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Sample records for schizophrenia model induced

  1. The gut microbiota influence behavior in the subchronic PCP induced animal model of schizophrenia

    DEFF Research Database (Denmark)

    Jørgensen, Bettina Merete Pyndt; Redrobe, Paul; Brønnum Pedersen, Tina

    The gut microbiota has major impact on the individual. Here we show that the gut microbiota influence behavior in the subchronic PCP induced animal model of schizophrenia. The gut microbiota were changed in the group treated subchronic with PCP, and restoration coincided with normalisation...... of memory performance in lister hooded rats. Furthermore the individual gut microbiota correlated to the individual behavior abserved in the tests conducted. In conclusion results show an influence of the gut microbiota on behavior in this model, and therefore it might be relavant to include the information...

  2. 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...

  3. Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine.

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    Sampaio, Luis Rafael L; Borges, Lucas T N; Silva, Joyse M F; de Andrade, Francisca Roselin O; Barbosa, Talita M; Oliveira, Tatiana Q; Macedo, Danielle; Lima, Ricardo F; Dantas, Leonardo P; Patrocinio, Manoel Cláudio A; do Vale, Otoni C; Vasconcelos, Silvânia M M

    2018-02-01

    The use of ketamine (Ket) as a pharmacological model of schizophrenia is an important tool for understanding the main mechanisms of glutamatergic regulated neural oscillations. Thus, the aim of the current study was to evaluate Ket-induced changes in the average spectral power using the hippocampal quantitative electroencephalography (QEEG). To this end, male Wistar rats were submitted to a stereotactic surgery for the implantation of an electrode in the right hippocampus. After three days, the animals were divided into four groups that were treated for 10 consecutive days with Ket (10, 50, or 100 mg/kg). Brainwaves were captured on the 1st or 10th day, respectively, to acute or repeated treatments. The administration of Ket (10, 50, or 100 mg/kg), compared with controls, induced changes in the hippocampal average spectral power of delta, theta, alpha, gamma low or high waves, after acute or repeated treatments. Therefore, based on the alterations in the average spectral power of hippocampal waves induced by Ket, our findings might provide a basis for the use of hippocampal QEEG in animal models of schizophrenia. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  4. The Effects of Nicotine on MK-801-induced Attentional Deficits: An Animal Model of Schizophrenia

    Science.gov (United States)

    2002-01-01

    purely hedonistic and pleasure-seeking reasons, inclinations that a non-disordered population is better able to control. Finally, the MK-801 model...schizophrenia, and boredom . American Journal of Psychiatry, 153, 583. Smith, J.A., Boyer-Millar, C., & Goudie, A.J. (1999). Does MK-801 discrimination

  5. The amphetamine sensitization model of schizophrenia symptoms and its effect on schedule-induced polydipsia in the rat.

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    Hawken, Emily R; Beninger, Richard J

    2014-05-01

    Amphetamine enhances dopamine (DA) transmission and induces psychotic states or exacerbates psychosis in at-risk individuals. Amphetamine sensitization of the DA system has been proposed as a rodent model of schizophrenia-like symptoms. In humans, excessive nonphysiologic drinking or primary polydipsia is significantly associated with a diagnosis of schizophrenia. In rodents, nonphysiologic drinking can be induced by intermittent presentation of food in the presence of a drinking spout to a hungry animal; this phenomenon is termed, "schedule-induced polydipsia" (SIP). This study aims to determine the effects of amphetamine sensitization on SIP. We injected rats with amphetamine (1.5 mg/kg) daily for 5 days. Following 4 weeks of withdrawal, animals were food restricted and exposed to the SIP protocol (noncontingent fixed-time 1-min food schedule) for daily 2-h sessions for 24 days. Results showed that previously amphetamine-injected animals drank more in the SIP protocol and drank more than controls when the intermittent food presentation schedule was removed. These findings suggest that hyperdopaminergia associated with schizophrenia may contribute to the development of polydipsia in this population. Whether animals that develop SIP have DA dysfunction or aberrant activity of other circuits that modulate DA activity has yet to be clearly defined.

  6. Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade

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    Tope eLanre-Amos

    2010-09-01

    Full Text Available Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity—theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.

  7. [123I]Epidepride neuroimaging of dopamine D2/D3 receptor in chronic MK-801-induced rat schizophrenia model

    International Nuclear Information System (INIS)

    Huang, Yuan-Ruei; Shih, Jun-Ming; Chang, Kang-Wei; Huang, Chieh; Wu, Yu-Lung; Chen, Chia-Chieh

    2012-01-01

    Purpose: [ 123 I]Epidepride is a radio-tracer with very high affinity for dopamine D 2 /D 3 receptors in brain. The importance of alteration in dopamine D 2 /D 3 receptor binding condition has been wildly verified in schizophrenia. In the present study we set up a rat schizophrenia model by chronic injection of a non-competitive NMDA receptor antagonist, MK-801, to examine if [ 123 I]epidepride could be used to evaluate the alterations of dopamine D 2 /D 3 receptor binding condition in specific brain regions. Method: Rats were given repeated injection of MK-801 (dissolved in saline, 0.3 mg/kg) or saline for 1 month. Afterwards, total distance traveled (cm) and social interaction changes were recorded. Radiochemical purity of [ 123 I]epidepride was analyzed by Radio-Thin-Layer Chromatography (chloroform: methanol, 9:1, v/v) and [ 123 I]epidepride neuroimages were obtained by ex vivo autoradiography and small animal SPECT/CT. Data obtained were then analyzed to determine the changes of specific binding ratio. Result: Chronic MK-801 treatment for a month caused significantly increased local motor activity and induced an inhibition of social interaction. As shown in [ 123 I]epidepride ex vivo autoradiographs, MK-801 induced a decrease of specific binding ratio in the striatum (24.01%), hypothalamus (35.43%), midbrain (41.73%) and substantia nigra (37.93%). In addition, [ 123 I]epidepride small animal SPECT/CT neuroimaging was performed in the striatum and midbrain. There were statistically significant decreases in specific binding ratio in both the striatum (P 123 I]epidepride is a useful radio-tracer to reveal the alterations of dopamine D 2 /D 3 receptor binding in a rat schizophrenia model and is also helpful to evaluate therapeutic effects of schizophrenia in the future.

  8. 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.

  9. Aripiprazole-induced adverse metabolic alterations in polyl:C neurodevelopmental model of schizophrenia in rats

    Czech Academy of Sciences Publication Activity Database

    Horská, K.; Rudá-Kučerová, J.; Dražanová, Eva; Karpíšek, M.; Demlová, R.; Kašpárek, T.; Kotolová, H.

    2017-01-01

    Roč. 123, SEP (2017), s. 148-158 ISSN 0028-3908 Institutional support: RVO:68081731 Keywords : adipokine * aripiprazole * leptin * polyl:C * schizophrenia * wistar rats Subject RIV: FH - Neurology OBOR OECD: 1.7 Other natural sciences Impact factor: 5.012, year: 2016

  10. Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

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    Chunmei Guo

    2010-01-01

    Full Text Available Neonatal blockade of N-methyl-D-aspartic acid (NMDA receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

  11. Advantages of the Alpha-lipoic Acid Association with Chlorpromazine in a Model of Schizophrenia Induced by Ketamine in Rats: Behavioral and Oxidative Stress evidences.

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    Sampaio, Luis Rafael Leite; Cysne Filho, Francisco Maurício Sales; de Almeida, Jamily Cunha; Diniz, Danilo Dos Santos; Patrocínio, Cláudio Felipe Vasconcelos; de Sousa, Caren Nádia Soares; Patrocínio, Manoel Cláudio Azevedo; Macêdo, Danielle; Vasconcelos, Silvânia Maria Mendes

    2018-03-01

    Schizophrenia is a chronic mental disorder reported to compromise about 1% of the world's population. Although its pathophysiological process is not completely elucidated, evidence showing the presence of an oxidative imbalance has been increasingly highlighted in the literature. Thus, the use of antioxidant substances may be of importance for schizophrenia treatment. The objective of this study was to evaluate the behavioral and oxidative alterations by the combination of chlorpromazine (CP) and alpha-lipoic acid (ALA), a potent antioxidant, in the ketamine (KET) model of schizophrenia in rats. Male Wistar rats (200-300 g) were treated for 10 days with saline, CP or ALA alone or in combination with CP previous to KET and the behavioral (open field, Y-maze and PPI tests) and oxidative tests were performed on the last day of treatment. The results showed that KET induced hyperlocomotion, impaired working memory and decreased PPI. CP alone or in combination with ALA prevented KET-induced behavioral effects. In addition, the administration of KET decreased GSH and increased nitrite, lipid peroxidation and myeloperoxidase activity. CP alone or combined with ALA prevented the oxidative alterations induced by KET. In conclusion, the treatment with KET in rats induced behavioral impairments accompanied by hippocampal oxidative alterations, possibly related to NMDA receptors hypofunction. Besides that, CP alone or combined with ALA prevented these effects, showing a beneficial activity as antipsychotic agents. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

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    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.

  13. Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

    NARCIS (Netherlands)

    F.M.S. Vrij (Femke); C.G. Bouwkamp (Christian); N. Gunhanlar (Nilhan); G. Shpak (Guy); B. Lendemeijer (Bert); Baghdadi, M. (Maarouf); Gopalakrishna, S. (Shreekara); M. Ghazvini (Mehrnaz); T. Li (Tracy); M. Quadri (Marialuisa); S. Olgiati (Simone); G.J. Breedveld (Guido); M.P.H. Coesmans (Michiel); E.J. Mientjes (Edwin); de Wit, T. (Ton); F.W. Verheijen (Frans); H.B. Beverloo (Berna); Cohen, D. (Dan); Kok, R.M. (Rob M.); P.R. Bakker (Roberto); Nijburg, A. (Aviva); A.T. Spijker (Anne); P.M.J. Haffmans (P.M. Judith); Hoencamp, E. (Erik); V. Bergink (Veerle); J.A.S. Vorstman; Wu, T. (Timothy); L.M. Olde Loohuis (Loes M.); Amin, N. (Najaf); C.D. Langen (Carolyn); Hofman, A. (Albert); W.J.G. Hoogendijk (Witte); van Duijn, C.M. (Cornelia M.); Ikram, M.A. (M. A.); M.W. Vernooij (Meike); H.W. Tiemeier (Henning); Uitterlinden, A.G. (André G.); Y. Elgersma (Ype); B. Distel (Ben); J.H. Gribnau (Joost); T.J.H. White (Tonya); V. Bonifati (Vincenzo); Kushner, S.A. (Steven A.)

    2018-01-01

    textabstractSchizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular

  14. Disruption in a Neurodevelopmental Model of Schizophrenia

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    Benjamin Rolland

    2012-01-01

    Full Text Available Oxidative stress has been implicated in neurodevelopmental theories of schizophrenia. Antioxidant Peroxysome Proliferator-Activated Receptors α (PPARα agonist fenofibrate has neuroprotective properties and could reverse early preclinical infringements that could trigger the illness. We have evaluated the neuroprotective interest of fenofibrate in a neurodevelopmental rat model of schizophrenia. The oxidative lesion induced by Kainic Acid (KA injection at postnatal day (PND 7 has previously been reported to disrupt Prepulse Inhibition (PPI at PND56 but not at PND35. In 4 groups of 15 male rats each, KN (KA-PND7 + normal postweaning food, KF (KA-PND7 + fenofibrate 0.2% food, ON (saline-PND7 + normal food, and OF (saline + fenofibrate food, PPI was recorded at PND35 and PND56. Three levels of prepulse were used: 73 dB, 76 dB, and 82 dB for a pulse at 120 dB. Four PPI scores were analyzed: PPI73, PPI76, PPI82, and mean PPI (PPIm. Two-way ANOVAs were used to evaluate the effects of both factors (KA + fenofibrate, and, in case of significant results, intergroup Student’s t-tests were performed. We notably found a significant difference (P<0.05 in PPIm between groups KN and KF at PND56, which supposes that fenofibrate could be worthy of interest for early neuroprotection in schizophrenia.

  15. Two-hit model of schizophrenia induced by neonatal immune activation and peripubertal stress in rats: Study of sex differences and brain oxidative alterations.

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    Monte, Aline Santos; Mello, Bruna Stefânia Ferreira; Borella, Vládia Célia Moreira; da Silva Araujo, Tatiane; da Silva, Francisco Eliclécio Rodrigues; Sousa, Francisca Cléa F de; de Oliveira, Antônio Carlos Pinheiro; Gama, Clarissa Severino; Seeman, Mary V; Vasconcelos, Silvânia Maria Mendes; Lucena, David Freitas De; Macêdo, Danielle

    2017-07-28

    Schizophrenia is considered to be a developmental disorder with distinctive sex differences. Aiming to simulate the vulnerability of the third trimester of human pregnancy to the developmental course of schizophrenia, an animal model was developed, using neonatal poly(I:C) as a first-hit, and peripubertal stress as a second-hit, i.e. a two-hit model. Since, to date, there have been no references to sex differences in the two-hit model, our study sought to determine sex influences on the development of behavior and brain oxidative change in adult rats submitted to neonatal exposure to poly(I:C) on postnatal days 5-7 as well as peripubertal unpredictable stress (PUS). Our results showed that adult two-hit rats present sex-specific behavioral alterations, with females showing more pronounced deficits in prepulse inhibition of the startle reflex and hyperlocomotion, while males showing more deficits in social interaction. Male and female animals exhibited similar working memory deficits. The levels of the endogenous antioxidant, reduced glutathione, were decreased in the prefrontal cortex (PFC) of both male and female animals exposed to both poly(I:C) and poly(I:C)+PUS. Only females presented decrements in GSH levels in the striatum. Nitrite levels were increased in the PFC of male and in the striatum of female poly(I:C)+PUS rats. Increased lipid peroxidation was observed in the PFC of females and in the striatum of males and females exposed to poly(I:C) and poly(I:C)+PUS. Thus, the present study presents evidence for sex differences in behavior and oxidative brain change induced by a two-hit model of schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801.

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    Liu, Yong; Tang, Yamei; Pu, Weidan; Zhang, Xianghui; Zhao, Jingping

    2011-08-01

    To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and γ-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, Bid), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (PGABA concentration and Glu utilization rate in the mPFC also decreased (PGABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats.

  17. Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis.

    Science.gov (United States)

    Starzer, Marie Stefanie Kejser; Nordentoft, Merete; Hjorthøj, Carsten

    2018-04-01

    The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion. All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates. Overall, 32.2% (95% CI=29.7-34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7-52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years. Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.

  18. Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia.

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    Buhusi, Mona; Obray, Daniel; Guercio, Bret; Bartlett, Mitchell J; Buhusi, Catalin V

    2017-08-30

    Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Retrieval-induced forgetting in schizophrenia.

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    Nestor, Paul G; Piech, Richard; Allen, Christopher; Niznikiewicz, Margaret; Shenton, Martha; McCarley, Robert W

    2005-06-15

    Retrieving category associates (e.g., FRUIT-ORANGE) may induce forgetting other category members (e.g., FRUIT-BANANA), a phenomenon known as retrieval-induced forgetting (RIF). We designed 2 experiments to examine the role of RIF in the associative memory impairment of schizophrenia (SZ). Subjects studied 36 category-exemplar pairs, generated from 6 categories composed of 6 members each. For half of the studied category-exemplar pairs, subjects practiced retrieval by completing word stems, followed by a delayed category-cued recall on all of the practiced and unpracticed items. Experiment 1 used unrelated category exemplars-pairs (e.g., FRUIT-ORANGE, METALS-IRON), whereas experiment 2 included related category exemplar pairs (e.g., COTTON-SHIRT, LEATHER-SKIRT). SZ showed reduced associative memory but normal RIF for unrelated categories used in experiment 1. For experiment 2, SZ showed a significant decline in associative memory for related but not unrelated category-exemplars in comparison to controls. Results suggested faulty specificity/distinctiveness for encoding and retrieval, but not abnormal RIF in the associative memory disturbance of SZ.

  20. Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.

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    Mingyan Lin

    Full Text Available Schizophrenia (SZ and autism spectrum disorders (ASD are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA, play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05, including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs, although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.

  1. Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

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    Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

    2018-04-01

    The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Recovery from schizophrenia and the recovery model.

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    Warner, Richard

    2009-07-01

    The recovery model refers to subjective experiences of optimism, empowerment and interpersonal support, and to a focus on collaborative treatment approaches, finding productive roles for user/consumers, peer support and reducing stigma. The model is influencing service development around the world. This review will assess whether optimism about outcome from serious mental illness and other tenets of the recovery model are borne out by recent research. Remission of symptoms has been precisely defined, but the definition of 'recovery' is a more diffuse concept that includes such factors as being productive and functioning independently. Recent research and a large, earlier body of data suggest that optimism about outcome from schizophrenia is justified. A substantial proportion of people with the illness will recover completely and many more will regain good social functioning. Outcome is better for people in the developing world. Mortality for people with schizophrenia is increasing but is lower in the developing world. Working appears to help people recover from schizophrenia, and recent advances in vocational rehabilitation have been shown to be effective in countries with differing economies and labor markets. A growing body of research supports the concept that empowerment is an important component of the recovery process. Key tenets of the recovery model - optimism about recovery from schizophrenia, the importance of access to employment and the value of empowerment of user/consumers in the recovery process - are supported by the scientific research. Attempts to reduce the internalized stigma of mental illness should enhance the recovery process.

  3. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia.

    Science.gov (United States)

    Umbricht, D; Schmid, L; Koller, R; Vollenweider, F X; Hell, D; Javitt, D C

    2000-12-01

    In patients with schizophrenia, deficient generation of mismatch negativity (MMN)-an event-related potential (ERP) indexing auditory sensory ("echoic") memory-and a selective increase of "context dependent" ("BX") errors in the "A-X" version of the Continuous Performance Test (AX-CPT) indicate an impaired ability to form and use transient memory traces. Animal and human studies implicate deficient N-methyl-D-aspartate receptor (NMDAR) functioning in such abnormalities. In this study, effects of the NMDAR antagonists ketamine on MMN generation and AX-CPT performance were investigated in healthy volunteers to test the hypothesis that NMDARs are critically involved in human MMN generation, and to assess the nature of ketamine-induced deficits in AX-CPT performance. In a single-blind placebo-controlled study, 20 healthy volunteers underwent an infusion with subanesthetic doses of ketamine. The MMN-to-pitch and MMN-to-duration deviants were obtained while subjects performed an AX-CPT. Ketamine significantly decreased the peak amplitudes of the MMN-to-pitch and MMN-to-duration deviants by 27% and 21%, respectively. It induced performance deficits in the AX-CPT characterized by decreased hit rates and specific increases of errors (BX errors), reflecting a failure to form and use transient memory traces of task relevant information. The NMDARs are critically involved in human MMN generation. Deficient MMN in schizophrenia thus suggests deficits in NMDAR-related neurotransmission. N-methyl-D-aspartate receptor dysfunction may also contribute to the impairment of patients with schizophrenia in forming and using transient memory traces in more complex tasks, such as the AX-CPT. Thus, NMDAR-related dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia. Arch Gen Psychiatry. 2000;57:1139-1147.

  4. 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.

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

    Science.gov (United States)

    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.

  6. [Intervention of Schizophrenia From the Community Model].

    Science.gov (United States)

    Taborda Zapata, Eliana María; Montoya González, Laura Elisa; Gómez Sierra, Natalia María; Arteaga Morales, Laura María; Correa Rico, Oscar Andrés

    2016-01-01

    Schizophrenia is a complex disease for which pharmacological management is an insufficient therapeutic measure to ensure adaptation to the community and restoring the quality of life of the patient, with a multidimensional management and community interventions being necessary. Case report. This case report illustrates a multidisciplinary treatment response, based on a community care model for mental health from Envigado, Colombia. The management of schizophrenia requires multimodal interventions that include community screening, psychoeducation of individuals, their families and society, addressing different areas of operation that allow adaptation of the subject to his social environment. A integrated intervention that can be provided on a Community scale, with the implementation of policies that allow it to be applied. Copyright © 2015 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  7. 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.

  8. Dopamine D2/D3 receptor binding of [123I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging

    International Nuclear Information System (INIS)

    Huang, Y.R.; Pai, C.W.; Cheng, K.H.; Kuo, W.I.; Chen, M.W.; Chang, K.W.

    2014-01-01

    Introduction: Epidepride is a compound with an affinity in picomolar range for D 2 /D 3 receptors. The aim of this work was designed to investigate the diagnostic possibility of [ 123 I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model. Methods: Rats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3 mg/kg/day) or saline for 4 weeks. After 1-week administration of MK-801, rats in MK-801 + risperidone group received risperidone (0.5 mg/kg/day) intraperitoneally 15 min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [ 123 I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain. Results: Risperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D 2 R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [ 123 I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [ 123 I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively. Conclusions: We established a rat schizophrenia model by chronic MK-801 administration for 4 weeks. [ 123 I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D 2 R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [ 123 I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model

  9. Antipsychotic-induced somnolence in mothers with schizophrenia.

    Science.gov (United States)

    Seeman, Mary V

    2012-03-01

    Although it is known that many antipsychotic drugs, at the doses prescribed for schizophrenia, are sedative and cause daytime drowsiness, the effect of potentially diminished vigilance on parenting parameters has not been studied. The aim of this paper is to advise clinicians about sedative load in mothers who are prescribed antipsychotic medication. A Medline search was conducted into the sedative effects of antipsychotics, with the following search terms: sleep; sedation; somnolence; wakefulness; antipsychotics; schizophrenia, parenting, maternal behavior, and custody. The results showed that antipsychotic drugs differ in their propensity to induce sedation and do so via their effects on a variety of neurotransmitter systems. It is important to note that mothers with schizophrenia risk losing custody of their infants if they are perceived as potentially neglectful because of excessive daytime sleepiness. Clinicians must choose antipsychotic medications carefully and monitor for sedative effects whenever the patient has important responsibilities that require the maintenance of vigilance.

  10. Modelling approaches - The case of schizophrenia : the case of schizophrenia

    NARCIS (Netherlands)

    Heeg, Bart M.S.; Damen, Joep; Buskens, Erik; Caleo, Sue; de Charro, F.; van Hout, B.A.

    2008-01-01

    Schizophrenia is a chronic disease characterized by periods of relative stability interrupted by acute episodes (or relapses). The course of the disease may vary considerably between patients. Patient histories show considerable inter- and even intra-individual variability. We provide a critical

  11. Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia

    DEFF Research Database (Denmark)

    Karlsen, Anna S; Kaalund, Sanne Simone; Møller, Morten

    2013-01-01

    Administration of N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal......-associated protein of 25 kDa (Snap25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in...

  12. 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.

  13. Schizophrenia: an integrated sociodevelopmental-cognitive model

    Science.gov (United States)

    Howes, Oliver D; Murray, Robin M

    2014-01-01

    Schizophrenia remains a major burden1. The dopamine (DA) and neurodevelopmental hypotheses attempt to explain the pathogenic mechanisms and origins of the disorder respectively2-4. Recently an alternative, the cognitive model, has gained popularity5. However the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of DA, neurodevelopment, or indeed the brain5. Here we show that developmental alterations secondary to variant genes, early hazards to the brain and childhood adversity, sensitise the DA system, and result in excessive presynaptic DA synthesis and DA release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated DA release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated DA dysregulation hard-wires the psychotic beliefs. Finally we consider the implications of this model for understanding and treating schizophrenia. PMID:24315522

  14. Clozapine and GABA transmission in schizophrenia disease models: establishing principles to guide treatments.

    Science.gov (United States)

    O'Connor, William T; O'Shea, Sean D

    2015-06-01

    Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia

    Directory of Open Access Journals (Sweden)

    Colin Kehrer

    2008-04-01

    Full Text Available Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDAreceptor subtype in the etiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

  16. 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.

  17. Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis

    DEFF Research Database (Denmark)

    Starzer, Marie Stefanie Kejser; Nordentoft, Merete; Hjorthøj, Carsten

    2017-01-01

    . Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar...

  18. Modelling the cognitive and neuropathological features of schizophrenia with phencyclidine.

    Science.gov (United States)

    Reynolds, Gavin P; Neill, Joanna C

    2016-11-01

    Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model. © The Author(s) 2016.

  19. 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.

  20. 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.

  1. Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review.

    Science.gov (United States)

    Grayson, B; Barnes, S A; Markou, A; Piercy, C; Podda, G; Neill, J C

    that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).

  2. Fear memory in a neurodevelopmental model of schizophrenia based on the postnatal blockade of NMDA receptors.

    Science.gov (United States)

    Latusz, Joachim; Radaszkiewicz, Aleksandra; Bator, Ewelina; Wędzony, Krzysztof; Maćkowiak, Marzena

    2017-02-01

    Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  3. Poly(I:C) model of schizophrenia in rats induces sex-dependent functional brain changes detected by MRI that are not reversed by aripiprazole treatment

    Czech Academy of Sciences Publication Activity Database

    Dražanová, Eva; Rudá-Kučerová, J.; Krátká, Lucie; Horská, K.; Demlová, R.; Starčuk jr., Zenon; Kašpárek, T.

    2018-01-01

    Roč. 137, MAR (2018), s. 146-155 ISSN 0361-9230 R&D Projects: GA MŠk(CZ) LM2015062; GA MŠk(CZ) LO1212 Institutional support: RVO:68081731 Keywords : aripiprazole * arterial spin labelling * wistar rats * schizophrenia * sex * MRI Impact factor: 3.033, year: 2016

  4. Implications of Information Theory for Computational Modeling of Schizophrenia.

    Science.gov (United States)

    Silverstein, Steven M; Wibral, Michael; Phillips, William A

    2017-10-01

    Information theory provides a formal framework within which information processing and its disorders can be described. However, information theory has rarely been applied to modeling aspects of the cognitive neuroscience of schizophrenia. The goal of this article is to highlight the benefits of an approach based on information theory, including its recent extensions, for understanding several disrupted neural goal functions as well as related cognitive and symptomatic phenomena in schizophrenia. We begin by demonstrating that foundational concepts from information theory-such as Shannon information, entropy, data compression, block coding, and strategies to increase the signal-to-noise ratio-can be used to provide novel understandings of cognitive impairments in schizophrenia and metrics to evaluate their integrity. We then describe more recent developments in information theory, including the concepts of infomax, coherent infomax, and coding with synergy, to demonstrate how these can be used to develop computational models of schizophrenia-related failures in the tuning of sensory neurons, gain control, perceptual organization, thought organization, selective attention, context processing, predictive coding, and cognitive control. Throughout, we demonstrate how disordered mechanisms may explain both perceptual/cognitive changes and symptom emergence in schizophrenia. Finally, we demonstrate that there is consistency between some information-theoretic concepts and recent discoveries in neurobiology, especially involving the existence of distinct sites for the accumulation of driving input and contextual information prior to their interaction. This convergence can be used to guide future theory, experiment, and treatment development.

  5. 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.

  6. Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrzole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals.

    Science.gov (United States)

    Mishra, Amrita; Mishra, Arun K; Jha, Shivesh

    2018-03-01

    Brahmi vati (BV) is an Ayurvedic polyherbal formulation used since ancient times and has been prescribed in seizures associated with schizophrenia and related memory loss by Ayurvedic practitioners in India. The aim of the study was to investigate these claims by evaluation of anticonvulsant, antischizophreniac, and memory-enhancing activities. Antioxidant condition of brain was determined by malondialdehyde (MDA) and reduced glutathione (GSH) levels estimations. Acetylcholinesterase (AChE) was quantitatively estimated in the brain tissue. Brahmi vati was prepared in-house by strictly following the traditional Ayurvedic formula. Bacoside A rich fraction (BA) of Bacopa monnieri was prepared by extraction and fractionation. It was than standardized by High Performance Liquid Chromatography (HPLC) and given in the dose of 32.5mg/kg body weight to the different groups of animals for 7days. On the seventh day, activities were performed adopting standard procedures. Brahmi vati showed significant anticonvulsant, memory-enhancing and antischizophrenia activities, when compared with the control groups and BA. It cause significantly higher brain glutathione levels. Acetylcholinesterase activity was found to be significantly low in BV-treated group. The finding of the present study suggests that BV may be used to treat seizures associated with schizophrenia and related memory loss. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Increased GABAB receptor signaling in a rat model for schizophrenia

    NARCIS (Netherlands)

    Selten, M.M.; Meyer, F.; Ba, W.; Valles, A.; Maas, D.A.; Negwer, M.J.; Eijsink, V.D.; Vugt, R.W.M. van; Hulten, J.A; Bakel, N.H.M. van; Roosen, J.; Linden, R.J. van der; Schubert, D.; Verheij, M.M.M.; Nadif Kasri, N.; Martens, G.J.M.

    2016-01-01

    Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an

  8. A heuristic model for working memory deficit in schizophrenia.

    Science.gov (United States)

    Qi, Zhen; Yu, Gina P; Tretter, Felix; Pogarell, Oliver; Grace, Anthony A; Voit, Eberhard O

    2016-11-01

    The life of schizophrenia patients is severely affected by deficits in working memory. In various brain regions, the reciprocal interactions between excitatory glutamatergic neurons and inhibitory GABAergic neurons are crucial. Other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine, modulate the local balance between glutamate and GABA and therefore regulate the function of brain regions. Persistent alterations in the balances between the neurotransmitters can result in working memory deficits. Here we present a heuristic computational model that accounts for interactions among neurotransmitters across various brain regions. The model is based on the concept of a neurochemical interaction matrix at the biochemical level and combines this matrix with a mobile model representing physiological dynamic balances among neurotransmitter systems associated with working memory. The comparison of clinical and simulation results demonstrates that the model output is qualitatively very consistent with the available data. In addition, the model captured how perturbations migrated through different neurotransmitters and brain regions. Results showed that chronic administration of ketamine can cause a variety of imbalances, and application of an antagonist of the D2 receptor in PFC can also induce imbalances but in a very different manner. The heuristic computational model permits a variety of assessments of genetic, biochemical, and pharmacological perturbations and serves as an intuitive tool for explaining clinical and biological observations. The heuristic model is more intuitive than biophysically detailed models. It can serve as an important tool for interdisciplinary communication and even for psychiatric education of patients and relatives. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. 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

  10. 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.

  11. Phencyclidine increased while isolation rearing did not affect progressive ratio responding in rats: Investigating potential models of amotivation in schizophrenia.

    Science.gov (United States)

    Amitai, Nurith; Powell, Susan B; Young, Jared W

    2017-11-22

    Schizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population with heterogeneous symptoms including positive, negative, and cognitive. While treatment for positive symptoms exists, none have been developed to treat negative symptoms. Animal models of schizophrenia are required to test targeted treatments and since patients exhibit reduced effort (breakpoints) for reward in a progressive ratio (PR) task, we examined the PR breakpoints of rats treated with the NMDA receptor antagonist phencyclidine or those reared in isolation - two common manipulations used to induce schizophrenia-relevant behaviors in rodents. In two cohorts, the PR breakpoint for a palatable food reward was examined in Long Evans rats after: 1) a repeated phencyclidine regimen; 2) A subchronic phencyclidine regimen followed by drug washout; and 3) post-weaning social isolation. Rats treated with repeated phencyclidine and those following washout from phencyclidine exhibited higher PR breakpoints than vehicle-treated rats. The breakpoint of isolation reared rats did not differ from those socially reared, despite abnormalities of these rats in other schizophrenia-relevant behaviors. Despite their common use for modeling other schizophrenia-relevant behaviors neither phencyclidine treatment nor isolation rearing recreated the motivational deficits observed in patients with schizophrenia, as measured by PR breakpoint. Other manipulations, and negative symptom-relevant behaviors, require investigation prior to testing putative therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Towards the development of improved tests for negative symptoms of schizophrenia in a validated animal model.

    Science.gov (United States)

    Sahin, Ceren; Doostdar, Nazanin; Neill, Joanna C

    2016-10-01

    Negative symptoms in schizophrenia remain an unmet clinical need. There is no licensed treatment specifically for this debilitating aspect of the disorder and effect sizes of new therapies are too small to make an impact on quality of life and function. Negative symptoms are multifactorial but often considered in terms of two domains, expressive deficit incorporating blunted affect and poverty of speech and avolition incorporating asociality and lack of drive. There is a clear need for improved understanding of the neurobiology of negative symptoms which can be enabled through the use of carefully validated animal models. While there are several tests for assessing sociability in animals, tests for blunted affect in schizophrenia are currently lacking. Two paradigms have recently been developed for assessing negative affect of relevance to depression in rats. Here we assess their utility for studying negative symptoms in schizophrenia using our well validated model for schizophrenia of sub-chronic (sc) treatment with Phencyclidine (PCP) in adult female rats. Results demonstrate that sc PCP treatment produces a significant negative affect bias in response to a high value reward in the optimistic and affective bias tests. Our results are not easily explained by the known cognitive deficits induced by sc PCP and support the hypothesis of a negative affective bias in this model. We suggest that further refinement of these two tests will provide a means to investigate the neurobiological basis of negative affect in schizophrenia, thus supporting the assessment of efficacy of new targets for this currently untreated symptom domain. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Zonisamide-induced weight loss in schizophrenia: case series.

    Science.gov (United States)

    Yang, Jaewon; Lee, Moon-Soo; Joe, Sook-Haeng; Jung, In-Kwa; Kim, Seung-Hyun

    2010-01-01

    Weight gain and metabolic disturbances constitute bothersome problems in schizophrenic patients treated with atypical antipsychotics. Several medications, exercise regimens, and lifestyle changes have been used in attempts to ameliorate these problems. We describe 3 patients with schizophrenia who manifested distinct weight loss and reduction in waist circumference during medication with zonisamide. This report suggests that zonisamide might be associated with weight loss in patients with schizophrenia.

  14. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients.

    Science.gov (United States)

    Janno, Sven; Holi, Matti; Tuisku, Katinka; Wahlbeck, Kristian

    2004-01-01

    Since most of the world's schizophrenia patients are treated with conventional antipsychotics, the authors evaluated various methods for establishing the prevalence of neuroleptic-induced movement disorders in these patients. DSM-IV criteria and established score thresholds on a movement disorder rating scale were used to identify cases of neuroleptic-induced movement disorder in a representative Estonian patient sample of 99 chronic institutionalized schizophrenia patients, 18-65 years old, treated with conventional neuroleptics (79.8%) or clozapine (20.2%). Neuroleptic-induced movement disorders according to DSM-IV criteria were found in 61.6% of the group: 31.3% had neuroleptic-induced akathisia, 23.2% had neuroleptic-induced parkinsonism, and 32.3% had neuroleptic-induced tardive dyskinesia. Prevalence rates for akathisia and tardive dyskinesia were similar when either DSM-IV criteria or rating scale scores were used, but the prevalence rate for parkinsonism was much lower per DSM-IV criteria than according to rating scale score. Nearly two-thirds of chronic schizophrenia patients suffered from a neuroleptic-induced movement disorder. Globally, extrapyramidal adverse effects still impose a huge burden on the majority of neuroleptic-treated individuals with schizophrenia. The discrepancy between the standard identification methods for neuroleptic-induced movement disorder indicate the need for further research.

  15. Anxiety does not contribute to social withdrawal in the subchronic phencyclidine rat model of schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2017-10-01

    Social withdrawal should not be considered a direct measure of the negative symptoms of schizophrenia as it may result not only from asociality (primary negative symptom) but also from other altered processes such as anxiety. To understand the contribution of these two factors to social deficit, we investigated whether the social withdrawal observed in the subchronic phencyclidine (PCP) rat model of schizophrenia could be attributed to increased anxiety. Compared to saline controls, PCP-treated rats (5 mg/kg, twice daily for 7 days, followed by a washout period) spent significantly less time in social interaction, but did not show anxiety-like behaviors in different relevant behavioral paradigms. In addition, their social deficit was not affected by a behavioral procedure known to reduce anxiety-like behavior (repeated exposure to the same partner) nor by systemic administration of the classical anxiolytic diazepam. In contrast, PCP-induced social withdrawal was reversed by the cannabinoid agonist CP55,940, a drug with known anxiogenic properties. Furthermore, when using the social approach task, PCP-treated animals performed similarly to control animals treated with diazepam, but not to those treated with the anxiogenic compound pentylenetetrazole. Taken together, our results indicate that PCP-induced social withdrawal cannot be attributed to increased anxiety. These data are discussed in the context of primary versus secondary negative symptoms and the deficit syndrome of schizophrenia.

  16. Cognitive functions in methamphetamine induced psychosis compared to schizophrenia and normal subjects.

    Directory of Open Access Journals (Sweden)

    Zahra Ezzatpanah

    2014-09-01

    Full Text Available The purpose of this research was to study the cognitive functions in patients with methamphetamine-induced psychosis (MIP in comparison with schizophrenia patients and normal subjects.This was a cross-sectional study, 30 patients with MIP, 30 patients with schizophrenia and 30 normal individuals were selected via convenient sampling and were matched on age, sex and education. Wisconsin Cards Sorting, Stroop, Visual Search and Attention and Wechsler Memory Tests were used to assess the subjects.The study showed that patients with MIP and schizophrenia have more deficits in executive functions, selective attention, sustained attention and memory than normal subjects. There were no significant differences in cognitive functions between patients with MIP and schizophrenia except for visual search and attention that showed more impairment in patients with schizophrenia.Although, cognitive dysfunctions of patients with MIP are mostly similar to patients with schizophrenia, some differences seem to exist, especially in those functions that are not primarily dependent on frontal lobe.

  17. 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...

  18. 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...

  19. 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.

  20. 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.

  1. Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia.

    Science.gov (United States)

    Moran, Lauren V; Stoeckel, Luke E; Wang, Kristina; Caine, Carolyn E; Villafuerte, Rosemond; Calderon, Vanessa; Baker, Justin T; Ongur, Dost; Janes, Amy C; Evins, A Eden; Pizzagalli, Diego A

    2018-03-01

    Nicotine improves attention and processing speed in individuals with schizophrenia. Few studies have investigated the effects of nicotine on cognitive control. Prior functional magnetic resonance imaging (fMRI) research demonstrates blunted activation of dorsal anterior cingulate cortex (dACC) and rostral anterior cingulate cortex (rACC) in response to error and decreased post-error slowing in schizophrenia. Participants with schizophrenia (n = 13) and healthy controls (n = 12) participated in a randomized, placebo-controlled, crossover study of the effects of transdermal nicotine on cognitive control. For each drug condition, participants underwent fMRI while performing the stop signal task where participants attempt to inhibit prepotent responses to "go (motor activation)" signals when an occasional "stop (motor inhibition)" signal appears. Error processing was evaluated by comparing "stop error" trials (failed response inhibition) to "go" trials. Resting-state fMRI data were collected prior to the task. Participants with schizophrenia had increased nicotine-induced activation of right caudate in response to errors compared to controls (DRUG × GROUP effect: p corrected  state functional connectivity analysis, relative to controls, participants with schizophrenia had significantly decreased connectivity between the right caudate and dACC/bilateral dorsolateral prefrontal cortices. In sum, we replicated prior findings of decreased post-error slowing in schizophrenia and found that nicotine was associated with more adaptive (i.e., increased) post-error reaction time (RT). This proof-of-concept pilot study suggests a role for nicotinic agents in targeting cognitive control deficits in schizophrenia.

  2. Effects of omega-3 supplementation on interleukin and neurotrophin levels in an animal model of schizophrenia

    Directory of Open Access Journals (Sweden)

    ALEXANDRA I. ZUGNO

    2015-08-01

    Full Text Available ABSTRACTNew studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL and neurotrophin brain-derived neurotrophic factor (BDNF levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat's life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg was started and maintained until the last day of the experiment. BDNF levels in the rat's prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1β and IL6. These findings suggest that the similarity of IL-1β and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

  3. Rivastigmine treatment for the prevention of electroconvulsive therapy-induced memory deficits in patients with schizophrenia.

    Science.gov (United States)

    Stryjer, Rafael; Ophir, Dana; Bar, Faina; Spivak, Baruch; Weizman, Abraham; Strous, Rael D

    2012-01-01

    Electroconvulsive therapy (ECT) is an effective strategy in some treatment-resistant patients with schizophrenia. However, ECT is associated with cognitive adverse effects, most notably, memory loss. This study examined the effects of rivastigmine, a selective central nervous system acetylcholinesterase inhibitor, with benefits on cognition in Alzheimer disease, on memory performance in patients with schizophrenia treated with ECT. Thirty inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision schizophrenia treated with ECT were coadministered rivastigmine (3-4.5 mg/d) or placebo in a prospective, randomized, double-blind, placebo-controlled trial (maximum period of 4 weeks). Over the ECT course, scores on the cognitive subscale of the Alzheimer's Disease Assessment in subjects receiving placebo showed no significant change, whereas subjects receiving rivastigmine displayed decreased cognitive subscale of the Alzheimer's Disease Assessment scores, indicating cognitive improvement (P ECT and indicate possible beneficial effects of rivastigmine coadministration in minimizing some of these ECT-induced cognitive impairments.

