performance in the schizophrenia non-user group. Our own results confirm the overall impression from the literature review of better cognitive performance in the cannabis user group. These paradoxical findings may have several explanations, which are discussed. We suggest that cannabis causes a transient cognitive breakdown enabling the development of psychosis, imitating the typical cognitive vulnerability seen in schizophrenia. This is further supported by an earlier age of onset and fewer neurological soft signs in the cannabis-related schizophrenia group, suggesting an alternative pathway to psychosis.

  1. Working memory impairment in probands with schizoaffective disorder and first degree relatives of schizophrenia probands extend beyond deficits predicted by generalized neuropsychological impairment.

    Science.gov (United States)

    Kristian Hill, S; Buchholz, Alison; Amsbaugh, Hayley; Reilly, James L; Rubin, Leah H; Gold, James M; Keefe, Richard S E; Pearlson, Godfrey D; Keshavan, Matcheri S; Tamminga, Carol A; Sweeney, John A

    2015-08-01

    Working memory impairment is well established in psychotic disorders. However, the relative magnitude, diagnostic specificity, familiality pattern, and degree of independence from generalized cognitive deficits across psychotic disorders remain unclear. Participants from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study included probands with schizophrenia (N=289), psychotic bipolar disorder (N=227), schizoaffective disorder (N=165), their first-degree relatives (N=315, N=259, N=193, respectively), and healthy controls (N=289). All were administered the WMS-III Spatial Span working memory test and the Brief Assessment of Cognition in Schizophrenia (BACS) battery. All proband groups displayed significant deficits for both forward and backward span compared to controls. However, after covarying for generalized cognitive impairments (BACS composite), all proband groups showed a 74% or greater effect size reduction with only schizoaffective probands showing residual backward span deficits compared to controls. Significant familiality was seen in schizophrenia and bipolar pedigrees. In relatives, both forward and backward span deficits were again attenuated after covarying BACS scores and residual backward span deficits were seen in relatives of schizophrenia patients. Overall, both probands and relatives showed a similar pattern of robust working memory deficits that were largely attenuated when controlling for generalized cognitive deficits. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Febrile seizures and risk of schizophrenia

    DEFF Research Database (Denmark)

    Vestergaard, Mogens; Pedersen, Carsten Bøcker; Christensen, Jakob

    2005-01-01

    BACKGROUND: Febrile seizure is a benign condition for most children, but experiments in animals and neuroimaging studies in humans suggest that some febrile seizures may damage the hippocampus, a brain area of possible importance in schizophrenia. METHODS: A population-based cohort of all children...... with schizophrenia. A history of febrile seizures was associated with a 44% increased risk of schizophrenia [relative risk (RR)=1.44; 95% confidence interval (CI), 1.07-1.95] after adjusting for confounding factors. The association between febrile seizures and schizophrenia remained virtually unchanged when...... restricting the analyses to people with no history of epilepsy. A history of both febrile seizures and epilepsy was associated with a 204% increased risk of schizophrenia (RR=3.04; 95% CI, 1.36-6.79) as compared with people with no such history. CONCLUSIONS: We found a slightly increased risk of schizophrenia...

  3. Predicting severity of paranoid schizophrenia

    OpenAIRE

    Kolesnichenko Elena Vladimirovna

    2015-01-01

    Clinical symptoms, course and outcomes of paranoid schizophrenia are polymorphic. 206 cases of paranoid schizophrenia were investigated. Clinical predictors were collected from hospital records and interviews. Quantitative assessment of the severity of schizophrenia as special indexes was used. Schizoid, epileptoid, psychasthenic and conformal accentuation of personality in the premorbid, early onset of psychosis, paranoid and hallucinatory-paranoid variants of onset predicted more expressed ...

  4. Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

    DEFF Research Database (Denmark)

    Steinberg, Stacy; de Jong, Simone; Andreassen, Ole A

    2011-01-01

    Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association (GWA) study and meta-analysis (totalling 7,946 cases and 19,036 controls) by examining...... an expanded set of variants using an enlarged follow-up sample (up to 10,260 cases and 23,500 controls). In addition to previously-reported alleles in the major histocompatibility complex (MHC) region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants...... showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) (OR = 1.09, P = 1.9 x 10(-9)), and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously-described risk allele, but not accounted for by its...