  4. Antipsychotic switching for people with schizophrenia who have neuroleptic-induced weight or metabolic problems.

    Science.gov (United States)

    Mukundan, Anitha; Faulkner, Guy; Cohn, Tony; Remington, Gary

    2010-12-08

    Weight gain is common for people with schizophrenia and this has serious implications for a patient's health and well being. Switching strategies have been recommended as a management option. To determine the effects of antipsychotic medication switching as a strategy for reducing or preventing weight gain and metabolic problems in people with schizophrenia. We searched key databases and the Cochrane Schizophrenia Group's trials register (January 2005 and June 2007), reference sections within relevant papers and contacted the first author of each relevant study and other experts to collect further information. All clinical randomised controlled trials comparing switching of antipsychotic medication as an intervention for antipsychotic induced weight gain and metabolic problems with continuation of medication and/or other weight loss treatments (pharmacological and non pharmacological) in people with schizophrenia or schizophrenia-like illnesses. Studies were reliably selected, quality assessed and data extracted. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. The primary outcome measures were weight loss, metabolic syndrome, relapse and general mental state. We included four studies for the review with a total of 636 participants. All except one study had a duration of 26 weeks or less. There was a mean weight loss of 1.94 kg (2 RCT, n = 287, CI -3.9 to 0.08) when switched to aripiprazole or quetiapine from olanzapine. BMI also decreased when switched to quetiapine (1 RCT, n = 129, MD -0.52 CI -1.26 to 0.22) and aripiprazole (1 RCT, n = 173, RR 0.28 CI 0.13 to 0.57) from olanzapine.Fasting blood glucose showed a significant decrease when switched to aripiprazole or quetiapine from olanzapine. (2 RCT, MD -2.53 n = 280 CI -2.94 to -2.11). One RCT also showed a favourable lipid profile when switched to aripiprazole but these measures were reported as percentage

  5. Animal Models of Schizophrenia with a Focus on Models Targeting NMDA Receptors

    Czech Academy of Sciences Publication Activity Database

    Svojanovská, Markéta; Stuchlík, Aleš

    2015-01-01

    Roč. 4, č. 1 (2015), s. 3-18 ISSN 1805-7225 R&D Projects: GA MZd(CZ) NT13386 Institutional support: RVO:67985823 Keywords : schizophrenia * animal models * pharmacological models * genetic models * neurodevelopmental models * preclinical studies Subject RIV: FH - Neurology

  6. Schizophrenia and Depression Co-morbidity: What We Have Learned from Animal Models

    Directory of Open Access Journals (Sweden)

    James Nicholas Samsom

    2015-02-01

    Full Text Available Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of: CSMD1, PDLIM5, GluD1, diabetic db/db mice, NPY, DISC1 and its interacting partners, Reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia.

  7. 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.

  8. Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

    Directory of Open Access Journals (Sweden)

    Paula Moran

    2016-01-01

    Full Text Available The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

  9. Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models.

    Science.gov (United States)

    Moran, Paula; Stokes, Jennifer; Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John; O'Tuathaigh, Colm

    2016-01-01

    The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

  10. Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

    Science.gov (United States)

    Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John

    2016-01-01

    The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia. PMID:27725886

  11. Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

    NARCIS (Netherlands)

    D. Martins-de-Souza (Daniel); M. Alsaif (Murtada); A. Ernst (Agnes); L.W. Harris (Laura); N. Aerts (Nancy); I. Lenaerts (Ilse); P.J. Peeters (Pieter); K. Amess (Kevin); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)

    2012-01-01

    textabstractBackground: Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore,

  14. Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

    Directory of Open Access Journals (Sweden)

    GILDA NEVES

    2017-08-01

    Full Text Available ABSTRACT Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

  15. Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects.

    Science.gov (United States)

    Neves, Gilda; Borsoi, Milene; Antonio, Camila B; Pranke, Mariana A; Betti, Andresa H; Rates, Stela M K

    2017-01-01

    Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

  16. Drug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light

    Directory of Open Access Journals (Sweden)

    Alessandra Paparelli

    2011-01-01

    Full Text Available 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 relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychomimetic drugs (LSD, amphetamines, cannabis, PCP and schizophrenia.

  17. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

    Science.gov (United States)

    Neill, Jo C; Grayson, Ben; Kiss, Béla; Gyertyán, István; Ferguson, Paul; Adham, Nika

    2016-01-01

    Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  18. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    Science.gov (United States)

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

  19. Genetic modelling in schizophrenia according to HLA typing.

    Science.gov (United States)

    Smeraldi, E; Macciardi, F; Gasperini, M; Orsini, A; Bellodi, L; Fabio, G; Morabito, A

    1986-09-01

    Studying families of schizophrenic patients, we observed that the risk of developing the overt form of the illness could be enhanced by some factors. Among these various factors we focused our attention on a biological variable, namely the presence or the absence of particular HLA antigens: partitioning our schizophrenic patients according to their HLA structure (i.e. those with HLA-A1 or CRAG-A1 antigens and those with HLA-non-CRAG-A1 antigens, respectively), revealed different illness distribution in the two groups. From a genetic point of view, this finding suggests the presence of heterogeneity in the hypothetical liability system related to schizophrenia and we evaluated the heterogeneity hypothesis by applying alternative genetic models to our data, trying to detect more biologically homogeneous subgroups of the disease.

  20. Cognitive decision modelling of emotion-based learning impairment in schizophrenia: the role of awareness.

    Science.gov (United States)

    Cella, Matteo; Dymond, Simon; Cooper, Andrew; Turnbull, Oliver H

    2012-03-30

    Individuals with schizophrenia often lack insight or awareness. Resulting impairment has been observed in various cognitive domains and, recently, linked to problems in emotion-based learning. The Iowa Gambling Task (IGT) has been used to assess emotion-based decision-making in patients with schizophrenia, but results have been inconclusive. The current study further investigates emotion-based decision-making in schizophrenia by elucidating the unique contribution of awareness. Twenty-five patients with schizophrenia and 24 healthy controls were assessed with a modified version of the IGT recording awareness at regular intervals. Symptom assessment, medication and medical history were recorded for the clinical group. Patients with schizophrenia underperformed on the IGT compared to controls. Subjective awareness levels were significantly lower in the schizophrenia group and were associated with hallucination severity. Cognitive decision modelling further indicated that patients with schizophrenia had impaired attention to losses, compared to controls. This parameter was positively correlated with awareness. We also found that positive symptoms altered awareness levels and suggest that this disruption may contribute to sub-optimal decision-making. Overall, a lack of awareness may be an important aspect in understanding impaired social cognitive functioning and emotion-based learning observed in schizophrenia. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. 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.

  2. Modelling the treated course of schizophrenia: Development of a discrete event simulation model

    NARCIS (Netherlands)

    Heeg, Bart; Buskens, Erik; Knapp, Martin; van Aalst, Gerda; Dries, Pieter J. T.; de Haan, Lieuwe; van Hout, Ben A.

    2005-01-01

    In schizophrenia, modelling techniques may be needed to estimate the long-term costs and effects of new interventions. However, it seems that a simple direct link between symptoms and costs does not exist. Decisions about whether a patient will be hospitalized or admitted to a different healthcare

  3. Reversal of olanzapine-induced weight gain in a patient with schizophrenia by switching to asenapine: a case report

    Directory of Open Access Journals (Sweden)

    Okazaki K

    2017-11-01

    Full Text Available Kosuke Okazaki, Kazuhiko Yamamuro, Toshifumi Kishimoto Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Japan Aims: Antipsychotics are effective for treating schizophrenia, but atypical antipsychotics can cause several adverse side effects including weight gain, hyperprolactinemia, and extrapyramidal symptoms. Moreover, weight gain increases the risk of metabolic diseases.Methods: We treated a case of olanzapine-induced weight gain in a 41-year-old man with schizophrenia by switching his medication from olanzapine to asenapine.Results: The weight gain improved after switching the medication, from 80.3 to 75.0 kg, a weight loss of 6.6%, and there was no significant worsening of psychological symptoms or other adverse effects.Conclusions: Asenapine might be effective for treating patients with schizophrenia who experience olanzapine-induced weight gain. Keywords: olanzapine, weight gain, schizophrenia, asenapine

  4. 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

  5. Developmental vitamin D deficiency and schizophrenia: the role of animal models.

    Science.gov (United States)

    Schoenrock, S A; Tarantino, L M

    2016-01-01

    Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  6. Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case–control sample of schizophrenia

    DEFF Research Database (Denmark)

    Ingason, Andrés; Giegling, Ina; Harmann, AM

    2015-01-01

    Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA re...

  7. Animal models of prenatal immune challenge and their contribution to the study of schizophrenia: a systematic review

    Directory of Open Access Journals (Sweden)

    D.S. Macêdo

    2012-03-01

    Full Text Available Prenatal immune challenge (PIC in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism. Based on this, the goal of this article was to review the main contributions of PIC models, especially the one using the viral-mimetic particle polyriboinosinic-polyribocytidylic acid (poly-I:C, to the understanding of the etiology, biological basis and treatment of schizophrenia. This systematic review consisted of a search of available web databases (PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge for original studies published in the last 10 years (May 2001 to October 2011 concerning animal models of PIC, focusing on those using poly-I:C. The results showed that the PIC model with poly-I:C is able to mimic the prodrome and both the positive and negative/cognitive dimensions of schizophrenia, depending on the specific gestation time window of the immune challenge. The model resembles the neurobiology and etiology of schizophrenia and has good predictive value. In conclusion, this model is a robust tool for the identification of novel molecular targets during prenatal life, adolescence and adulthood that might contribute to the development of preventive and/or treatment strategies (targeting specific symptoms, i.e., positive or negative/cognitive for this devastating mental disorder, also presenting biosafety as compared to viral infection models. One limitation of this model is the incapacity to model the full spectrum of immune responses normally induced by viral exposure.

  8. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia-Gating of auditory-evoked potentials and prepulse inhibition

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Oranje, Bob; Yding, Birte

    2010-01-01

    The use of translational approaches to validate animal models is needed for the development of treatments that can effectively alleviate cognitive impairments associated with schizophrenia, which are unsuccessfully treated by the current available therapies. Deficits in pre-attentive stages...... of sensory information processing seen in schizophrenia patients, can be assessed by highly homologues methods in both humans and rodents, evident by the prepulse inhibition (PPI) of the auditory startle response and the P50 (termed P1 here) suppression paradigms. Treatment with the NMDA receptor antagonist...... PCP on postnatal days 7, 9, and 11 reliably induce cognitive impairments resembling those presented by schizophrenia patients. Here we evaluate the potential of early postnatal PCP (20mg/kg) treatment in Lister Hooded rats to induce post-pubertal deficits in PPI and changes, such as reduced gating...

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

    Science.gov (United States)

    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

  10. Effectiveness of a structured diet program in antipsychotic-induced weight gain in patients with schizophrenia.

    Science.gov (United States)

    Direk, Nese; Ucok, Alp

    2008-01-01

    Objective.The aim of this study was to evaluate the effectiveness of a structured diet program in weight loss in patients with schizophrenia. Methods. A total of 38 outpatients diagnosed with schizophrenia according to DSM-IV and who had complaints of weight gain during treatment with various antipsychotic drugs were invited to participate in a 3-month structured diet program. Thirty-two patients and another 40 patients were included as the control group. At the beginning of the diet program, the patients were given a form in order to evaluate their eating habits, and blood samples were taken to measure plasma lipid profile, and fasting blood glucose (FBG) level. Patients' baseline weight, body mass index (BMI), and basal metabolism rate (BMR) were recorded. Results. Thirty-two patients with schizophrenia, who attended a 3-month structured diet program had mean weight loss of 6.19 kg, whereas patients in the control group gained 1.6 kg. Conclusion. Our findings show that a diet program is effective in managing antipsychotic-induced weight gain. The degree of weight loss seems to be correlated with the duration in which the patient is on the diet program. However; younger patients had less benefit from the diet program.

  11. Reconsidering Clinical Staging Model: A Case of Genetic High Risk for Schizophrenia

    OpenAIRE

    Lee, Tae Young; Kim, Minah; Kim, Sung Nyun; Kwon, Jun Soo

    2016-01-01

    The clinical staging model is considered a useful and practical method not only in dealing with the early stage of psychosis overcoming the debate about diagnostic boundaries but also in emerging mood disorder. However, its one limitation is that it cannot discriminate the heterogeneity of individuals at clinical high risk for psychosis, but lumps them all together. Even a healthy offspring of schizophrenia can eventually show clinical symptoms and progress to schizophrenia under the influenc...

  12. 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.

  13. Schizophrenia and induced abortions: A national register-based follow-up study among Finnish women born between 1965-1980 with schizophrenia or schizoaffective disorder.

    Science.gov (United States)

    Simoila, Laura; Isometsä, Erkki; Gissler, Mika; Suvisaari, Jaana; Sailas, Eila; Halmesmäki, Erja; Lindberg, Nina

    2018-02-01

    The objectives of this study were to investigate, in women with schizophrenia or schizoaffective disorder, the number and incidence of induced abortions (= pregnancy terminations performed by a physician), their demographic characteristics, use of contraceptives, plus indications of and complications related to pregnancy termination. Using the Care Register for Health Care, we identified Finnish women born between the years 1965-1980 who were diagnosed with either schizophrenia or schizoaffective disorder during the follow-up period ending 31.12.2013. For each case, five age- and place-of-birth- matched controls were obtained from the Population Register of Finland. Information about births and induced abortions were obtained from the Medical Birth Register and the Induced Abortion Register. The number and incidence of induced abortions per 1000 follow-up years did not differ between cases and their controls. However, due to fewer pregnancies, cases exhibited an over 2-fold increased risk of pregnancy termination (RR 2.28; 95% CI 2.20-2.36). Cases were younger, were more often without a partner at the time of induced abortion, and their pregnancies resulted more often from a lack of contraception. Among cases, the indication for pregnancy termination was more often mother-to-be's medical condition. Induced abortions after 12weeks gestation were more common among cases. However, cases had no more complications related to termination. The incidence of induced abortions among Finnish women with schizophrenia or schizoaffective disorder is similar to the general population, but their risk per pregnancy over two-fold. They need effective, affordable family planning services and long-term premeditated contraception. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  15. Association Study of 60 Candidate Genes with Antipsychotic-induced Weight Gain in Schizophrenia Patients.

    Science.gov (United States)

    Ryu, S; Huh, I-S; Cho, E-Y; Cho, Y; Park, T; Yoon, S C; Joo, Y H; Hong, K S

    2016-03-01

    This study aimed to investigate the association of multiple candidate genes with weight gain and appetite change during antipsychotic treatment. A total of 233 single nucleotide polymorphisms (SNPs) within 60 candidate genes were genotyped. BMI changes for up to 8 weeks in 84 schizophrenia patients receiving antipsychotic medication were analyzed using a linear mixed model. In addition, we assessed appetite change during antipsychotic treatment in a different group of 46 schizophrenia patients using the Drug-Related Eating Behavior Questionnaire. No SNP showed a statistically significant association with BMI or appetite change after correction for multiple testing. We observed trends of association (PGHRL showed suggestive evidence of association with not only weight gain (P=0.001) but also appetite change (P=0.042). Patients carrying the GG genotype of rs696217 exhibited higher increase in both BMI and appetite compared to patients carrying the GT/TT genotype. Our findings suggested the involvement of a GHRL polymorphism in weight gain, which was specifically mediated by appetite change, during antipsychotic treatment in schizophrenia patients. © Georg Thieme Verlag KG Stuttgart · New York.

  16. The Five-Factor Model personality traits in schizophrenia: A meta-analysis.

    Science.gov (United States)

    Ohi, Kazutaka; Shimada, Takamitsu; Nitta, Yusuke; Kihara, Hiroaki; Okubo, Hiroaki; Uehara, Takashi; Kawasaki, Yasuhiro

    2016-06-30

    Personality is one of important factors in the pathogenesis of schizophrenia because it affects patients' symptoms, cognition and social functioning. Several studies have reported specific personality traits in patients with schizophrenia compared with healthy subjects. However, the results were inconsistent among studies. The NEO Five-Factor Inventory (NEO-FFI) measures five personality traits: Neuroticism (N), Extraversion (E), Openness (O), Agreeableness (A) and Conscientiousness (C). Here, we performed a meta-analysis of these personality traits assessed by the NEO-FFI in 460 patients with schizophrenia and 486 healthy subjects from the published literature and investigated possible associations between schizophrenia and these traits. There was no publication bias for any traits. Because we found evidence of significant heterogeneity in all traits among the studies, we applied a random-effect model to perform the meta-analysis. Patients with schizophrenia showed a higher score for N and lower scores for E, O, A and C compared with healthy subjects. The effect sizes of these personality traits ranged from moderate to large. These differences were not affected by possible moderator factors, such as gender distribution and mean age in each study, expect for gender effect for A. These findings suggest that patients with schizophrenia have a different personality profile compared with healthy subjects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. hiPSC-derived neural stem cells from patients with schizophrenia induce an impaired angiogenesis.

    Science.gov (United States)

    Casas, Bárbara S; Vitória, Gabriela; do Costa, Marcelo N; Madeiro da Costa, Rodrigo; Trindade, Pablo; Maciel, Renata; Navarrete, Nelson; Rehen, Stevens K; Palma, Verónica

    2018-02-22

    Schizophrenia is a neurodevelopmental disease characterized by cerebral connectivity impairment and loss of gray matter. It was described in adult schizophrenia patients (SZP) that concentration of VEGFA, a master angiogenic factor, is decreased. Recent evidence suggests cerebral hypoperfusion related to a dysfunctional Blood Brain Barrier (BBB) in SZP. Since neurogenesis and blood-vessel formation occur in a coincident and coordinated fashion, a defect in neurovascular development could result in increased vascular permeability and, therefore, in poor functionality of the SZP's neurons. Here, we characterized the conditioned media (CM) of human induced Pluripotent Stem Cells (hiPSC)-derived Neural Stem Cells of SZP (SZP NSC) versus healthy subjects (Ctrl NSC), and its impact on angiogenesis. Our results reveal that SZP NSC have an imbalance in the secretion and expression of several angiogenic factors, among them non-canonical neuro-angiogenic guidance factors. SZP NSC migrated less and their CM was less effective in inducing migration and angiogenesis both in vitro and in vivo. Since SZP originates during embryonic brain development, our findings suggest a defective crosstalk between NSC and endothelial cells (EC) during the formation of the neuro-angiogenic niche.

  18. Weight Gain, Schizophrenia and Antipsychotics: New Findings from Animal Model and Pharmacogenomic Studies

    Directory of Open Access Journals (Sweden)

    Fabio Panariello

    2011-01-01

    Full Text Available Excess body weight is one of the most common physical health problems among patients with schizophrenia that increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, and hypertension, and accounts in part for 20% shorter life expectancy than in general population. Among patients with severe mental illness, obesity can be attributed to an unhealthy lifestyle, personal genetic profile, as well as the effects of psychotropic medications, above all antipsychotic drugs. Novel “atypical” antipsychotic drugs represent a substantial improvement on older “typical” drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. Animal models of antipsychotic-related weight gain and animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been largely evaluated by scientific community for changes in obesity-related gene expression or phenotypes. Moreover, pharmacogenomic approaches have allowed to detect more than 300 possible candidate genes for antipsychotics-induced body weight gain. In this paper, we summarize current thinking on: (1 the role of polymorphisms in several candidate genes, (2 the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction, and (3 the state of development of animal models in this matter. We also outline major areas for future research.

  19. Irradiation in adulthood as a new model of schizophrenia.

    Directory of Open Access Journals (Sweden)

    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.

  20. 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 schizophrenia – like psychosis, 2) with schizophrenia, and 2) without psychotic symptoms. Material. In the study 3 groups of subjects were included: 30 amphet...

  1. Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801

    Science.gov (United States)

    Bygrave, A M; Masiulis, S; Nicholson, E; Berkemann, M; Barkus, C; Sprengel, R; Harrison, P J; Kullmann, D M; Bannerman, D M; Kätzel, D

    2016-01-01

    It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1ΔPV mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1ΔPVmice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease. PMID:27070406

  2. Dominance of objects over context in a mediotemporal lobe model of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Lucia M Talamini

    Full Text Available BACKGROUND: A large body of evidence suggests impaired context processing in schizophrenia. Here we propose that this impairment arises from defective integration of mediotemporal 'what' and 'where' routes, carrying object and spatial information to the hippocampus. METHODOLOGY AND FINDINGS: We have previously shown, in a mediotemporal lobe (MTL model, that the abnormal connectivity between MTL regions observed in schizophrenia can explain the episodic memory deficits associated with the disorder. Here we show that the same neuropathology leads to several context processing deficits observed in patients with schizophrenia: 1 failure to choose subordinate stimuli over dominant ones when the former fit the context, 2 decreased contextual constraints in memory retrieval, as reflected in increased false alarm rates and 3 impaired retrieval of contextual information in source monitoring. Model analyses show that these deficits occur because the 'schizophrenic MTL' forms fragmented episodic representations, in which objects are overrepresented at the expense of spatial contextual information. CONCLUSIONS AND SIGNIFICANCE: These findings highlight the importance of MTL neuropathology in schizophrenia, demonstrating that it may underlie a broad spectrum of deficits, including context processing and memory impairments. It is argued that these processing deficits may contribute to central schizophrenia symptoms such as contextually inappropriate behavior, associative abnormalities, conversational drift, concreteness and delusions.

  3. Topiramate-induced weight loss in schizophrenia: a retrospective case series study.

    Science.gov (United States)

    Lévy, Emmanuel; Agbokou, Catherine; Ferreri, Florian; Chouinard, Guy; Margolese, Howard C

    2007-01-01

    Atypical antipsychotics have been associated with weight gain. This study examines the efficacy of adjunctive topiramate in patients with schizophrenia and schizoaffective disorder with antipsychotic-induced weight gain. A 2-year retrospective case analysis was performed in all 300 patients of the outpatient Special Follow-up Clinic for chronic schizophrenia and related psychoses at the Allan Memorial Institute, McGill University Health Centre (Montreal, Canada), a tertiary care University teaching hospital. 10 patients met study inclusion criteria. Mean daily topiramate dose was 197.5 mg (A+/-77) (range, 125-400 mg). Topiramate produced continued weight loss throughout the study duration without tolerance. Patients treated for 6 months and more had significantly higher Body Mass Index (BMI) differences than those treated for shorter durations (BMI-d6 months=-4.7A+/-2.4; BMI-d2 months=-3.2A+/-2.3; P=0.015). BMI changes were similar across genders. This study supports topiramate use to target weight loss in stable overweight schizophrenic patients as a potential therapy that requires further investigation.

  4. Schizophrenia as a disconnection syndrome. Studies with functional magnetic resonance imaging and structural equation modeling

    International Nuclear Information System (INIS)

    Schloesser, R.; Wagner, G.; Koehler, S.; Sauer, H.

    2005-01-01

    Aside from characteristic psychopathological symptoms, cognitive deficits are a core feature of schizophrenia. These deficits can only be addressed within the context of widespread functional interactions among different brain areas. To examine these interactions, structural equation modeling (SEM) was used for the analysis of fMRI datasets. In a series of studies, both in antipsychotic-treated and drug-free schizophrenic patients, a pattern of enhanced thalamocortical functional connectivity could be observed as an indicator for possible disruptions of frontostriatal thalamocortical circuitry. Moreover, drug-free patients and those receiving typical antipsychotic drugs were characterized by reduced interhemispheric corticocortical connectivity. This difference relative to normal controls was less in patients under atypical antipsychotic drugs. The results could be interpreted as a beneficial effect of atypical antipsychotic drugs on information processing in schizophrenic patients. The present findings are consistent with the model of schizophrenia as a disconnection syndrome and earlier concepts of ''cognitive dysmetria'' in schizophrenia. (orig.) [de

  5. Successful Management of Psychotropics Induced Stuttering Priapism with Pseudoephedrine in a Patient with Schizophrenia.

    Science.gov (United States)

    Thippaiah, Srinagesh Mannekote; Nagaraja, Soumya; Birur, Badari; Pandurangi, Ananda

    2018-02-05

    Stuttering Priapism is a recurrent, persistent penile erection in the absence of sexual desire due to altered genital hemodynamics, affecting the arterial component (high flow, non-ischemic) or the veno-occlusive mechanism (low flow, ischemic). Both typical and atypical antipsychotics increase the risk for priapism with greater implications in typicals than atypicals. Prompt recognition and treatment are important as 40% to 50% of patients with stuttering priapism may develop an erectile dysfunction if left untreated. There are several case reports in the literature about the association between psychotropic agents and priapism. However, there are no reports of successfully treating stuttering priapism using pseudoephedrine (sudafed) in the adult population. Here we present successful management of psychotropics induced stuttering priapism with pseudoephedrine in a male patient with schizophrenia.

  6. Animal models of gene-environment interaction in schizophrenia: A dimensional perspective.

    Science.gov (United States)

    Ayhan, Yavuz; McFarland, Ross; Pletnikov, Mikhail V

    2016-01-01

    Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (G × E) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of G × E relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Animal models of gene-environment interaction in schizophrenia: a dimensional perspective

    Science.gov (United States)

    Ayhan, Yavuz; McFarland, Ross; Pletnikov, Mikhail V.

    2015-01-01

    Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (GxE) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of GxE relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders. PMID:26510407

  8. Behavioural and biochemical profiles in rats infected with Toxoplasma gondii or lipopolysaccharide: animal models of schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Tejkalová, H.; Kodym, P.; Kačer, P.; Klaschka, Jan; Horáček, J.

    2013-01-01

    Roč. 24, e-Suppl. 1 (2013), e22 ISSN 0955-8810. [Biennal meeting of the EBPS /15./. 06.09.2013-09.09.2013, La Rochelle] Institutional support: RVO:67985807 Keywords : animal models * schizophrenia * behaviour * LPS * Toxoplasma gondii Subject RIV: FH - Neurology

  9. Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

    Directory of Open Access Journals (Sweden)

    Tatiana M. N. Rezende

    Full Text Available Abstract Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP, a nitric oxide (NO donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38 were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min. First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

  10. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model.

    Directory of Open Access Journals (Sweden)

    Qi Li

    Full Text Available OBJECTIVES: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. METHOD: We used an established mouse model of maternal immune activation (MIA by the viral mimic PolyI:C administered in early (day 9 or late (day 17 gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. RESULTS: PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4(th ventricle volume but did not disrupt sensorimotor gating. CONCLUSIONS: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

  11. Schizophrenia affects speech-induced functional connectivity of the superior temporal gyrus under cocktail-party listening conditions.

    Science.gov (United States)

    Li, Juanhua; Wu, Chao; Zheng, Yingjun; Li, Ruikeng; Li, Xuanzi; She, Shenglin; Wu, Haibo; Peng, Hongjun; Ning, Yuping; Li, Liang

    2017-09-17

    The superior temporal gyrus (STG) is involved in speech recognition against informational masking under cocktail-party-listening conditions. Compared to healthy listeners, people with schizophrenia perform worse in speech recognition under informational speech-on-speech masking conditions. It is not clear whether the schizophrenia-related vulnerability to informational masking is associated with certain changes in FC of the STG with some critical brain regions. Using sparse-sampling fMRI design, this study investigated the differences between people with schizophrenia and healthy controls in FC of the STG for target-speech listening against informational speech-on-speech masking, when a listening condition with either perceived spatial separation (PSS, with a spatial release of informational masking) or perceived spatial co-location (PSC, without the spatial release) between target speech and masking speech was introduced. The results showed that in healthy participants, but not participants with schizophrenia, the contrast of either the PSS or PSC condition against the masker-only condition induced an enhancement of functional connectivity (FC) of the STG with the left superior parietal lobule and the right precuneus. Compared to healthy participants, participants with schizophrenia showed declined FC of the STG with the bilateral precuneus, right SPL, and right supplementary motor area. Thus, FC of the STG with the parietal areas is normally involved in speech listening against informational masking under either the PSS or PSC conditions, and declined FC of the STG in people with schizophrenia with the parietal areas may be associated with the increased vulnerability to informational masking. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Neuroleptic-induced movement disorders in a naturalistic schizophrenia population: diagnostic value of actometric movement patterns

    Directory of Open Access Journals (Sweden)

    Tuisku Katinka

    2008-04-01

    Full Text Available Abstract Background Neuroleptic-induced movement disorders (NIMDs have overlapping co-morbidity. Earlier studies have described typical clinical movement patterns for individual NIMDs. This study aimed to identify specific movement patterns for each individual NIMD using actometry. Methods A naturalistic population of 99 schizophrenia inpatients using conventional antipsychotics and clozapine was evaluated. Subjects with NIMDs were categorized using the criteria for NIMD found in the Diagnostic and Statistical Manual for Mental Disorders – Fourth Edition (DSM-IV. Two blinded raters evaluated the actometric-controlled rest activity data for activity periods, rhythmical activity, frequencies, and highest acceleration peaks. A simple subjective question was formulated to test patient-based evaluation of NIMD. Results The patterns of neuroleptic-induced akathisia (NIA and pseudoakathisia (PsA were identifiable in actometry with excellent inter-rater reliability. The answers to the subjective question about troubles with movements distinguished NIA patients from other patients rather well. Also actometry had rather good screening performances in distinguishing akathisia from other NIMD. Actometry was not able to reliably detect patterns of neuroleptic-induced parkinsonism and tardive dyskinesia. Conclusion The present study showed that pooled NIA and PsA patients had a different pattern in lower limb descriptive actometry than other patients in a non-selected sample. Careful questioning of patients is a useful method of diagnosing NIA in a clinical setting.

  13. Neuroleptic-induced movement disorders in a naturalistic schizophrenia population: diagnostic value of actometric movement patterns.

    Science.gov (United States)

    Janno, Sven; Holi, Matti M; Tuisku, Katinka; Wahlbeck, Kristian

    2008-04-18

    Neuroleptic-induced movement disorders (NIMDs) have overlapping co-morbidity. Earlier studies have described typical clinical movement patterns for individual NIMDs. This study aimed to identify specific movement patterns for each individual NIMD using actometry. A naturalistic population of 99 schizophrenia inpatients using conventional antipsychotics and clozapine was evaluated. Subjects with NIMDs were categorized using the criteria for NIMD found in the Diagnostic and Statistical Manual for Mental Disorders - Fourth Edition (DSM-IV).Two blinded raters evaluated the actometric-controlled rest activity data for activity periods, rhythmical activity, frequencies, and highest acceleration peaks. A simple subjective question was formulated to test patient-based evaluation of NIMD. The patterns of neuroleptic-induced akathisia (NIA) and pseudoakathisia (PsA) were identifiable in actometry with excellent inter-rater reliability. The answers to the subjective question about troubles with movements distinguished NIA patients from other patients rather well. Also actometry had rather good screening performances in distinguishing akathisia from other NIMD. Actometry was not able to reliably detect patterns of neuroleptic-induced parkinsonism and tardive dyskinesia. The present study showed that pooled NIA and PsA patients had a different pattern in lower limb descriptive actometry than other patients in a non-selected sample. Careful questioning of patients is a useful method of diagnosing NIA in a clinical setting.

  14. Handwriting Movement Analyses for Monitoring Drug-Induced Motor Side Effects in Schizophrenia Patients Treated with Risperidone

    Science.gov (United States)

    Caligiuri, Michael P.; Teulings, Hans-Leo; Dean, Charles E.; Niculescu, Alexander B.; Lohr, James

    2009-01-01

    Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 46 healthy comparison participants were enrolled. Participants performed a 20-minute handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r = .91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients. PMID:19692133

  15. The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: implications for pharmacological modelling of core symptoms of schizophrenia.

    Science.gov (United States)

    Honey, Garry D; O'loughlin, Chris; Turner, Danielle C; Pomarol-Clotet, Edith; Corlett, Philip R; Fletcher, Paul C

    2006-02-01

    Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) x 2(depth of processing) x 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.

  16. AN ANIMAL MODEL OF SCHIZOPHRENIA BASED ON CHRONIC LSD ADMINISTRATION: OLD IDEA, NEW RESULTS

    Science.gov (United States)

    Marona-Lewicka, Danuta; Nichols, Charles D.; Nichols, David E.

    2011-01-01

    Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as “clearly a paranoid state.” We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. PMID:21352832

  17. An animal model of schizophrenia based on chronic LSD administration: old idea, new results.

    Science.gov (United States)

    Marona-Lewicka, Danuta; Nichols, Charles D; Nichols, David E

    2011-09-01

    Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Varieties of Self Disorder: A Bio-Pheno-Social Model of Schizophrenia.

    Science.gov (United States)

    Sass, Louis; Borda, Juan P; Madeira, Luis; Pienkos, Elizabeth; Nelson, Barnaby

    2018-02-05

    The self-disorder model offers a unifying way of conceptualizing schizophrenia's highly diverse symptoms (positive, negative, disorganized), of capturing their distinctive bizarreness, and of conceiving their longitudinal development. These symptoms are viewed as differing manifestations of an underlying disorder of ipseity or core-self: hyper-reflexivity/diminished-self-presence with accompanying disturbances of "grip" or "hold" on reality. Recent revision to this phenomenological theory, in particular distinguishing primary-vs-secondary factors, offers a bio-pheno-social model that is consistent with recent empirical findings and offers several advantages: (1) It helps account for the temporal variations of the symptoms or syndrome, including longitudinal progression, but also the shorter-term, situationally reactive, and sometimes defensive or quasi-intentional variability of symptom-expression that can occur in schizophrenia (consistent with understanding some aspects of ipseity-disturbance as dynamic and mutable, involving shifting attitudes or experiential orientations). (2) It accommodates the overlapping of some key schizophrenic symptoms with certain nonschizophrenic conditions involving dissociation (depersonalization, derealization), including depersonalization disorder and panic disorder, thereby acknowledging both shared and distinguishing symptoms. (3) It integrates recent neurocognitive and neurobiological as well as psychosocial (eg, influence of trauma and culture) findings into a coherent but multi-factorial neuropsychological account. An adequate model of schizophrenia will postulate shared disturbances of core-self experiences that nevertheless can follow several distinct pathways and occur in various forms. Such a model is preferable to uni-dimensional alternatives-whether of schizophrenia or ipseity-disturbance-given its ability to account for distinctive yet varying experiential and neurocognitive abnormalities found in research on

  19. 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

  20. Wendan decoction improves learning and memory deficits in a rat model of schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Cuiping Yang; Changchun Cai; Xiaojin Yang; Yanping Yang; Zhigang Zhou; Jianhua Liu; Heping Ye; Hongjiao Wan

    2012-01-01

    An experimental model of schizophrenia was established using dizocilpine (MK-801). Rats were intragastrically administered with Wendan decoction or clozapine for 21 days prior to establishing the model. The results revealed that the latency of schizophrenia model rats to escape from the hidden platform in the Morris water maze was significantly shortened after administration of Wendan decoction or clozapine. In addition, the treated rats crossed the platform significantly more times than the untreated model rats. Moreover, the rate of successful long-term potentiation induction in the Wendan decoction group and clozapine group were also obviously increased compared with the model group, and the population spike peak latency was significantly shortened. These experimental findings suggest that Wendan decoction can improve the learning and memory ability of schizophrenic rats to the same extent as clozapine treatment.

  1. 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.

  2. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

    Science.gov (United States)

    Wu, Ren-Rong; Jin, Hua; Gao, Keming; Twamley, Elizabeth W; Ou, Jian-Jun; Shao, Ping; Wang, Juan; Guo, Xiao-Feng; Davis, John M; Chan, Philip K; Zhao, Jing-Ping

    2012-08-01

    Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

  3. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

    Science.gov (United States)

    Réus, Gislaine Z; Becker, Indianara R T; Scaini, Giselli; Petronilho, Fabricia; Oses, Jean P; Kaddurah-Daouk, Rima; Ceretta, Luciane B; Zugno, Alexandra I; Dal-Pizzol, Felipe; Quevedo, João; Barichello, Tatiana

    2018-02-02

    Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Reversal of olanzapine-induced weight gain in a patient with schizophrenia by switching to asenapine: a case report

    OpenAIRE

    Okazaki, Kosuke; Yamamuro, Kazuhiko; Kishimoto, Toshifumi

    2017-01-01

    Kosuke Okazaki, Kazuhiko Yamamuro, Toshifumi Kishimoto Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Japan Aims: Antipsychotics are effective for treating schizophrenia, but atypical antipsychotics can cause several adverse side effects including weight gain, hyperprolactinemia, and extrapyramidal symptoms. Moreover, weight gain increases the risk of metabolic diseases.Methods: We treated a case of olanzapine-induced weight gain in a 41-year-old man with s...

  5. Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia.

    Science.gov (United States)

    Thomas, Michael L; Green, Michael F; Hellemann, Gerhard; Sugar, Catherine A; Tarasenko, Melissa; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Radant, Allen D; Seidman, Larry J; Shiluk, Alexandra L; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L; Light, Gregory A

    2017-01-01

    Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia. Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment. Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test-Second Edition, the Wechsler Memory Scale-Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing had a direct effect on cognition (β = 0.37, P model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms

  6. Electroconvulsive therapy-induced brain functional connectivity predicts therapeutic efficacy in patients with schizophrenia: a multivariate pattern recognition study.

    Science.gov (United States)

    Li, Peng; Jing, Ri-Xing; Zhao, Rong-Jiang; Ding, Zeng-Bo; Shi, Le; Sun, Hong-Qiang; Lin, Xiao; Fan, Teng-Teng; Dong, Wen-Tian; Fan, Yong; Lu, Lin

    2017-05-11

    Previous studies suggested that electroconvulsive therapy can influence regional metabolism and dopamine signaling, thereby alleviating symptoms of schizophrenia. It remains unclear what patients may benefit more from the treatment. The present study sought to identify biomarkers that predict the electroconvulsive therapy response in individual patients. Thirty-four schizophrenia patients and 34 controls were included in this study. Patients were scanned prior to treatment and after 6 weeks of treatment with antipsychotics only (n = 16) or a combination of antipsychotics and electroconvulsive therapy (n = 13). Subject-specific intrinsic connectivity networks were computed for each subject using a group information-guided independent component analysis technique. Classifiers were built to distinguish patients from controls and quantify brain states based on intrinsic connectivity networks. A general linear model was built on the classification scores of first scan (referred to as baseline classification scores) to predict treatment response. Classifiers built on the default mode network, the temporal lobe network, the language network, the corticostriatal network, the frontal-parietal network, and the cerebellum achieved a cross-validated classification accuracy of 83.82%, with specificity of 91.18% and sensitivity of 76.47%. After the electroconvulsive therapy, psychosis symptoms of the patients were relieved and classification scores of the patients were decreased. Moreover, the baseline classification scores were predictive for the treatment outcome. Schizophrenia patients exhibited functional deviations in multiple intrinsic connectivity networks which were able to distinguish patients from healthy controls at an individual level. Patients with lower classification scores prior to treatment had better treatment outcome, indicating that the baseline classification scores before treatment is a good predictor for treatment outcome. CONNECTIVITY NETWORKS

  7. From theory to PrACTice: a cognitive remediation program based on a neuropsychological model of schizophrenia

    Directory of Open Access Journals (Sweden)

    Delphine eFabre

    2015-12-01

    Full Text Available Cognitive dysfunction is one of the hallmark deficits of schizophrenia. A wide range of studies illustrate how it is strongly interconnected to clinical presentation and daily life functioning (see Green, 1996 and Green et al., 2000. Hence, cognition is an important treatment target in schizophrenia. To address the challenge of cognitive enhancement in schizophrenia, a large number of cognitive remediation programs have been developed and evaluated over the past several decades. First, an overview of these programs is presented highlighting their specificity to cognitive deficit in schizophrenia using an integrated method. In this case, cognitive training focuses on enhancing several elementary cognitive functions considered as a prerequisite to social skills or vocational training modules. These programs are based on the neurodevelopmental hypothesis of schizophrenia. However, moderate improvement for patients who benefit from these therapies has been observed as described in Wykes et al review (2011. Next, neuropsychological models of schizophrenia are then presented. They highlight the critical role of the internally generated intentions in appropriate willful actions. The cognitive control mechanism deals with this ability. Interestingly, available cognitive remediation programs have not been influenced by these models. Hence, we propose another alternative to set up a specific cognitive remediation program for schizophrenia patients by targeting the cognitive control mechanism. We describe the PrACTice program which is in the process of being validated.

  8. Using human brain imaging studies as a guide towards animal models of schizophrenia

    Science.gov (United States)

    BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

    2015-01-01

    Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

  9. Insight, self-stigma and psychosocial outcomes in Schizophrenia: a structural equation modelling approach.

    Science.gov (United States)

    Lien, Y-J; Chang, H-A; Kao, Y-C; Tzeng, N-S; Lu, C-W; Loh, C-H

    2018-04-01

    Poor insight is prevalent in patients with schizophrenia and has been associated with acute illness severity, medication non-adherence and poor treatment outcomes. Paradoxically, high insight has been associated with various undesirable outcomes, including low self-esteem, depression and low subjective quality of life (QoL) in patients with schizophrenia. Despite the growing body of studies conducted in Western countries supporting the pernicious effects of improved insight in psychosis, which bases on the level of self-stigma, the effects are unclear in non-Western societies. The current study examined the role of self-stigma in the relationship between insight and psychosocial outcomes in a Chinese population. A total of 170 outpatients with schizophrenia spectrum disorders were recruited from two general university hospitals. Sociodemographic data and clinical variables were recorded and self-report scales were employed to measure self-stigma, depression, insight, self-esteem and subjective QoL. Structural equation modelling (SEM) was used to analyse the cross-sectional data. High levels of self-stigma were reported by 39% of the participants (n = 67). The influences of insight, self-stigma, self-esteem and depression on subjective QoL were confirmed by the SEM results. Our model with the closest fit to the data (χ 2 = 33.28; df = 20; p = 0.03; χ 2/df = 1.66; CFI = 0.98; TLI = 0.97; RMSEA = 0.06) demonstrated that self-stigma might fully mediate the association of insight with low self-esteem, depression and poor subjective QoL. High insight into illness contributed to self-stigma, which caused low self-esteem and depression and, consequently, low QoL. Notably, insight did not directly affect self-esteem, depression or QoL. Furthermore, the association of insight with poor psychosocial outcomes was not moderated by self-stigma. Our findings support the mediating model of insight relevant to the poor psychosocial outcomes of individuals diagnosed with

  10. Inhibition of repair activity induced by γ-radiation, UV-rays and radiomimetics in the in vitro cultured cells of patients wiyh schizophrenia

    International Nuclear Information System (INIS)

    Zasukhina, G.D.; Zharikov, N.M.; L'vova, G.N.; Vasil'eva, I.M.; Chekova, V.V.; Alekhina, N.I.; Ivanova, T.N.

    1986-01-01

    A study was made of the processes of repair, virus reactivation, and formation of sister chromatid exchages (SCE) in blood cells of patients with schizophrenia after the effect of γ-radiation and 4-nitroquinoline-1-oxide. These processes were estimated by 12 criteria. The mutagen-induced disturbances in the processes of repair and SCE formation were found in cells of patients with schizophrenia and were absent in the control cells of healthy donors

  11. A diagnostic model incorporating P50 sensory gating and neuropsychological tests for schizophrenia.

    Directory of Open Access Journals (Sweden)

    Jia-Chi Shan

    Full Text Available OBJECTIVES: Endophenotypes in schizophrenia research is a contemporary approach to studying this heterogeneous mental illness, and several candidate neurophysiological markers (e.g. P50 sensory gating and neuropsychological tests (e.g. Continuous Performance Test (CPT and Wisconsin Card Sorting Test (WCST have been proposed. However, the clinical utility of a single marker appears to be limited. In the present study, we aimed to construct a diagnostic model incorporating P50 sensory gating with other neuropsychological tests in order to improve the clinical utility. METHODS: We recruited clinically stable outpatients meeting DSM-IV criteria of schizophrenia and age- and gender-matched healthy controls. Participants underwent P50 sensory gating experimental sessions and batteries of neuropsychological tests, including CPT, WCST and Wechsler Adult Intelligence Scale Third Edition (WAIS-III. RESULTS: A total of 106 schizophrenia patients and 74 healthy controls were enrolled. Compared with healthy controls, the patient group had significantly a larger S2 amplitude, and thus poorer P50 gating ratio (gating ratio = S2/S1. In addition, schizophrenia patients had a poorer performance on neuropsychological tests. We then developed a diagnostic model by using multivariable logistic regression analysis to differentiate patients from healthy controls. The final model included the following covariates: abnormal P50 gating (defined as P50 gating ratio >0.4, three subscales derived from the WAIS-III (Arithmetic, Block Design, and Performance IQ, sensitivity index from CPT and smoking status. This model had an adequate accuracy (concordant percentage = 90.4%; c-statistic = 0.904; Hosmer-Lemeshow Goodness-of-Fit Test, p = 0.64>0.05. CONCLUSION: To the best of our knowledge, this is the largest study to date using P50 sensory gating in subjects of Chinese ethnicity and the first to use P50 sensory gating along with other neuropsychological tests

  12. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia.

    Science.gov (United States)

    Kim, Eosu; Park, Dong-Wha; Choi, Song-Hee; Kim, Jae-Jin; Cho, Hyun-Sang

    2008-04-01

    Weight gain and other metabolic disturbances have now become discouraging, major side effects of atypical antipsychotic drugs (AAPDs). The novel strategies required to counteract these serious consequences, however, should avoid modulating the activities of the neurotransmitter receptors involved because those receptors are the therapeutic targets of AAPDs. Adenosine monophosphate-activated protein kinase is an enzyme that plays a pivotal role in energy homeostasis. We hypothesized that alpha-lipoic acid (ALA), which is known to modulate adenosine monophosphate-activated protein kinase activity in the hypothalamus and peripheral tissues, would ameliorate AAPD-induced weight gain. We describe the case series of a 12-week ALA trial in schizophrenia patients treated with AAPDs. Two of 7 enrolled subjects were dropped from the study because of noncompliance and demand for new medication to treat depressive symptoms, respectively. The mean (SD) weight loss was 3.16 (3.20) kg (P = 0.043, last observation carried forward; median, 3.03 kg; range, 0-8.85 kg). On average, body mass index showed a significant reduction (P = 0.028) over the 12 weeks. During the same period, a statistically significant reduction was also observed in total cholesterol levels (P = 0.042), and there was a weak trend toward the reduction in insulin resistance (homeostasis model assessment of insulin resistance) (P = 0.080). Three subjects reported increased energy subjectively. The total scores on the Brief Psychiatric Rating Scale and the Montgomery-Asberg Depression Rating Scale did not vary significantly during the study. These preliminary data suggest the possibility that ALA can ameliorate the adverse metabolic effects induced by AAPDs. To confirm the benefits of ALA, more extended study is warranted.

  13. Possible Effects of Synaptic Imbalances on Oligodendrocyte-Axonic Interactions in Schizophrenia: a Hypothetical Model

    Directory of Open Access Journals (Sweden)

    Bernhard Joseph Mitterauer

    2011-04-01

    Full Text Available AbstractA model of glial-neuronal interactions is proposed that could be explanatory for the demyelination identified in brains with schizophrenia. According to this model, receptors on astrocytes in glial-neuronal synaptic units are not functional, loosing their modulatory influence on synaptic neurotransmission. Hence, an unconstrained neurotransmission flux occurs that hyperactivates the axon and floods the cognate receptors of neurotransmitters on oligodendrocytes. The excess of neurotransmitters may have a toxic effect on oligodendrocytes and myelin, causing demyelination. In parallel, an increasing impairment of axons may disconnect neuronal networks. It is formally shown how oligodendrocytes normally categorize axonic information processing via their processes. Demyelination decomposes the oligodendrocyte-axonic system making it incapable to generate categories of information. This incoherence may be responsible for symptoms of disorganization in schizophrenia, such as thought disorder, inappropriate affect and incommunicable motor behavior. In parallel, the loss of oligodendrocytes affects gap junctions in the panglial syncytium, presumably responsible for memory impairment in schizophrenia.

  14. An investigation of models of illness in carers of schizophrenia patients using the Illness Perception Questionnaire.

    Science.gov (United States)

    Barrowclough, C; Lobban, F; Hatton, C; Quinn, J

    2001-11-01

    Although carers' reactions to schizophrenic illness in a close family member may have important implications for the patient and for themselves, little is known of factors that influence the way carers respond. In the area of physical health problems, people's models of their illness or illness representations have been found to be related to the ways they react and cope with their illness. This study examines the use of a modified form of the Illness Perception Questionnaire (IPQ) to investigate illness models in a sample of carers of schizophrenia patients. Forty-seven carers participated. The psychometric properties of the modified IPQ were examined, and a number of carer and patient outcomes were investigated in relation to carer scores on the illness identity, consequences, control-cure and timeline subscales of the modified IPQ. These outcomes included measures of carer distress and burden, expressed emotion dimensions, and patient functioning. The modified IPQ was found to be a reliable measure of carers' perceptions of schizophrenia. Carer functioning, the patient-carer relationship and patient illness characteristics were associated with different dimensions of illness perceptions. The findings support the proposal that carer cognitive representations of the illness may have important implications for both carer and patient outcomes in schizophrenia.

  15. Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.

    Science.gov (United States)

    Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

    2013-10-01

    Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

  16. Cost-effectiveness model of long-acting risperidone in schizophrenia in the US.

    Science.gov (United States)

    Edwards, Natalie C; Rupnow, Marcia F T; Pashos, Chris L; Botteman, Marc F; Diamond, Ronald J

    2005-01-01

    Schizophrenia is a devastating and costly illness that affects 1% of the population in the US. Effective pharmacological therapies are available but suboptimal patient adherence to either acute or long-term therapeutic regimens reduces their effectiveness. The availability of a long-acting injection (LAI) formulation of risperidone may increase adherence and improve clinical and economic outcomes for people with schizophrenia. To assess the cost effectiveness of risperidone LAI compared with oral risperidone, oral olanzapine and haloperidol decanoate LAI over a 1-year time period in outpatients with schizophrenia who had previously suffered a relapse requiring hospitalisation. US healthcare system. Published medical literature, unpublished data from clinical trials and a consumer health database, and a clinical expert panel were used to populate a decision-analysis model comparing the four treatment alternatives. The model captured: rates of patient compliance; rates, frequency and duration of relapse; incidence of adverse events (bodyweight gain and extrapyramidal effects); and healthcare resource utilisation and associated costs. Primary outcomes were: the proportion of patients with relapse; the frequency of relapse per patient; the number of relapse days per patient; and total direct medical cost per patient per year. Costs are in year 2002 US dollars. Based on model projections, the proportions of patients experiencing a relapse requiring hospitalisation after 1 year of treatment were 66% for haloperidol decanoate LAI, 41% for oral risperidone and oral olanzapine and 26% for risperidone LAI, while the proportion of patients with a relapse not requiring hospitalisation were 60%, 37%, 37% and 24%, respectively. The mean number of days of relapse requiring hospitalisation per patient per year was 28 for haloperidol decanoate LAI, 18 for oral risperidone and oral olanzapine and 11 for risperidone LAI, while the mean number of days of relapse not requiring

  17. Supernatural beliefs, aetiological models and help seeking behaviour in patients with schizophrenia.

    Science.gov (United States)

    Kate, Natasha; Grover, Sandeep; Kulhara, Parmanand; Nehra, Ritu

    2012-01-01

    Few studies have evaluated the supernatural beliefs of patients with schizophrenia. This study aimed to study the personal beliefs, aetiological models and help seeking behaviour of patients with schizophrenia using a self-rated questionnaire. Seventy three patients returned the completed supernatural Attitude questionnaire. 62% of patients admitted that people in their community believed in sorcery and other magico-religious phenomena. One fourth to half of patients believed in ghosts/evil spirit (26%), spirit intrusion (28.8%) and sorcery (46.6%). Two-third patients believed that mental illness can occur either due to sorcery, ghosts/evil spirit, spirit intrusion, divine wrath, planetary/astrological influences, dissatisfied or evil spirits and bad deeds of the past. 40% of the subjects attributed mental disorders to more than one of these beliefs. About half of the patients (46.6%) believed that only performance of prayers was sufficient to improve their mental status. Few patients (9.6%) believed that magico-religious rituals were sufficient to improve their mental illness but about one-fourth (24.7%) admitted that during recent episode either they or their caregivers performed magico-religious rituals. Supernatural beliefs are common in patients with schizophrenia and many of them attribute the symptoms of mental disorders to these beliefs.

  18. 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.

  19. Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

    Directory of Open Access Journals (Sweden)

    Tim eKarl

    2013-08-01

    Full Text Available Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the ‘two-hit hypothesis’ of schizophrenia predicting that genetic and environmental risk factors (GxE interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1 with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g. transmembrane domain Nrg1, Type II Nrg1, which have been exposed to different forms of stress (acute versus chronic, restraint versus social and housing conditions (standard laboratory versus minimally enriched housing. These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms.

  20. 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...

  1. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

  2. 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.

  3. Decision-making deficits in patients with chronic schizophrenia: Iowa Gambling Task and Prospect Valence Learning model.

    Science.gov (United States)

    Kim, Myung-Sun; Kang, Bit-Na; Lim, Jae Young

    2016-01-01

    Decision-making is the process of forming preferences for possible options, selecting and executing actions, and evaluating the outcome. This study used the Iowa Gambling Task (IGT) and the Prospect Valence Learning (PVL) model to investigate deficits in risk-reward related decision-making in patients with chronic schizophrenia, and to identify decision-making processes that contribute to poor IGT performance in these patients. Thirty-nine patients with schizophrenia and 31 healthy controls participated. Decision-making was measured by total net score, block net scores, and the total number of cards selected from each deck of the IGT. PVL parameters were estimated with the Markov chain Monte Carlo sampling scheme in OpenBugs and BRugs, its interface to R, and the estimated parameters were analyzed with the Mann-Whitney U-test. The schizophrenia group received significantly lower total net scores compared to the control group. In terms of block net scores, an interaction effect of group × block was observed. The block net scores of the schizophrenia group did not differ across the five blocks, whereas those of the control group increased as the blocks progressed. The schizophrenia group obtained significantly lower block net scores in the fourth and fifth blocks of the IGT and selected cards from deck D (advantageous) less frequently than the control group. Additionally, the schizophrenia group had significantly lower values on the utility-shape, loss-aversion, recency, and consistency parameters of the PVL model. These results indicate that patients with schizophrenia experience deficits in decision-making, possibly due to failure in learning the expected value of each deck, and incorporating outcome experiences of previous trials into expectancies about options in the present trial.

  4. Evaluation of a neurodevelopmental model of schizophrenia - Early postnatal PCP treatment in attentional set-shifting

    DEFF Research Database (Denmark)

    Broberg, B.V.; Dias, R.; Olsen, C.K.

    2008-01-01

    Phencyclidine (PCP) was administered to male and female Lister hooded rats on postnatal days (PND) 7, 9 and 11. All PCP animals tested in adulthood (PND 53-93) showed deficits in cognitive flexibility, specifically in their ability to shift attentional set, compared to controls. This novel finding...... is reminiscent of the impairment observed in schizophrenia patients, and supports the validity of the early postnatal PCP regimen as a disease-like model. (c) 2008 Elsevier B.V. All rights reserved Udgivelsesdato: 2008...

  5. Challenges of Analysing Gene-Environment Interactions in Mouse Models of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Peter L. Oliver

    2011-01-01

    Full Text Available The modelling of neuropsychiatric disease using the mouse has provided a wealth of information regarding the relationship between specific genetic lesions and behavioural endophenotypes. However, it is becoming increasingly apparent that synergy between genetic and nongenetic factors is a key feature of these disorders that must also be taken into account. With the inherent limitations of retrospective human studies, experiments in mice have begun to tackle this complex association, combining well-established behavioural paradigms and quantitative neuropathology with a range of environmental insults. The conclusions from this work have been varied, due in part to a lack of standardised methodology, although most have illustrated that phenotypes related to disorders such as schizophrenia are consistently modified. Far fewer studies, however, have attempted to generate a “two-hit” model, whereby the consequences of a pathogenic mutation are analysed in combination with environmental manipulation such as prenatal stress. This significant, yet relatively new, approach is beginning to produce valuable new models of neuropsychiatric disease. Focussing on prenatal and perinatal stress models of schizophrenia, this review discusses the current progress in this field, and highlights important issues regarding the interpretation and comparative analysis of such complex behavioural data.

  6. 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

  7. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.

    Science.gov (United States)

    LaMarca, Elizabeth A; Powell, Samuel K; Akbarian, Schahram; Brennand, Kristen J

    2018-01-01

    Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional "mini-brains" and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson's disease, and consider the future of this groundbreaking research.

  8. A model of memory impairment in schizophrenia: cognitive and clinical factors associated with memory efficiency and memory errors.

    Science.gov (United States)

    Brébion, Gildas; Bressan, Rodrigo A; Ohlsen, Ruth I; David, Anthony S

    2013-12-01

    Memory impairments in patients with schizophrenia have been associated with various cognitive and clinical factors. Hallucinations have been more specifically associated with errors stemming from source monitoring failure. We conducted a broad investigation of verbal memory and visual memory as well as source memory functioning in a sample of patients with schizophrenia. Various memory measures were tallied, and we studied their associations with processing speed, working memory span, and positive, negative, and depressive symptoms. Superficial and deep memory processes were differentially associated with processing speed, working memory span, avolition, depression, and attention disorders. Auditory/verbal and visual hallucinations were differentially associated with specific types of source memory error. We integrated all the results into a revised version of a previously published model of memory functioning in schizophrenia. The model describes the factors that affect memory efficiency, as well as the cognitive underpinnings of hallucinations within the source monitoring framework. © 2013.

  9. The Effect of an NCAM Mimetic on Learning and Memory Impairment in an Animal Model of Schizophrenia

    DEFF Research Database (Denmark)

    Secher, Thomas

    2009-01-01

    by immunohistochemical investigation of neurodegeneration and NMDA receptor activation in relevant brain regions. The results show that neonatal PCP treatment induces long-term impairment in spatial learning and memory. The higher PCP dose produced more robust deficits in all three tasks of the water maze, whereas...... for schizophrenia. Neonatal treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on postnatal days 7, 9, and 11 has been shown to induce acute neurodegeneration and long-term cognitive deficits and other behavioral abnormalities relevant to schizophrenia. To evaluate the effect...... results indicated that FGL treatment was able to reduce apoptotic cell death in the frontal cortex in pups and to increase NMDA receptor activation in the hippocampus in adults In the present project, further evidence was obtained that neonatal PCP treatment induces long-term impairment in spatial...

  10. Insight, psychopathology, explanatory models and outcome of schizophrenia in India: a prospective 5-year cohort study

    Directory of Open Access Journals (Sweden)

    Johnson Shanthi

    2012-09-01

    Full Text Available Abstract Background The sole focus of models of insight on bio-medical perspectives to the complete exclusion of local, non-medical and cultural constructs mandates review. This study attempted to investigate the impact of insight, psychopathology, explanatory models of illness on outcome of first episode schizophrenia. Method Patients diagnosed to have DSM IV schizophrenia (n = 131 were assessed prospectively for insight, psychopathology, explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Multiple linear and logistic regression and generalized estimating equations (GEE were employed to assess predictors of outcome. Results We could follow up 95 (72.5% patients. Sixty-five of these patients (68.4% achieved remission. There was a negative relationship between psychosis rating and insight scores. Urban residence, fluctuating course of the initial illness, and improvement in global functioning at 6 months and lower psychosis rating at 12 months were significantly related to remission at 5 years. Insight scores, number of non-medical explanatory models and individual explanatory models held during the later course of the illness were significantly associated with outcome. Analysis of longitudinal data using GEE showed that women, rural residence, insight scores and number of non-medical explanatory models of illness held were significantly associated with BPRS scores during the study period. Conclusions Insight, the disease model and the number of non-medical model positively correlated with improvement in psychosis arguing for a complex interaction between the culture, context and illness variables. These finding argue that insight and explanatory models are secondary to psychopathology, course and outcome of the illness. The awareness of mental illness is a narrative act in which people make personal sense of the many challenges they face. The course and outcome of the illness, cultural context

  11. Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia.

    Science.gov (United States)

    Simpson, Eleanor H; Kellendonk, Christoph; Ward, Ryan D; Richards, Vanessa; Lipatova, Olga; Fairhurst, Stephen; Kandel, Eric R; Balsam, Peter D

    2011-05-15

    Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits. Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice. We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. 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

  13. The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain.

    Science.gov (United States)

    Kanji, S; Fonseka, T M; Marshe, V S; Sriretnakumar, V; Hahn, M K; Müller, D J

    2018-02-01

    With the emergence of knowledge implicating the human gut microbiome in the development and regulation of several physiological systems, evidence has accumulated to suggest a role for the gut microbiome in psychiatric conditions and drug response. A complex relationship between the enteric nervous system, the gut microbiota and the central nervous system has been described which allows for the microbiota to influence and respond to a variety of behaviors and psychiatric conditions. Additionally, the use of pharmaceuticals may interact with and alter the microbiota to potentially contribute to adverse effects of the drug. The gut microbiota has been described in several psychiatric disorders including depression and anxiety, but only a few reports have discussed the role of the microbiome in schizophrenia. The following review examines the evidence surrounding the gut microbiota in behavior and psychiatric illness, the role of the microbiota in schizophrenia and the potential for antipsychotics to alter the gut microbiota and promote adverse metabolic events.

  14. Risk of transition to schizophrenia following first admission with substance-induced psychotic disorder: a population-based longitudinal cohort study.

    Science.gov (United States)

    Alderson, H L; Semple, D M; Blayney, C; Queirazza, F; Chekuri, V; Lawrie, S M

    2017-10-01

    The potential for drugs of abuse to induce acute psychotic symptoms is well recognised. However, the likelihood of transition from initial substance-induced psychotic disorder (SIPD) to chronic psychosis is much less well understood. This study investigated the rate of SIPD transition to schizophrenia (F20), the time to conversion and other possible related factors. Using data from the Scottish Morbidity Record, we examined all patients (n = 3486) since their first admission to psychiatric hospital with a diagnosis of SIPD [International Classification of Diseases, Tenth Revision (ICD-10) codes F10-F19, with third digit five] from January 1997 to July 2012. Patients were followed until first episode of schizophrenia (ICD-10 code F20, with any third digit) or July 2012. Any change in diagnosis was noted in the follow-up period, which ranged from 1 day to 15.5 years across the groups. The 15.5-year cumulative hazard rate was 17.3% (s.e. = 0.007) for a diagnosis of schizophrenia. Cannabis, stimulant, opiate and multiple drug-induced psychotic disorder were all associated with similar hazard rates. The mean time to transition to a diagnosis of schizophrenia was around 13 years, although over 50% did so within 2 years and over 80% of cases presented within 5 years of SIPD diagnosis. Risk factors included male gender, younger age and longer first admission. SIPD episodes requiring hospital admission for more than 2 weeks are more likely to be associated with later diagnosis of schizophrenia. Follow-up periods of more than 2 years are needed to detect the majority of those individuals who will ultimately develop schizophrenia.

  15. Investigating the empirical support for therapeutic targets proposed by the temporal experience of pleasure model in schizophrenia: A systematic review.

    Science.gov (United States)

    Edwards, Clementine J; Cella, Matteo; Tarrier, Nicholas; Wykes, Til

    2015-10-01

    Anhedonia and amotivation are substantial predictors of poor functional outcomes in people with schizophrenia and often present a formidable barrier to returning to work or building relationships. The Temporal Experience of Pleasure Model proposes constructs which should be considered therapeutic targets for these symptoms in schizophrenia e.g. anticipatory pleasure, memory, executive functions, motivation and behaviours related to the activity. Recent reviews have highlighted the need for a clear evidence base to drive the development of targeted interventions. To review systematically the empirical evidence for each TEP model component and propose evidence-based therapeutic targets for anhedonia and amotivation in schizophrenia. Following PRISMA guidelines, PubMed and PsycInfo were searched using the terms "schizophrenia" and "anhedonia". Studies were included if they measured anhedonia and participants had a diagnosis of schizophrenia. The methodology, measures and main findings from each study were extracted and critically summarised for each TEP model construct. 80 independent studies were reviewed and executive functions, emotional memory and the translation of motivation into actions are highlighted as key deficits with a strong evidence base in people with schizophrenia. However, there are many relationships that are unclear because the empirical work is limited by over-general tasks and measures. Promising methods for research which have more ecological validity include experience sampling and behavioural tasks assessing motivation. Specific adaptations to Cognitive Remediation Therapy, Cognitive Behavioural Therapy and the utilisation of mobile technology to enhance representations and emotional memory are recommended for future development. Copyright © 2015. Published by Elsevier B.V.

  16. Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia.

    Science.gov (United States)

    Enomoto, Takeshi; Tse, Maric T; Floresco, Stan B

    2011-03-01

    Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming. We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons. Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity. These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed in schizophrenia. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. Understanding noise stress-induced cognitive impairment in healthy adults and its implications for schizophrenia

    Directory of Open Access Journals (Sweden)

    Bernice Wright

    2014-01-01

    Full Text Available Noise stress (NS is detrimental to many aspects of human health and behavior. Understanding the effect of noise stressors on human cognitive function is a growing area of research and is crucial to helping clinical populations, such as those with schizophrenia, which are particularly sensitive to stressors. A review of electronic databases for studies assessing the effect of acute NS on cognitive functions in healthy adults revealed 31 relevant studies. The review revealed (1 NS exerts a clear negative effect on attention, working memory and episodic recall, and (2 personality characteristics, in particular neuroticism, and sleep influence the impact of noise stressors on performance in interaction with task complexity. Previous findings of consistent impairment in NS-relevant cognitive domains, heightened sensitivity to stressors, elevated neuroticism and sleep disturbances in schizophrenia, taken together with the findings of this review, highlight the need for empirical studies to elucidate whether NS, a common aspect of urban environments, exacerbates cognitive deficits and other symptoms in schizophrenia and related clinical populations.

  18. 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.

  19. New insights into the nature of cerebellar-dependent eyeblink conditioning deficits in schizophrenia: A hierarchical linear modeling approach

    Directory of Open Access Journals (Sweden)

    Amanda R Bolbecker

    2016-01-01

    Full Text Available Evidence of cerebellar dysfunction in schizophrenia has mounted over the past several decades, emerging from neuroimaging, neuropathological, and behavioral studies. Consistent with these findings, cerebellar-dependent delay eyeblink conditioning (dEBC deficits have been identified in schizophrenia. While repeated measures analysis of variance (ANOVA is traditionally used to analyze dEBC data, hierarchical linear modeling (HLM more reliably describes change over time by accounting for the dependence in repeated measures data. This analysis approach is well suited to dEBC data analysis because it has less restrictive assumptions and allows unequal variances. The current study examined dEBC measured with electromyography in a single-cue tone paradigm in an age-matched sample of schizophrenia participants and healthy controls (N=56 per group using HLM. Subjects participated in 90 trials (10 blocks of dEBC, during which a 400 ms tone co-terminated with a 50 ms air puff delivered to the left eye. Each block also contained 1 tone-alone trial. The resulting block averages of dEBC data were fitted to a 3-parameter logistic model in HLM, revealing significant differences between schizophrenia and control groups on asymptote and inflection point, but not slope. These findings suggest that while the learning rate is not significantly different compared to controls, associative learning begins to level off later and a lower ultimate level of associative learning is achieved in schizophrenia. Given the large sample size in the present study, HLM may provide a more nuanced and definitive analysis of differences between schizophrenia and controls on dEBC.

  20. Yi-gan san restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia.

    Science.gov (United States)

    Makinodan, Manabu; Yamauchi, Takahira; Tatsumi, Kouko; Okuda, Hiroaki; Noriyama, Yoshinobu; Sadamatsu, Miyuki; Kishimoto, Toshifumi; Wanaka, Akio

    2009-01-01

    The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

  1. Yi-Gan San Restores Behavioral Alterations and a Decrease of Brain Glutathione Level in a Mouse Model of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Manabu Makinodan M.D.

    2009-01-01

    Full Text Available The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

  2. 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...

  3. Oxytocin, Dopamine, and the Amygdala: A Neurofunctional Model of Social Cognitive Deficits in Schizophrenia

    OpenAIRE

    Rosenfeld, Andrew J.; Lieberman, Jeffrey A.; Jarskog, L. Fredrik

    2010-01-01

    Until recently, the social cognitive impairment in schizophrenia has been underappreciated and remains essentially untreated. Deficits in emotional processing, social perception and knowledge, theory of mind, and attributional bias may contribute to functional social cognitive impairments in schizophrenia. The amygdala has been implicated as a key component of social cognitive circuitry in both animal and human studies. In addition, structural and functional studies of schizophrenia reproduci...

  4. Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5.

    Science.gov (United States)

    Burrows, Emma L; McOmish, Caitlin E; Buret, Laetitia S; Van den Buuse, Maarten; Hannan, Anthony J

    2015-07-01

    Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

  5. Further support for the role of dysfunctional attitudes in models of real-world functioning in schizophrenia.

    Science.gov (United States)

    Horan, William P; Rassovsky, Yuri; Kern, Robert S; Lee, Junghee; Wynn, Jonathan K; Green, Michael F

    2010-06-01

    According to A.T. Beck and colleagues' cognitive formulation of poor functioning in schizophrenia, maladaptive cognitive appraisals play a key role in the expression and persistence of negative symptoms and associated real-world functioning deficits. They provided initial support for this model by showing that dysfunctional attitudes are elevated in schizophrenia and account for significant variance in negative symptoms and subjective quality of life. The current study used structural equation modeling to further evaluate the contribution of dysfunctional attitudes to outcome in schizophrenia. One hundred eleven outpatients and 67 healthy controls completed a Dysfunctional Attitudes Scale, and patients completed a competence measure of functional capacity, clinical ratings of negative symptoms, and interview-based ratings of real-world functioning. Patients reported higher defeatist performance beliefs than controls and these were significantly related to lower functional capacity, higher negative symptoms, and worse community functioning. Consistent with Beck and colleagues' formulation, modeling analyses indicated a significant indirect pathway from functional capacity-->dysfunctional attitudes-->negative symptoms-->real-world functioning. These findings support the value of dysfunctional attitudes for understanding the determinants of outcome in schizophrenia and suggest that therapeutic interventions targeting these attitudes may facilitate functional recovery. (c) 2009 Elsevier Ltd. All rights reserved.

  6. A Survey of the Tardive Dyskinesia Induced by Antipsychotic Drugs in Patients with Schizophrenia

    Directory of Open Access Journals (Sweden)

    Naser tabibi

    2010-11-01

    Full Text Available "nObjective: Tardive Dyskinesia (TD, is one of the important problems of the patients with schizophrenia. The emergence of these side effects depends on so many factors such as the patients' age and the duration of antipsychotic treatment. By discovering new drugs (Atypical, there has been an outstanding decrease in the emergence of these side effects. The present study investigates the symptoms of TD in the Patients with schizophrenia who were under  treatments for more than 6 months. "nMethod: The sample of this study was 200 Patients with schizophrenia of four wards in Razi hospital (two acute and two chronic wards who were hospitalized in the winter of 2006 and were qualified for this study. The subjects were 101 males and 99 females who were younger than 60 and had received antipsychotic drugs for at least 6 months. After psychiatric interview and filling the demographic questionnaire by the patients, the required information about the drugs and the intensity of the symptoms was acquired. Then clinical and physical examinations of tardive dyskinesia were done. Next, the tardive dyskinesia disorders' check list (AIMS was used. Findings of this cross-sectional, descriptive study were analyzed by SPSS. "nResults: There was a high ratio of 95% between TD and the age factor (P=0.05. There was no relationship between symptoms frequency and duration of treatment (P=0.68. Facial muscles and oral zones were mostly involved in T.D disorder (72%. "nConclusion: No significant difference was observed between nine fold symptoms of T.D in patients who were using traditional drugs and those who were using the new ones (typical and atypical. Findings showed that in the intensity of the symptoms, gender does not play a major role.

  7. Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.

    Science.gov (United States)

    Ewing, Samuel G; Grace, Anthony A

    2013-02-01

    Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Permeability-diffusivity modeling vs. fractional anisotropy on white matter integrity assessment and application in schizophrenia.

    Science.gov (United States)

    Kochunov, P; Chiappelli, J; Hong, L E

    2013-01-01

    Diffusion tensor imaging (DTI) assumes a single pool of anisotropically diffusing water to calculate fractional anisotropy (FA) and is commonly used to ascertain white matter (WM) deficits in schizophrenia. At higher b-values, diffusion-signal decay becomes bi-exponential, suggesting the presence of two, unrestricted and restricted, water pools. Theoretical work suggests that semi-permeable cellular membrane rather than the presence of two physical compartments is the cause. The permeability-diffusivity (PD) parameters measured from bi-exponential modeling may offer advantages, over traditional DTI-FA, in identifying WM deficits in schizophrenia. Imaging was performed in N = 26/26 patients/controls (age = 20-61 years, average age = 40.5 ± 12.6). Imaging consisted of fifteen b-shells: b = 250-3800 s/mm(2) with 30 directions/shell, covering seven slices of mid-sagittal corpus callosum (CC) at 1.7 × 1.7 × 4.6 mm. 64-direction DTI was also collected. Permeability-diffusivity-index (PDI), the ratio of restricted to unrestricted apparent diffusion coefficients, and the fraction of unrestricted compartment (Mu) were calculated for CC and cingulate gray matter (GM). FA values for CC were calculated using tract-based-spatial-statistics. Patients had significantly reduced PDI in CC (p ≅ 10(- 4)) and cingulate GM (p = 0.002), while differences in CC FA were modest (p ≅ .03). There was no group-related difference in Mu. Additional theoretical-modeling analysis suggested that reduced PDI in patients may be caused by reduced cross-membrane water molecule exchanges. PDI measurements for cerebral WM and GM yielded more robust patient-control differences than DTI-FA. Theoretical work offers an explanation that patient-control PDI differences should implicate abnormal active membrane permeability. This would implicate abnormal activities in ion-channels that use water as substrate for ion exchange, in cerebral tissues of schizophrenia patients.

  9. 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...

  10. 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.

  11. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  12. Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

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    Anna A. Igolkina

    2018-06-01

    Full Text Available Schizophrenia (SCZ is a psychiatric disorder of unknown etiology. There is evidence suggesting that aberrations in neurodevelopment are a significant attribute of schizophrenia pathogenesis and progression. To identify biologically relevant molecular abnormalities affecting neurodevelopment in SCZ we used cultured neural progenitor cells derived from olfactory neuroepithelium (CNON cells. Here, we tested the hypothesis that variance in gene expression differs between individuals from SCZ and control groups. In CNON cells, variance in gene expression was significantly higher in SCZ samples in comparison with control samples. Variance in gene expression was enriched in five molecular pathways: serine biosynthesis, PI3K-Akt, MAPK, neurotrophin and focal adhesion. More than 14% of variance in disease status was explained within the logistic regression model (C-value = 0.70 by predictors accounting for gene expression in 69 genes from these five pathways. Structural equation modeling (SEM was applied to explore how the structure of these five pathways was altered between SCZ patients and controls. Four out of five pathways showed differences in the estimated relationships among genes: between KRAS and NF1, and KRAS and SOS1 in the MAPK pathway; between PSPH and SHMT2 in serine biosynthesis; between AKT3 and TSC2 in the PI3K-Akt signaling pathway; and between CRK and RAPGEF1 in the focal adhesion pathway. Our analysis provides evidence that variance in gene expression is an important characteristic of SCZ, and SEM is a promising method for uncovering altered relationships between specific genes thus suggesting affected gene regulation associated with the disease. We identified altered gene-gene interactions in pathways enriched for genes with increased variance in expression in SCZ. These pathways and loci were previously implicated in SCZ, providing further support for the hypothesis that gene expression variance plays important role in the etiology

  13. Neurocognition, insight and medication nonadherence in schizophrenia: a structural equation modeling approach.

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    Laurent Boyer

    Full Text Available OBJECTIVE: The aim of this study was to examine the complex relationships among neurocognition, insight and nonadherence in patients with schizophrenia. METHODS: DESIGN: Cross-sectional study. INCLUSION CRITERIA: Diagnosis of schizophrenia according to the DSM-IV-TR criteria. DATA COLLECTION: Neurocognition was assessed using a global approach that addressed memory, attention, and executive functions; insight was analyzed using the multidimensional 'Scale to assess Unawareness of Mental Disorder;' and nonadherence was measured using the multidimensional 'Medication Adherence Rating Scale.' ANALYSIS: Structural equation modeling (SEM was applied to examine the non-straightforward relationships among the following latent variables: neurocognition, 'awareness of positive symptoms' and 'negative symptoms', 'awareness of mental disorder' and nonadherence. RESULTS: One hundred and sixty-nine patients were enrolled. The final testing model showed good fit, with normed χ(2 = 1.67, RMSEA = 0.063, CFI = 0.94, and SRMR = 0.092. The SEM revealed significant associations between (1 neurocognition and 'awareness of symptoms,' (2 'awareness of symptoms' and 'awareness of mental disorder' and (3 'awareness of mental disorder' and nonadherence, mainly in the 'attitude toward taking medication' dimension. In contrast, there were no significant links between neurocognition and nonadherence, neurocognition and 'awareness of mental disorder,' and 'awareness of symptoms' and nonadherence. CONCLUSIONS: Our findings support the hypothesis that neurocognition influences 'awareness of symptoms,' which must be integrated into a higher level of insight (i.e., the 'awareness of mental disorder' to have an impact on nonadherence. These findings have important implications for the development of effective strategies to enhance medication adherence.

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

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    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.

  15. Decision-making deficits in patients with chronic schizophrenia: Iowa Gambling Task and Prospect Valence Learning model

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    Kim MS

    2016-04-01

    Full Text Available Myung-Sun Kim,1 Bit-Na Kang,1 Jae Young Lim2 1Department of Psychology, Sungshin Women’s University, Seoul, Republic of Korea; 2Department of Psychiatry, Keyo Medical Foundation, Keyo Hospital, Uiwang, Republic of Korea Purpose: Decision-making is the process of forming preferences for possible options, selecting and executing actions, and evaluating the outcome. This study used the Iowa Gambling Task (IGT and the Prospect Valence Learning (PVL model to investigate deficits in risk-reward related decision-making in patients with chronic schizophrenia, and to identify decision-making processes that contribute to poor IGT performance in these patients. Materials and methods: Thirty-nine patients with schizophrenia and 31 healthy controls participated. Decision-making was measured by total net score, block net scores, and the total number of cards selected from each deck of the IGT. PVL parameters were estimated with the Markov chain Monte Carlo sampling scheme in OpenBugs and BRugs, its interface to R, and the estimated parameters were analyzed with the Mann–Whitney U-test.Results: The schizophrenia group received significantly lower total net scores compared to the control group. In terms of block net scores, an interaction effect of group × block was observed. The block net scores of the schizophrenia group did not differ across the five blocks, whereas those of the control group increased as the blocks progressed. The schizophrenia group obtained significantly lower block net scores in the fourth and fifth blocks of the IGT and selected cards from deck D (advantageous less frequently than the control group. Additionally, the schizophrenia group had significantly lower values on the utility-shape, loss-aversion, recency, and consistency parameters of the PVL model. Conclusion: These results indicate that patients with schizophrenia experience deficits in decision-making, possibly due to failure in learning the expected value of each deck

  16. Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia

    DEFF Research Database (Denmark)

    Agerbo, Esben; Mortensen, Preben Bo; Wiuf, Carsten

    2012-01-01

    Epidemiological studies indicate that having any family member with schizophrenia increases the risk of schizophrenia in the probands. However, genome-wide association studies (GWAS) have accounted for little of this variation. The aim of this study was to use a population-based sample to explore...

  17. Expression of schizophrenia biomarkers in extraocular muscles from patients with strabismus: an explanation for the link between exotropia and schizophrenia?

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    Andrea B. Agarwal

    2017-12-01

    Full Text Available Recent studies have implicated exotropia as a risk factor for schizophrenia. We determined whether schizophrenia biomarkers have abnormal levels of expression in extraocular muscles from patients with strabismus and explored whether differences in gene expression between medial and lateral rectus muscles may explain the specific association of schizophrenia with exotropia but not esotropia. Samples from horizontal extraocular muscles were obtained during strabismus surgery and compared with age- and muscle type-matched normal muscles from organ donors. We used PCR arrays to identify differences in gene expression among 417 signaling molecules. We then focused on established schizophrenia-related growth factors, cytokines, and regulators of the extracellular matrix. Among 36 genes with significantly altered gene expression in dysfunctional horizontal rectus muscles, over one third were schizophrenia-related: CTGF, CXCR4, IL1B, IL10RA, MIF, MMP2, NPY1R, NRG1, NTRK2, SERPINA3, TIMP1, TIMP2, and TNF (adjusted p value ≤ 0.016667. By PCR array, expression of three of these genes was significantly different in medial rectus muscles, while eleven were significantly altered in lateral rectus muscles. Comparing baseline levels between muscle types, three schizophrenia-related genes (NPY1R, NTRK2, TIMP2 had lower levels of expression in medial rectus muscles. Despite the surprisingly large number of schizophrenia-related genes with altered gene expression levels in dysfunctional muscles, the lack of specificity for medial rectus muscles undermines a model of shared, region-specific gene expression abnormalities between exotropia and schizophrenia, but rather suggests consideration of the alternative model: that exotropia-induced aberrant early visual experiences may enable and/or contribute as a causative factor to the development of schizophrenia.

  18. Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: A preliminary investigation.