  5. Schizophrenia and psychotic symptoms in families of two American Indian tribes

    Directory of Open Access Journals (Sweden)

    Albaugh Bernard

    2007-06-01

    population isolates and in the general population. Vulnerabilities to early onset alcohol and drug use disorders do not lend convincing support to a diathesis-stressor model with these stressors, commonly reported with these tribes. Nearly one-fifth of the respondents reported experiencing psychotic-like symptoms, reaffirming the need to examine sociocultural factors actively before making positive diagnoses of psychosis or schizophrenia.

  6. Schizophrenia and Metacognition

    DEFF Research Database (Denmark)

    Austin, Stephen F.; Mors, Ole; Nordentoft, Merete

    2014-01-01

    tested for relationships between course of illness and levels of specific metacognitions in schizophrenia spectrum disorders. A large cohort of people with first episode psychosis (n = 578) recruited as part the OPUS trial (1998–2000) were tested. Information about course of illness (remitted, episodic...... beliefs may also impact on positive symptoms and course of illness within schizophrenia....

  7. Neurodevelopmental correlates in schizophrenia

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    Ivković Maja

    2003-01-01

    Full Text Available Contemporary aetiopathogenetic considerations, based on neuro-imaging genetic and developmental neurobiology studies, suggest neurodevelopmental origin of schizophrenia. Several lines of evidence including structural abnormalities on in vivo brain imaging, the excess of prenatal and obstetric complications and the association of congenital and minor physical anomalies with schizophrenia, strongly indicate the neurodevelopmental pathogenesis of schizophrenia. On the other hand, controversial concept of psychotic continuum suggests schizophrenia and depression sharing the same genetic contribution to the pathogenesis. If this would be the case, depression could also be considered as neuro developmental disorder. The aims of the study were to investigate the association between: a pregnancy and birth complications (PBC, and b minor physical anomalies (MPA and schizophrenia or depression. Experimental groups consisted of 60 schizophrenic, 28 major depression patients and 30 healthy controls. All patients were diagnosed according to DSM-IV. Schizophrenic group was divided with regard to PANSS score into positive (n=32 and negative form (n=28 subgroups. PBC information were gathered from maternal recall while MPA were examined by using Waldrop scale for adults. The results showed that negative and positive schizophrenic subgroups had significantly more PBC than depressive group (p<0,05, as well than controls (p<0,001; p<0,05; respectively. There was no significant trend for more PBC in negative than in positive subgroup. All schizophrenic patients had higher rates of MPA than depressives (p<0,05. This trend for more MPA was not significant in comparison with healthy controls. These findings suggest that schizophrenia, especially its negative forms, could be considered as a member of the spectrum of neuro developmental disorders, which does not seem to be the case with depression. PBC and MPA could also be valuable in evaluation of risks for

  8. Treating schizophrenia during menopause.

    Science.gov (United States)

    Brzezinski, Amnon; Brzezinski-Sinai, Noa A; Seeman, Mary V

    2017-05-01

    The aim of this review is to examine three questions: What are the risks and benefits of treating women with schizophrenia with hormone therapy (HT) at menopause? Should the antipsychotic regimen be changed at menopause? Do early- and late-onset women with schizophrenia respond differently to HT at menopause? MEDLINE databases for the years 1990 to 2016 were searched using the following interactive terms: schizophrenia, gender, menopause, estrogen, and hormones. The selected articles (62 out of 800 abstracts) were chosen on the basis of their applicability to the objectives of this targeted narrative review. HT during the perimenopause in women with schizophrenia ameliorates psychotic and cognitive symptoms, and may also help affective symptoms. Vasomotor, genitourinary, and sleep symptoms are also reduced. Depending on the woman's age and personal risk factors and antipsychotic side effects, the risk of breast cancer and cardiovascular disease may be increased. Antipsychotic types and doses may need to be adjusted at menopause, as may be the mode of administration. Both HT and changes in antipsychotic management should be considered for women with schizophrenia at menopause. The question about differences in response between early- and late-onset women cannot yet be answered.