    Science.gov (United States)

    McLean, Samantha L; Harte, Michael K; Neill, Joanna C; Young, Andrew Mj

    2017-06-01

    Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p dopamine increase was observed. These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

  19. Maturation- and sex-sensitive depression of hippocampal excitatory transmission in a rat schizophrenia model.

    Science.gov (United States)

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Schizophrenia is associated with behavioral and brain structural abnormalities, of which the hippocampus appears to be one of the most consistent region affected. Previous studies performed on the poly I:C model of schizophrenia suggest that alterations in hippocampal synaptic transmission and plasticity take place in the offspring. However, these investigations yielded conflicting results and the neurophysiological alterations responsible for these deficits are still unclear. Here we performed for the first time a longitudinal study examining the impact of prenatal poly I:C treatment and of gender on hippocampal excitatory neurotransmission. In addition, we examined the potential preventive/curative effects of risperidone (RIS) treatment during the peri-adolescence period. Excitatory synaptic transmission was determined by stimulating Schaffer collaterals and monitoring fiber volley amplitude and slope of field-EPSP (fEPSP) in CA1 pyramidal neurons in male and female offspring hippocampal slices from postnatal days (PNDs) 18-20, 34, 70 and 90. Depression of hippocampal excitatory transmission appeared at juvenile age in male offspring of the poly I:C group, while it expressed with a delay in female, manifesting at adulthood. In addition, a reduced hippocampal size was found in both adult male and female offspring of poly I:C treated dams. Treatment with RIS at the peri-adolescence period fully restored in males but partly repaired in females these deficiencies. A maturation- and sex-dependent decrease in hippocampal excitatory transmission occurs in the offspring of poly I:C treated pregnant mothers. Pharmacological intervention with RIS during peri-adolescence can cure in a gender-sensitive fashion early occurring hippocampal synaptic deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia.

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    Linda J Bristow

    Full Text Available The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R-N-(6-(1H-imidazol-1-yl-4-pyrimidinyl-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043, in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat and 0.29 micromolar (human. BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM. BMS-933043 treatment i improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc, ii reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc and set shift performance in rats (1-10 mg/kg, po and iii reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po. BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc and mismatch negativity (0.03-3 mg/kg, sc in rats treated with S(+ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

  1. Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia.

    Science.gov (United States)

    Watanabe, Kenya; Miura, Itaru; Kanno-Nozaki, Keiko; Horikoshi, Sho; Mashiko, Hirobumi; Niwa, Shin-Ichi; Yabe, Hirooki

    2015-12-15

    The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia

    DEFF Research Database (Denmark)

    Eyjolfsson, Elvar M; Nilsen, Linn Hege; Kondziella, Daniel

    2011-01-01

    Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days...... in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia....

  3. Blinded prospective evaluation of computer-based mechanistic schizophrenia disease model for predicting drug response.

    Directory of Open Access Journals (Sweden)

    Hugo Geerts

    Full Text Available The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2 antagonist and ocaperidone, a very high affinity dopamine D(2 antagonist, using only pharmacology and human positron emission tomography (PET imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS total score and the higher extra-pyramidal symptom (EPS liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

  4. A Danish Twin Study of Schizophrenia Liability

    DEFF Research Database (Denmark)

    Kläning, Ulla; Trumbetta, Susan L; Gottesman, Irving I

    2016-01-01

    whether variance in schizophrenia liability attributable to environmental factors may have decreased with successive cohorts exposed to improvements in public health. ICD-10 diagnoses were determined by clinical interview. Although the best-fitting, most parsimonious biometric model of schizophrenia...

  5. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

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    Agnieszka Nikiforuk

    Full Text Available A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg or amisulpride (3 mg/kg ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.

  6. Evaluation of a neurodevelopmental model of schizophrenia--early postnatal PCP treatment in attentional set-shifting

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Dias, Rebecca; Glenthøj, Birte Yding

    2008-01-01

    Phencyclidine (PCP) was administered to male and female Lister hooded rats on postnatal days (PND) 7, 9 and 11. All PCP animals tested in adulthood (PND 53-93) showed deficits in cognitive flexibility, specifically in their ability to shift attentional set, compared to controls. This novel finding...... is reminiscent of the impairment observed in schizophrenia patients, and supports the validity of the early postnatal PCP regimen as a disease-like model....

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

    NARCIS (Netherlands)

    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

  8. 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.

  9. Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.

    Science.gov (United States)

    Sotoyama, Hidekazu; Namba, Hisaaki; Chiken, Satomi; Nambu, Atsushi; Nawa, Hiroyuki

    2013-08-01

    Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia. © 2013 International Society for Neurochemistry.

  10. Qualitative descriptive study exploring schizophrenia and the everyday effect of medication-induced weight gain.

    Science.gov (United States)

    Vandyk, Amanda Digel; Baker, Cynthia

    2012-08-01

    Weight gain and obesity are serious side effects of the medications used to manage psychotic disorders and successful, long-term weight loss interventions are not yet available. One reason for this may be that current interventions are designed without consideration of the patient's perspective. The purpose of this study was to explore the subjective experience of weight and lifestyle from the perspective of people with schizophrenia. A qualitative, constructivist research design was used and conversational interviews were conducted with 18 purposefully recruited participants from an outpatient clinic at a psychiatric hospital in Eastern Ontario. Data were analysed according to the method of constant comparison and three central themes emerged: a life altering diagnosis, weight management as complex, and today's experiences shape tomorrow's outcomes. Weight management was seen as difficult yet important to the participants. The findings of this study provide insight into the views and opinions of the participants regarding weight and lifestyle and may be used to support the design of tailored heath initiatives for persons with mental illness. © 2012 The Authors. International Journal of Mental Health Nursing © 2012 Australian College of Mental Health Nurses Inc.

  11. Beyond the first episode: candidate factors for a risk prediction model of schizophrenia.

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    Murphy, Brendan P

    2010-01-01

    Many early psychosis services are financially compromised and cannot offer a full tenure of care to all patients. To maintain viability of services it is important that those with schizophrenia are identified early to maximize long-term outcomes, as are those with better prognoses who can be discharged early. The duration of untreated psychosis remains the mainstay in determining those who will benefit from extended care, yet its ability to inform on prognosis is modest in both the short and medium term. There are a number of known or putative genetic and environmental risk factors that have the potential to improve prognostication, though a multivariate risk prediction model combining them with clinical characteristics has yet to be developed. Candidate risk factors for such a model are presented, with an emphasis on environmental risk factors. More work is needed to corroborate many putative factors and to determine which of the established factors are salient and which are merely proxy measures. Future research should help clarify how gene-environment and environment-environment interactions occur and whether risk factors are dose-dependent, or if they act additively or synergistically, or are redundant in the presence (or absence) of other factors.

  12. Identifying a predictive model for response to atypical antipsychotic monotherapy treatment in south Indian schizophrenia patients.

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    Gupta, Meenal; Moily, Nagaraj S; Kaur, Harpreet; Jajodia, Ajay; Jain, Sanjeev; Kukreti, Ritushree

    2013-08-01

    Atypical antipsychotic (AAP) drugs are the preferred choice of treatment for schizophrenia patients. Patients who do not show favorable response to AAP monotherapy are subjected to random prolonged therapeutic treatment with AAP multitherapy, typical antipsychotics or a combination of both. Therefore, prior identification of patients' response to drugs can be an important step in providing efficacious and safe therapeutic treatment. We thus attempted to elucidate a genetic signature which could predict patients' response to AAP monotherapy. Our logistic regression analyses indicated the probability that 76% patients carrying combination of four SNPs will not show favorable response to AAP therapy. The robustness of this prediction model was assessed using repeated 10-fold cross validation method, and the results across n-fold cross-validations (mean accuracy=71.91%; 95%CI=71.47-72.35) suggest high accuracy and reliability of the prediction model. Further validations of these results in large sample sets are likely to establish their clinical applicability. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing.

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    Duan, Jubao

    2015-02-01

    Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences. MicroRNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specific to cell type and/or developmental stage. The emerging genome-editing technology enables the creation of isogenic iPSCs and neurons to efficiently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic, glutamatergic, and GABAergic neurotransmissions. SZ GWAS findings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

  14. Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning.

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    Mizuno, Makoto; Iwakura, Yuriko; Shibuya, Masako; Zheng, Yingjun; Eda, Takeyoshi; Kato, Taisuke; Takasu, Yohei; Nawa, Hiroyuki

    2010-01-01

    Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

  15. Interaction of genotype and environment: Effect of strain and housing condition on cognitive behaviour in rodent models of schizophrenia

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    Karly M. Turner

    2013-07-01

    Full Text Available Schizophrenia is associated with many genetic and environmental risk factors and there is growing evidence that the interactions between genetic and environmental ‘hits’ are critical for disease onset. Animal models of schizophrenia have traditionally used specific strain and housing conditions to test potential risk factors. As the field moves towards testing gene (G x environment (E interactions the impact of these choices should be considered. Given the surge of research focused on cognitive deficits, we have examined studies of cognition in rodents from the perspective of GxE interactions, in which strain or housing manipulations have been varied. Behaviour is clearly altered by these factors, yet few animal models of schizophrenia have investigated cognitive deficits using different strain and housing conditions. It is important to recognise the large variation in behaviour observed when using different strain and housing combinations because GxE interactions may mask or exacerbate cognitive outcomes. Further consideration will improve our understanding of GxE interactions and the underlying neurobiology of cognitive impairments in neuropsychiatric disorders.

  16. Model of Management (Mo.Ma) for the patient with schizophrenia: crisis control, maintenance, relapse prevention, and recovery with long-acting injectable antipsychotics (LAIs).

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    Brugnoli, Roberto; Rapinesi, Chiara; Kotzalidis, Georgios D; Marcellusi, Andrea; Mennini, Francesco S; De Filippis, Sergio; Carrus, Dario; Ballerini, Andrea; Francomano, Antonio; Ducci, Giuseppe; Del Casale, Antonio; Girardi, Paolo

    2016-01-01

    Schizophrenia is a severe mental disease that affects approximately 1% of the population with a relevant chronic impact on social and occupational functioning and daily activities. People with schizophrenia are 2-2.5 times more likely to die early than the general population. Non-adherence to antipsychotic medications, both in chronic and first episode schizophrenia, is one of the most important risk factors for relapse and hospitalization, that consequently contributes to increased costs due to psychiatric hospitalization. Atypical long-acting injectable (LAI) antipsychotics can improve treatment adherence and decrease re-hospitalization rates in patients with schizophrenia since its onset. The primary goals in the management of schizophrenia are directed not only at symptom reduction in the short and long term, but also at maintaining physical and mental functioning, improving quality of life, and promoting patient recovery. To propose a scientific evidence-based integrated model that provides an algorithm for recovery of patients with schizophrenia and to investigate the effectiveness and safety of antipsychotics LAI in the treatment, maintenance, relapse prevention, and recovery of schizophrenia. After an accurate literature review we identified, collected and analyzed the crucial points in taking care schizophrenia patients, through which we defined the steps described in the model of management and the choice of the better treatment option. Results. In the management model we propose, the choice of a second generation long acting antipsychotic, could allow from the earliest stages of illness better patient management, especially for young individuals with schizophrenia onset, a better recovery and significant reductions of relapse and health care costs. LAI formulations of antipsychotics are valuable, because they help patients to remain adherent to their medication through regular contact with healthcare professionals and to prevent covert non-adherence. The

  17. Sibutramine in the treatment of antipsychotic-induced weight gain: a pilot study in patients with schizophrenia.

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    Biedermann, Falko; Fleischhacker, W Wolfgang; Kemmler, Georg; Ebenbichler, Christoph F; Lechleitner, Monika; Hofer, Alex

    2014-05-01

    Weight gain represents a frequent side effect of antipsychotic drug treatment. The current trial investigated the effect of add-on treatment with sibutramine in schizophrenia outpatients who had gained more than 7% of weight during the course of treatment. This 24-week placebo-controlled study evaluated the effects of sibutramine added to ongoing antipsychotic treatment. Weight, waist-hip ratio, BMI, blood pressure/pulse and ECG were monitored regularly. In addition, several laboratory tests were performed. Psychopathological symptoms and side effects were assessed frequently. Fifteen patients were assigned randomly to add-on treatment with sibutramine 10 mg or placebo. The two groups did not differ in weight, sociodemographic, or clinical data. Eleven patients were considered for statistical analysis. Significant weight loss was observed in the sibutramine group (mean = -6.1 kg), whereas patients on placebo experienced a mean weight gain of 1.9 kg. A reduction in HbA1c was apparent in the sibutramine but not in the placebo group. No significant between-group differences were found in changes in psychopathology or drug safety. This pilot trial suggests that adjunctive treatment with sibutramine may be safe and effective in schizophrenic patients with antipsychotic-induced weight gain.

  18. Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

    Science.gov (United States)

    Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

    2017-03-01

    Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

  19. Structure models of G72, the product of a susceptibility gene to schizophrenia.

    Science.gov (United States)

    Kato, Yusuke; Fukui, Kiyoshi

    2017-02-01

    The G72 gene is one of the most susceptible genes to schizophrenia and is contained exclusively in the genomes of primates. The product of the G72 gene modulates the activity of D-amino acid oxidase (DAO) and is a small protein prone to aggregate, which hampers its structural studies. In addition, lack of a known structure of a homologue makes it difficult to use the homology modelling method for the prediction of the structure. Thus, we first developed a hybrid ab initio approach for small proteins prior to the prediction of the structure of G72. The approach uses three known ab initio algorithms. To evaluate the hybrid approach, we tested our prediction of the structure of the amino acid sequences whose structures were already solved and compared the predicted structures with the experimentally solved structures. Based on these comparisons, the average accuracy of our approach was calculated to be ∼5 Å. We then applied the approach to the sequence of G72 and successfully predicted the structures of the N- and C-terminal domains (ND and CD, respectively) of G72. The predicted structures of ND and CD were similar to membrane-bound proteins and adaptor proteins, respectively. © The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  20. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells

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    Elizabeth A. LaMarca

    2018-04-01

    Full Text Available Human-induced pluripotent stem cells (hiPSCs have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional “mini-brains” and clustered, regularly interspersed short palindromic repeats (CRISPR-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson’s disease, and consider the future of this groundbreaking research.

  1. Unique and Overlapping Symptoms in Schizophrenia Spectrum and Dissociative Disorders in Relation to Models of Psychopathology: A Systematic Review

    Science.gov (United States)

    Renard, Selwyn B.; Huntjens, Rafaele J. C.; Lysaker, Paul H.; Moskowitz, Andrew; Aleman, André; Pijnenborg, Gerdina H. M.

    2017-01-01

    Schizophrenia spectrum disorders (SSDs) and dissociative disorders (DDs) are described in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) and tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) as 2 categorically distinct diagnostic categories. However, several studies indicate high levels of co-occurrence between these diagnostic groups, which might be explained by overlapping symptoms. The aim of this systematic review is to provide a comprehensive overview of the research concerning overlap and differences in symptoms between schizophrenia spectrum and DDs. For this purpose the PubMed, PsycINFO, and Web of Science databases were searched for relevant literature. The literature contained a large body of evidence showing the presence of symptoms of dissociation in SSDs. Although there are quantitative differences between diagnoses, overlapping symptoms are not limited to certain domains of dissociation, nor to nonpathological forms of dissociation. In addition, dissociation seems to be related to a history of trauma in SSDs, as is also seen in DDs. There is also evidence showing that positive and negative symptoms typically associated with schizophrenia may be present in DD. Implications of these results are discussed with regard to different models of psychopathology and clinical practice. PMID:27209638

  2. Where's the problem? Considering Laing and Esterson's account of schizophrenia, social models of disability, and extended mental disorder.

    Science.gov (United States)

    Cooper, Rachel

    2017-08-01

    In this article, I compare and evaluate R. D. Laing and A. Esterson's account of schizophrenia as developed in Sanity, Madness and the Family (1964), social models of disability, and accounts of extended mental disorder. These accounts claim that some putative disorders (schizophrenia, disability, certain mental disorders) should not be thought of as reflecting biological or psychological dysfunction within the afflicted individual, but instead as external problems (to be located in the family, or in the material and social environment). In this article, I consider the grounds on which such claims might be supported. I argue that problems should not be located within an individual putative patient in cases where there is some acceptable test environment in which there is no problem. A number of cases where such an argument can show that there is no internal disorder are discussed. I argue, however, that Laing and Esterson's argument-that schizophrenia is not within diagnosed patients-does not work. The problem with their argument is that they fail to show that the diagnosed women in their study function adequately in any environment.

  3. A Computational Model of Pattern Separation Efficiency in the Dentate Gyrus with Implications in Schizophrenia

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    Faramarz eFaghihi

    2015-03-01

    Full Text Available Information processing in the hippocampus begins by transferring spiking activity of the Entorhinal Cortex (EC into the Dentate Gyrus (DG. Activity pattern in the EC is separated by the DG such that it plays an important role in hippocampal functions including memory. The structural and physiological parameters of these neural networks enable the hippocampus to be efficient in encoding a large number of inputs that animals receive and process in their life time. The neural encoding capacity of the DG depends on its single neurons encoding and pattern separation efficiency. In this study, encoding by the DG is modelled such that single neurons and pattern separation efficiency are measured using simulations of different parameter values. For this purpose, a probabilistic model of single neurons efficiency is presented to study the role of structural and physiological parameters. Known neurons number of the EC and the DG is used to construct a neural network by electrophysiological features of neuron in the DG. Separated inputs as activated neurons in the EC with different firing probabilities are presented into the DG. For different connectivity rates between the EC and DG, pattern separation efficiency of the DG is measured. The results show that in the absence of feedback inhibition on the DG neurons, the DG demonstrates low separation efficiency and high firing frequency. Feedback inhibition can increase separation efficiency while resulting in very low single neuron’s encoding efficiency in the DG and very low firing frequency of neurons in the DG (sparse spiking. This work presents a mechanistic explanation for experimental observations in the hippocampus, in combination with theoretical measures. Moreover, the model predicts a critical role for impaired inhibitory neurons in schizophrenia where deficiency in pattern separation of the DG has been observed.

  4. A computational model of pattern separation efficiency in the dentate gyrus with implications in schizophrenia

    Science.gov (United States)

    Faghihi, Faramarz; Moustafa, Ahmed A.

    2015-01-01

    Information processing in the hippocampus begins by transferring spiking activity of the entorhinal cortex (EC) into the dentate gyrus (DG). Activity pattern in the EC is separated by the DG such that it plays an important role in hippocampal functions including memory. The structural and physiological parameters of these neural networks enable the hippocampus to be efficient in encoding a large number of inputs that animals receive and process in their life time. The neural encoding capacity of the DG depends on its single neurons encoding and pattern separation efficiency. In this study, encoding by the DG is modeled such that single neurons and pattern separation efficiency are measured using simulations of different parameter values. For this purpose, a probabilistic model of single neurons efficiency is presented to study the role of structural and physiological parameters. Known neurons number of the EC and the DG is used to construct a neural network by electrophysiological features of granule cells of the DG. Separated inputs as activated neurons in the EC with different firing probabilities are presented into the DG. For different connectivity rates between the EC and DG, pattern separation efficiency of the DG is measured. The results show that in the absence of feedback inhibition on the DG neurons, the DG demonstrates low separation efficiency and high firing frequency. Feedback inhibition can increase separation efficiency while resulting in very low single neuron’s encoding efficiency in the DG and very low firing frequency of neurons in the DG (sparse spiking). This work presents a mechanistic explanation for experimental observations in the hippocampus, in combination with theoretical measures. Moreover, the model predicts a critical role for impaired inhibitory neurons in schizophrenia where deficiency in pattern separation of the DG has been observed. PMID:25859189

  5. Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

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    Morris Brian J

    2011-05-01

    Full Text Available Abstract Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. Results We present and justify a new technique for comparing pairs of networks--in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD, which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA receptor antagonist phencyclidine (PCP. This provides us with a means to quantify which predefined metabolic pathways (Kyoto

  6. Testing long-term memory in animal models of schizophrenia: suggestions from CNTRICS.

    Science.gov (United States)

    Bussey, Timothy J; Barch, Deanna M; Baxter, Mark G

    2013-11-01

    This paper reports the results of discussions at the fourth meeting of Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) meeting, held over two days in Washington, DC in April 2011. The meeting focused on animal paradigms for assessing the cognitive constructs relevant to schizophrenia identified in previous CNTRICS meetings. This report focuses on the outcome of discussions in the general area of long-term memory. A number of candidate animal paradigms were discussed. Two of these - one for rodents and one for non-human primates - were recommended as particularly promising for further development. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Neurodevelopmental Animal Models Reveal the Convergent Role of Neurotransmitter Systems, Inflammation, and Oxidative Stress as Biomarkers of Schizophrenia: Implications for Novel Drug Development.

    Science.gov (United States)

    Möller, M; Swanepoel, T; Harvey, B H

    2015-07-15

    Schizophrenia is a life altering disease with a complex etiology and pathophysiology, and although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the biobehavioral manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g., postnatal inflammation, environmental adversity, or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this Review, we will discuss SIR, PPNI, as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioral alterations of schizophrenia. Finally, based on these models, we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways.

  8. S-Ketamine-Induced NMDA Receptor Blockade during Natural Speech Production and Its Implications for Formal Thought Disorder in Schizophrenia: A Pharmaco-fMRI Study.

    Science.gov (United States)

    Nagels, Arne; Cabanis, Maurice; Oppel, Andrea; Kirner-Veselinovic, Andre; Schales, Christian; Kircher, Tilo

    2018-05-01

    Structural and functional changes in the lateral temporal language areas have been related to formal thought disorder (FTD) in schizophrenia. Continuous, natural speech production activates the right lateral temporal lobe in schizophrenia, as opposed to the left in healthy subjects. Positive and negative FTD can be elicited in healthy subjects by glutamatergic NMDA blockade with ketamine. It is unclear whether the glutamate system is related to the reversed hemispheric lateralization during speaking in patients. In a double-blind, crossover, placebo-controlled study, 15 healthy, male, right-handed volunteers overtly described 7 pictures for 3 min each while BOLD signal changes were acquired with fMRI. As a measure of linguistic demand, the number of words within 20 s epochs was correlated with BOLD responses. Participants developed S-ketamine-induced psychotic symptoms, particularly positive FTD. Ketamine vs placebo was associated with enhanced neural responses in the right middle and inferior temporal gyri. Similar to a previous fMRI study in schizophrenia patients vs healthy controls applying the same design, S-ketamine reversed functional lateralization during speech production in healthy subjects. Results demonstrate an association between glutamatergic imbalance, dysactivations in lateral temporal brain areas, and FTD symptom formation.

  9. 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

  10. Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research.

    Science.gov (United States)

    Tse, Maric T; Piantadosi, Patrick T; Floresco, Stan B

    2015-06-01

    Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  11. Clinical characteristics of synthetic cannabinoid-induced psychosis in relation to schizophrenia: a single-center cross-sectional analysis of concurrently hospitalized patients

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    Altintas M

    2016-08-01

    Full Text Available Merih Altintas,1 Leman Inanc,2 Gamze Akcay Oruc,1 Selim Arpacioglu,1 Huseyin Gulec1 1Department of Psychiatry, Erenköy Mental and Neurological Diseases Training and Research Hospital, Istanbul, 2Department of Psychiatry, Dr Cevdet Aykan Mental Health and Diseases Hospital, Tokat, Turkey Background: This study aimed to evaluate synthetic cannabinoid (SC-induced psychosis in terms of patient profile and clinical characteristics with reference to concurrently hospitalized schizophrenic patients. Methods: A total of 81 male patients diagnosed with psychotic disorder induced by the use of SCs (n=50; mean (standard deviation [SD] age: 25.9 (5.5 years or with schizophrenia (n=31, mean (SD age: 42.9 (11.6 years based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnosis criteria who were concurrently hospitalized at Erenköy Mental and Neurological Diseases Training and Research Hospital were included in this cross-sectional study. Data on sociodemographic characteristics, Brief Psychiatric Rating Scale (BPRS, Positive and Negative Syndrome Scale (PANSS, Frontal Assessment Battery (FAB, Hamilton Rating Scale for Depression (HRSD, and Hamilton Anxiety Rating Scale (HAM-A were recorded in all the patients. Results: Mean (SD age at disease onset in SC-induced psychosis patients was 22.3 (5.6 years; 26.0% had suicidal ideation and 58.4% were hospitalized involuntarily. Marijuana was the most common first used substance (72.0%, and solitary use of SC was noted in 38.0% of patients. SC-induced psychosis patients had similar PANSS positive, BPRS, HRSD, and FAB scores and significantly lower PANSS negative scores (18.0 [6.5] vs 22.3 [6.0], P=0.004 than patients with schizophrenia, while they had similar HAM-A scores (17.8 [10.3] vs 21.6 [5.5], P=0.085 as young schizophrenics. Age at onset for SC (r=0.364, P=0.05 or substance (r=0.395, P=0.01 use was correlated positively with total FAB scores.Conclusion: In conclusion, our

  12. Bifactor Modeling of the Positive and Negative Syndrome Scale: Generalized Psychosis Spans Schizoaffective, Bipolar, and Schizophrenia Diagnoses.

    Science.gov (United States)

    Anderson, Ariana E; Marder, Stephen; Reise, Steven P; Savitz, Adam; Salvadore, Giacomo; Fu, Dong Jing; Li, Qingqin; Turkoz, Ibrahim; Han, Carol; Bilder, Robert M

    2018-02-06

    Common genetic variation spans schizophrenia, schizoaffective and bipolar disorders, but historically, these syndromes have been distinguished categorically. A symptom dimension shared across these syndromes, if such a general factor exists, might provide a clearer target for understanding and treating mental illnesses that share core biological bases. We tested the hypothesis that a bifactor model of the Positive and Negative Syndrome Scale (PANSS), containing 1 general factor and 5 specific factors (positive, negative, disorganized, excited, anxiety), explains the cross-diagnostic structure of symptoms better than the traditional 5-factor model, and examined the extent to which a general factor reflects the overall severity of symptoms spanning diagnoses in 5094 total patients with a diagnosis of schizophrenia, schizoaffective, and bipolar disorder. The bifactor model provided superior fit across diagnoses, and was closer to the "true" model, compared to the traditional 5-factor model (Vuong test; P schizoaffective, and bipolar disorder. © The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com

  13. Factoring neurotrophins into a neurite-based pathophysiological model of schizophrenia.

    Science.gov (United States)

    Bellon, Alfredo; Krebs, Marie-Odile; Jay, Thérèse M

    2011-06-01

    Neurotrophins are growth factors that, through variations in concentration and changes in receptor expression, regulate the formation of axons and dendrites during development and throughout adult life. Here we review these growth factors, particularly in the context of schizophrenia, a psychiatric disorder characterized by neurodevelopmental abnormalities. We first discuss emerging information derived from physiologically relevant organotypic cultures and in vivo studies regarding the effects of neurotrophins on the neuronal structure including pruning and GABAergic neurons. We then review postmortem studies of neurotrophin levels and their receptors in brains of individuals with schizophrenia, and compare them with what is known about neurotrophin effects on neuronal structure. This comparison indicates that only some neuropathological defects encountered in patients with schizophrenia can be explained by the single action of neurotrophins on dendrites and axons. However, we propose that a number of inconsistent findings and apparently unrelated results in the schizophrenia field can be reconciled if neurons are considered structurally plastic cells capable of extending and retracting dendrites and axons throughout life. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Dominance of objects over context in a mediotemporal lobe model of schizophrenia

    NARCIS (Netherlands)

    Talamini, L.M.; Meeter, M.

    2009-01-01

    Background: A large body of evidence suggests impaired context processing in schizophrenia. Here we propose that this impairment arises from defective integration of mediotemporal 'what' and 'where routes, carrying object and spatial information to the hippocampus. Methodology and Findings: We have

  15. Dominance of objects over context in a mediotemporal lobe model of schizophrenia

    NARCIS (Netherlands)

    Talamini, L.M.; Meeter, M.

    2009-01-01

    Background: A large body of evidence suggests impaired context processing in schizophrenia. Here we propose that this impairment arises from defective integration of mediotemporal ‘what’ and ‘where’ routes, carrying object and spatial information to the hippocampus. Methodology and Findings: We have

  16. Childhood Schizophrenia

    Science.gov (United States)

    ... Trouble sleeping Irritability or depressed mood Lack of motivation Strange behavior Substance use Compared with schizophrenia symptoms ... may neglect personal hygiene or appear to lack emotion ― doesn't make eye contact, doesn't change ...

  17. Behavioral predictors of alcohol drinking in a neurodevelopmental rat model of schizophrenia and co-occurring alcohol use disorder.

    Science.gov (United States)

    Khokhar, Jibran Y; Todd, Travis P

    2018-04-01

    Alcohol use disorder commonly occurs in patients with schizophrenia and contributes greatly to its morbidity. Unfortunately, the neural and behavioral underpinnings of alcohol drinking in these patients are not well understood. In order to begin to understand the cognitive and reward-related changes that may contribute to alcohol drinking, this study was designed to address: 1) latent inhibition; 2) conditioning; and 3) extinction of autoshaping in a neurodevelopmental rat model with relevance to co-occurring schizophrenia and alcohol use disorders, the neonatal ventral hippocampal lesioned (NVHL) rat. NVHL lesions (or sham surgeries) were performed on post-natal day 7 (PND7) and animals were given brief exposure to alcohol during adolescent (PND 28-42). Latent inhibition of autoshaping, conditioning and extinction were assessed between PND 72-90. On PND90 animals were given alcohol again and allowed to establish stable drinking. Latent inhibition of autoshaping was found to be prolonged in the NVHL rats; the NVHL rats pre-exposed to the lever stimulus were slower to acquire autoshaping than sham pre-exposed rats. NVHL rats that were not pre-exposed to the lever stimulus did not differ during conditioning, but were slower to extinguish conditioned responding compared to sham controls. Finally, the NVHL rats from both groups drank significantly more alcohol than sham rats, and the extent of latent inhibition predicted future alcohol intake in the pre-exposed animals. These findings suggest that the latent inhibition of autoshaping procedure can be used to model cognitive- and reward-related dysfunctions in schizophrenia, and these dysfunctions may contribute to the development of co-occurring alcohol use. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Dissociation of hedonic reaction to reward and incentive motivation in an animal model of the negative symptoms of schizophrenia.

    Science.gov (United States)

    Ward, Ryan D; Simpson, Eleanor H; Richards, Vanessa L; Deo, Gita; Taylor, Kathleen; Glendinning, John I; Kandel, Eric R; Balsam, Peter D

    2012-06-01

    We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and video-scored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia.

  19. Acute phencyclidine treatment induces extensive and distinct protein phosphorylation in rat frontal cortex

    DEFF Research Database (Denmark)

    Palmowski, Pawel; Rogowska-Wrzesinska, Adelina; Williamson, James

    2014-01-01

    Phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate receptor antagonist, induces psychotomimetic effects in humans and animals. Administration of PCP to rodents is used as a preclinical model for schizophrenia; however, the molecular mechanisms underlying the symptoms remain largely unknown...... data sets to date of a preclinical model of schizophrenia. Our findings contribute to the understanding of alterations in glutamatergic neurotransmission in schizophrenia and provide a foundation for discovery of novel targets for pharmacological intervention. © 2014 American Chemical Society....

  20. Schizophrenia and viral infection in animal model: chronic administration of haloperidol and clozapine

    Czech Academy of Sciences Publication Activity Database

    Tejkalová, H.; Ruml, T.; Rumlová, M.; Klaschka, Jan; Šťastný, František

    2007-01-01

    Roč. 18, Suppl. 1 (2007), s68-s69 ISSN 0955-8810. [Biennial Meeting of the European Behavioural Pharmacology Society /12./. 31.08.2007-03.09.2007, Tübingen] R&D Projects: GA MZd NF7626 Institutional research plan: CEZ:AV0Z10300504; CEZ:AV0Z50110509 Keywords : schizophrenia * rat * clozapine * haloperidole * behaviour Subject RIV: BB - Applied Statistics, Operational Research

  1. Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

    OpenAIRE

    Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

    2013-01-01

    Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for ...

  2. 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

  3. Facial emotion linked cooperation in patients with paranoid schizophrenia: a test on the Interpersonal Communication Model.

    Science.gov (United States)

    Tse, Wai S; Yan Lu; Bond, Alyson J; Chan, Raymond Ck; Tam, Danny W H

    2011-09-01

    Patients with schizophrenia consistently show deficits in facial affect perception and social behaviours. It is illusive to suggest that these deficits in facial affect perception cause poor social behaviours. The present research aims to study how facial affects influence ingratiation, cooperation and punishment behaviours of the patients. Forty outpatients with paranoid schizophrenia, 26 matched depressed patients and 46 healthy volunteers were recruited. After measurement of clinical symptoms and depression, their facial emotion recognition, neurocognitive functioning and the facial affects dependent cooperative behaviour were measured using a modified version of Mixed-Motive Game. The depressed control group showed demographic characteristics, depression levels and neurocognitive functioning similar to the schizophrenic group. Patients with schizophrenia committed significantly more errors in neutral face identification than the other two groups. They were significantly more punitive on the Mixed-Motive Game in the neutral face condition. Neutral face misidentification was a unique emotion-processing deficit in the schizophrenic group. Their increase in punitive behaviours in the neutral face condition might confuse their family members and trigger more expressed emotion from them, thus increasing the risk of relapse. Family members might display more happy faces to promote positive relationships with patients.

  4. The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.

    Science.gov (United States)

    Mihaljevic, Marina; Zeljic, Katarina; Soldatovic, Ivan; Andric, Sanja; Mirjanic, Tijana; Richards, Alexander; Mantripragada, Kiran; Pekmezovic, Tatjana; Novakovic, Ivana; Maric, Nadja P

    2017-09-01

    Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.

  5. Schizophrenia and second language acquisition.

    Science.gov (United States)

    Bersudsky, Yuly; Fine, Jonathan; Gorjaltsan, Igor; Chen, Osnat; Walters, Joel

    2005-05-01

    Language acquisition involves brain processes that can be affected by lesions or dysfunctions in several brain systems and second language acquisition may depend on different brain substrates than first language acquisition in childhood. A total of 16 Russian immigrants to Israel, 8 diagnosed schizophrenics and 8 healthy immigrants, were compared. The primary data for this study were collected via sociolinguistic interviews. The two groups use language and learn language in very much the same way. Only exophoric reference and blocking revealed meaningful differences between the schizophrenics and healthy counterparts. This does not mean of course that schizophrenia does not induce language abnormalities. Our study focuses on those aspects of language that are typically difficult to acquire in second language acquisition. Despite the cognitive compromises in schizophrenia and the manifest atypicalities in language of speakers with schizophrenia, the process of acquiring a second language seems relatively unaffected by schizophrenia.

  6. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia-Gating of auditory-evoked potentials and prepulse inhibition

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Oranje, Bob; Yding, Birte

    2010-01-01

    of sensory information processing seen in schizophrenia patients, can be assessed by highly homologues methods in both humans and rodents, evident by the prepulse inhibition (PPI) of the auditory startle response and the P50 (termed P1 here) suppression paradigms. Treatment with the NMDA receptor antagonist...... findings confirm measures of early information processing to show high resemblance between rodents and humans, and indicate that early postnatal PCP-treated rats show deficits in pre-attentional processing, which are distinct from those observed in schizophrenia patients.......The use of translational approaches to validate animal models is needed for the development of treatments that can effectively alleviate cognitive impairments associated with schizophrenia, which are unsuccessfully treated by the current available therapies. Deficits in pre-attentive stages...

  7. A path model investigation of neurocognition, theory of mind, social competence, negative symptoms and real-world functioning in schizophrenia.

    Science.gov (United States)

    Couture, Shannon M; Granholm, Eric L; Fish, Scott C

    2011-02-01

    Problems in real-world functioning are pervasive in schizophrenia and much recent effort has been devoted to uncovering factors which contribute to poor functioning. The goal of this study was to examine the role of four such factors: social cognition (theory of mind), neurocognition, negative symptoms, and functional capacity (social competence). 178 individuals with schizophrenia or schizoaffective disorder completed measures of theory of mind, neurocognition, negative symptoms, social competence, and self-reported functioning. Path models sought to determine the relationships among these variables. Theory of mind as indexed by the Hinting Task partially mediated the relationship between neurocognition and social competence, and negative symptoms and social competence demonstrated significant direct paths with self-reported functioning. Study results suggest theory of mind serves as an important mediator in addition to previously investigated social cognitive domains of emotional and social perception. The current study also highlights the need to determine variables which mediate the relationship between functional capacity and real-world functioning. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. 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.

  9. 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.

  10. Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats.

    Science.gov (United States)

    Kekesi, Orsolya; Tuboly, Gabor; Szucs, Maria; Birkas, Erika; Morvay, Zita; Benedek, Gyorgy; Horvath, Gyongyi

    2011-07-01

    Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of μ-opioid receptors by saturation binding experiments using a specific μ-opioid agonist [(3)H]DAMGO were determined. G-protein signaling was investigated in DAMGO-stimulated [(35)S]GTPγS functional assays. Ketamine treatment significantly decreased the bladder volume and isolation decreased the receptor density in cortical membranes. Among all groups, the only change in binding affinity was an increase induced by social isolation in the cortex. G-protein signaling was significantly decreased by either ketamine or social isolation in this tissue. Ketamine treatment, but not housing, significantly increased μ-opioid receptor densities in hippocampal membranes. Both ketamine and isolation increased the efficacy, while the potency of signaling was decreased by any treatment. Ketamine increased the receptor density and G-protein activation; while isolation decreased the efficacy of G-protein signaling in hippocampal membranes. The changes in the co-treated group were similar to those of the isolated animals in most tests. The distinct changes of opioid receptor functioning in different areas of the CNS may, at least partially, explain the augmented nociceptive threshold and morphine potency observed in these animals. Changes in the relative urinary bladder suggest a detrusor hyperreflexia, another sign of schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. 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

  12. Swallowing Disorders in Schizophrenia.

    Science.gov (United States)

    Kulkarni, Deepika P; Kamath, Vandan D; Stewart, Jonathan T

    2017-08-01

    Disorders of swallowing are poorly characterized but quite common in schizophrenia. They are a source of considerable morbidity and mortality in this population, generally as a result of either acute asphyxia from airway obstruction or more insidious aspiration and pneumonia. The death rate from acute asphyxia may be as high as one hundred times that of the general population. Most swallowing disorders in schizophrenia seem to fall into one of two categories, changes in eating and swallowing due to the illness itself and changes related to psychotropic medications. Behavioral changes related to the illness are poorly understood and often involve eating too quickly or taking inappropriately large boluses of food. Iatrogenic problems are mostly related to drug-induced extrapyramidal side effects, including drug-induced parkinsonism, dystonia, and tardive dyskinesia, but may also include xerostomia, sialorrhea, and changes related to sedation. This paper will provide an overview of common swallowing problems encountered in patients with schizophrenia, their pathophysiology, and management. While there is a scarcity of quality evidence in the literature, a thorough history and examination will generally elucidate the predominant problem or problems, often leading to effective management strategies.

  13. 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, ...

  14. Modeling human neurological disorders with induced pluripotent stem cells.

    Science.gov (United States)

    Imaizumi, Yoichi; Okano, Hideyuki

    2014-05-01

    Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained

  15. The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy.

    Science.gov (United States)

    Crook, Jeremy Micah; Wallace, Gordon; Tomaskovic-Crook, Eva

    2015-03-01

    There is an urgent need for new and advanced approaches to modeling the pathological mechanisms of complex human neurological disorders. This is underscored by the decline in pharmaceutical research and development efficiency resulting in a relative decrease in new drug launches in the last several decades. Induced pluripotent stem cells represent a new tool to overcome many of the shortcomings of conventional methods, enabling live human neural cell modeling of complex conditions relating to aberrant neurodevelopment, such as schizophrenia, epilepsy and autism as well as age-associated neurodegeneration. This review considers the current status of induced pluripotent stem cell-based modeling of neurological disorders, canvassing proven and putative advantages, current constraints, and future prospects of next-generation culture systems for biomedical research and translation.

  16. [Schizophrenia, environment and epigenetics].

    Science.gov (United States)

    Must, Anita; Janka, Zoltan; Horvath, Szatmar

    2011-12-01

    Psychotic, cognitive and affective symptoms defining schizophrenia may, though much less severe, manifest themselves in up to 10 to 20% of the general population. What explains the fact that in certain cases the symptoms require even constant medical supervision, while others are capable of living a normal life within social conventions? Which factors lead to the transition of mild, subclinical manifestations and vulnerability indicators towards the outburst of one of the most severe and depriving mental disorders? Genetic susceptibility is undoubtedly crucial. More recent research findings emphasize the modifying effect of specific environmental factors on gene expression. The gene-environment interplay may induce so-called epigenetic alterations which may manifest themselves over several generations. Future integrative, multi-dimensional and flexible schizophrenia research approaches focusing on the identification of neurobiological and cognitive outcomes are much needed to understand disease vulnerability, susceptibility mechanisms, periods and interactions. Research methods may differ, but our aim is common - establishing more effective diagnostic and therapeutic interventions.