  9. Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

    Science.gov (United States)

    Riordan, Daniel Vincent

    2017-10-01

    Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. [Risk factors of schizophrenia].

    Science.gov (United States)

    Suvisaari, Jaana

    2010-01-01

    Schizophrenia is a multifactorial, neurodevelopmental disorder caused by a combination of genetic and environmental risk factors. Disturbances of brain development begin prenatally, while different environmental insults further affect postnatal brain maturation during childhood and adolescence. Genome-wide association studies (GWAS) have succeeded in identifying hundreds of new risk variants for common, multifactorial diseases. In schizophrenia research, GWAS have found several rare copy number variants that considerably increase the risk of schizophrenia, and have shown an association between schizophrenia and the major histocompatibility complex. Research on environmental risk factors in recent years has provided new information particularly on risk factors related to pregnancy and childhood rearing environment. Gene-environment interactions have become a central research topic. There is evidence that genetically susceptible children are more vulnerable to the effects of unstable childhood rearing environment and other environmental risk factors.

  11. CONFERENCE: Nuclear visions

    International Nuclear Information System (INIS)

    Anon.

    1986-01-01

    Last summer, four hundred visitors of about 30 different nationalities descended on the ancient town of Visby on the Swedish island of Gotland for the Second International Conference on Nucleus-Nucleus Collisions. For the conference itself, sessions were organized not according to conventional topics like low, intermediate and high energy reactions, but along phenomena-related lines that brought listeners together instead of splitting them up. Examples were 'phase transitions', 'new facilities' and 'breaking nuclear matter into pieces'

  12. Schizophrenia: a review of neuropharmacology.

    Science.gov (United States)

    Lyne, J; Kelly, B D; O'Connor, W T

    2004-01-01

    The last few decades have seen significant advances in our understanding of the neurochemical basis of schizophrenia. To describe the neurotransmitter systems and nerve circuits implicated in schizophrenia; to compare the neuropharmacology of typical and atypical anti-psychotic agents; and to describe recent developments in the pharmacological treatment of schizophrenia. Relevant pharmacological, neurophysiological and psychiatric literature was examined and reviewed. Schizophrenia is associated with abnormalities of multiple neurotransmitter systems, including dopamine, serotonin, gamma-aminobutyric acid and glutamate. Typical and atypical antipsychotic agents differ in their receptor-binding affinities, which are related to their differing side-effect profiles. Novel therapeutic strategies include normalisation of synaptic dopamine or serotonin levels, serotonin receptor antagonism and modulation of cerebral protein synthesis. The ideal treatment for schizophrenia may not be a single pharmacological agent but several agents that match the different expressions of the illness, in combination with psycho-social interventions.

  13. Impaired glutathione synthesis in schizophrenia

    DEFF Research Database (Denmark)

    Gysin, René; Kraftsik, Rudolf; Sandell, Julie

    2007-01-01

    Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit...... of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.......002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P schizophrenia in two...

  14. Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.

    Directory of Open Access Journals (Sweden)

    Kiyoko Yamamoto

    Full Text Available Patients in the chronic phase (CP of chronic myelogenous leukemia (CML have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt. AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.

  15. Successful treatment of schizophrenia with melperone augmentation in a patient with phenotypic CYP2D6 ultrarapid metabolization: a case report

    Directory of Open Access Journals (Sweden)

    Gahr Maximilian

    2012-02-01

    Full Text Available Abstract Introduction There are limited treatment options for people with schizophrenia with cytochrome P450 2D6 ultrarapid metabolizer status who do not respond to amisulpride. Furthermore, the literature does not provide evidence-based guidelines for this particular constellation. Case presentation We report the case of a 50-year-old Caucasian female patient with schizophrenia and cytochrome P450 2D6 ultrarapid metabolizer status who experienced an insufficient antipsychotic effect with amisulpride. She was successfully treated with melperone-augmented haloperidol. Conclusion This report yields melperone-augmented haloperidol as a possible pharmacological strategy in the described situation. In addition, our observations support the available evidence for the potential of melperone to act as an inhibitor of cytochrome P450 2D6.