  17. The Utility of the Health Action Process Approach Model for Predicting Physical Activity Intentions and Behavior in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Kelly P. Arbour-Nicitopoulos

    2017-08-01

    Full Text Available Research is needed to develop evidence-based behavioral interventions for preventing and treating obesity that are specific to the schizophrenia population. This study is the precursor to such intervention research where we examined the utility of the social cognitions outlined within the Health Action Process Approach (HAPA model for predicting moderate to vigorous physical activity (MVPA intentions and behavior among individuals with schizophrenia or schizoaffective disorder. A prospective cohort design [baseline (T1, week 2 (T2, and week 4 (T3] was used to examine the HAPA constructs and MVPA across a sample of 101 adults (Mage = 41.5 ± 11.7 years; MBMI = 31.2 ± 7.8 kg/m2; 59% male. Two hierarchical regression analyses were conducted controlling for age, gender, BMI, and previous self-reported MVPA. In the first regression, intentions at T1 were regressed onto the T1 motivational HAPA constructs (risk perception, affective attitudes, task self-efficacy and social support; MVPA status (meeting vs. not meeting the MVPA guidelines assessed via accelerometry at T3 was regressed onto T1 social support and intentions followed by T2 action and coping planning, and maintenance self-efficacy in the second analysis. Overall, the motivational and social support variables accounted for 28% of the variance in intentions, with affective attitudes (β = 0.33, p < 0.01 and task self-efficacy (β = 0.25, p < 0.05 exhibiting significant, positive relationships. For MVPA status, the model as a whole explained 39% of the variance, with the volitional HAPA constructs explaining a non-significant 3% of this total variance. These findings suggest a need for interventions targeting self-efficacy and affective attitudes within this clinical population.

  18. Exploring social cognition in schizophrenia

    DEFF Research Database (Denmark)

    Revsbech, Rasmus; Mortensen, Erik Lykke; Frederiksen, Julie Elisabeth Nordgaard

    2017-01-01

    The aim of the study was to compare social cognition between groups of patients diagnosed with schizophrenia and healthy controls and to replicate two previous studies using tests of social cognition that may be particularly sensitive to social cognitive deficits in schizophrenia. Thirty......-eight first-admitted patients with schizophrenia and 38 healthy controls solved 11 “imaginary conversation (i.e., theory of mind)” items, 10 “psychological understanding” items, and 10 “practical understanding” items. Statistical tests were made of unadjusted and adjusted group differences in models adjusting...... nonsignificant. When intelligence and global cognitive functioning is taken into account, schizophrenia patients and healthy controls perform similarly on social cognitive tests. © 2016 Springer-Verlag Berlin Heidelberg...

  19. Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia--sub-chronic and early postnatal PCP treatment in attentional set-shifting

    DEFF Research Database (Denmark)

    Broberg, Brian Villumsen; Glenthøj, Birte Yding; Dias, Rebecca

    2009-01-01

    RATIONALE: Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present. OBJECTIVE: The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of...... that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task....... of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models. METHODS: Animals were subjected to (a) sub-chronic or (b) early...

  20. 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...

  1. Schizophrenia: A Systemic Disorder

    Science.gov (United States)

    Kirkpatrick, Brian; Miller, Brian; García-Rizo, Clemente; Fernandez-Egea, Emilio

    2015-01-01

    The concept of schizophrenia that is most widely taught is that it is a disorder in which psychotic symptoms are the main problem, and a dysregulation of dopamine signaling is the main feature of pathophysiology. However, this concept limits clinical assessment, the treatments offered to patients, research, and the development of therapeutics. A more appropriate conceptual model is that: 1) schizophrenia is not a psychotic disorder, but a disorder of essentially every brain function in which psychosis is present; 2) it is not a brain disease, but a disorder with impairments throughout the body; 3) for many patients, neuropsychiatric problems other than psychosis contribute more to impairment in function and quality of life than does psychosis; and, 4) some conditions that are considered to be comorbid are integral parts of the illness. In conclusion, students, patients, and family members should be taught this model, along with its implications for assessment, research, and therapeutics. PMID:23518782

  2. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

    Directory of Open Access Journals (Sweden)

    Gottesman Irving I

    2005-02-01

    Full Text Available Abstract Background Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. Discussion A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular

  3. Effects of Cannabinoid Drugs on the Deficit of Prepulse Inhibition of Startle in an Animal Model of Schizophrenia: the SHR Strain

    Directory of Open Access Journals (Sweden)

    Raquel eLevin

    2014-02-01

    Full Text Available Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the Spontaneously Hypertensive Rats (SHR strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition of startle (PPI, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: 1 WIN55212,2 (cannabinoid agonist, 2 rimonabant (CB1 antagonist, 3 AM404 (anandamide uptake inhibitor, and 4 cannabidiol (indirect CB1/CB2 receptor antagonist, among other effects. Wistar rats (WR and SHRs were treated with vehicle or different doses of WIN55212 (0.3, 1 or 3 mg/kg, rimonabant (0.75, 1.5 or 3 mg/kg, AM404 (1, 5 or 10 mg/kg or cannabidiol (15, 30 or 60 mg/kg. Vehicle-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg cannabidiol. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.

  4. Family therapy for schizophrenia: cultural challenges and ...

    African Journals Online (AJOL)

    Family therapy is an effective, evidence based intervention for schizophrenia. This literature review explores the impact of culture on family therapy as a treatment model for schizophrenia and examines how cultural beliefs impact on access to care. Although there is a good deal of evidence to suggest that certain principles ...

  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. Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

    Science.gov (United States)

    Chambers, R Andrew; Self, David W

    2002-12-01

    The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

  7. Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia.

    Science.gov (United States)

    Calcagno, B; Eyles, D; van Alphen, B; van Swinderen, B

    2013-01-08

    It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the "dopamine ontogeny hypothesis of schizophrenia". To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia.

  8. The puzzle box as a simple and efficient behavioral test for exploring impairments of general cognition and executive functions in mouse models of schizophrenia.

    Science.gov (United States)

    Ben Abdallah, Nada M-B; Fuss, Johannes; Trusel, Massimo; Galsworthy, Michael J; Bobsin, Kristin; Colacicco, Giovanni; Deacon, Robert M J; Riva, Marco A; Kellendonk, Christoph; Sprengel, Rolf; Lipp, Hans-Peter; Gass, Peter

    2011-01-01

    Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem-solving test in which mice are required to complete escape tasks of increasing difficulty within a limited amount of time. Previous data have indicated that it is a quick but highly reliable test of higher-order cognitive functioning. We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub-chronically with the NMDA-receptor antagonist MK-801, mice constitutively lacking the GluA1 subunit of AMPA-receptors, and mice over-expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits were strongest in hippocampus-lesioned and GluA1 knockout mice, while more subtle deficits but specific to problem solving were found in the medial prefrontal-lesioned mice, MK-801-treated mice, and in mice with striatal overexpression of D2 receptors. Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive functions in general and for schizophrenia mouse models in particular. Published by Elsevier Inc.

  9. An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model.

    Science.gov (United States)

    Schmidt-Kastner, R; van Os, J; Esquivel, G; Steinbusch, H W M; Rutten, B P F

    2012-12-01

    Investigating and understanding gene-environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

  10. Joint modelling of longitudinal outcome and interval-censored competing risk dropout in a schizophrenia clinical trial

    Science.gov (United States)

    Gueorguieva, Ralitza; Rosenheck, Robert; Lin, Haiqun

    2011-01-01

    Summary The ‘Clinical antipsychotic trials in intervention effectiveness’ study, was designed to evaluate whether there were significant differences between several antipsychotic medications in effectiveness, tolerability, cost and quality of life of subjects with schizophrenia. Overall, 74 % of patients discontinued the study medication for various reasons before the end of 18 months in phase I of the study. When such a large percentage of study participants fail to complete the study schedule, it is not clear whether the apparent profile in effectiveness reflects genuine changes over time or is influenced by selection bias, with participants with worse (or better) outcome values being more likely to drop out or to discontinue. To assess the effect of dropouts for different reasons on inferences, we construct a joint model for the longitudinal outcome and cause-specific dropouts that allows for interval-censored dropout times. Incorporating the information regarding the cause of dropout improves inferences and provides better understanding of the association between cause-specific dropout and the outcome process. We use simulations to demonstrate the advantages of the joint modelling approach in terms of bias and efficiency. PMID:22468033

  11. Cost-effectiveness of the Mental Health and Development model for schizophrenia-spectrum and bipolar disorders in rural Kenya.

    Science.gov (United States)

    de Menil, V; Knapp, M; McDaid, D; Raja, S; Kingori, J; Waruguru, M; Wood, S K; Mannarath, S; Lund, C

    2015-10-01

    The treatment gap for serious mental disorders across low-income countries is estimated to be 89%. The model for Mental Health and Development (MHD) offers community-based care for people with mental disorders in 11 low- and middle-income countries. In Kenya, using a pre-post design, 117 consecutively enrolled participants with schizophrenia-spectrum and bipolar disorders were followed-up at 10 and 20 months. Comparison outcomes were drawn from the literature. Costs were analysed from societal and health system perspectives. From the societal perspective, MHD cost Int$ 594 per person in the first year and Int$ 876 over 2 years. The cost per healthy day gained was Int$ 7.96 in the first year and Int$ 1.03 over 2 years - less than the agricultural minimum wage. The cost per disability-adjusted life year averted over 2 years was Int$ 13.1 and Int$ 727 from the societal and health system perspectives, respectively, on par with antiretrovirals for HIV. MHD achieved increasing returns over time. The model appears cost-effective and equitable, especially over 2 years. Its affordability relies on multi-sectoral participation nationally and internationally.

  12. The effect of betahistine, a histamine H1 receptor agonist/H3 antagonist, on olanzapine-induced weight gain in first-episode schizophrenia patients.

    Science.gov (United States)

    Poyurovsky, Michael; Pashinian, Artashes; Levi, Aya; Weizman, Ronit; Weizman, Abraham

    2005-03-01

    Histamine antagonism has been implicated in antipsychotic drug-induced weight gain. Betahistine, a histamine enhancer with H1 agonistic/H3 antagonistic properties (48 mg t.i.d.), was coadministered with olanzapine (10 mg/day) in three first-episode schizophrenia patients for 6 weeks. Body weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and at week 6. All participants gained weight (mean weight gain 3.1+/-0.9 kg) and a similar pattern of weight gain was observed: an increase during the first 2 weeks and no additional weight gain (two patients) or minor weight loss (one patient) from weeks 3 to 6. None gained 7% of baseline weight, which is the cut-off for clinically significant weight gain. Betahistine was safe and well tolerated and did not interfere with the antipsychotic effect of olanzapine. Our findings justify a placebo-controlled evaluation of the putative weight-attenuating effect of betahistine in olanzapine-induced weight gain.

  13. Glutamate in schizophrenia: clinical and research implications.

    Science.gov (United States)

    Goff, D C; Wine, L

    1997-10-30

    The excitatory amino acids, glutamate and aspartate, are of interest to schizophrenia research because of their roles in neurodevelopment, neurotoxicity and neurotransmission. Recent evidence suggests that densities of glutamatergic receptors and the ratios of subunits composing these receptors may be altered in schizophrenia, although it is unclear whether these changes are primary or compensatory. Agents acting at the phencyclidine binding site of the NMDA receptor produce symptoms of schizophrenia in normal subjects, and precipitate relapse in patients with schizophrenia. The improvement of negative symptoms with agents acting at the glycine modulatory site of the NMDA receptor, as well as preliminary evidence that clozapine may differ from conventional neuroleptic agents in its effects on glutamatergic systems, suggest that clinical implications may follow from this model. While geriatric patients may be at increased risk for glutamate-mediated neurotoxicity, very little is known about the specific relevance of this model to geriatric patients with schizophrenia.

  14. The Role of Inflammation in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Norbert eMüller

    2015-10-01

    Full Text Available AbstractHigh levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA system and other immune functions. Another line of evidence demonstrates that chronic (disstress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis

  15. 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...

  16. A CCA+ICA based model for multi-task brain imaging data fusion and its application to schizophrenia.

    Science.gov (United States)

    Sui, Jing; Adali, Tülay; Pearlson, Godfrey; Yang, Honghui; Sponheim, Scott R; White, Tonya; Calhoun, Vince D

    2010-05-15

    Collection of multiple-task brain imaging data from the same subject has now become common practice in medical imaging studies. In this paper, we propose a simple yet effective model, "CCA+ICA", as a powerful tool for multi-task data fusion. This joint blind source separation (BSS) model takes advantage of two multivariate methods: canonical correlation analysis and independent component analysis, to achieve both high estimation accuracy and to provide the correct connection between two datasets in which sources can have either common or distinct between-dataset correlation. In both simulated and real fMRI applications, we compare the proposed scheme with other joint BSS models and examine the different modeling assumptions. The contrast images of two tasks: sensorimotor (SM) and Sternberg working memory (SB), derived from a general linear model (GLM), were chosen to contribute real multi-task fMRI data, both of which were collected from 50 schizophrenia patients and 50 healthy controls. When examining the relationship with duration of illness, CCA+ICA revealed a significant negative correlation with temporal lobe activation. Furthermore, CCA+ICA located sensorimotor cortex as the group-discriminative regions for both tasks and identified the superior temporal gyrus in SM and prefrontal cortex in SB as task-specific group-discriminative brain networks. In summary, we compared the new approach to some competitive methods with different assumptions, and found consistent results regarding each of their hypotheses on connecting the two tasks. Such an approach fills a gap in existing multivariate methods for identifying biomarkers from brain imaging data.

  17. [Cognition, schizophrenia and the effect of antipsychotics].

    Science.gov (United States)

    Stip, E

    2006-01-01

    In this review, we conclude that cognitive impairments are as important as positive and negative symptoms in the clinical assessment and management of patients with schizophrenia. This is not a comprehensive review, considering that the new Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) model will soon provide valuable data. It is however a product of the collective efforts of a French Canadian clinical research team that proposes a synthesis of data of pragmatic interest to clinicians. Medication with improved safety and cognition profile, gene-rally lead to better outcomes by facilitating compliance with drug regimens and rehabilitation programs. In addition, measures of attention and executive function (EF) appear to improve with novel antipsychotics when compared to traditional neuroleptics. Nevertheless, evaluating cognitive performance is not a routine procedure outside the domain of research. For example, procedural learning (PL) -- an important measure of cognitive function -- refers to cognitive and motor learning processes in which execution strategies cannot be explicitly described (ie learning by doing). These actions or procedures are then progressively learned through trial and error until automation of optimal performance is established. Procedural learning is rarely assessed in clinical practice. Inconsistent findings regarding the effects of neuroleptic drugs on PL have been reported. Trials using acute administration of chlorpromazine in normal subjects induced PL deficits, suggesting the direct effect of neuroleptics, presumably via a D(2) dopamine blockade in the striatum. In a recent study by our group, schizophrenia patients, divided into three groups according to their pharmacological treatment (haloperidol, clozapine and risperidone) were compared to normal controls on two PL tasks; a visuomotor learning task (mirror drawing) and a problem solving learning task (Tower of Toronto). No deficits were detected

  18. 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.

  19. Multicomponent ensemble models to forecast induced seismicity

    Science.gov (United States)

    Király-Proag, E.; Gischig, V.; Zechar, J. D.; Wiemer, S.

    2018-01-01

    In recent years, human-induced seismicity has become a more and more relevant topic due to its economic and social implications. Several models and approaches have been developed to explain underlying physical processes or forecast induced seismicity. They range from simple statistical models to coupled numerical models incorporating complex physics. We advocate the need for forecast testing as currently the best method for ascertaining if models are capable to reasonably accounting for key physical governing processes—or not. Moreover, operational forecast models are of great interest to help on-site decision-making in projects entailing induced earthquakes. We previously introduced a standardized framework following the guidelines of the Collaboratory for the Study of Earthquake Predictability, the Induced Seismicity Test Bench, to test, validate, and rank induced seismicity models. In this study, we describe how to construct multicomponent ensemble models based on Bayesian weightings that deliver more accurate forecasts than individual models in the case of Basel 2006 and Soultz-sous-Forêts 2004 enhanced geothermal stimulation projects. For this, we examine five calibrated variants of two significantly different model groups: (1) Shapiro and Smoothed Seismicity based on the seismogenic index, simple modified Omori-law-type seismicity decay, and temporally weighted smoothed seismicity; (2) Hydraulics and Seismicity based on numerically modelled pore pressure evolution that triggers seismicity using the Mohr-Coulomb failure criterion. We also demonstrate how the individual and ensemble models would perform as part of an operational Adaptive Traffic Light System. Investigating seismicity forecasts based on a range of potential injection scenarios, we use forecast periods of different durations to compute the occurrence probabilities of seismic events M ≥ 3. We show that in the case of the Basel 2006 geothermal stimulation the models forecast hazardous levels

  20. The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia.

    Science.gov (United States)

    Ward, Ryan D; Winiger, Vanessa; Higa, Kerin K; Kahn, Julia B; Kandel, Eric R; Balsam, Peter D; Simpson, Eleanor H

    2015-06-01

    Interactions between motivation and cognition are implicated in producing functional impairments and poor quality of life in psychiatric patients. This interaction, however, is not well understood at either the behavioral or neural level. We developed a procedure for mice in which a cognitive measure, sustained attention, is modulated by a motivationally relevant signal that predicts reward probability on a trial-by-trial basis. Using this paradigm, we tested the interaction between motivation and cognition in mice that model the increased striatal D2 receptor activity observed in schizophrenia patients (D2R-OE mice). In control mice, attention was modulated by signaled-reward probability. In D2R-OE mice, however, attention was not modulated by reward-related cues. This impairment was not due to any global deficits in attention or maintenance of the trial-specific information in working memory. Turning off the transgene in D2R-OE mice rescued the motivational modulation of attention. These results indicate that deficits in motivation impair the ability to use reward-related cues to recruit attention and that improving motivation improves functional cognitive performance. These results further suggest that addressing motivational impairments in patients is critical to achieving substantive cognitive and functional gains. (c) 2015 APA, all rights reserved).

  1. Nicotine, auditory sensory memory and attention in a human ketamine model of schizophrenia: moderating influence of a hallucinatory trait

    Directory of Open Access Journals (Sweden)

    Verner eKnott

    2012-09-01

    Full Text Available Background: The procognitive actions of the nicotinic acetylcholine receptor (nAChR agonist nicotine are believed, in part, to motivate the excessive cigarette smoking in schizophrenia, a disorder associated with deficits in multiple cognitive domains, including low level auditory sensory processes and higher order attention-dependent operations. Objectives: As N-methyl-D-aspartate receptor (NMDAR hypofunction has been shown to contribute to these cognitive impairments, the primary aims of this healthy volunteer study were to: a to shed light on the separate and interactive roles of nAChR and NMDAR systems in the modulation of auditory sensory memory (and sustained attention, as indexed by the auditory event-related brain potential (ERP – mismatch negativity (MMN, and b to examine how these effects are moderated by a predisposition to auditory hallucinations/delusions (HD. Methods: In a randomized, double-blind, placebo controlled design involving a low intravenous dose of ketamine (.04 mg/kg and a 4 mg dose of nicotine gum, MMN and performance on a rapid visual information processing (RVIP task of sustained attention were examined in 24 healthy controls psychometrically stratified as being lower (L-HD, n = 12 or higher (H-HD for HD propensity. Results: Ketamine significantly slowed MMN, and reduced MMN in H-HD, with amplitude attenuation being blocked by the co-administration of nicotine. Nicotine significantly enhanced response speed (reaction time and accuracy (increased % hits and d΄ and reduced false alarms on the RIVIP, with improved performance accuracy being prevented when nicotine was administered with ketamine. Both % hits and d΄, as well as reaction time were poorer in H-HD (vs. L-HD and while hit rate and d΄ was increased by nicotine in H-HD, reaction time was slowed by ketamine in L-HD. Conclusions: Nicotine alleviated ketamine-induced sensory memory impairments and improved attention, particularly in individuals prone to HD.

  2. Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

    Science.gov (United States)

    Kesby, James P; Cui, Xiaoying; Burne, Thomas H J; Eyles, Darryl W

    2013-01-01

    Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

  3. Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia

    Directory of Open Access Journals (Sweden)

    James P. Kesby

    2013-07-01

    Full Text Available Schizophrenia is a heterogeneous group of disorders with unknown aetiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesised that abnormal dopamine signalling in the adult patient may result from altered dopamine signalling during foetal brain development. Environmental and genetic risk factors can be modelled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the aetiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD deficiency. DVD-deficient adult rats display an altered behavioural profile in response to dopamine releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters dopamine metabolism in the developing brain. We speculate such alterations in foetal brain development may change the trajectory of dopamine neuron ontogeny to induce the behavioural abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in dopamine ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

  4. Probing GABA Receptor Function in Schizophrenia with Iomazenil

    OpenAIRE

    Ahn, Kyungheup; Gil, Roberto; Seibyl, John; Sewell, Richard Andrew; D'Souza, Deepak Cyril

    2010-01-01

    Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients,...

  5. Exploring social cognition in schizophrenia

    DEFF Research Database (Denmark)

    Revsbech, R.; Mortensen, E. L.; Nordgaard, J.

    2017-01-01

    The aim of the study was to compare social cognition between groups of patients diagnosed with schizophrenia and healthy controls and to replicate two previous studies using tests of social cognition that may be particularly sensitive to social cognitive deficits in schizophrenia. Thirty......-eight first-admitted patients with schizophrenia and 38 healthy controls solved 11 “imaginary conversation (i.e., theory of mind)” items, 10 “psychological understanding” items, and 10 “practical understanding” items. Statistical tests were made of unadjusted and adjusted group differences in models adjusting...... for intelligence and neuropsychological test performance. Healthy controls performed better than patients on all types of social cognitive tests, particularly on “psychological understanding.” However, after adjusting for intelligence and neuropsychological test performance, all group differences became...

  6. 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...

  7. Further insight into the role of metacognitive beliefs in schizophrenia and OCD patients: testing a mediation model.

    Science.gov (United States)

    Bortolon, Catherine; Larøi, Frank; Stephan, Yannick; Capdevielle, Delphine; Yazbek, Hanan; Boulenger, Jean-Philippe; Gely-Nargeot, Marie-Christine; Raffard, Stéphane

    2014-12-15

    This study explored the mediation effect of metacognitive beliefs on the relationship between intrusive thoughts and emotional distress in schizophrenia (N=49) and obsessive-compulsive disorder (OCD) (N=35). Intrusive thoughts impact on anxiety and depression through beliefs about uncontrollability and danger of thoughts in schizophrenia. Negative beliefs in general mediated the effect of intrusive thoughts on anxiety in obsessive-compulsive disorder. The results suggest that metacognitive beliefs may be a vulnerability factor for emotional and psychological disorder. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. THE EFFECT OF FAMILY THERAPY WITH SPIRITUAL APPROACH TOWARD FAMILY’S HEALTH BELIEF MODEL IN TAKING CARE OF PATIENT WITH SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    Ah. Yusuf

    2017-04-01

    Full Text Available Introduction: Schizophrenia is the problem with kognitive, mal-adaptive thought and behavior. Family who have a member with mental disorder can experience serious conflict, become an objective and subjective burden, blame each other, get involved in hostility among family members. Various negative effect faced by family can caused by wrong family’s health belief model about Schizophrenia, hence the failure on choosing the treatment and taking care of patient at home. Someone with severe stress will seek comfort and strength from God. But so far, the most effective spiritual models to improve the health belief model of the family in caring for patients with schizophrenia has not been found. Method: Design used in this study was experimental (pre post test control group design. The population was every family of patient with mental disorder in Menur Mental Hospital along the year of 2010, chosen by alocation simple random. Samples were 13 persons in each treatment and control group. The intervention was given in 60–120 minute in 8 times meeting with average interval about 1 week. Data analysis was done using paired t-test and independent t-test. Results: There were significant changes in total of family’s health belief model (p=0,004, there was significantly change in aspects of (1 perceptions about bene fi ts (p=0,009, (2 perception about barriers (p=0,035 and perception about self efficacy (p=0,002. There were no significant changing in perception about susceptibility and severity (p=0,052. Discussion: Family believes that all events experienced by the patient and the family is God's will, hoping the patient can be more independent, and believe mental disorders can be changed for the better. The conclusion of this study is that family therapy with a spiritual approach can improve the health belief model of the family in caring for patients with mental disorders.

  9. Quetiapine versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Schmid, Franziska; Hunger, Heike; Schwarz, Sandra; Srisurapanont, Manit; Kissling, Werner; Leucht, Stefan

    2014-01-01

    Background In many countries of the industrialised world second generation (’atypical’) antipsychotic drugs have become the first line drug treatment for people with schizophrenia. It is not clear how the effects of the various second generation antipsychotic drugs differ. Objectives To evaluate the effects of quetiapine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychosis. Search methods We searched the Cochrane Schizophrenia Group Trials Register (April 2007), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. Selection criteria We included all randomised control trials comparing oral quetiapine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone or zotepine in 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. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model. Main results The review currently includes 21 randomised control trials (RCTs) with 4101 participants. These trials provided data on four comparisons - quetiapine versus clozapine, olanzapine, risperidone or ziprasidone. A major limitation to all findings is the high number of participants leaving studies prematurely (57.6%) and the substantial risk of biases in studies. Efficacy data favoured olanzapine and risperidone compared with quetiapine (PANSS total score versus olanzapine:10 RCTs, n=1449, WMD 3.66 CI 1.93 to 5.39; versus risperidone: 9 RCTs, n=1953, WMD 3.09 CI 1.01 to 5.16), but clinical meaning is unclear

  10. GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies

    Science.gov (United States)

    de Jonge, Jeroen C.; Vinkers, Christiaan H.; Hulshoff Pol, Hilleke E.; Marsman, Anouk

    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 of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course. PMID:28848455

  11. GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies

    Directory of Open Access Journals (Sweden)

    Jeroen C. de Jonge

    2017-08-01

    Full Text Available 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 of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course.

  12. 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…

  13. 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.

  14. Induced subgraph searching for geometric model fitting

    Science.gov (United States)

    Xiao, Fan; Xiao, Guobao; Yan, Yan; Wang, Xing; Wang, Hanzi

    2017-11-01

    In this paper, we propose a novel model fitting method based on graphs to fit and segment multiple-structure data. In the graph constructed on data, each model instance is represented as an induced subgraph. Following the idea of pursuing the maximum consensus, the multiple geometric model fitting problem is formulated as searching for a set of induced subgraphs including the maximum union set of vertices. After the generation and refinement of the induced subgraphs that represent the model hypotheses, the searching process is conducted on the "qualified" subgraphs. Multiple model instances can be simultaneously estimated by solving a converted problem. Then, we introduce the energy evaluation function to determine the number of model instances in data. The proposed method is able to effectively estimate the number and the parameters of model instances in data severely corrupted by outliers and noises. Experimental results on synthetic data and real images validate the favorable performance of the proposed method compared with several state-of-the-art fitting methods.

  15. Imaging dopamine transmission in schizophrenia

    International Nuclear Information System (INIS)

    Laruelle, M.

    1998-01-01

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D 2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D 2 receptor density parameters, under the assumption that all tracers labeled the same population of D 2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D 2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D 2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

  16. Risk architecture of schizophrenia: the role of epigenetics.

    Science.gov (United States)

    Svrakic, Dragan M; Zorumski, Charles F; Svrakic, Nenad M; Zwir, Igor; Cloninger, Claude R

    2013-03-01

    To systematize existing data and review new findings on the cause of schizophrenia and outline an improved mixed model of schizophrenia risk. Multiple and variable genetic and environmental factors interact to influence the risk of schizophrenia. Both rare variants with large effect and common variants with small effect contribute to genetic risk of schizophrenia, with no indication for differential impact on its clinical features. Accumulating evidence supports a genetic architecture of schizophrenia with multiple scenarios, including additive polygenic, heterogeneity, and mixed polygenic-heterogeneity. The epigenetic mechanisms that mediate gene-environment (GxE) interactions provide a framework to incorporate environmental factors into models of schizophrenia risk. Environmental pathogens with small effect on risk have robust effects in the context of family history of schizophrenia. Hence, genetic risk for schizophrenia may be expressed in part as sensitivity to environmental factors. We propose an improved mixed model of schizophrenia risk in which abnormal epigenetic states with large effects are superimposed on a polygenic liability to schizophrenia. This scenario can account for GxE interactions and shared family environment, which in many cases are not explained by a single structural variant of large effect superimposed on polygenes (the traditional mixed model).

  17. MRI anatomy of schizophrenia.

    Science.gov (United States)

    McCarley, R W; Wible, C G; Frumin, M; Hirayasu, Y; Levitt, J J; Fischer, I A; Shenton, M E

    1999-05-01

    Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer-reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was the brain parenchymal region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe functional abnormalities, structural MRI investigations less consistently found abnormalities, with 55% describing volume reduction. It may be that frontal lobe volume changes are small, and near the threshold for MRI detection. The parietal and occipital lobes were much less studied; about half of the studies showed positive findings. Most studies of cortical gray matter (86%) found volume reductions were not diffuse, but more pronounced in certain areas. About two thirds of the studies of subcortical structures of thalamus, corpus callosum and basal ganglia (which tend to increase volume with typical neuroleptics), show positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP). Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a "two-hit" model of schizophrenia, for which a cellular hypothesis is discussed. The relationship of clinical

  18. Modelling of settlement induced building damage

    NARCIS (Netherlands)

    Giardina, G.

    2013-01-01

    This thesis focuses on the modelling of settlement induced damage to masonry buildings. In densely populated areas, the need for new space is nowadays producing a rapid increment of underground excavations. Due to the construction of new metro lines, tunnelling activity in urban areas is growing.

  19. New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function.

    Science.gov (United States)

    Uehara, Takashi; Sumiyoshi, Tomiki; Kurachi, Masayoshi

    2015-01-01

    Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia.

  20. Unique and Overlapping Symptoms in Schizophrenia Spectrum and Dissociative Disorders in Relation to Models of Psychopathology : A Systematic Review

    NARCIS (Netherlands)

    Renard, Selwyn B.; Huntjens, Rafaele J. C.; Lysaker, Paul H.; Moskowitz, Andrew; Aleman, André; Pijnenborg, Gerdina H. M.

    Schizophrenia spectrum disorders (SSDs) and dissociative disorders (DDs) are described in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) and tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) as 2

  1. 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....

  2. Modeling and simulation of placebo response and dropout patterns in treatment of schizophrenia

    NARCIS (Netherlands)

    Pilla Reddy, Venkatesh; Kozielska, Magdalena; Johnson, Martin; Vermeulen, An; de Greef, Rik; Liu, Jing; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2010-01-01

    Objectives: Unpredictable variation in placebo response within and among clinical trials can substantially affect conclusions about the efficacy of new antipsychotic medications. Developing a robust placebo model accounting for factors like dropouts, disease progression and trial design is crucial

  3. Impaired reward responsiveness in schizophrenia.

    Science.gov (United States)

    Taylor, Nicholas; Hollis, Jeffrey P; Corcoran, Sarah; Gross, Robin; Cuthbert, Bruce; Swails, Lisette W; Duncan, Erica

    2018-03-08

    Anhedonia is a core negative symptom of schizophrenia. Schizophrenia patients report largely intact pleasure in consuming rewards, but have impairments in generating motivated behavior to pursue rewards, and show reduced fMRI activation of the reward pathway during presentation of rewarded stimuli. A computer based task measuring the development of a response bias in favor of rewarded stimuli permits assessment of reward-induced motivation. We hypothesized that subjects with schizophrenia would be impaired on this task. 58 schizophrenia subjects (SCZ) and 52 healthy controls (CON) were studied with a signal detection task to assess reward responsiveness. In multiple trials over three blocks subjects were asked to correctly identify two stimuli that were paired with unequal chance of monetary reward. The critical outcome variable was response bias, the development of a greater percent correct identification of the stimulus that was rewarded more often. An ANOVA on response bias with Block as a repeated-measures factor and Diagnosis as a between-group factor indicated that SCZ subjects achieved a lower bias to rewarded stimuli than CON subjects (F(1,105)=8.82, p=0.004, η 2 =0.078). Post hoc tests indicated that SCZ subjects had significantly impaired bias in Block 1 (p=0.002) and Block 2 (p=0.05), indicating that SCZ were slower to achieve normal levels of bias during the session. SCZ subjects were slower to develop response bias to rewarded stimuli than CON subjects. This finding is consonant with the hypothesis that people with schizophrenia have a blunted capacity to modify behavior in response to reward. Copyright © 2018. Published by Elsevier B.V.

  4. In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology.

    Science.gov (United States)

    Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

    2017-05-31

    Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current

  5. Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits.

    Science.gov (United States)

    Stevens, Karen E; Zheng, Lijun; Floyd, Kirsten L; Stitzel, Jerry A

    2015-06-22

    Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. 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.

  7. [Schizophrenia and modern culture: reasons for insanity].

    Science.gov (United States)

    Pérez-Álvarez, Marino

    2012-02-01

    After pointing out the uncertainty and confusion to which neurobiological research has led schizophrenia, as shown and acknowledged in recent reviews, we offer seven reasons for reconsidering schizophrenia a disorder of the self, rather than of the brain. The first reason starts out conceiving schizophrenia as a disorder of the self, in the perspective of current phenomenology. The second relates the fact of its recent origin (as of 1750) with the particular configuration of the modern self and with the great transformation of the community into a society of individuals (industrialization, urbanization). The third reason emphasizes the affinity between schizophrenia and adolescence, a critical age in the formation of the self, which started to be problematic at the end of the 18th century. The fourth is the better prognosis of schizophrenia in developing countries, in comparison to developed countries, which probably has to do with the process of modernization (which still maintains community structures in less developed countries). The fifth is the high incidence of schizophrenia among immigrants, as a fact to be explained in terms of a socio-evolutionary model. The sixth reason reviews the genetic legend of schizophrenia, and how epigenetics gives protagonism back to the environment. The seventh and last reason refers to the reconsideration of psychological therapy as the possible treatment of choice and not merely an adjunct to medication, as it is known that, for patients, interpersonal chemistry is more important than neurochemistry.

  8. Structural Models Describing Placebo Treatment Effects in Schizophrenia and Other Neuropsychiatric Disorders

    NARCIS (Netherlands)

    Reddy, Venkatesh Pilla; Kozielska, Magdalena; Johnson, Martin; Vermeulen, An; de Greef, Rik; Liu, Jing; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2011-01-01

    Large variation in placebo response within and among clinical trials can substantially affect conclusions about the efficacy of new medications in psychiatry. Developing a robust placebo model to describe the placebo response is important to facilitate quantification of drug effects, and eventually

  9. Translational PKPD modeling in schizophrenia: linking receptor occupancy of antipsychotics to efficacy and safety

    NARCIS (Netherlands)

    Pilla Reddy, Venkatesh; Kozielska, Magdalena; Johnson, Martin; Vermeulen, An; Liu, Jing; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2012-01-01

    Objectives: To link the brain dopamine D2 receptor occupancy (D2RO) of antipsychotic drugs with clinical endpoints of efficacy and safety to assess the therapeutic window of D2RO. Methods: Pharmacokinetic-Pharmacodynamic (PK-PD) models were developed to predict the D2 receptor occupancy of

  10. 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.

  11. Translational Modeling in Schizophrenia: Predicting Human Dopamine D2 Receptor Occupancy.

    Science.gov (United States)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M M; Danhof, Meindert; Proost, Johannes H

    2016-04-01

    To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs. A hybrid PBPKPD model, previously developed using information on plasma concentrations, brain exposure and D2RO in rats, was used as the basis for the prediction of D2RO in human. The rat pharmacokinetic and brain physiology parameters were substituted with human population pharmacokinetic parameters and human physiological information. To predict the passive transport across the human blood-brain barrier, apparent permeability values were scaled based on rat and human brain endothelial surface area. Active efflux clearance in brain was scaled from rat to human using both human brain endothelial surface area and MDR1 expression. Binding constants at the D2 receptor were scaled based on the differences between in vitro and in vivo systems of the same species. The predictive power of this physiology-based approach was determined by comparing the D2RO predictions with the observed human D2RO of six antipsychotics at clinically relevant doses. Predicted human D2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted human D2RO well for most of the compounds evaluated in this analysis. However, human D2RO was under-predicted for haloperidol. The rat hybrid PBPKPD model structure, integrated with in vitro information and human pharmacokinetic and physiological information, constitutes a scientific basis to predict the time course of D2RO in man.

  12. Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia.

    Science.gov (United States)

    Ruda-Kucerova, Jana; Babinska, Zuzana; Stark, Tibor; Micale, Vincenzo

    2017-07-01

    Ketamine may prove to be a potential candidate in treating the widespread drug addiction/substance abuse epidemic among patients with schizophrenia. Clinical studies have shown ketamine to reduce cocaine and heroin cravings. However, the use of ketamine remains controversial as it may exacerbate the symptoms of schizophrenia. Therefore, the aim of this study is to characterize the effects of ketamine on drug addiction in schizophrenia using the methylazoxymethanol (MAM) acetate rat model on operant IV methamphetamine (METH) self-administration. MAM was administered intraperitoneally (22 mg/kg) on gestational day 17. Locomotor activity test and later IV self-administration (IVSA) were then performed in the male offspring followed by a period of forced abstinence and relapse of METH taking. After reaching stable intakes in the relapse phase, ketamine (5 mg/kg) was administered intraperitoneally 30 min prior to the self-administration session. As documented previously, the MAM rats showed a lack of habituation in the locomotor activity test but developed stable maintenance of METH self-administration with no difference in operant behaviour to control animals. Results show that ketamine treatment significantly reduced the METH intake in the control animals but not in MAM animals. Ketamine effect on METH self-administration may be explained by increased glutamatergic signalling in the prefrontal cortex caused by the N-methyl-D-aspartate antagonism and disinhibition of GABA interneurons which was shown to be impaired in the MAM rats. This mechanism may at least partly explain the clinically proven anti-craving potential of ketamine and allow development of more specific anti-craving medications with fewer risks.

  13. Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model: implications for polypharmacy in schizophrenia

    Science.gov (United States)

    Sparkman, Nathan L.; Li, Ming

    2016-01-01

    Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug–drug interactions. However, the pharmacological and behavioral mechanisms underlying drug–drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug–drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the

  14. Modeling of Corrosion-induced Concrete Damage

    DEFF Research Database (Denmark)

    Thybo, Anna Emilie A.; Michel, Alexander; Stang, Henrik

    2013-01-01

    In the present paper a finite element model is introduced to simulate corrosion-induced damage in concrete. The model takes into account the penetration of corrosion products into the concrete as well as non-uniform formation of corrosion products around the reinforcement. To ac-count for the non...... of corrosion products affects both the time-to cover cracking and the crack width at the concrete surface.......In the present paper a finite element model is introduced to simulate corrosion-induced damage in concrete. The model takes into account the penetration of corrosion products into the concrete as well as non-uniform formation of corrosion products around the reinforcement. To ac-count for the non......-uniform formation of corrosion products at the concrete/reinforcement interface, a deterministic approach is used. The model gives good estimates of both deformations in the con-crete/reinforcement interface and crack width when compared to experimental data. Further, it is shown that non-uniform deposition...

  15. Oxytocin model of formation of psychotic symptoms and its implications for research on oxytocinergic pathway in schizophrenia

    OpenAIRE

    Holka-Pokorska, Justyna; Jarema, Marek

    2014-01-01

    There are more and more data to support the dysregulation of the oxytocinergic pathway in schizophrenia. The development of the above branch of knowledge began to evolve alongside the mainstream of studies concerning gene polymorphisms for dopaminergic, glutamatergic and serotoninergic systems. Both experimental studies and clinical trials have demonstrated an antipsychotic effect of oxytocin. Starting with the pioneering neuroendocrinobehavioral experiment which demonstrated that oxytocin na...

  16. Amisulpride versus other atypical antipsychotics for schizophrenia

    Science.gov (United States)

    Komossa, Katja; Rummel-Kluge, Christine; Hunger, Heike; Schmid, Franziska; Schwarz, Sandra; da Mota Neto, Joaquim I Silveira; 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 amisulpride differs from that of other second generation antipsychotics. Objectives To evaluate the effects of amisulpride compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. Search methods We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE and PsycINFO. We updated this search in July 2012 and added 47 new trials to the awaiting classification section. Selection criteria We included randomised, at least single-blind, trials comparing oral amisulpride with oral forms of aripiprazole, 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 continuous data we calculated weighted mean differences (MD), 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. Main results The review currently includes ten short to medium term trials with 1549 participants on three comparisons: amisulpride versus olanzapine, risperidone and ziprasidone. The overall attrition rate was considerable (34.7%) with no significant difference between groups. Amisulpride was similarly effective as olanzapine and risperidone and more effective than ziprasidone (leaving the study early due to inefficacy: n=123, 1 RCT, RR 0.21 CI 0.05 to 0.94, NNT 8 CI 5 to 50

  17. 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)

  18. 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.

  19. Mefenamic Acid Induced Nephrotoxicity: An Animal Model

    Directory of Open Access Journals (Sweden)

    Muhammad Nazrul Somchit

    2014-12-01

    Full Text Available Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. Methods: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day. Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN and creatinine activities were measured. Results: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. Conclusion: Results from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model.

  20. Alterations of the occipital lobe in schizophrenia.

    Science.gov (United States)

    Tohid, Hassaan; Faizan, Muhammad; Faizan, Uzma

    2015-07-01

    The relationship of the occipital lobe of the brain with schizophrenia is not commonly studied; however, this topic is considered an essential subject matter among clinicians and scientists. We conducted this systematic review to elaborate the relationship in depth. We found that most schizophrenic patients show normal occipital anatomy and physiology, a minority showed dwindled values, and some demonstrated augmented function and structure. The findings are laborious to incorporate within single disease models that present the involvement of the occipital lobe in schizophrenia. Schizophrenia progresses clinically in the mid-twenties and thirties and its prognosis is inadequate. Changes in the volume, the gray matter, and the white matter in the occipital lobe are quite evident; however, the mechanism behind this involvement is not yet fully understood. Therefore, we recommend further research to explore the occipital lobe functions and volumes across the different stages of schizophrenia.

  1. Alterations of the occipital lobe in schizophrenia

    Science.gov (United States)

    Tohid, Hassaan; Faizan, Muhammad; Faizan, Uzma

    2015-01-01

    The relationship of the occipital lobe of the brain with schizophrenia is not commonly studied; however, this topic is considered an essential subject matter among clinicians and scientists. We conducted this systematic review to elaborate the relationship in depth. We found that most schizophrenic patients show normal occipital anatomy and physiology, a minority showed dwindled values, and some demonstrated augmented function and structure. The findings are laborious to incorporate within single disease models that present the involvement of the occipital lobe in schizophrenia. Schizophrenia progresses clinically in the mid-twenties and thirties and its prognosis is inadequate. Changes in the volume, the gray matter, and the white matter in the occipital lobe are quite evident; however, the mechanism behind this involvement is not yet fully understood. Therefore, we recommend further research to explore the occipital lobe functions and volumes across the different stages of schizophrenia. PMID:26166588

  2. Problem solving skills for schizophrenia.

    Science.gov (United States)

    Xia, J; Li, Chunbo

    2007-04-18

    The severe and long-lasting symptoms of schizophrenia are often the cause of severe disability. Environmental stress such as life events and the practical problems people face in their daily can worsen the symptoms of schizophrenia. Deficits in problem solving skills in people with schizophrenia affect their independent and interpersonal functioning and impair their quality of life. As a result, therapies such as problem solving therapy have been developed to improve problem solving skills for people with schizophrenia. To review the effectiveness of problem solving therapy compared with other comparable therapies or routine care for those with schizophrenia. We searched the Cochrane Schizophrenia Group's Register (September 2006), which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. We included all clinical randomised trials comparing problem solving therapy with other comparable therapies or routine care. We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD) using a random effects statistical model. We included only three small trials (n=52) that evaluated problem solving versus routine care, coping skills training or non-specific interaction. Inadequate reporting of data rendered many outcomes unusable. We were unable to undertake meta-analysis. Overall results were limited and inconclusive with no significant differences between treatment groups for hospital admission, mental state, behaviour, social skills or leaving the study early. No data were presented for global state, quality of life or satisfaction. We found insufficient evidence to confirm or refute the benefits of problem solving therapy as an additional

  3. 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; ...

  4. 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...

  5. Animal Models of Virus-Induced Neurobehavioral Sequelae: Recent Advances, Methodological Issues, and Future Prospects

    Directory of Open Access Journals (Sweden)

    Marco Bortolato

    2010-01-01

    Full Text Available Converging lines of clinical and epidemiological evidence suggest that viral infections in early developmental stages may be a causal factor in neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism-spectrum disorders. This etiological link, however, remains controversial in view of the lack of consistent and reproducible associations between viruses and mental illness. Animal models of virus-induced neurobehavioral disturbances afford powerful tools to test etiological hypotheses and explore pathophysiological mechanisms. Prenatal or neonatal inoculations of neurotropic agents (such as herpes-, influenza-, and retroviruses in rodents result in a broad spectrum of long-term alterations reminiscent of psychiatric abnormalities. Nevertheless, the complexity of these sequelae often poses methodological and interpretational challenges and thwarts their characterization. The recent conceptual advancements in psychiatric nosology and behavioral science may help determine new heuristic criteria to enhance the translational value of these models. A particularly critical issue is the identification of intermediate phenotypes, defined as quantifiable factors representing single neurochemical, neuropsychological, or neuroanatomical aspects of a diagnostic category. In this paper, we examine how the employment of these novel concepts may lead to new methodological refinements in the study of virus-induced neurobehavioral sequelae through animal models.

  6. The maternal immune activation (MIA) model of schizophrenia produces pre-pulse inhibition (PPI) deficits in both juvenile and adult rats but these effects are not associated with maternal weight loss.

    Science.gov (United States)

    Wolff, Amy R; Bilkey, David K

    2010-12-01

    The developmental onset of deficits in sensorimotor-gating was examined in the maternal immune activation (MIA) animal model of schizophrenia. Pre-pulse inhibition (PPI) deficits were evident in juvenile MIA rats. This parallels the sensorimotor-gating deficits observed in groups at high-risk of schizophrenia. PPI deficits were independent of maternal weight loss following the MIA manipulation, suggesting that this measure may not be a useful marker of treatment efficacy. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  7. A nonlinear model for AC induced corrosion

    Directory of Open Access Journals (Sweden)

    N. Ida

    2012-09-01

    Full Text Available The modeling of corrosion poses particular difficulties. The understanding of corrosion as an electrochemical process has led to simple capacitive-resistive models that take into account the resistance of the electrolytic cell and the capacitive effect of the surface potential at the interface between conductors and the electrolyte. In some models nonlinear conduction effects have been added to account for more complex observed behavior. While these models are sufficient to describe the behavior in systems with cathodic protection, the behavior in the presence of induced AC currents from power lines and from RF sources cannot be accounted for and are insufficient to describe the effects observed in the field. Field observations have shown that a rectifying effect exists that affects the cathodic protection potential and this effect is responsible for corrosion in the presence of AC currents. The rectifying effects of the metal-corrosion interface are totally missing from current models. This work proposes a nonlinear model based on finite element analysis that takes into account the nonlinear behavior of the metal-oxide interface and promises to improve modeling by including the rectification effects at the interface.

  8. 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)

  9. 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...

  10. Altered intrinsic and extrinsic connectivity in schizophrenia.

    Science.gov (United States)

    Zhou, Yuan; Zeidman, Peter; Wu, Shihao; Razi, Adeel; Chen, Cheng; Yang, Liuqing; Zou, Jilin; Wang, Gaohua; Wang, Huiling; Friston, Karl J

    2018-01-01

    Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self-connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia.

  11. Psychoeducation for schizophrenia

    Science.gov (United States)

    Xia, Jun; Merinder, Lars Bertil; Belgamwar, Madhvi R

    2014-01-01

    Background Schizophrenia can be a severe and chronic illness characterised by lack of insight and poor compliance with treatment. Psychoeducational approaches have been developed to increase patients’ knowledge of, and insight into, their illness and its treatment. It is supposed that this increased knowledge and insight will enable people with schizophrenia to cope in a more effective way with their illness, thereby improving prognosis. Objectives To assess the effects of psychoeducational interventions compared with standard levels of knowledge provision. Search methods We searched the Cochrane Schizophrenia Group Trials Register (February 2010). We updated this search November 2012 and added 27 new trials to the awaiting assessment section. Selection criteria All relevant randomised controlled trials focusing on psychoeducation for schizophrenia and/or related serious mental illnesses involving individuals or groups. We excluded quasi-randomised trials. Data collection and analysis At least two review authors extracted data independently from included papers. We contacted authors of trials for additional and missing data. We calculated risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data. We used a fixed-effects model for heterogeneous dichotomous data. Where possible we also calculated the numbers needed to treat (NNT), as well as weighted means for continuous data. Main results This review includes a total of 5142 participants (mostly inpatients) from 44 trials conducted between 1988 and 2009 (median study duration ~ 12 weeks, risk of bias - moderate). We found that incidences of non-compliance were lower in the psychoeducation group in the short term (n = 1400, RR 0.52 CI 0.40 to 0.67, NNT 11 CI 9 to 16). This finding holds for the medium and long term. Relapse appeared to be lower in psychoeducation group (n = 1214, RR 0.70 CI 0.61 to 0.81, NNT 9 CI 7 to 14) and this also applied to readmission (n = 206, RR 0.71 CI 0.56 to 0

  12. To See or Not To See: That is The Question.The Protection-Against-Schizophrenia (PaSZ Model: Evidence from Congenital Blindness and Visuo-Cognitive Aberrations.

    Directory of Open Access Journals (Sweden)

    Steffen eLandgraf

    2013-07-01

    Full Text Available The causes of schizophrenia are still unknown. For the last one hundred years, though, both absent and perfect vision have been associated with a lower risk for schizophrenia. Hence, vision itself and aberrations in visual functioning may be fundamental to the development and etiological explanations of the disorder. In this paper, we present the Protection-Against-Schizophrenia (PaSZ model, which grades the risk for developing schizophrenia as a function of an individual’s visual capacity. We review two vision perspectives: (1 Absent vision or how congenital blindness contributes to PaSZ and (2 perfect vision or how aberrations in visual functioning are associated with psychosis. First, we illustrate that, although congenitally blind and sighted individuals acquire similar world representations, blind individuals compensate for behavioral shortcomings through neurofunctional and multisensory reorganization. These reorganizations may indicate etiological explanations for their protection against schizophrenia. Second, we demonstrate that visuo-cognitive impairments are fundamental for the development of schizophrenia. Deteriorated visual information acquisition and processing contribute to higher-order cognitive dysfunctions and subsequently to schizophrenic symptoms. Finally, we provide different specific therapeutic recommendations for individuals who suffer from visual impairments (who never developed normal vision and individuals who suffer from visual deterioration (who previously had normal visual skills. Rather than categorizing individuals as normal and mentally disordered, the PaSZ model uses a continuous scale to represent psychiatrically relevant human behavior. This not only provides a scientific basis for more fine-grained diagnostic assessments, earlier detection, and more appropriate therapeutic assignments, but it also outlines a trajectory for unraveling the causes of abnormal psychotic human self- and world-perception.

  13. Reduced context effects on retrieval in first-episode schizophrenia.

    Directory of Open Access Journals (Sweden)

    Lucia M Talamini

    Full Text Available BACKGROUND: A recent modeling study by the authors predicted that contextual information is poorly integrated into episodic representations in schizophrenia, and that this is a main cause of the retrieval deficits seen in schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: We have tested this prediction in patients with first-episode schizophrenia and matched controls. The benefit from contextual cues in retrieval was strongly reduced in patients. On the other hand, retrieval based on item cues was spared. CONCLUSIONS/SIGNIFICANCE: These results suggest that reduced integration of context information into episodic representations is a core deficit in schizophrenia and one of the main causes of episodic memory impairment.

  14. Radiation induced peroxidation in model lipid systems

    International Nuclear Information System (INIS)

    Dahlan, K.Z.B.H.M.

    1981-08-01

    In the studies of radiation induced lipid peroxidation, lecithin-liposomes and aqueous micellar solutions of sodium linoleate (or linoleic acid) have been used as models of lipid membrane systems. The liposomes and aqueous linoleate micelles were irradiated in the presence of O 2 and N 2 O/O 2 (80/20 v/v). The peroxidation was initiated using gamma radiation from 60 Co radiation source and was monitored by measuring the increase in absorbance of conjugated diene at 232 nm and by the thiobarbituric acid (TBA) test. The oxidation products were also identified by GLC and GLC-MS analysis. (author)

  15. Schizophrenia as a disconnection syndrome. Studies with functional magnetic resonance imaging and structural equation modeling; Schizophrenie als Diskonnektionssyndrom. Studien mit funktioneller Magnetresonanztomographie und Strukturgleichungsmodellen

    Energy Technology Data Exchange (ETDEWEB)

    Schloesser, R. [Universitaet Jena, Psychiatrische Klinik (Germany); Universitaet Jena, Psychiatrische Klinik, Jena (Germany); Wagner, G.; Koehler, S.; Sauer, H. [Universitaet Jena, Psychiatrische Klinik (Germany)

    2005-02-01

    Aside from characteristic psychopathological symptoms, cognitive deficits are a core feature of schizophrenia. These deficits can only be addressed within the context of widespread functional interactions among different brain areas. To examine these interactions, structural equation modeling (SEM) was used for the analysis of fMRI datasets. In a series of studies, both in antipsychotic-treated and drug-free schizophrenic patients, a pattern of enhanced thalamocortical functional connectivity could be observed as an indicator for possible disruptions of frontostriatal thalamocortical circuitry. Moreover, drug-free patients and those receiving typical antipsychotic drugs were characterized by reduced interhemispheric corticocortical connectivity. This difference relative to normal controls was less in patients under atypical antipsychotic drugs. The results could be interpreted as a beneficial effect of atypical antipsychotic drugs on information processing in schizophrenic patients. The present findings are consistent with the model of schizophrenia as a disconnection syndrome and earlier concepts of ''cognitive dysmetria'' in schizophrenia. (orig.) [German] Neben der charakteristischen psychopathologischen Symptomatik stellen kognitive Defizite ein zentrales Merkmal der Schizophrenie dar. Diese Defizite koennen nur im Kontext miteinander interagierender Hirnareale verstanden werden. Zur Untersuchung dieser funktionellen Wechselbeziehungen wurden Strukturgleichungsmodelle (''structural equation modeling'', SEM) zur Auswertung von fMRT-Datensaetzen verwendet. In einer Untersuchungsreihe bei schizophrenen Patienten ergab sich sowohl bei antipsychotisch behandelten als auch bei unbehandelten Patienten ein Muster gesteigerter thalamokortikaler funktioneller Konnektivitaet als Hinweis auf eine moegliche Stoerung fronto-striato-thalamo-kortikaler Regelkreise. Unbehandelte Patienten und Patienten unter typischen Antipsychotika

  16. One patient with schizophrenia showed reduced drug-induced extrapyramidal symptoms as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day.

    Science.gov (United States)

    Suzuki, Hidenobu; Hibino, Hiroyuki; Inoue, Yuichi; Matsumoto, Hideo; Mikami, Katsunaka

    2017-01-01

    Schizophrenia is a chronic disease that requires long-term management with antipsychotics. Antipsychotic drugs are given by tapering their dose, extending the dosing interval, and so on, as part of a treatment strategy to minimize the adverse effects while at the same time maintaining efficacy. We report the case of one patient with schizophrenia in whom the clinical symptoms were alleviated after treatment with 6 mg paliperidone. However, the patient developed extrapyramidal syndrome, for which 3 and 6 mg paliperidone were administered alternately every other day. Extrapyramidal syndrome was assessed using the Drug-Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary Movement Scale, or Barnes Akathisia Scale. There was improvement in Drug-Induced Extrapyramidal Symptoms Scale score and Abnormal Involuntary Movement Scale score. However, there was almost no change in the Positive and Negative Syndrome Scale total score, positive score, negative score, or general score. The results indicate the possibility of lessened adverse effects as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day in the maintenance phase.

  17. MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.

    Directory of Open Access Journals (Sweden)

    Dejian Zhao

    Full Text Available We are using induced pluripotent stem cell (iPSC technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del, the most common known schizophrenia (SZ-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA biogenesis. We carried out miRNA expression profiling (miRNA-seq on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher. Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05, including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p. Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

  18. A heuristic model linking yoga philosophy and self-reflection to examine underlying mechanisms of add-on yoga treatment in schizophrenia.

    Science.gov (United States)

    Rao, Naren; Menon, Sangeetha

    2016-06-01

    Preliminary evidence suggests efficacy of yoga as add-on treatment for schizophrenia, but the underlying mechanism by which yoga improves the symptoms of schizophrenia is not completely understood. Yoga improves self-reflection in healthy individuals, and self-reflection abnormalities are typically seen in schizophrenia. However, whether yoga treatment improves impairments in self-reflection typically seen in patients with schizophrenia is not examined. This paper discusses the potential mechanism of yoga in the treatment of schizophrenia and proposes a testable hypothesis for further empirical studies. It is proposed that self-reflection abnormalities in schizophrenia improve with yoga and the neurobiological changes associated with this can be examined using empirical behavioural measures and neuroimaging measures such as magnetic resonance imaging.

  19. 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.

  20. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

    DEFF Research Database (Denmark)

    Nielsen, Jacob; Fejgin, Kim; Sotty, Florence

    2017-01-01

    on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1...... and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced...

  1. Patterns of Dysmorphic Features in Schizophrenia

    Science.gov (United States)

    Scutt, L.E.; Chow, E.W.C.; Weksberg, R.; Honer, W.G.; Bassett, Anne S.

    2011-01-01

    Congenital dysmorphic features are prevalent in schizophrenia and may reflect underlying neurodevelopmental abnormalities. A cluster analysis approach delineating patterns of dysmorphic features has been used in genetics to classify individuals into more etiologically homogeneous subgroups. In the present study, this approach was applied to schizophrenia, using a sample with a suspected genetic syndrome as a testable model. Subjects (n = 159) with schizophrenia or schizoaffective disorder were ascertained from chronic patient populations (random, n=123) or referred with possible 22q11 deletion syndrome (referred, n = 36). All subjects were evaluated for presence or absence of 70 reliably assessed dysmorphic features, which were used in a three-step cluster analysis. The analysis produced four major clusters with different patterns of dysmorphic features. Significant between-cluster differences were found for rates of 37 dysmorphic features (P dysmorphic features (P = 0.0001), and validating features not used in the cluster analysis: mild mental retardation (P = 0.001) and congenital heart defects (P = 0.002). Two clusters (1 and 4) appeared to represent more developmental subgroups of schizophrenia with elevated rates of dysmorphic features and validating features. Cluster 1 (n = 27) comprised mostly referred subjects. Cluster 4 (n= 18) had a different pattern of dysmorphic features; one subject had a mosaic Turner syndrome variant. Two other clusters had lower rates and patterns of features consistent with those found in previous studies of schizophrenia. Delineating patterns of dysmorphic features may help identify subgroups that could represent neurodevelopmental forms of schizophrenia with more homogeneous origins. PMID:11803519

  2. 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.

  3. Intellectual functioning and the long-term course of schizophrenia-spectrum illness

    DEFF Research Database (Denmark)

    Carter, Jessica; Parnas, J; Urfer-Parnas, A

    2010-01-01

    BACKGROUND: Recent neurodevelopmental models of schizophrenia, together with substantial evidence of neurocognitive dysfunction among people with schizophrenia, have led to a widespread view that general cognitive deficits are a central aspect of schizophrenic pathology. However, the temporal...... with an evident family history of schizophrenia....

  4. 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.

  5. Modeling aircraft noise induced sleep disturbance

    Science.gov (United States)

    McGuire, Sarah M.

    occurrence of rapid eye movements, sleep spindles, and slow wave sleep. Using these features an approach for classifying sleep stages every one second during the night was developed. From observation of the results of the sleep stage classification, it was determined how to add faster dynamics to the nonlinear dynamic model. Slow and fast REM activity are modeled separately and the activity in the gamma frequency band of the EEG signal is used to model both spontaneous and noise-induced awakenings. The nonlinear model predicts changes in sleep structure similar to those found by other researchers and reported in the sleep literature and similar to those found in obtained survey data. To compare sleep disturbance model predictions, flight operations data from US airports were obtained and sleep disturbance in communities was predicted for different operations scenarios using the modified Markov model, the nonlinear dynamic model, and other aircraft noise awakening models. Similarities and differences in model predictions were evaluated in order to determine if the use of the developed sleep structure model leads to improved predictions of the impact of nighttime noise on communities.

  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. Effect of semantic coherence on episodic memory processes in schizophrenia.

    Science.gov (United States)

    Battal Merlet, Lâle; Morel, Shasha; Blanchet, Alain; Lockman, Hazlin; Kostova, Milena

    2014-12-30

    Schizophrenia is associated with severe episodic retrieval impairment. The aim of this study was to investigate the possibility that schizophrenia patients could improve their familiarity and/or recollection processes by manipulating the semantic coherence of to-be-learned stimuli and using deep encoding. Twelve schizophrenia patients and 12 healthy controls of comparable age, gender, and educational level undertook an associative recognition memory task. The stimuli consisted of pairs of words that were either related or unrelated to a given semantic category. The process dissociation procedure was used to calculate the estimates of familiarity and recollection processes. Both groups showed enhanced memory performances for semantically related words. However, in healthy controls, semantic relatedness led to enhanced recollection, while in schizophrenia patients, it induced enhanced familiarity. The familiarity estimates for related words were comparable in both groups, indicating that familiarity could be used as a compensatory mechanism in schizophrenia patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. 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.

  9. 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.

  10. Reduced Context Effects on Retrieval in First-Episode Schizophrenia

    NARCIS (Netherlands)

    Talamini, Lucia M.; de Haan, Lieuwe; Nieman, Dorien H.; Linszen, Don H.; Meeter, Martijn

    2010-01-01

    Background: A recent modeling study by the authors predicted that contextual information is poorly integrated into episodic representations in schizophrenia, and that this is a main cause of the retrieval deficits seen in schizophrenia. Methodology/Principal Findings: We have tested this prediction

  11. Reduced context effects on retrieval in first-episode schizophrenia

    NARCIS (Netherlands)

    Talamini, L.M.; de Haan, L.; Nieman, D.H.; Linszen, D.H.; Meeter, M.

    2010-01-01

    Background: A recent modeling study by the authors predicted that contextual information is poorly integrated into episodic representations in schizophrenia, and that this is a main cause of the retrieval deficits seen in schizophrenia. Methodology/Principal Findings: We have tested this prediction

  12. Reduced context effects on retrieval in first-episode schizophrenia

    NARCIS (Netherlands)

    Talamini, L.M.; Haan, L.; Nieman, D.H.; Linszen, D.H.; Meeter, M.

    2010-01-01

    Background: A recent modeling study by the authors predicted that contextual information is poorly integrated into episodic representations in schizophrenia, and that this is a main cause of the retrieval deficits seen in schizophrenia. & Methodology/Principal Findings: We have tested this

  13. Vulnerable self, poor understanding of others' minds, threat anticipation and cognitive biases as triggers for delusional experience in schizophrenia: a theoretical model.

    Science.gov (United States)

    Salvatore, Giampaolo; Lysaker, Paul H; Popolo, Raffaele; Procacci, Michele; Carcione, Antonino; Dimaggio, Giancarlo

    2012-01-01

    It remains unclear what processes lead to the establishment of persecutory delusions in acute phases of schizophrenia. Recently, it has been argued that persecutory delusions arise from an interaction among a range of emotional, cognitive and social factors. In this work, we explored this possibility by first discussing the relevant aspects of recent theoretical models of the causes of persecutory delusions. Then, we offered an analysis of the literature, illustrated with clinical observations suggesting that persecutory delusions are triggered during stressful intersubjective transactions by the interactions of (a) an alteration in empathetic perspective taking and in pragmatic understanding of others' minds; (b) a perception/representation of the self as vulnerable or subordinate and of the other as dominant and threatening; and (c) a hyperfunctioning of the threat/self-protection system when faced with perceived danger. Implications for future research and treatment of people suffering from this symptom are discussed. Copyright © 2011 John Wiley & Sons, Ltd.

  14. Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology

    DEFF Research Database (Denmark)

    Bak, N.; Ebdrup, B.H.; Oranje, B

    2017-01-01

    Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically...... and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per...... day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups...

  15. The Neurobiology of Methamphetamine Induced Psychosis

    Directory of Open Access Journals (Sweden)

    Jennifer Hsin-Wen Hsieh

    2014-07-01

    Full Text Available Chronic methamphetamine abuse commonly leads to psychosis, with positive and cognitive symptoms that are similar to those of schizophrenia. Methamphetamine induced psychosis (MAP can persist and diagnoses of MAP often change to a diagnosis of schizophrenia over time. Studies in schizophrenia have found much evidence of cortical GABAergic dysfunction. Methamphetamine psychosis is a well studied model for schizophrenia, however there is little research on the effects of methamphetamine on cortical GABAergic function in the model, and the neurobiology of MAP is unknown. This paper reviews the effects of methamphetamine on dopaminergic pathways, with focus on its ability to increase glutamate release in the cortex. Excess cortical glutamate would likely damage GABAergic interneurons, and evidence of this disturbance as a result of methamphetamine treatment will be discussed. We propose that cortical GABAergic interneurons are particularly vulnerable to glutamate overflow as a result of subcellular location of NMDA receptors on interneurons in the cortex. Damage to cortical GABAergic function would lead to dysregulation of cortical signals, resulting in psychosis, and further support methamphetamine induced psychosis as a model for schizophrenia.

  16. Heart rate variability response to mental arithmetic stress in patients with schizophrenia Autonomic response to stress in schizophrenia

    NARCIS (Netherlands)

    Castro, Mariana N.; Vigo, Daniel E.; Weidema, Hylke; Fahrer, Rodolfo D.; Chu, Elvina M.; De Achaval, Delfina; Nogues, Martin; Leiguarda, Ramon C.; Cardinali, Daniel P.; Guinjoan, Salvador N.

    Background: The vulnerability-stress hypothesis is an established model of schizophrenia symptom formation. We sought to characterise the pattern of the cardiac autonomic response to mental arithmetic stress in patients with stable schizophrenia. Methods: We performed heart rate variability (HRV)

  17. 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

  18. 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.

  19. Memantine reverses social withdrawal induced by ketamine in rats.

    Science.gov (United States)

    Uribe, Ezequiel; Landaeta, José; Wix, Richard; Eblen, Antonio

    2013-03-01

    The objective of this study was to determine the effect of memantine on schizophrenia-like symptoms in a ketamine-induced social withdrawal model in rats. We examined therapeutic effects of memantine, an NMDA antagonist, and haloperidol, a classic antipsychotic drug, on this behavioral model. Administration of memantine (10 or 15 mg·kg(-1)) significantly reduced ketamine-induced social withdrawal, and this effect was more effective than that of haloperidol (0.25 mg·kg(-1)) by restoring the social interaction between rats with no modification in general motor activity. These results suggest that memantine could have a therapeutic potential for schizophrenia.

  20. 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.

  1. Computational Psychiatry and the Challenge of Schizophrenia

    Science.gov (United States)

    Murray, John D.; Chekroud, Adam M.; Corlett, Philip R.; Yang, Genevieve; Wang, Xiao-Jing; Anticevic, Alan

    2017-01-01

    Abstract Schizophrenia research is plagued by enormous challenges in integrating and analyzing large datasets and difficulties developing formal theories related to the etiology, pathophysiology, and treatment of this disorder. Computational psychiatry provides a path to enhance analyses of these large and complex datasets and to promote the development and refinement of formal models for features of this disorder. This presentation introduces the reader to the notion of computational psychiatry and describes discovery-oriented and theory-driven applications to schizophrenia involving machine learning, reinforcement learning theory, and biophysically-informed neural circuit models. PMID:28338845

  2. [Chronical care of schizophrenia].

    Science.gov (United States)

    Lustygier, V

    2010-09-01

    Schizophrenia is a complex mental disease leading to many deficits that needs a broad range of therapeutic interventions. The recent data raises the importance of the cognitive revalidation even though other interventions are also necessary in the treatment. The asylums of the former century have experienced a slow and continuous process of patient's deinstitutionalization. The global knowledge of the disorder having progressed, new multidisciplinary and multidimensional models of managing are now proposed. The psychiatric rehabilitation is one of those models having as goal the global taking charge of the disease, from the managing of the symptoms to the return to a life with good quality. The great specificity of this rehabilitation work is that it's multidisciplinary and involves a strong collaboration between the medical and the psychosocial intervening party's around a common therapeutic project. This model brings up the notion of recovery witch is, not the cure but, the experience that a patient acquires as he accepts the situation and as he recovers the feeling of being able to get going again.

  3. Cognition-Emotion Dysinteraction in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Alan eAnticevic

    2012-10-01

    Full Text Available Evolving theories of schizophrenia emphasize a ‘disconnection’ in distributed fronto-striatal-limbic neural systems, which may give rise to breakdowns in cognition and emotional function. We discuss these diverse domains of function from the perspective of disrupted neural circuits involved in ‘cold’ cognitive vs. ‘hot’ affective operations and the interplay between these processes. We focus on three research areas that highlight cognition-emotion dysinteractions in schizophrenia: First, we discuss the role of cognitive deficits in the ‘maintenance’ of emotional information. We review recent evidence suggesting that motivational abnormalities in schizophrenia may in part arise due to a disrupted ability to ‘maintain’ affective information over time. Here, dysfunction in a prototypical ‘cold’ cognitive operation may result in ‘affective’ deficits in schizophrenia. Second, we discuss abnormalities in the detection and ascription of salience, manifest as excessive processing of non-emotional stimuli and inappropriate distractibility. We review emerging evidence suggesting deficits in some, but not other, specific emotional processes in schizophrenia – namely an intact ability to perceive emotion ‘in the moment’ but poor prospective valuation of stimuli and heightened reactivity to stimuli that ought to be filtered. Third, we discuss abnormalities in learning mechanisms that may give rise to delusions, the fixed, false and often emotionally charged beliefs that accompany psychosis. We discuss the role of affect in aberrant belief formation, mostly ignored by current theoretical models. Together, we attempt to provide a consilient overview for how breakdowns in neural systems underlying affect and cognition in psychosis interact across symptom domains. We conclude with a brief treatment of the neurobiology of schizophrenia and the need to close our explanatory gap between cellular-level hypotheses and complex

  4. Dopamine, nitric oxide and their interactions in models for the study of schizophrenia / Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

    Directory of Open Access Journals (Sweden)

    Cristiane Salum

    2008-01-01

    Full Text Available Experimental models based on the increase of dopaminergic neurotransmission mimic behavioral and neurochemical schizophrenia-like aspects. Psychostimulants, as amphetamine, are used with this purpose because they increase extracellular dopamine levels in mesocorticolimbic and mesostriatal pathways. The limitations of direct manipulation uniquely based on the dopamine system in animal models have encouraged the use of new approaches. Nitric oxide (NO, an atypical neurotransmitter which inhibits dopamine reuptake and stimulates its release, seems to modulate dopamine-controlled behaviors. The prepulse inhibition test reveals deficits on the sensorimotor filter found in schizophrenics or after psichotomimetic treatments. This review presents evidences for the interaction between NO and DA systems on schizophrenia models as a new tool for the investigation of this pathology.

  5. Treatment-Resistant Schizophrenia

    DEFF Research Database (Denmark)

    Howes, Oliver D; McCutcheon, Rob; Agid, Ofer

    2017-01-01

    OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD: A systematic review of randomize...

  6. [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.

  7. 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.

  8. GABA level, gamma oscillation, and working memory performance in schizophrenia

    OpenAIRE

    Chen, Chi-Ming A.; Stanford, Arielle D.; Mao, Xiangling; Abi-Dargham, Anissa; Shungu, Dikoma C.; Lisanby, Sarah H.; Schroeder, Charles E.; Kegeles, Lawrence S.

    2014-01-01

    A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case–control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance ...

  9. NEUROPSYCHOLOGY OF SCHIZOPHRENIA

    OpenAIRE

    Hugo Selma Sánchez

    2008-01-01

    Neuropsychology has had an explosive grow in the last decades. It contributions to the fields of Psychiatry are growing in an exponential rate. Research related to schizophrenia has bringing new views of the nature of the disease, at the same time offering contradictions and questions pending to resolve. The present article exposes the most relevant discoveries in the neuropshychology of schizophrenia neuroanatomy dysfunctions, development neurofuntionality, alterations in neurotransmitters a...

  10. Finding Genes for Schizophrenia

    OpenAIRE

    Åberg, Karolina

    2005-01-01

    Schizophrenia is one of our most common psychiatric diseases. It severely affects all aspects of psychological functions and results in loss of contact with reality. No cure exists and the treatments available today produce only partial relief for disease symptoms. The aim of this work is to better understand the etiology of schizophrenia by identification of candidate genes and gene pathways involved in the development of the disease. In a preliminarily study, the effects of medication and g...

  11. NEUROPSYCHOLOGY OF SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    Hugo Selma Sánchez

    2008-11-01

    Full Text Available Neuropsychology has had an explosive grow in the last decades. It contributions to the fields of Psychiatry are growing in an exponential rate. Research related to schizophrenia has bringing new views of the nature of the disease, at the same time offering contradictions and questions pending to resolve. The present article exposes the most relevant discoveries in the neuropshychology of schizophrenia neuroanatomy dysfunctions, development neurofuntionality, alterations in neurotransmitters and cognitive deficiencies and areas for exploring.

  12. 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.

  13. Evidence for regional hippocampal damage in patients with schizophrenia

    International Nuclear Information System (INIS)

    Singh, Sadhana; Khushu, Subash; Kumar, Pawan; Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N.

    2018-01-01

    Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ( 1 H MRS) procedures. 1 H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

  14. Evidence for regional hippocampal damage in patients with schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Sadhana; Khushu, Subash; Kumar, Pawan [DRDO, NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi (India); Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N. [RML Hospital, Post Graduate Institute of Medical Education and Research (PGIMER), New Delhi (India)

    2018-02-15

    Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ({sup 1}H MRS) procedures. {sup 1}H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

  15. Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento Translational neuropsychiatry of genetic and neurodevelopmental animal models of schizophrenia

    Directory of Open Access Journals (Sweden)

    Michael G. Gottschalk

    2013-01-01

    Full Text Available Sintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human

  16. Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento Translational neuropsychiatry of genetic and neurodevelopmental animal models of schizophrenia

    Directory of Open Access Journals (Sweden)

    Michael G Gottschalk

    2012-01-01

    Full Text Available Sintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human

  17. Hierarchical Bayesian Modeling of Fluid-Induced Seismicity

    Science.gov (United States)

    Broccardo, M.; Mignan, A.; Wiemer, S.; Stojadinovic, B.; Giardini, D.

    2017-11-01

    In this study, we present a Bayesian hierarchical framework to model fluid-induced seismicity. The framework is based on a nonhomogeneous Poisson process with a fluid-induced seismicity rate proportional to the rate of injected fluid. The fluid-induced seismicity rate model depends upon a set of physically meaningful parameters and has been validated for six fluid-induced case studies. In line with the vision of hierarchical Bayesian modeling, the rate parameters are considered as random variables. We develop both the Bayesian inference and updating rules, which are used to develop a probabilistic forecasting model. We tested the Basel 2006 fluid-induced seismic case study to prove that the hierarchical Bayesian model offers a suitable framework to coherently encode both epistemic uncertainty and aleatory variability. Moreover, it provides a robust and consistent short-term seismic forecasting model suitable for online risk quantification and mitigation.

  18. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia

    Directory of Open Access Journals (Sweden)

    Tomiki eSumiyoshi

    2013-10-01

    Full Text Available Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT receptors in ameliorating cognitive deficits of schizophrenia.It is noteworthy that atypical antipsychotic drugs, e.g. clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence.The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and GABA neurons. A novel strategy for cognitive enhancement in psychosis may be benefitted by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g. event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some atypical antipsychotic drugs acting directly or indirectly on 5-HT1A receptors.These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

  19. The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model.

    Science.gov (United States)

    Murai, Kiyohito; Sun, Guoqiang; Ye, Peng; Tian, E; Yang, Su; Cui, Qi; Sun, Guihua; Trinh, Daniel; Sun, Olivia; Hong, Teresa; Wen, Zhexing; Kalkum, Markus; Riggs, Arthur D; Song, Hongjun; Ming, Guo-li; Shi, Yanhong

    2016-03-11

    Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation.

  20. Comparing implicit and explicit semantic access of direct and indirect word pairs in schizophrenia to evaluate models of semantic memory.

    Science.gov (United States)

    Neill, Erica; Rossell, Susan Lee

    2013-02-28

    Semantic memory deficits in schizophrenia (SZ) are profound, yet there is no research comparing implicit and explicit semantic processing in the same participant sample. In the current study, both implicit and explicit priming are investigated using direct (LION-TIGER) and indirect (LION-STRIPES; where tiger is not displayed) stimuli comparing SZ to healthy controls. Based on a substantive review (Rossell and Stefanovic, 2007) and meta-analysis (Pomarol-Clotet et al., 2008), it was predicted that SZ would be associated with increased indirect priming implicitly. Further, it was predicted that SZ would be associated with abnormal indirect priming explicitly, replicating earlier work (Assaf et al., 2006). No specific hypotheses were made for implicit direct priming due to the heterogeneity of the literature. It was hypothesised that explicit direct priming would be intact based on the structured nature of this task. The pattern of results suggests (1) intact reaction time (RT) and error performance implicitly in the face of abnormal direct priming and (2) impaired RT and error performance explicitly. This pattern confirms general findings regarding implicit/explicit memory impairments in SZ whilst highlighting the unique pattern of performance specific to semantic priming. Finally, priming performance is discussed in relation to thought disorder and length of illness. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. The genetic validation of heterogeneity in schizophrenia.

    Science.gov (United States)

    Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

    2011-10-07

    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. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  2. Unrecognised myocardial infarction in patients with schizophrenia

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Juel, Jacob; Alzuhairi, Karam

    2015-01-01

    OBJECTIVE: Schizophrenia is associated with a reduction of the lifespan by 20 years, with type II diabetes and cardiovascular disease contributing the most to the increased mortality. Unrecognised or silent myocardial infarction (MI) occurs in ~30% of the population, but the rates of unrecognised...... MI in patients with schizophrenia have only been sparsely investigated. METHOD: Electrocardiograms (ECG) from three psychiatric hospitals in Denmark were manually interpreted for signs of previous MI. Subsequently, ECGs were linked to the National Patient Registry in order to determine whether...... with unrecognised MI in a stepwise multiple logistic regression model compared with patients with no history of MI, OR: 1.03 per year of age, 95% CI: 1.00-1.06, p=0.021. CONCLUSION: Unrecognised MI is common among patients with schizophrenia and may contribute to the increased mortality found in this patient group....

  3. Social priming increases nonverbal expressive behaviors in schizophrenia.

    Directory of Open Access Journals (Sweden)

    Jonathan Del-Monte

    Full Text Available Semantic priming tasks are classically used to influence and implicitly promote target behaviors. Recently, several studies have demonstrated that prosocial semantic priming modulated feelings of social affiliation. The main aim of this study was to determine whether inducing feelings of social affiliation using priming tasks could modulate nonverbal social behaviors in schizophrenia. We used the Scrambled Sentence Task to prime schizophrenia patients according to three priming group conditions: pro-social, non-social or anti-social. Forty-five schizophrenia patients, diagnosed according to DSM-IV-TR, were randomly assigned to one of the three priming groups of 15 participants. We evaluated nonverbal social behaviors using the Motor-Affective subscale of the Motor-Affective-Social-Scale. Results showed that schizophrenia patients with pro-social priming had significantly more nonverbal behaviors than schizophrenia patients with anti-social and non-social priming conditions. Schizophrenia patient behaviors are affected by social priming. Our results have several clinical implications for the rehabilitation of social skills impairments frequently encountered among individuals with schizophrenia.

  4. Examining Belief and Confidence in Schizophrenia

    Science.gov (United States)

    Joyce, Dan W.; Averbeck, Bruno B.; Frith, Chris D.; Shergill, Sukhwinder S.

    2018-01-01

    Background People with psychoses often report fixed, delusional beliefs that are sustained even in the presence of unequivocal contrary evidence. Such delusional beliefs are the result of integrating new and old evidence inappropriately in forming a cognitive model. We propose and test a cognitive model of belief formation using experimental data from an interactive “Rock Paper Scissors” game. Methods Participants (33 controls and 27 people with schizophrenia) played a competitive, time-pressured interactive two-player game (Rock, Paper, Scissors). Participant’s behavior was modeled by a generative computational model using leaky-integrator and temporal difference methods. This model describes how new and old evidence is integrated to form both a playing strategy to beat the opponent and provide a mechanism for reporting confidence in one’s playing strategy to win against the opponent Results People with schizophrenia fail to appropriately model their opponent’s play despite consistent (rather than random) patterns that can be exploited in the simulated opponent’s play. This is manifest as a failure to weigh existing evidence appropriately against new evidence. Further, participants with schizophrenia show a ‘jumping to conclusions’ bias, reporting successful discovery of a winning strategy with insufficient evidence. Conclusions The model presented suggests two tentative mechanisms in delusional belief formation – i) one for modeling patterns in other’s behavior, where people with schizophrenia fail to use old evidence appropriately and ii) a meta-cognitive mechanism for ‘confidence’ in such beliefs where people with schizophrenia overweight recent reward history in deciding on the value of beliefs about the opponent. PMID:23521846

  5. Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology

    DEFF Research Database (Denmark)

    Bak, N.; Ebdrup, B.H.; Oranje, B

    2017-01-01

    Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically...... different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients...... be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors...

  6. Neurodevelopmental correlates in schizophrenia

    Directory of Open Access Journals (Sweden)

    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

  7. Spontaneous Gamma Activity in Schizophrenia.

    Science.gov (United States)

    Hirano, Yoji; Oribe, Naoya; Kanba, Shigenobu; Onitsuka, Toshiaki; Nestor, Paul G; Spencer, Kevin M

    2015-08-01

    A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30

  8. Self construction in schizophrenia: a discourse analysis.

    Science.gov (United States)

    Meehan, Trudy; MacLachlan, Malcolm

    2008-06-01

    Lysaker and Lysaker (Theory and Psychology, 12(2), 207-220, 2002) employ a dialogical theory of self in their writings on self disruption in schizophrenia. It is argued here that this theory could be enriched by incorporating a discursive and social constructionist model of self. Harr's model enables researchers to use subject positions to identify self construction in people with a diagnosis of schizophrenia that the dialogical model, using analysis of narrative, does not as easily recognize. The paper presents a discourse analysis of self construction in eight participants with a diagnosis of schizophrenia. Transcripts from semi-structured interviews are analysed, wherein focus falls on how participants construct self in talk through the use of subject positioning. The findings indicate that Harr's theory of self and the implied method of discourse analysis enables more subtle and nuanced constructions of self to be identified than those highlighted by Lysaker and Lysaker (Theory and Psychology, 12(2), 207-220, 2002). The analysis of subject positions revealed that participants constructed self in the form of Harr's (The singular self: An introduction to the psychology of personhood, 1998, London: Sage) self1, self2, and self3. The findings suggest that there may be constructions of self used by people diagnosed with schizophrenia that are not recognized by the current research methods focusing on narrative. The paper argues for the recognition of these constructions and by implication a model of self that takes into account different levels of visibility of self construction in talk.