  16. Wellness within illness: happiness in schizophrenia.

    Science.gov (United States)

    Palmer, Barton W; Martin, Averria Sirkin; Depp, Colin A; Glorioso, Danielle K; Jeste, Dilip V

    2014-10-01

    Schizophrenia is typically a chronic disorder and among the most severe forms of serious mental illnesses in terms of adverse impact on quality of life. Yet, there have been suggestions that some people with schizophrenia can experience an overall sense of happiness in their lives. We investigated happiness among 72 outpatients with non-remitted chronic schizophrenia with a mean duration of illness of 24.4 years, and 64 healthy comparison subjects (HCs). Despite continued treatment with antipsychotic medications, the individuals with schizophrenia manifested a mild to moderate level of psychopathology. People with schizophrenia reported lower mean levels of happiness than HCs, but there was substantial heterogeneity within the schizophrenia group. Level of happiness in persons with schizophrenia was significantly correlated with higher mental health-related quality of life, and several positive psychosocial factors (lower perceived stress, and higher levels of resilience, optimism, and personal mastery). However, level of happiness was not related to sociodemographic characteristics, duration of illness, severity of positive or negative symptoms, physical function, medical comorbidity, or cognitive functioning. Except for an absence of an association with resilience, the pattern of correlations of happiness with other variables seen among HCs was similar to that in individuals with schizophrenia. Although happiness may be harder to achieve in the context of a serious mental illness, it nonetheless appears to be a viable treatment goal in schizophrenia. Psychotherapies targeting positive coping factors such as resilience, optimism, and personal mastery warrant further investigation. Copyright © 2014. Published by Elsevier B.V.

  17. Spirituality, religiousness and coping in patients with schizophrenia: A cross sectional study in a tertiary care hospital.

    Science.gov (United States)

    Das, Soumitra; Punnoose, Varghese Panickasseril; Doval, Nimisha; Nair, Vijayakrishnan Yathindran

    2018-04-24

    Religion is a form of coping that helps individuals to deal with a wide variety of difficult life situations. But most of the research in this field has been in acute patients of schizophrenia. Also, most of the research on religion and schizophrenia has focused on religion and spirituality as coping mechanisms, and research evaluating the relationship between spirituality/religiousness and repertoire of other coping skills is sparse. Our objective was to evaluate the association between spirituality, religiousness and coping skills in patients with schizophrenia in remission. Hence, a total of 48 consecutive patients with schizophrenia were assessed on Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), WHO Quality of Life-Spirituality, Religiousness and Personal Belief scale (WHOQOL-SRPB) and Ways of Coping Checklist - Revised (WCC). Findings were described as patients who used more religiosity and spirituality as measured with WHO-SRPB domain score were better in their managing their stress as they used all the adaptive strategies like planful problem solving, positive reappraisal, distancing, self-controlling, seeking social support rather than maladaptive skills like confrontive coping and escape avoidance. A sound spiritual, religious, or personal belief system positively affects active and adaptive coping skills in patients with schizophrenia during remission, thus helping the individual to cope with illness related stressors. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties

    DEFF Research Database (Denmark)

    St Pourcain, B; Robinson, E B; Anttila, V

    2017-01-01

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic......-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34...... 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD...

  19. 2012 IEEE Vehicular Networking Conference (VNC)

    NARCIS (Netherlands)

    Altintas, Onur; Chen, Wai; Heijenk, Geert; Oh, Hyun Seo; Chung, Jong-Moon; Dressler, Falko; Kargl, Frank; Pau, Giovanni; Schoch, Elmar

    2012-01-01

    On behalf of the Organizing Committee, we would like to welcome you to the fourth edition of the IEEE Vehicular Networking Conference in Seoul, Korea. IEEE VNC is a unique conference sponsored by both IEEE Communications Society and Intelligent Transportation Systems Society. It brings together

  20. Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

    Science.gov (United States)

    Harrison, Paul J; Pritchett, David; Stumpenhorst, Katharina; Betts, Jill F; Nissen, Wiebke; Schweimer, Judith; Lane, Tracy; Burnet, Philip W J; Lamsa, Karri P; Sharp, Trevor; Bannerman, David M; Tunbridge, Elizabeth M

    2012-03-01

    Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue. Copyright © 2011 Elsevier Ltd. All rights reserved.