  9. Delayed early proprioceptive information processing in schizophrenia

    DEFF Research Database (Denmark)

    Arnfred, Sidse M; Hemmingsen, RP; Parnas, Josef

    2006-01-01

    . In the patients, the early contralateral parietal activity was delayed and later central activity had increased amplitude, but gating was unaffected. The results could be understood within the "deficiency of corollary discharge" model of schizophrenia but not within the "filtering" theory. Further studies...

  10. 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 ...

  11. Fetal programming of schizophrenia: select mechanisms.

    Science.gov (United States)

    Debnath, Monojit; Venkatasubramanian, Ganesan; Berk, Michael

    2015-02-01

    Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Three-factor model of premorbid adjustment in a sample with chronic schizophrenia and first-episode psychosis.

    Science.gov (United States)

    Barajas, Ana; Usall, Judith; Baños, Iris; Dolz, Montserrat; Villalta-Gil, Victoria; Vilaplana, Miriam; Autonell, Jaume; Sánchez, Bernardo; Cervilla, Jorge A; Foix, Alexandrina; Obiols, Jordi E; Haro, Josep Maria; Ochoa, Susana

    2013-12-01

    The dimensionality of premorbid adjustment (PA) has been a debated issue, with attempts to determine whether PA is a unitary construct or composed of several independent domains characterized by a differential deterioration pattern and specific outcome correlates. This study examines the factorial structure of PA, as well as, the course and correlates of its domains. Retrospective study of 84 adult patients experiencing first-episode psychosis (FEP) (n=33) and individuals with schizophrenia (SCH) (n=51). All patients were evaluated with a comprehensive battery of instruments including clinical, functioning and neuropsychological variables. A principal component analysis accompanied by a varimax rotation method was used to examine the factor structure of the PAS-S scale. Paired t tests and Wilcoxon rank tests were used to assess the changes in PAS domains over time. Bivariate correlation analyses were performed to analyse the relationship between PAS factors and clinical, social and cognitive variables. PA was better explained by three factors (71.65% of the variance): Academic PA, Social PA and Socio-sexual PA. The academic domain showed higher scores of PA from childhood. Social and clinical variables were more strongly related to Social PA and Socio-sexual PA domains, and the Academic PA domain was exclusively associated with cognitive variables. This study supports previous evidence, emphasizing the validity of dividing PA into its sub-components. A differential deterioration pattern and specific correlates were observed in each PA domains, suggesting that impairments in each PA domain might predispose individuals to develop different expressions of psychotic dimensions. © 2013.

  13. 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.

  14. 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.

  15. The neuroproteomics of schizophrenia.

    LENUS (Irish Health Repository)

    English, Jane A

    2011-01-15

    Proteomics is the study of global gene expression of an organ, body system, fluid, or cellular compartment at the protein level. Proteomic findings are reflective of complex gene × environment interactions, and the importance of this is increasingly appreciated in schizophrenia research. In this review, we outline the main proteomic methods available to researchers in this area and summarize, for the first time, the findings of the main quantitative neuroproteomic investigations of schizophrenia brain. Our review of these data revealed 16 gray matter proteins, and eight white matter proteins that were differentially expressed in the same direction in two or more investigations. Pathway analysis identified cellular assembly and organization as particularly disrupted in both gray and white matter, whereas the glycolysis-gluconeogenesis pathway was the major signaling pathway significantly altered in both. Reassuringly, these findings show remarkable convergence with functional pathways and positional candidate genes implicated from genomic studies. The specificity of schizophrenia proteomic findings are also addressed in the context of neuroproteomic investigations of neurodegenerative disorders and bipolar disorder. Finally, we discuss the major challenges in the field of neuroproteomics, such as the need for high throughput validation methods and optimal sample preparation. Future directions in the neuroproteomics of schizophrenia, including the use of blood-based biomarker work, the need to focus on subproteomes, and the increasing use of mass spectrometry-based methods are all discussed. This area of research is still in its infancy and offers huge potential to our understanding of schizophrenia on a cellular level.

  16. Cognition-emotion dysinteraction in schizophrenia.

    Science.gov (United States)

    Anticevic, Alan; Corlett, Philip R

    2012-01-01

    Evolving theories of schizophrenia emphasize a "disconnection" in distributed fronto-striatal-limbic neural systems, which may give rise to breakdowns in cognition and emotional function. We discuss these diverse domains of function from the perspective of disrupted neural circuits involved in "cold" cognitive vs. "hot" affective operations and the interplay between these processes. We focus on three research areas that highlight cognition-emotion dysinteractions in schizophrenia: First, we discuss the role of cognitive deficits in the "maintenance" of emotional information. We review recent evidence suggesting that motivational abnormalities in schizophrenia may in part arise due to a disrupted ability to "maintain" affective information over time. Here, dysfunction in a prototypical "cold" cognitive operation may result in "affective" deficits in schizophrenia. Second, we discuss abnormalities in the detection and ascription of salience, manifest as excessive processing of non-emotional stimuli and inappropriate distractibility. We review emerging evidence suggesting deficits in some, but not other, specific emotional processes in schizophrenia - namely an intact ability to perceive emotion "in-the-moment" but poor prospective valuation of stimuli and heightened reactivity to stimuli that ought to be filtered. Third, we discuss abnormalities in learning mechanisms that may give rise to delusions, the fixed, false, and often emotionally charged beliefs that accompany psychosis. We highlight the role of affect in aberrant belief formation, mostly ignored by current theoretical models. Together, we attempt to provide a consilient overview for how breakdowns in neural systems underlying affect and cognition in psychosis interact across symptom domains. We conclude with a brief treatment of the neurobiology of schizophrenia and the need to close our explanatory gap between cellular-level hypotheses and complex behavioral symptoms observed in this illness.

  17. Effects of induced stress on seismic forward modelling and inversion

    Science.gov (United States)

    Tromp, Jeroen; Trampert, Jeannot

    2018-05-01

    We demonstrate how effects of induced stress may be incorporated in seismic modelling and inversion. Our approach is motivated by the accommodation of pre-stress in global seismology. Induced stress modifies both the equation of motion and the constitutive relationship. The theory predicts that induced pressure linearly affects the unstressed isotropic moduli with a slope determined by their adiabatic pressure derivatives. The induced deviatoric stress produces anisotropic compressional and shear wave speeds; the latter result in shear wave splitting. For forward modelling purposes, we determine the weak form of the equation of motion under induced stress. In the context of the inverse problem, we determine induced stress sensitivity kernels, which may be used for adjoint tomography. The theory is illustrated by considering 2-D propagation of SH waves and related Fréchet derivatives based on a spectral-element method.

  18. Geographical and temporal variations in clozapine prescription for schizophrenia

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Røge, Rasmus; Schjerning, Ole

    2012-01-01

    Despite its unsurpassed efficacy in treatment-resistant schizophrenia, clozapine remains underutilized. Trends in the prescription of clozapine in patients with ICD-10 F20.x schizophrenia were assessed using data from Danish national registers. Three substudies were carried out: (i) an assessment...... of differences in national prescription patterns between 1996 and 2007 using a cross-sectional design; (ii) a comparison of time from first schizophrenia diagnosis to first prescription of clozapine in a five-year cohort study, using the Cox regression model, of two patient groups who were first diagnosed...

  19. Mysticism and schizophrenia

    DEFF Research Database (Denmark)

    Parnas, Josef; Henriksen, Mads Gram

    2016-01-01

    Mysticism and schizophrenia are different categories of human existence and experience. Nonetheless, they exhibit important phenomenological affinities, which, however, remain largely unaddressed. In this study, we explore structural analogies between key features of mysticism and major clinical......-phenomenological aspects of the schizophrenia spectrum disorders-i.e. attitudes, the nature of experience, and the 'other', mystical or psychotic reality. Not only do these features gravitate around the issue of the basic dimensions of consciousness, they crucially seem to implicate and presuppose a specific alteration...

  20. 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.

  1. [Epigenetics of schizophrenia: a review].

    Science.gov (United States)

    Rivollier, F; Lotersztajn, L; Chaumette, B; Krebs, M-O; Kebir, O

    2014-10-01

    -translational histone modifications. First, in terms of epidemiology and transmission, the theoretical model of epigenetics applies to schizophrenia. Then, most environmental factors that have proved a link with this disease, may generate epigenetic mechanisms. Next, mutations have been found in regions implied in epigenetic mechanism among populations with schizophrenia. Some epigenetic alterations in DNA regions have been previously linked with neurodevelopmental abnormalities. In psychosis, some authors have found methylation differences in COMT gene, in reelin gene and in some genes implicated in dopaminergic, serotoninergic, GABAergic and glutamatergic pathways. Histone modifications have been described, in particular the H3L4 histone methylation. Finally, we tried to underline the difficulties in epigenetic research, notably in psychiatry, and the limits in this matter. The epigenetic field may explain a lot of questions around the physiopathology of the complex psychiatric disease that is schizophrenia. It may be a substratum to the prevailing hypothesis of gene x environment interaction. The research in the matter is definitely expanding. It justifies easily the need to improve the effort in the domain to overpass some limits inherent to the matter. Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  2. Impairment of probabilistic reward-based learning in schizophrenia.

    Science.gov (United States)

    Weiler, Julia A; Bellebaum, Christian; Brüne, Martin; Juckel, Georg; Daum, Irene

    2009-09-01

    Recent models assume that some symptoms of schizophrenia originate from defective reward processing mechanisms. Understanding the precise nature of reward-based learning impairments might thus make an important contribution to the understanding of schizophrenia and the development of treatment strategies. The present study investigated several features of probabilistic reward-based stimulus association learning, namely the acquisition of initial contingencies, reversal learning, generalization abilities, and the effects of reward magnitude. Compared to healthy controls, individuals with schizophrenia exhibited attenuated overall performance during acquisition, whereas learning rates across blocks were similar to the rates of controls. On the group level, persons with schizophrenia were, however, unable to learn the reversal of the initial reward contingencies. Exploratory analysis of only the subgroup of individuals with schizophrenia who showed significant learning during acquisition yielded deficits in reversal learning with low reward magnitudes only. There was further evidence of a mild generalization impairment of the persons with schizophrenia in an acquired equivalence task. In summary, although there was evidence of intact basic processing of reward magnitudes, individuals with schizophrenia were impaired at using this feedback for the adaptive guidance of behavior.

  3. Toward a comprehensive areal model of earthquake-induced landslides

    Science.gov (United States)

    Miles, S.B.; Keefer, D.K.

    2009-01-01

    This paper provides a review of regional-scale modeling of earthquake-induced landslide hazard with respect to the needs for disaster risk reduction and sustainable development. Based on this review, it sets out important research themes and suggests computing with words (CW), a methodology that includes fuzzy logic systems, as a fruitful modeling methodology for addressing many of these research themes. A range of research, reviewed here, has been conducted applying CW to various aspects of earthquake-induced landslide hazard zonation, but none facilitate comprehensive modeling of all types of earthquake-induced landslides. A new comprehensive areal model of earthquake-induced landslides (CAMEL) is introduced here that was developed using fuzzy logic systems. CAMEL provides an integrated framework for modeling all types of earthquake-induced landslides using geographic information systems. CAMEL is designed to facilitate quantitative and qualitative representation of terrain conditions and knowledge about these conditions on the likely areal concentration of each landslide type. CAMEL is highly modifiable and adaptable; new knowledge can be easily added, while existing knowledge can be changed to better match local knowledge and conditions. As such, CAMEL should not be viewed as a complete alternative to other earthquake-induced landslide models. CAMEL provides an open framework for incorporating other models, such as Newmark's displacement method, together with previously incompatible empirical and local knowledge. ?? 2009 ASCE.

  4. Neurological Soft Signs, Spontaneous and Treatment Emergent Extrapyramidal Syndromes in Black Africans With First Episode Schizophrenia

    Directory of Open Access Journals (Sweden)

    Akin Ojagbemi

    2018-05-01

    Full Text Available Background: Very little is known about the relationship between spontaneous and treatment-induced motor syndromes in Africans with first episode schizophrenia.Objective: We investigated the association between spontaneous NSS and EPS, with treatment-induced EPS in a homogenous sample of Black Africans with first episode schizophrenia.Methods: We examined Xhosa (South Africa and Yoruba (Nigeria patients, using the Neurological Evaluation Scale and extrapyramidal symptoms scale before and at 3 months after exposure to low dose flupenthixol decanoate. Pearson's correlations and Linear regression models, controlling for duration of untreated psychosis (D.U.P and premorbid adjustments, were used in examining associations.Results: Among 99 participants in the baseline sample, 91 (91.8% and 20 (20.2% had at least one definite NSS and EPS, respectively, before exposure to antipsychotics. Treatment-induced EPS were recorded in 34 (38.6%. Spontaneous EPS was associated with treatment-emergent Akathisia in participants with a longer D.U.P (r = 0.75, β = 0.70, p = 0.008. This association was specific for Parkinsonism (r = 0.75, β = 0.85, p = 0.008 and dyskinesia (r = 0.75, β = 1.70, p = 0.008.Conclusion: Similar to previous findings for tardive dyskinesia in studies implementing longer-term follow-up, spontaneous EPS may also predict short-term antipsychotic-induced EPS such as akathisia. These results may be important for early identification of patients at risk of treatment-induced Akathisia-linked psychomotor agitation in first episode schizophrenia.

  5. A brief overview of models of nucleon-induced reactions

    International Nuclear Information System (INIS)

    Carlson, B.V.

    2003-01-01

    The basic features of low to intermediate energy nucleon-induced reactions are discussed within the contexts of the optical model, the statistical model, preequilibrium and intranuclear cascade models. The calculation of cross sections and other scattering quantities are described. (author)

  6. Literature review on induced exposure models, Task 2 HS-270

    Science.gov (United States)

    1982-02-01

    Sections 1, 2 and 3 of this report describe the development of : induced exposure models, together with d discussion of questions : of validity. These Sections focus on the most important and : relevant results from the literature, while Appendix A c...

  7. Hubble induced mass after inflation in spectator field models

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Tomohiro [Stanford Institute for Theoretical Physics and Department of Physics, Stanford University, Stanford, CA 94306 (United States); Harigaya, Keisuke, E-mail: tomofuji@stanford.edu, E-mail: keisukeh@icrr.u-tokyo.ac.jp [Department of Physics, University of California, Berkeley, CA 94720 (United States)

    2016-12-01

    Spectator field models such as the curvaton scenario and the modulated reheating are attractive scenarios for the generation of the cosmic curvature perturbation, as the constraints on inflation models are relaxed. In this paper, we discuss the effect of Hubble induced masses on the dynamics of spectator fields after inflation. We pay particular attention to the Hubble induced mass by the kinetic energy of an oscillating inflaton, which is generically unsuppressed but often overlooked. In the curvaton scenario, the Hubble induced mass relaxes the constraint on the property of the inflaton and the curvaton, such as the reheating temperature and the inflation scale. We comment on the implication of our discussion for baryogenesis in the curvaton scenario. In the modulated reheating, the predictions of models e.g. the non-gaussianity can be considerably altered. Furthermore, we propose a new model of the modulated reheating utilizing the Hubble induced mass which realizes a wide range of the local non-gaussianity parameter.

  8. Animal Models of Chemotherapy-induced Mucositis

    DEFF Research Database (Denmark)

    Sangild, Per T; Shen, René Liang; Pontoppidan, Peter Erik Lotko

    2018-01-01

    constitution). Here, we briefly describe CIM pathophysiology, particularly the basic knowledge that has been obtained from CIM animal models. These model studies have indicated potential new preventive and ameliorating interventions, including supplementation with natural bioactive diets (e.g. milk fractions...... easier make clinically-relevant treatment regimens possible. In synergy, animal models improve the basic pathophysiological understanding of CIM and provide new ideas for treatment that are required to make competent decisions in clinical practice....

  9. Mania associated with paliperidone treatment in schizophrenia: A case report

    Directory of Open Access Journals (Sweden)

    Süleyman Demir

    2015-09-01

    Full Text Available Paliperidone is an atypical antipsychotic drug used to treat schizophrenia. Paliperidone can cause some rare side effects during treatment. Despite many publications of mania and hypomania induced by antipsychotics, mania cases induced by paliperidone are few in the literature. In this case a schizophrenia patient showing symptoms of mania during usage of paliperidone with a dose of 9 mg/day in which the symptoms rapidly disappeared after discontinuation of paliperidone and initiation of aripiprazole was reported. Clinicians should be aware of that Paliperidone treatment may trigger mania symptoms. J Clin Exp Invest 2015; 6 (3: 321-323

  10. Schizophrenia, Sleep and Acupuncture

    NARCIS (Netherlands)

    Bosch, M.P.C.; Noort, M.W.M.L. van den

    2008-01-01

    This book is an introduction for professionals in Western medicine and for acupuncturists on the use of acupuncture in treatment of schizophrenia and sleep disorders. Acupuncture has long been used in Traditional Chinese Medicine (TCM) in mental health and sleep disorders. This book aims to build a

  11. Depression in Kraepelinian schizophrenia

    African Journals Online (AJOL)

    related problems and poorer social and family relationships, show a lower level of ... Furthermore, suicide terminates the lives of an estimated 10 - 15% ... deterioration of functioning in social, work and self-care domains. .... quality of life in outpatients with schizophrenia spectrum disorders? ... Acta Psychiatr Scand 2002;.

  12. Neural chaos and schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Bob, P.; Chládek, Jan; Šusta, M.; Glaslová, K.; Jagla, F.; Kukleta, M.

    2007-01-01

    Roč. 26, č. 4 (2007), s. 298-305 ISSN 0231-5882 Institutional research plan: CEZ:AV0Z20650511 Keywords : EDA * Lyapunov exponent * schizophrenia * chaos Subject RIV: FL - Psychiatry, Sexuology Impact factor: 1.286, year: 2007

  13. Glutamatergic System and Schizophrenia

    Directory of Open Access Journals (Sweden)

    Osman Ozdemir

    2016-12-01

    Full Text Available Glutamate is the major excitatory neurotransmitter in the brain. It has a role several cognitive functions including learning, memory and perception. Glutamatergic neurotransmission is also involved in regulating neuronal migration, synaptogenesis, and the pruning neurons. Glutamatergic exci-totoxicity has been implicated in various neuropsychiatric disorders. Accumulating evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia. The N-methyl-D-aspartic acid (NMDA receptor antagonists such as phencyclidine and ketamine can cause both the positive and negative symptoms psychotic symptoms in normal humans, and worsen these symptoms in persons with schizophrenia. Hence, it has been hypotesized that schizophrenia may be associated with decreased NMDA-receptor activity. According to the hypothesis, NMDA reseptor hypofunction can lead to decreased inhibition of glutamatergic neurons and excessive glutamate release. Finally, the reduction of gray matter in several brain regions seen in patients with schizophrenia has been suggested to be the result of neurotoxicity mediated by NMDA receptors. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2016; 8(4.000: 394-405

  14. Social cognition in schizophrenia

    NARCIS (Netherlands)

    Maat, A.

    2014-01-01

    Schizophrenia is a chronic psychiatric disorder, incorporating a wide range of symptoms that may occur at certain stages of the disease. The core symptoms can largely be divided into positive symptoms, e.g. hallucinations and delusions, and negative symptoms, e.g. apathia and emotional flattening.

  15. Iconic decay in schizophrenia.

    Science.gov (United States)

    Hahn, Britta; Kappenman, Emily S; Robinson, Benjamin M; Fuller, Rebecca L; Luck, Steven J; Gold, James M

    2011-09-01

    Working memory impairment is considered a core deficit in schizophrenia, but the precise nature of this deficit has not been determined. Multiple lines of evidence implicate deficits at the encoding stage. During encoding, information is held in a precategorical sensory store termed iconic memory, a literal image of the stimulus with high capacity but rapid decay. Pathologically increased iconic decay could reduce the number of items that can be transferred into working memory before the information is lost and could thus contribute to the working memory deficit seen in the illness. The current study used a partial report procedure to test the hypothesis that patients with schizophrenia (n = 37) display faster iconic memory decay than matched healthy control participants (n = 28). Six letters, arranged in a circle, were presented for 50 ms. Following a variable delay of 0-1000 ms, a central arrow cue indicated the item to be reported. In both patients and control subjects, recall accuracy decreased with increasing cue delay, reflecting decay of the iconic representation of the stimulus array. Patients displayed impaired memory performance across all cue delays, consistent with an impairment in working memory, but the rate of iconic memory decay did not differ between patients and controls. This provides clear evidence against faster loss of iconic memory representations in schizophrenia, ruling out iconic decay as an underlying source of the working memory impairment in this population. Thus, iconic decay rate can be added to a growing list of unimpaired cognitive building blocks in schizophrenia.

  16. Aberrant cerebellar connectivity in motor and association networks in schizophrenia

    Directory of Open Access Journals (Sweden)

    Ann K. Shinn

    2015-03-01

    Full Text Available Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the cognitive dysmetria and dysmetria of thought models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of

  17. D-galactose-induced brain ageing model

    DEFF Research Database (Denmark)

    Sadigh-Eteghad, Saeed; Majdi, Alireza; McCann, Sarah K.

    2017-01-01

    Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent...

  18. 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.

  19. Early and sustained dynamic intervention in schizophrenia

    DEFF Research Database (Denmark)

    Rosenbaum, Bent; Rosenbaum, Bent

    2009-01-01

    This paper is based on the Danish National Schizophrenia Project manual for psychodynamic individual psychotherapy with persons in states of schizophrenia. The methods for engaging with and treating a patient with schizophrenia in a supportive, psychodynamic way are described....

  20. Smoking improves divided attention in schizophrenia.

    Science.gov (United States)

    Ahlers, Eike; Hahn, Eric; Ta, Thi Minh Tam; Goudarzi, Elnaz; Dettling, Michael; Neuhaus, Andres H

    2014-10-01

    Smoking is highly prevalent in schizophrenia, and there is evidence for beneficial effects on neurocognition. Smoking is therefore hypothesized a self-medication in schizophrenia. Although much effort is devoted to characterize those cognitive domains that potentially benefit from smoking, divided attention has not yet been investigated. The aim of this study was to analyze the interactional effects of diagnosis of schizophrenia and smoking history on divided attention. We investigated behavioral measures of divided attention in a sample of 48 schizophrenic patients and 48 controls (24 current smokers and non-smokers each) carefully matched for age, sex, education, verbal IQ, and smoking status with general linear models. Most important within the scope of this study, significant interactions were found for valid reactions and errors of omission: Performance substantially increased in smoking schizophrenic patients, but not in controls. Further, these interactions were modified by sex, driven by female schizophrenic patients who showed a significant behavioral advantage of smokers over non-smokers, other than male schizophrenic patients or healthy controls who did not express this sex-specific pattern. Results suggest a positive effect of smoking history on divided attention in schizophrenic patients. This study provides first evidence that the complex attention domain of divided attention is improved by smoking, which further substantiates the self-medication hypothesis of smoking in schizophrenia, although this has been shown mainly for sustained and selective attention. Gender-specific effects on cognition need to be further investigated.

  1. Is schizophrenia developmental adaptation to environmental menaces?

    Science.gov (United States)

    Goto, Yukiori; Lee, Young-A

    2011-11-01

    Schizophrenia is a devastating mental disorder, with its symptoms typically emerging during late adolescence to young adulthood. In contrast, accumulating evidence suggests that schizophrenia is a developmental disorder in which brain abnormalities may occur even before birth. This has brought the major challenge to explain such discrepancy of brain deficits occurring during prenatal period and emergence of symptoms during adulthood. A number of ideas have been proposed to explain delayed emergence of symptoms at adulthood in relation to maturational processes of various brain systems during adolescence. However, these still lack clear relationship to prenatal deficits. Thus, a key to better understand the pathology of schizophrenia is to unveil a theory or model that can explain the relationship between prenatal deficits and post-pubertal onset of symptoms. Here we propose a novel hypothesis, along with discussion of several lines of evidences supporting it, that schizophrenia may not be a disorder in a strict sense, but rather be understood as the biological state occurring as consequence of adaptation to severe environmental conditions during the prenatal periods, which explains the relationship between prenatal developmental deficits and the postnatal maturational process for onset of symptoms. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Smeared crack modelling approach for corrosion-induced concrete damage

    DEFF Research Database (Denmark)

    Thybo, Anna Emilie Anusha; Michel, Alexander; Stang, Henrik

    2017-01-01

    In this paper a smeared crack modelling approach is used to simulate corrosion-induced damage in reinforced concrete. The presented modelling approach utilizes a thermal analogy to mimic the expansive nature of solid corrosion products, while taking into account the penetration of corrosion...... products into the surrounding concrete, non-uniform precipitation of corrosion products, and creep. To demonstrate the applicability of the presented modelling approach, numerical predictions in terms of corrosion-induced deformations as well as formation and propagation of micro- and macrocracks were......-induced damage phenomena in reinforced concrete. Moreover, good agreements were also found between experimental and numerical data for corrosion-induced deformations along the circumference of the reinforcement....

  3. Computer modelling of radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Khvostunov, Igor K.; Nikjoo, Hooshang

    2002-01-01

    Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be a protein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles. (author)

  4. Olanzapine-induced weight gain: lessons learned from developing rat models

    OpenAIRE

    van der Zwaal, E.M.

    2011-01-01

    Olanzapine is an effective and commonly prescribed antipsychotic drug, used for the treatment of schizophrenia and bipolar disorder. Unfortunately significant weight gain is a common side effect. In order to effectively address this side effect, it is crucial to gain insight into the underlying mechanisms. Therefore, this thesis describes the development of a number of rat models that were designed to determine the effects of olanzapine on different aspects of energy balance. In both short- a...

  5. Modeling of glutamate-induced dynamical patterns

    DEFF Research Database (Denmark)

    Faurby-Bentzen, Christian Krefeld; Zhabotinsky, A.M.; Laugesen, Jakob Lund

    2009-01-01

    Based on established physiological mechanisms, the paper presents a detailed computer model, which supports the hypothesis that temporal lobe epilepsy may be caused by failure of glutamate reuptake from the extracellular space. The elevated glutamate concentration causes an increased activation...

  6. induced cerebral injury in a rat model

    African Journals Online (AJOL)

    Results: There was a significant decrease in neurological deficit, brain oedema, and volume of ... This is an Open Access article that uses a funding model which does not charge readers or .... Moreover, the percentage of infarct volume was.

  7. SU-F-I-67: Neurometabolic Effect Induced by Repeated Exposure to Dizocilpine On Prefrontal Cortex of Schizophrenic Animal Model Using In Vivo Proton Magnetic Resonance Spectroscopy at 9.4 T

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, C-H; Lim, S-I [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Song, K-H; Choe, B-Y [Department of Biomedical Engineering, and Research Institute of Biomedical Engineering, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Woo, D-C [Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of)

    2016-06-15

    Purpose: Repeated exposure of dizocilpine (MK-801) can provide a pathophysiological model for progressive development of schizophrenia. In vivo proton magnetic resonance spectroscopy ({sup 1}H MRS) was widely used for non-invasive measurement of neurometabolites, and assessment of disease-induced neurometabolic alterations. The purpose of this study was to investigate neurometabolic alteration in prefrontal cortex (PFC) with respect to progression (from first-episode to chronic stage) of schizophrenia by using in vivo {sup 1}H MRS. Methods: We used high-field {sup 1}H MRS to investigate the neurometabolic alteration in the PFC region of the rats (N = 13) by comparing before and after 6 day of MK-801 (0.5 mg/kg) treatment. A point-resolved spectroscopy (PRESS) sequence was used to obtain spectra in a 22.5 µL of volume of interest carefully located in PFC region with parameters like follow; repetition time, 5000ms; echo time (TE), 13.4 ms; averages = 256. Another experiment group (N = 11) were conducted behavior test by recording the behavior for 20 min. Results: All the rats showed hyperlocomotion, stereotyped behaviors before initiation of MRS. Significantly increased level (N = 7, p < 0.05) of N-acetylasrparate (NAA), glutamate (Glu), taurine and decreased level (N = 6, p < 0.05) of NAA, Glu and phosphocreatine were observed between baseline and day 6. Both metabolic alterations are consistent with results of first-episode and chronic schizophrenia respectively. Conclusion: From our findings, the repeated MK-801 model could be a pathophysiological model which can provide an insight into the transition from first-episode to chronic stage. This is first time to investigate effects of repeated MK-801 using high-field in vivo 1H MRS. We expect our findings can contribute to combining previous diverging results into one pathophysiological interpretation, which can postulate the origin of diverging results to the progression of schizophrenia.

  8. SU-F-I-67: Neurometabolic Effect Induced by Repeated Exposure to Dizocilpine On Prefrontal Cortex of Schizophrenic Animal Model Using In Vivo Proton Magnetic Resonance Spectroscopy at 9.4 T

    International Nuclear Information System (INIS)

    Yoo, C-H; Lim, S-I; Song, K-H; Choe, B-Y; Woo, D-C

    2016-01-01

    Purpose: Repeated exposure of dizocilpine (MK-801) can provide a pathophysiological model for progressive development of schizophrenia. In vivo proton magnetic resonance spectroscopy ("1H MRS) was widely used for non-invasive measurement of neurometabolites, and assessment of disease-induced neurometabolic alterations. The purpose of this study was to investigate neurometabolic alteration in prefrontal cortex (PFC) with respect to progression (from first-episode to chronic stage) of schizophrenia by using in vivo "1H MRS. Methods: We used high-field "1H MRS to investigate the neurometabolic alteration in the PFC region of the rats (N = 13) by comparing before and after 6 day of MK-801 (0.5 mg/kg) treatment. A point-resolved spectroscopy (PRESS) sequence was used to obtain spectra in a 22.5 µL of volume of interest carefully located in PFC region with parameters like follow; repetition time, 5000ms; echo time (TE), 13.4 ms; averages = 256. Another experiment group (N = 11) were conducted behavior test by recording the behavior for 20 min. Results: All the rats showed hyperlocomotion, stereotyped behaviors before initiation of MRS. Significantly increased level (N = 7, p < 0.05) of N-acetylasrparate (NAA), glutamate (Glu), taurine and decreased level (N = 6, p < 0.05) of NAA, Glu and phosphocreatine were observed between baseline and day 6. Both metabolic alterations are consistent with results of first-episode and chronic schizophrenia respectively. Conclusion: From our findings, the repeated MK-801 model could be a pathophysiological model which can provide an insight into the transition from first-episode to chronic stage. This is first time to investigate effects of repeated MK-801 using high-field in vivo 1H MRS. We expect our findings can contribute to combining previous diverging results into one pathophysiological interpretation, which can postulate the origin of diverging results to the progression of schizophrenia.

  9. An integrated model for radiation induced cancer

    International Nuclear Information System (INIS)

    Hall, E.J.; Varma, M.

    1994-01-01

    Risk estimates for radiation induced cancer are based on epidemiological data, principally the Japanese A bomb survivors. These estimates for radiation are better known than for any other environmental pollutant, but they do not relate directly to exposure to low doses and low dose rate. Recent rapid advances in molecular genetics, coupled with steady gains in cellular biology, radiation physics and chemistry led to the notion that the time may not be far off when it may be possible to arrive at human cancer risk estimates entirely from laboratory data. Whether risk estimates based on laboratory data will ever replace estimates based on epidemiological studies is an open question. What is clear is that laboratory data can supplement the present risk estimates by providing information on the relative effectiveness of high LET radiations, the importance of dose rate and dose protraction, and by identifying subpopulations which are unusually sensitive or resistant to radiation carcinogenesis. (author)

  10. Radiation-induced segregation in model alloys

    Science.gov (United States)

    Ezawa, T.; Wakai, E.; Oshima, R.

    2000-12-01

    The dependence of the size factor of solutes on radiation-induced segregation (RIS) was studied. Ni-Si, Ni-Co, Ni-Cu, Ni-Mn, Ni-Pd, and Ni-Nb binary solid solution alloys were irradiated with electrons in a high voltage electron microscope at the same irradiation conditions. A focused beam and a grain boundary were utilized to generate a flow of point defects to cause RIS. From the concentration profile obtained by an energy dispersive X-ray analysis, the amount of RIS was calculated. The amount of RIS decreased as the size of the solute increased up to about 10%. However, as the size increased further, the amount of RIS increased. This result shows that RIS is not simply determined by the size effect rule.

  11. 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.

  12. Zuclopenthixol dihydrochloride for schizophrenia.

    Science.gov (United States)

    Bryan, Edward J; Purcell, Marie Ann; Kumar, Ajit

    2017-11-16

    Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra-pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses. To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register. All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data. We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.Data were unavailable for many of our pre-stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.Zuclopenthixol dihydrochloride versus: 1. placeboMovement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low-quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low-quality evidence). 2. chlorpromazineNo clear differences were found for

  13. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

    Science.gov (United States)

    Levite, Mia

    2014-08-01

    .g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1

  15. Can we use mice to study schizophrenia?

    Science.gov (United States)

    Canetta, Sarah; Kellendonk, Christoph

    2018-03-19

    The validity of rodent models for the study of psychiatric disorders is controversial. Despite great efforts from academic institutions and pharmaceutical companies, as of today, no major therapeutic intervention has been developed for the treatment of psychiatric disorders based on mechanistic insights from rodent models. Here, we argue that despite these historical shortcomings, rodent studies are nevertheless instrumental for identifying neuronal circuit mechanisms underlying behaviours that are affected in psychiatric disorders. Focusing on schizophrenia, we will give four examples of rodent models that were generated based on genetic and environmental risk factors or pathophysiological evidence as entry points. We will then discuss how circuit analysis in these specific examples can be used for testing hypotheses about neuronal mechanisms underlying symptoms of schizophrenia, which will then guide the development of new therapies.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'. © 2018 The Author(s).

  16. 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

  17. Anterior cingulate cortex-related connectivity in first-episode schizophrenia: a spectral dynamic causal modeling study with functional magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Long-Biao eCui

    2015-11-01

    Full Text Available Understanding the neural basis of schizophrenia (SZ is important for shedding light on the neurobiological mechanisms underlying this mental disorder. Structural and functional alterations in the anterior cingulate cortex (ACC, dorsolateral prefrontal cortex (DLPFC, hippocampus, and medial prefrontal cortex (MPFC have been implicated in the neurobiology of SZ. However, the effective connectivity among them in SZ remains unclear. The current study investigated how neuronal pathways involving these regions were affected in first-episode SZ using functional magnetic resonance imaging (fMRI. Forty-nine patients with a first-episode of psychosis and diagnosis of SZ—according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision—were studied. Fifty healthy controls (HCs were included for comparison. All subjects underwent resting state fMRI. We used spectral dynamic causal modeling (DCM to estimate directed connections among the bilateral ACC, DLPFC, hippocampus, and MPFC. We characterized the differences using Bayesian parameter averaging (BPA in addition to classical inference (t-test. In addition to common effective connectivity in these two groups, HCs displayed widespread significant connections predominantly involved in ACC not detected in SZ patients, but SZ showed few connections. Based on BPA results, SZ patients exhibited anterior cingulate cortico-prefrontal-hippocampal hyperconnectivity, as well as ACC-related and hippocampal-dorsolateral prefrontal-medial prefrontal hypoconnectivity. In summary, sDCM revealed the pattern of effective connectivity involving ACC in patients with first-episode SZ. This study provides a potential link between SZ and dysfunction of ACC, creating an ideal situation to associate mechanisms behind SZ with aberrant connectivity among these cognition and emotion-related regions.

  18. Preventing Noise-Induced Extinction in Discrete Population Models

    Directory of Open Access Journals (Sweden)

    Irina Bashkirtseva

    2017-01-01

    Full Text Available A problem of the analysis and prevention of noise-induced extinction in nonlinear population models is considered. For the solution of this problem, we suggest a general approach based on the stochastic sensitivity analysis. To prevent the noise-induced extinction, we construct feedback regulators which provide a low stochastic sensitivity and keep the system close to the safe equilibrium regime. For the demonstration of this approach, we apply our mathematical technique to the conceptual but quite representative Ricker-type models. A variant of the Ricker model with delay is studied along with the classic widely used one-dimensional system.

  19. A knowledge-Induced Operator Model

    Directory of Open Access Journals (Sweden)

    M.A. Choudhury

    2007-06-01

    Full Text Available Learning systems are in the forefront of analytical investigation in the sciences. In the social sciences they occupy the study of complexity and strongly interactive world-systems. Sometimes they are diversely referred to as symbiotics and semiotics when studied in conjunction with logical expressions. In the mathematical sciences the methodology underlying learning systems with complex behavior is based on formal logic or systems analysis. In this paper relationally learning systems are shown to transcend the space-time domain of scientific investigation into the knowledge dimension. Such a knowledge domain is explained by pervasive interaction leading to integration and followed by continuous evolution as complementary processes existing between entities and systemic domains in world-systems, thus the abbreviation IIE-processes. This paper establishes a mathematical characterization of the properties of knowledge-induced process-based world-systems in the light of the epistemology of unity of knowledge signified in this paper by extensive complementarities caused by the epistemic and ontological foundation of the text of unity of knowledge, the prime example of which is the realm of the divine laws. The result is formalism in mathematical generalization of the learning phenomenon by means of an operator. This operator summarizes the properties of interaction, integration and evolution (IIE in the continuum domain of knowledge formation signified by universal complementarities across entities, systems and sub-systems in unifying world-systems. The opposite case of ‘de-knowledge’ and its operator is also briefly formalized.

  20. Genetic correlates of insight in schizophrenia.

    Science.gov (United States)

    Xavier, Rose Mary; Vorderstrasse, Allison; Keefe, Richard S E; Dungan, Jennifer R

    2018-05-01

    Insight in schizophrenia is clinically important as it is associated with several adverse outcomes. Genetic contributions to insight are unknown. We examined genetic contributions to insight by investigating if polygenic risk scores (PRS) and candidate regions were associated with insight. Schizophrenia case-only analysis of the Clinical Antipsychotics Trials of Intervention Effectiveness trial. Schizophrenia PRS was constructed using Psychiatric Genomics Consortium (PGC) leave-one out GWAS as discovery data set. For candidate regions, we selected 105 schizophrenia-associated autosomal loci and 11 schizophrenia-related oligodendrocyte genes. We used regressions to examine PRS associations and set-based testing for candidate analysis. We examined data from 730 subjects. Best-fit PRS at p-threshold of 1e-07 was associated with total insight (R 2 =0.005, P=0.05, empirical P=0.054) and treatment insight (R 2 =0.005, P=0.048, empirical P=0.048). For models that controlled for neurocognition, PRS significantly predicted treatment insight but at higher p-thresholds (0.1 to 0.5) but did not survive correction. Patients with highest polygenic burden had 5.9 times increased risk for poor insight compared to patients with lowest burden. PRS explained 3.2% (P=0.002, empirical P=0.011) of variance in poor insight. Set-based analyses identified two variants associated with poor insight- rs320703, an intergenic variant (within-set P=6e-04, FDR P=0.046) and rs1479165 in SOX2-OT (within-set P=9e-04, FDR P=0.046). To the best of our knowledge, this is the first study examining genetic basis of insight. We provide evidence for genetic contributions to impaired insight. Relevance of findings and necessity for replication are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Values in First-Episode Schizophrenia.

    Science.gov (United States)

    Agid, Ofer; Mcdonald, Krysta; Fervaha, Gagan; Littrell, Romie; Thoma, Jessica; Zipursky, Robert B; Foussias, George; Remington, Gary

    2015-11-01

    Functional impairment continues to represent a major challenge in schizophrenia. Surprisingly, patients with schizophrenia report a level of happiness comparable with control subjects, even in the face of the prominent functional deficits, a finding at odds with evidence indicating a positive relation between happiness and level of functioning. In attempting to reconcile these findings, we chose to examine the issue of values, defined as affectively infused criteria or motivational goals used to select and justify actions, people, and the self, as values are related to both happiness and functioning. Fifty-six first-episode patients in remission and 56 healthy control subjects completed happiness and values measures. Statistical analyses included correlations, analysis of variance, structural equation modelling, and smallest space analysis. Results indicated that patients with schizophrenia placed significantly greater priority on the value dimensions of Tradition (P = 0.02) and Power (P = 0.03), and significantly less priority on Self-direction (P = 0.007) and Stimulation, (P = 0.008). Essentially, people with schizophrenia place more emphasis on the customs and ideas that traditional culture or religion provide in conjunction with a decreased interest in change, which is at odds with the expectations of early adulthood. This value difference could be related to functional deficits. To this point, we have assumed that people hold to the same values that guided them before the illness' onset, but this may not be the case. Our study indicates that values differ in people with schizophrenia, compared with control subjects, even early in the illness and in the face of symptomatic remission.

  2. Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

    NARCIS (Netherlands)

    Reddy, Venkatesh Pilla; Kozielska, Magdalena; Johnson, Martin; Mafirakureva, Nyashadzaishe; Vermeulen, An; Liu, Jing; de Greef, Rik; Rujescu, Dan; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.

    2013-01-01

    The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective

  3. 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...

  4. Modeling tsunamis induced by retrogressive submarine landslides

    Science.gov (United States)

    Løvholt, F.; Kim, J.; Harbitz, C. B.

    2015-12-01

    Enormous submarine landslides having volumes up to thousands of km3 and long run-out may cause tsunamis with widespread effects. Clay-rich landslides, such as Trænadjupet and Storegga offshore Norway commonly involve retrogressive mass and momentum release mechanisms that affect the tsunami generation. Therefore, such landslides may involve a large amount of smaller blocks. As a consequence, the failure mechanisms and release rate of the individual blocks are of importance for the tsunami generation. Previous attempts to model the tsunami generation due to retrogressive landslides are few, and limited to idealized conditions. Here, we review the basic effects of retrogression on tsunamigenesis in simple geometries. To this end, two different methods are employed for the landslide motion, a series block with pre-scribed time lags and kinematics, and a dynamic retrogressive model where the inter-block time lag is determined by the model. The effect of parameters such as time lag on wave-height, wave-length, and dispersion are discussed. Finally, we discuss how the retrogressive effects may have influenced the tsunamis due to large landslides such as the Storegga slide. The research leading to these results has received funding from the Research Council of Norway under grant number 231252 (Project TsunamiLand) and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 603839 (Project ASTARTE).

  5. Investigation of cigarette smoking among male schizophrenia patients.

    Directory of Open Access Journals (Sweden)

    Jundong Jiang

    Full Text Available Male schizophrenia patients are known to have a heavier smoking pattern compared with the general population. However, the mechanism for this association is not known, though hypothesis that smoking could alleviate symptomatology of schizophrenia and reduce side effects of antipsychotics has been suggested. The aims of this study were to validate the heavier smoking pattern among male schizophrenia patients and to investigate the possible mechanisms for the association. To enhance the reliability of the study, we recruited two large independent samples with 604 and 535 male Chinese schizophrenia patients, and compared their smoking pattern with that of 535 healthy male controls recruited from general population. Validated multiple indicators and multiple causes structure equation model and regression models were used to investigate the association of smoking with factors of schizophrenia symptomatology and with the usage of antipsychotics and their extra-pyramidal side effects (EPS. Schizophrenia patients had significantly heavier smoking pattern compared with healthy controls in our sample (42.4% vs. 16.8%, p<0.001 for current smoking prevalence; 23.5% vs. 43.3%, p<0.001 for smoking cessation rate; 24.5% vs. 3.0%, p<0.001 for heavy smoker proportion. Their smoking status was also found to be consistently and significantly associated with reduced negative factor scores for schizophrenia symptomatology (β = -0.123, p = 0.051 for sample-A; β = -0.103, p = 0.035 for sample-B; β = -0.082, p = 0.017 for the combined sample. However, no significant association was found between smoking and antipsychotics usage or risk of EPS. These results support that smoking is associated with improved negative symptoms, which could account for the heavier smoking pattern among schizophrenia patients.

  6. Source characterization and dynamic fault modeling of induced seismicity

    Science.gov (United States)

    Lui, S. K. Y.; Young, R. P.

    2017-12-01

    In recent years there are increasing concerns worldwide that industrial activities in the sub-surface can cause or trigger damaging earthquakes. In order to effectively mitigate the damaging effects of induced seismicity, the key is to better understand the source physics of induced earthquakes, which still remain elusive at present. Furthermore, an improved understanding of induced earthquake physics is pivotal to assess large-magnitude earthquake triggering. A better quantification of the possible causes of induced earthquakes can be achieved through numerical simulations. The fault model used in this study is governed by the empirically-derived rate-and-state friction laws, featuring a velocity-weakening (VW) patch embedded into a large velocity-strengthening (VS) region. Outside of that, the fault is slipping at the background loading rate. The model is fully dynamic, with all wave effects resolved, and is able to resolve spontaneous long-term slip history on a fault segment at all stages of seismic cycles. An earlier study using this model has established that aseismic slip plays a major role in the triggering of small repeating earthquakes. This study presents a series of cases with earthquakes occurring on faults with different fault frictional properties and fluid-induced stress perturbations. The effects to both the overall seismicity rate and fault slip behavior are investigated, and the causal relationship between the pre-slip pattern prior to the event and the induced source characteristics is discussed. Based on simulation results, the subsequent step is to select specific cases for laboratory experiments which allow well controlled variables and fault parameters. Ultimately, the aim is to provide better constraints on important parameters for induced earthquakes based on numerical modeling and laboratory data, and hence to contribute to a physics-based induced earthquake hazard assessment.

  7. On incomprehensibility in schizophrenia

    DEFF Research Database (Denmark)

    Henriksen, Mads Gram

    2013-01-01

    the notion of understanding that deems these delusions incomprehensible and to see if it is possible to comprehend these delusions if we apply another notion of understanding. First, I discuss the contemporary schizophrenia definitions and their inherent problems, and I argue that the notion...... of incomprehensibility in these definitions rests heavily on Jaspers’ notions of understanding and empathy. Secondly, I discuss two Wittgensteinian attempts to comprehend bizarre delusions: (a) Campbell’s proposal to conceive delusions as framework propositions and (b) Sass’s suggestion to interpret delusions...... in the light of solipsism. Finally, I discuss the phenomenological conception of schizophrenia, which conceives delusion formation as resulting from alterations of the structure of experiencing and from underlying self-disorders. I argue that although a psychological understanding that seeks to grasp meaning...

  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. Token economy for schizophrenia.

    LENUS (Irish Health Repository)

    McMonagle, T

    2000-01-01

    A token economy is a behavioural therapy technique in which the desired change is achieved by means of tokens administered for the performance of predefined behaviours according to a program. Though token economy programmes were widespread in the 1970s they became largely restricted to wards where long-stay patients from institutions are prepared for transfer into the community and were particularly aimed at changing negative symptoms of schizophrenia - poor motivation, poor attention and social withdrawal.

  10. MRI anatomy of schizophrenia

    OpenAIRE

    McCarley, Robert William; Wible, Cynthia Gayle; Frumin, Melissa; Hirayasu, Yoshio; Levitt, James Jonathan; Fischer, Iris A.; Shenton, Martha Elizabeth

    1999-01-01

    Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer–reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ven...

  11. Iconic Decay in Schizophrenia

    OpenAIRE

    Hahn, Britta; Kappenman, Emily S.; Robinson, Benjamin M.; Fuller, Rebecca L.; Luck, Steven J.; Gold, James M.

    2010-01-01

    Working memory impairment is considered a core deficit in schizophrenia, but the precise nature of this deficit has not been determined. Multiple lines of evidence implicate deficits at the encoding stage. During encoding, information is held in a precategorical sensory store termed iconic memory, a literal image of the stimulus with high capacity but rapid decay. Pathologically increased iconic decay could reduce the number of items that can be transferred into working memory before the info...

  12. Hypoxia-induced retinopathy model in adult zebrafish

    DEFF Research Database (Denmark)

    Cao, Ziquan; Jensen, Lasse D.; Rouhi, Pegah

    2010-01-01

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available....... In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia......-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs....

  13. Modeling of environmentally induced transients within satellites

    Science.gov (United States)

    Stevens, N. John; Barbay, Gordon J.; Jones, Michael R.; Viswanathan, R.

    1987-01-01

    A technique is described that allows an estimation of possible spacecraft charging hazards. This technique, called SCREENS (spacecraft response to environments of space), utilizes the NASA charging analyzer program (NASCAP) to estimate the electrical stress locations and the charge stored in the dielectric coatings due to spacecraft encounter with a geomagnetic substorm environment. This information can then be used to determine the response of the spacecraft electrical system to a surface discharge by means of lumped element models. The coupling into the electronics is assumed to be due to magnetic linkage from the transient currents flowing as a result of the discharge transient. The behavior of a spinning spacecraft encountering a severe substorm is predicted using this technique. It is found that systems are potentially vulnerable to upset if transient signals enter through the ground lines.

  14. Aging women with schizophrenia.

    Science.gov (United States)

    Pentland, Wendy; Miscio, Gina; Eastabrook, Shirley; Krupa, Terry

    2003-01-01

    The purpose of this study was to describe the aging experiences of women with schizophrenia. The research focused on how participants viewed their own aging with schizophrenia, their perceived worries and concerns and how they were coping with aging with the disorder. Using a qualitative approach, data were collected using multiple in-depth interviews with six participants selected purposefully from the client list of a community mental health center. Interview transcriptions were coded and analyzed according to the study questions using QSR Nudist 4 software. Several categories and sub-categories emerged. These included the improvement in the illness over time; physical and daily living activity limitations; specific positive and negative changes that the women report have accompanied aging; the profound losses experienced by the participants when they were younger as a result of having schizophrenia; and how these losses have affected their present lives in terms of limiting available informal support, creating dependency on formal programs and services, and participants' fears of the future. Based on the study findings, implications for mental health practice and services are considered and suggestions are made to guide future research.

  15. [Psychoeducation in schizophrenia].

    Science.gov (United States)

    Zapata Ospina, Juan Pablo; Rangel Martínez-Villalba, Andrés Mauricio; García Valencia, Jenny

    2015-01-01

    The treatment of schizophrenia includes the use of psychotropic drugs, psychotherapy, and psychosocial interventions that include psychoeducation. This strategy has been defined as the delivery of information about the disorder and its treatment in a systematic and structured way. To review the literature on the efficacy of psychoeducation in schizophrenia. A search in PubMed, SciELO, EMBASE and PsycINFO was made with the terms "psychoeducation", "schizophrenia" and "psychosocial intervention". Articles in Spanish and English language were reviewed. Psychoeducation can be applied to patients, family or both, and individually or in groups. The number of sessions can vary. There have been many studies that seek to determine the efficacy of psychoeducation in the clinical course, family dynamics and stigma, with results that favor its implementation, but so far it has not been possible to determine exactly how best to apply psychoeducation, mainly because of the great variability of designs. The studies on psychoeducation have shown efficacy. However, this might be an overestimation, as there is a high risk of bias. Consequently, there is not enough evidence. At least for now, it is reasonable to complement pharmacotherapy with psycoeducation. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  16. Scene construction in schizophrenia.

    Science.gov (United States)

    Raffard, Stéphane; D'Argembeau, Arnaud; Bayard, Sophie; Boulenger, Jean-Philippe; Van der Linden, Martial

    2010-09-01

    Recent research has revealed that schizophrenia patients are impaired in remembering the past and imagining the future. In this study, we examined patients' ability to engage in scene construction (i.e., the process of mentally generating and maintaining a complex and coherent scene), which is a key part of retrieving past experiences and episodic future thinking. 24 participants with schizophrenia and 25 healthy controls were asked to imagine new fictitious experiences and described their mental representations of the scenes in as much detail as possible. Descriptions were scored according to various dimensions (e.g., sensory details, spatial reference), and participants also provided ratings of their subjective experience when imagining the scenes (e.g., their sense of presence, the perceived similarity of imagined events to past experiences). Imagined scenes contained less phenomenological details (d = 1.11) and were more fragmented (d = 2.81) in schizophrenia patients compared to controls. Furthermore, positive symptoms were positively correlated to the sense of presence (r = .43) and the perceived similarity of imagined events to past episodes (r = .47), whereas negative symptoms were negatively related to the overall richness of the imagined scenes (r = -.43). The results suggest that schizophrenic patients' impairments in remembering the past and imagining the future are, at least in part, due to deficits in the process of scene construction. The relationships between the characteristics of imagined scenes and positive and negative symptoms could be related to reality monitoring deficits and difficulties in strategic retrieval processes, respectively. Copyright 2010 APA, all rights reserved.

  17. Shock-induced electrical activity in polymeric solids. A mechanically induced bond scission model

    International Nuclear Information System (INIS)

    Graham, R.A.

    1979-01-01

    When polymeric solids are subjected to high-pressure shock loading, two anomalous electrical phenomena, shock-induced conduction and shock-induced polarization, are observed. The present paper proposes a model of mechanically induced bond scission within the shock front to account for the effects. An experimental study of shock-induced polarization in poly(pyromellitimide) (Vespel SP-1) is reported for shock compressions from 17 to 23% (pressures from 2.5 to 5.4 GPa). Poly(pyromellitimide) is found to be a strong generator of such polarization and the polarization is found to reflect an irreversible or highly hysteretic process. The present measurements are combined with prior measurements to establish a correlation between monomer structure and strength of shock-induced polarization; feeble signals are observed in the simpler monomer repeat units of poly(tetrafluoroethylene) and polyethylene while the strongest signals are observed in more complex monomers of poly(methyl methacrylate) and poly(pyromellitimide). It is also noted that there is an apparent correlation between shock-induced conduction and shock-induced polarization. Such shock-induced electrical activity is also found to be well correlated with the propensity for mechanical bond scission observed in experiments carried out in conventional mechanochemical studies. The bond scission model can account for characteristics observed for electrical activity in shock-loaded polymers and their correlation to monomer structure. Localization of elastic energy within the monomer repeat unit or along the main chain leads to the different propensities for bond scission and resulting shock-induced electrical activity

  18. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

    Directory of Open Access Journals (Sweden)

    Sunil Vasu Kalmady

    Full Text Available Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6 in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic

  19. Mechanistic issues for modeling radiation-induced segregation

    International Nuclear Information System (INIS)

    Simonen, E.P.; Bruemmer, S.M.

    1993-03-01

    Model calculations of radiation-induced chromium depletion and radiation-induced nickel enrichment at grain boundaries are compared to measured depletions and enrichments. The model is calibrated to fit chromium depletion in commercial purity 304 stainless steel irradiated in boiling water reactor (BWR) environments. Predicted chromium depletion profiles and the dose dependence of chromium concentration at grain boundaries are in accord with measured trends. Evaluation of chromium and nickel profiles in three neutron, and two ion, irradiation environments reveal significant inconsistencies between measurements and predictions

  20. 1D models for condensation induced water hammer in pipelines

    International Nuclear Information System (INIS)

    Bloemeling, Frank; Neuhas, Thorsten; Schaffrath, Andreas

    2013-01-01

    Condensation induced water hammer (CIWH) are caused by contact of steam and subcooled water. Thus, modeling the direct contact condensation is a crucial step towards the simulation of condensation induced water hammer with 1D pressure surge codes. Therefore, also the TUeV NORD SysTec GmbH and Co. KG inhouse pressure surge code DYVRO has been equipped with a new contact condensation model. The validation of DYVRO against an experiment dealing with CIWH is presented in this contribution. (orig.)

  1. 1D models for condensation induced water hammer in pipelines

    Energy Technology Data Exchange (ETDEWEB)

    Bloemeling, Frank; Neuhas, Thorsten; Schaffrath, Andreas [TUEV NORD SysTec GmbH und Co. KG, Hamburg (Germany)

    2013-03-15

    Condensation induced water hammer (CIWH) are caused by contact of steam and subcooled water. Thus, modeling the direct contact condensation is a crucial step towards the simulation of condensation induced water hammer with 1D pressure surge codes. Therefore, also the TUeV NORD SysTec GmbH and Co. KG inhouse pressure surge code DYVRO has been equipped with a new contact condensation model. The validation of DYVRO against an experiment dealing with CIWH is presented in this contribution. (orig.)

  2. Atomistic modeling of ion beam induced amorphization in silicon

    International Nuclear Information System (INIS)

    Pelaz, Lourdes; Marques, Luis A.; Lopez, Pedro; Santos, Ivan; Aboy, Maria; Barbolla, Juan

    2005-01-01

    Ion beam induced amorphization in Si has attracted significant interest since the beginning of the use of ion implantation for the fabrication of Si devices. Nowadays, a renewed interest in the modeling of amorphization mechanisms at atomic level has arisen due to the use of preamorphizing implants and high dopant implantation doses for the fabrication of nanometric-scale Si devices. In this work, we briefly describe the existing phenomenological and defect-based amorphization models. We focus on the atomistic model we have developed to describe ion beam induced amorphization in Si. In our model, the building block for the amorphous phase is the bond defect or IV pair, whose stability increases with the number of surrounding IV pairs. This feature explains the regrowth behavior of different damage topologies and the kinetics of the crystalline to amorphous transition. The model provides excellent quantitative agreement with experimental results

  3. Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization.

    Science.gov (United States)

    Villacampa, Pilar; Menger, Katja E; Abelleira, Laura; Ribeiro, Joana; Duran, Yanai; Smith, Alexander J; Ali, Robin R; Luhmann, Ulrich F; Bainbridge, James W B

    2017-01-01

    Retinal ischemia and pathological angiogenesis cause severe impairment of sight. Oxygen-induced retinopathy (OIR) in young mice is widely used as a model to investigate the underlying pathological mechanisms and develop therapeutic interventions. We compared directly the conventional OIR model (exposure to 75% O2 from postnatal day (P) 7 to P12) with an alternative, accelerated version (85% O2 from P8 to P11). We found that accelerated OIR induces similar pre-retinal neovascularization but greater retinal vascular regression that recovers more rapidly. The extent of retinal gliosis is similar but neuroretinal function, as measured by electroretinography, is better maintained in the accelerated model. We found no systemic or maternal morbidity in either model. Accelerated OIR offers a safe, reliable and more rapid alternative model in which pre-retinal neovascularization is similar but retinal vascular regression is greater.

  4. Motivation and Social Cognition in Patients with Schizophrenia.

    Science.gov (United States)

    Fervaha, Gagan; Siddiqui, Ishraq; Foussias, George; Agid, Ofer; Remington, Gary

    2015-07-01

    Social cognition, referring to one's ability to perceive and process social cues, is an important domain in schizophrenia. Numerous studies have demonstrated that patients with schizophrenia have poorer performance on tests assessing social cognition relative to healthy comparison participants. However, whether variables such as motivation are related to performance on these tests in patients with schizophrenia is unclear. One thousand three-hundred and seventy-eight patients with schizophrenia completed the Facial Emotion Discrimination Task as a measure of emotional processing, a key facet of social cognition. Level of motivation was also evaluated in these patients using a derived measure from the Quality of Life Scale. The relationship between motivation and task performance was examined using bivariate correlations and logistic regression modeling, controlling for the impact of age and overall severity of psychopathology, the latter evaluated using the Positive and Negative Syndrome Scale. Motivation was positively related to performance on the social cognition test, and this relationship remained significant after controlling for potential confounding variables such as age and illness severity. Social cognition was also related to functioning, and the relationship was mediated by level of motivation. The present study found a significant relationship between motivation and performance on a test of social cognition in a large sample of patients with schizophrenia. These findings suggest that amotivation undermines task performance, or alternatively that poor social cognitive ability impedes motivation. Future studies evaluating social cognition in patients with schizophrenia should concurrently assess for variables such as effort and motivation.

  5. Gastroenterology issues in schizophrenia: why the gut matters.

    Science.gov (United States)

    Severance, Emily G; Prandovszky, Emese; Castiglione, James; Yolken, Robert H

    2015-05-01

    Genetic and environmental studies implicate immune pathologies in schizophrenia. The body's largest immune organ is the gastrointestinal (GI) tract. Historical associations of GI conditions with mental illnesses predate the introduction of antipsychotics. Current studies of antipsychotic-naïve patients support that gut dysfunction may be inherent to the schizophrenia disease process. Risk factors for schizophrenia (inflammation, food intolerances, Toxoplasma gondii exposure, cellular barrier defects) are part of biological pathways that intersect those operant in the gut. Central to GI function is a homeostatic microbial community, and early reports show that it is disrupted in schizophrenia. Bioactive and toxic products derived from digestion and microbial dysbiosis activate adaptive and innate immunity. Complement C1q, a brain-active systemic immune component, interacts with gut-related schizophrenia risk factors in clinical and experimental animal models. With accumulating evidence supporting newly discovered gut-brain physiological pathways, treatments to ameliorate brain symptoms of schizophrenia should be supplemented with therapies to correct GI dysfunction.

  6. 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.

  7. 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

  8. Aripiprazole in schizophrenia and schizoaffective disorder: A review.

    Science.gov (United States)

    Stip, Emmanuel; Tourjman, Valérie

    2010-01-01

    , insomnia, and agitation. These effects were usually transient. The evidence suggests that aripiprazole is unlikely to be associated with clinically significant weight gain or dyslipidemia, increased prolactin levels, or prolongation of the QTc interval. Compared with placebo, aripiprazole has been reported to have a relatively low potential for inducing metabolic syndrome. Based on the evidence reviewed, aripiprazole monotherapy appears to be effective and well tolerated in treating the positive, negative, and cognitive symptoms of schizophrenia and schizoaffective disorder. It was associated with a low risk for the common adverse effects of antipsychotic therapy, including metabolic and endocrine alterations. 2010 Excerpta Medica Inc. All rights reserved.

  9. 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

  10. Dietary models for inducing hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Sheyla Leite Matos

    2005-03-01

    Full Text Available The present work aimed at finding a dietetical model capable of promoting the highest hypercholesterolemia without affecting the development of the rats. Sixty female Fisher rats were divided into five groups. The first one was fed a control diet; the remaining four were fed hypercholesterolemic diets with cholesterol and different contents of soybean oil, starch, casein, micronutrients and fiber and, consequently, different caloric values. After eight weeks animals were evaluated in relation to growth, fecal excretion, liver weight and fat, cholesterol and its fractions, serum biochemical parameters and sistolic pressure and compared with controls. The best result was obtained with the diet containing 25 % soybean oil, 1.0 % cholesterol, 13 % fiber and 4,538.4 Kcal/Kg, since it promoted an increase in LDL-cholesterol, a decrease in the HDL fraction and affected less the hepatic function of the animals.Modelos animais têm sido usados para investigar a relação entre desordens no metabolismo do colesterol e a aterogênese. A estratégia utilizada a fim de induzir hipercolesterolemia (dietas com alto teor de gordura e com colesterol adicionado leva à redução de sua ingestão pelos animais, o que induz desnutrição. O presente trabalho objetivou encontrar um modelo dietético capaz de promover a maior hipercolesterolemia, sem afetar o desenvolvimento dos animais. Sessenta ratas Fisher foram divididas em cinco grupos. O primeiro foi alimentado com uma dieta controle; os quatros restantes receberam dietas hipercolesterolêmicas, com colesterol e diferentes teores de óleo de soja, amido, caseína, micronutrientes e fibra e, conseqüentemente, diferentes valores calóricos. Após oito semanas os animais foram avaliados em relação ao crescimento, excreção fecal, peso e teor de gordura do fígado, colesterol e suas frações, parâmetros bioquímicos séricos e pressão sistólica. Os melhores resultados foram obtidos com a dieta contendo 25

  11. Prevalence of schizophrenia: recent developments

    African Journals Online (AJOL)

    The long held view that schizophrenia affects about 1% of the population has been shown to be an overestimate and in fact derived from incorrect data.1 Also, for many years, it was believed that the prevalence of schizophrenia varied little between sites.2,3 It is in fact the case that the estimates of the prevalence of ...

  12. 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

  13. The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice.

    Science.gov (United States)

    Qvist, Per; Christensen, Jane Hvarregaard; Vardya, Irina; Rajkumar, Anto Praveen; Mørk, Arne; Paternoster, Veerle; Füchtbauer, Ernst-Martin; Pallesen, Jonatan; Fryland, Tue; Dyrvig, Mads; Hauberg, Mads Engel; Lundsberg, Birgitte; Fejgin, Kim; Nyegaard, Mette; Jensen, Kimmo; Nyengaard, Jens Randel; Mors, Ole; Didriksen, Michael; Børglum, Anders Dupont

    2017-07-01

    The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1 +/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters. Brd1 +/- mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1 +/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D 2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]). Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic

  14. Evaluation of induced seismicity forecast models in the Induced Seismicity Test Bench

    Science.gov (United States)

    Király, Eszter; Gischig, Valentin; Zechar, Jeremy; Doetsch, Joseph; Karvounis, Dimitrios; Wiemer, Stefan

    2016-04-01

    Induced earthquakes often accompany fluid injection, and the seismic hazard they pose threatens various underground engineering projects. Models to monitor and control induced seismic hazard with traffic light systems should be probabilistic, forward-looking, and updated as new data arrive. Here, we propose an Induced Seismicity Test Bench to test and rank such models. We apply the test bench to data from the Basel 2006 and Soultz-sous-Forêts 2004 geothermal stimulation projects, and we assess forecasts from two models that incorporate a different mix of physical understanding and stochastic representation of the induced sequences: Shapiro in Space (SiS) and Hydraulics and Seismics (HySei). SiS is based on three pillars: the seismicity rate is computed with help of the seismogenic index and a simple exponential decay of the seismicity; the magnitude distribution follows the Gutenberg-Richter relation; and seismicity is distributed in space based on smoothing seismicity during the learning period with 3D Gaussian kernels. The HySei model describes seismicity triggered by pressure diffusion with irreversible permeability enhancement. Our results show that neither model is fully superior to the other. HySei forecasts the seismicity rate well, but is only mediocre at forecasting the spatial distribution. On the other hand, SiS forecasts the spatial distribution well but not the seismicity rate. The shut-in phase is a difficult moment for both models in both reservoirs: the models tend to underpredict the seismicity rate around, and shortly after, shut-in. Ensemble models that combine HySei's rate forecast with SiS's spatial forecast outperform each individual model.

  15. Modeling compaction-induced energy dissipation of granular HMX

    Energy Technology Data Exchange (ETDEWEB)

    Gonthier, K.A. [Lamar Univ., Beaumont, TX (US). Dept. of Mechanical Engineering; Menikoff, R.; Son, S.F.; Asay, B.W. [Los Alamos National Lab., NM (US)

    1998-12-31

    A thermodynamically consistent model is developed for the compaction of granular solids. The model is an extension of the single phase limit of two-phase continuum models used to describe Deflagration-to-Detonation Transition (DDT) experiments. The focus is on the energetics and dissipation of the compaction process. Changes in volume fraction are partitioned into reversible and irreversible components. Unlike conventional DDT models, the model is applicable from the quasi-static to dynamic compaction regimes for elastic, plastic, or brittle materials. When applied to the compaction of granular HMX (a brittle material), the model predicts results commensurate with experiments including stress relaxation, hysteresis, and energy dissipation. The model provides a suitable starting point for the development of thermal energy localization sub-scale models based on compaction-induced dissipation.

  16. [Prevention of schizophrenia: a review].

    Science.gov (United States)

    Balhara, Yatan Pal Singh

    2013-01-01

    Research over the years has introduced multiple interventions for schizophrenia. Notwithstanding the nature of intervention pharmacological or psychological a complete cure for the condition remains a much-desired, yet unachieved goal. What is required is an exploration of alternative intervention strategies for treating schizophrenia a preventive approach is such an option. The chronic nature of schizophrenia and its associated disabilities have a tremendously negative affect the quality of life of patients, their families, and communities. Among the preferred approaches to reducing the negative consequences associated with the disorder is the prevention of its emergence. This review aimed to present the available data on the prevention of schizophrenia data that suggest some pharmacological and non-pharmacological interventions have a potential role in the prevention of schizophrenia. Nonetheless, the findings are restricted to a few sites and are at best preliminary; as such, the findings must be replicated in new studies that include large samples and different settings.

  17. 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.

  18. 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.

  19. Scale modeling flow-induced vibrations of reactor components

    International Nuclear Information System (INIS)

    Mulcahy, T.M.

    1982-06-01

    Similitude relationships currently employed in the design of flow-induced vibration scale-model tests of nuclear reactor components are reviewed. Emphasis is given to understanding the origins of the similitude parameters as a basis for discussion of the inevitable distortions which occur in design verification testing of entire reactor systems and in feature testing of individual component designs for the existence of detrimental flow-induced vibration mechanisms. Distortions of similitude parameters made in current test practice are enumerated and selected example tests are described. Also, limitations in the use of specific distortions in model designs are evaluated based on the current understanding of flow-induced vibration mechanisms and structural response

  20. Mass spectrum analysis of serum biomarker proteins from patients with schizophrenia.

    Science.gov (United States)

    Zhou, Na; Wang, Jie; Yu, Yaqin; Shi, Jieping; Li, Xiaokun; Xu, Bin; Yu, Qiong

    2014-05-01

    Diagnosis of schizophrenia does not have a clear objective test at present, so we aimed to identify the potential biomarkers for the diagnosis of schizophrenia by comparison of serum protein profiling between first-episode schizophrenia patients and healthy controls. The combination of a magnetic bead separation system with matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS) was used to analyze the serum protein spectra of 286 first-episode patients with schizophrenia, 41 chronic disease patients and 304 healthy controls. FlexAnlysis 3.0 and ClinProTools(TM) 2.1 software was used to establish a diagnostic model for schizophrenia. The results demonstrated that 10 fragmented peptides demonstrated an optimal discriminatory performance. Among these fragmented peptides, the peptide with m/z 1206.58 was identified as a fragment of fibrinopeptide A. Receiver operating characteristic analysis for m/z 1206.58 showed that the area under the curve was 0.981 for schizophrenia vs healthy controls, and 0.999 for schizophrenia vs other chronic disease controls. From our result, we consider that the analysis of serum protein spectrum using the magnetic bead separation system and MALDI-TOF/TOF-MS is an objective diagnostic tool. We conclude that fibrinopeptide A has the potential to be a biomarker for diagnosis of schizophrenia. This protein may also help to elucidate schizophrenia disease pathogenesis. Copyright © 2013 John Wiley & Sons, Ltd.

  1. Association of CCL11 promoter polymorphisms with schizophrenia in a Korean population.

    Science.gov (United States)

    Kang, Won Sub; Kim, Young Jong; Park, Hae Jeong; Kim, Su Kang; Paik, Jong-Woo; Kim, Jong Woo

    2018-05-20

    Immunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia. Four promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays. The genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p schizophrenia (p schizophrenia (p = 0.0044, p schizophrenia in a Korean population. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia.

    Science.gov (United States)

    Hedman, Anna M; van Haren, Neeltje E M; van Baal, G Caroline M; Brouwer, Rachel M; Brans, Rachel G H; Schnack, Hugo G; Kahn, René S; Hulshoff Pol, Hilleke E

    2016-06-01

    Cortical thickness and surface area changes have repeatedly been found in schizophrenia. Whether progressive loss in cortical thickness and surface area are mediated by genetic or disease related factors is unknown. Here we investigate to what extent genetic and/or environmental factors contribute to the association between change in cortical thickness and surface area and liability to develop schizophrenia. Longitudinal magnetic resonance imaging study over a 5-year interval. Monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia were compared with healthy control twin pairs using repeated measures analysis of variance (RM-ANOVA) and structural equation modeling (SEM). Twins discordant for schizophrenia and healthy control twins were recruited from the twin cohort at the University Medical Centre Utrecht, The Netherlands. A total of 90 individuals from 46 same sex twin pairs were included: 9 MZ and 10 DZ discordant for schizophrenia and 14 MZ and 13 (11 complete and 2 incomplete) DZ healthy twin-pairs. Age varied between 19 and 57years. Higher genetic liability for schizophrenia was associated with progressive global thinning of the cortex, particularly of the left superior temporal cortex. Higher environmental liability for schizophrenia was associated with global attenuated thinning of the cortex, and including of the left superior temporal cortex. Cortical surface area change was heritable, but not significantly associated with higher genetic or environmental liability for schizophrenia. Excessive cortical thinning, particularly of the left superior temporal cortex, may represent a genetic risk marker for schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. MODELING OF AN AIRPLANE WING MOMENTS INDUCED BY ATMOSPHERIC TURBULENCE

    Directory of Open Access Journals (Sweden)

    Anna Antonova

    2014-07-01

    Full Text Available We have used Diederich’s theory of wingspan average correlation functions to obtain analytical expressions for the local spectral density of aircraft wing moments induced by horizontal and vertical wind gusts. We have assumed that the correlation functions of atmospheric turbulence belong to the Bullen family which includes both partial cases of known Dryden’s model as well as von Karman’s  model.

  4. 3 alpha 5 beta-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Valeš, Karel; Rambousek, Lukáš; Holubová, Kristína; Svoboda, Jan; Bubeníková-Valešová, V.; Chodounská, Hana; Vyklický ml., Ladislav; Stuchlík, Aleš

    2012-01-01

    Roč. 235, č. 1 (2012), s. 82-88 ISSN 0166-4328 R&D Projects: GA MZd(CZ) NS10365 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : schizophrenia-like behavior * MK-801 * use-dependent * NMDA antagonist * anxiety * pregnanolone glutamate * Carousel maze Subject RIV: FH - Neurology Impact factor: 3.327, year: 2012

  5. The valproic acid-induced rodent model of autism.

    Science.gov (United States)

    Nicolini, Chiara; Fahnestock, Margaret

    2018-01-01

    Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Cysteine-rich whey protein isolate (Immunocal®) ameliorates deficits in the GFAP.HMOX1 mouse model of schizophrenia.

    Science.gov (United States)

    Song, Wei; Tavitian, Ayda; Cressatti, Marisa; Galindez, Carmela; Liberman, Adrienne; Schipper, Hyman M

    2017-09-01

    Schizophrenia is a neuropsychiatric disorder that features neural oxidative stress and glutathione (GSH) deficits. Oxidative stress is augmented in brain tissue of GFAP.HMOX1 transgenic mice which exhibit schizophrenia-relevant characteristics. The whey protein isolate, Immunocal® serves as a GSH precursor upon oral administration. In this study, we treated GFAP.HMOX1 transgenic mice daily with either Immunocal (33mg/ml drinking water) or equivalent concentrations of casein (control) between the ages of 5 and 6.5 months. Immunocal attenuated many of the behavioral, neurochemical and redox abnormalities observed in GFAP.HMOX1 mice. In addition to restoring GSH homeostasis in the CNS of the transgenic mice, the whey protein isolate augmented GSH reserves in the brains of wild-type animals. These results demonstrate that consumption of whey protein isolate augments GSH stores and antioxidant defenses in the healthy and diseased mammalian brain. Whey protein isolate supplementation (Immunocal) may constitute a safe and effective modality for the management of schizophrenia, an unmet clinical imperative. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Prenatal tobacco smoke exposure, risk of schizophrenia, and severity of positive/negative symptoms.

    Science.gov (United States)

    Stathopoulou, Anastasia; Beratis, Ion N; Beratis, Stavroula

    2013-08-01

    Prenatal exposure to cigarette smoke causes chronic fetal hypoxia, dysregulation of endocrine equilibrium, and disruption of fetal neurodevelopment associated with brain malfunction, all of which potentially could induce vulnerability to schizophrenia. A total of 212 schizophrenia patients aged 14-30years, and 212 matched controls were studied. Prenatal tobacco smoke exposure of the schizophrenia patients was compared to that of the normal controls by applying logistic regression analysis and controlling for several confounding factors. The outcomes of interest were comparison of the frequency of maternal and paternal smoking between patients and controls, as well as the severity of positive and negative symptoms between the offspring of smoking and nonsmoking parents. Among the mothers of schizophrenia patients and controls, 92 (43.4%) and 46 (21.7%) smoked, respectively. Maternal smoking during pregnancy had a significant unique contribution on increasing the risk for development of schizophrenia (p=0.001), and a greater severity of negative symptoms (p=0.023). Paternal smoking did not have a significant effect on the risk of schizophrenia, or severity of negative symptoms. The findings suggest that maternal smoking during pregnancy puts offspring at an increased risk for later schizophrenia, with increased severity of negative symptoms. Given the wide practice of smoking during pregnancy, fetal exposure to tobacco smoke could be a major preventable neurodevelopmental factor that increases vulnerability to schizophrenia. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: An effect of pretraining

    Czech Academy of Sciences Publication Activity Database

    Zemanová, Anna; Staňková, Anna; Lobellová, Veronika; Svoboda, Jan; Valeš, Karel; Vlček, Kamil; Kubík, Štěpán; Fajnerová, Iveta; Stuchlík, Aleš

    2013-01-01

    Roč. 106, May 2013 (2013), s. 117-123 ISSN 0091-3057 R&D Projects: GA MZd(CZ) NT13386 Institutional support: RVO:67985823 Keywords : working memory * place avoidance * rats * behavior Subject RIV: FH - Neurology Impact factor: 2.820, year: 2013

  9. Low dietary intake of n-3 fatty acids, niacin, folate, and vitamin C in Korean patients with schizophrenia and the development of dietary guidelines for schizophrenia.

    Science.gov (United States)

    Kim, Eun Jin; Lim, So Young; Lee, Hee Jae; Lee, Ju-Yeon; Choi, Seunggi; Kim, Seon-Young; Kim, Jae-Min; Shin, Il-Seon; Yoon, Jin-Sang; Yang, Soo Jin; Kim, Sung-Wan

    2017-09-01

    Inappropriate dietary intake and poor nutritional status are reported to be associated with metabolic syndrome and psychopathology in patients with schizophrenia. We hypothesized that inappropriate dietary habits and insufficient dietary intake of specific nutrients are associated with schizophrenia. To test the hypothesis, we assessed the dietary habits and nutritional intake of patients with schizophrenia and then developed suitable dietary guidelines. In total, 140 subjects (73 controls and 67 patients with schizophrenia from community mental health centers) were included, and dietary intakes were analyzed using a semi-quantitative food frequency questionnaire. As a result, the proportion of overweight or obese patients was significantly higher in schizophrenia subjects (64.2%) compared with control subjects (39.7%) (P=.004). The male schizophrenia patients had significantly lower dietary intakes of protein, polyunsaturated fatty acids (PUFAs), vitamin K, niacin, folate, and vitamin C than the male control subjects. In all multiple logistic regression models, subjects with the "low" dietary intake of protein, n-3 PUFAs, niacin, folate, and vitamin C had a significantly higher odds ratios for schizophrenia compared with those with the "high" dietary intake category of each nutrient. Therefore, maintenance of a healthy body weight and sufficient dietary intake of protein, PUFAs, niacin, folate, and vitamin C are recommended for Korean patients with schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study.

    Science.gov (United States)

    Schnack, Hugo G; van Haren, Neeltje E M; Nieuwenhuis, Mireille; Hulshoff Pol, Hilleke E; Cahn, Wiepke; Kahn, René S

    2016-06-01

    Despite the multitude of longitudinal neuroimaging studies that have been published, a basic question on the progressive brain loss in schizophrenia remains unaddressed: Does it reflect accelerated aging of the brain, or is it caused by a fundamentally different process? The authors used support vector regression, a supervised machine learning technique, to address this question. In a longitudinal sample of 341 schizophrenia patients and 386 healthy subjects with one or more structural MRI scans (1,197 in total), machine learning algorithms were used to build models to predict the age of the brain and the presence of schizophrenia ("schizophrenia score"), based on the gray matter density maps. Age at baseline ranged from 16 to 67 years, and follow-up scans were acquired between 1 and 13 years after the baseline scan. Differences between brain age and chronological age ("brain age gap") and between schizophrenia score and healthy reference score ("schizophrenia gap") were calculated. Accelerated brain aging was calculated from changes in brain age gap between two consecutive measurements. The age prediction model was validated in an independent sample. In schizophrenia patients, brain age was significantly greater than chronological age at baseline (+3.36 years) and progressively increased during follow-up (+1.24 years in addition to the baseline gap). The acceleration of brain aging was not constant: it decreased from 2.5 years/year just after illness onset to about the normal rate (1 year/year) approximately 5 years after illness onset. The schizophrenia gap also increased during follow-up, but more pronounced variability in brain abnormalities at follow-up rendered this increase nonsignificant. The progressive brain loss in schizophrenia appears to reflect two different processes: one relatively homogeneous, reflecting accelerated aging of the brain and related to various measures of outcome, and a more variable one, possibly reflecting individual variation and

  11. A model of hemorrhagic cystitis induced with acrolein in mice

    Directory of Open Access Journals (Sweden)

    C.K.L.P. Batista

    2006-11-01

    Full Text Available Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group received saline or acrolein (25, 75, 225 µg intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg or systemically (80 mg/kg 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 µg/bladder, as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid, which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

  12. 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

  13. EXECUTIVE FUNCTIONING IN SCHIZOPHRENIA

    Directory of Open Access Journals (Sweden)

    Gricel eOrellana

    2013-06-01

    Full Text Available The executive function (EF is a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously and locate episodes in time and place. EF includes divided attention and sustained attention, working memory, set-shifting, flexibility, planning and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states. EF is mostly associated with dorsolateral prefrontal cortex (PFC. Besides EF, PFC is involved in self-regulation of behavior, i.e. the ability to regulate behavior according to internal goals and constraints, particularly in less structured situations. Self-regulation of behavior is subtended by ventral medial /orbital PFC. Impairment of EF is one of the most commonly observed deficits in schizophrenia through the various disease stages. Impairment in tasks measuring conceptualization, planning, cognitive flexibility, verbal fluency, ability to solve complex problems and working memory occur in schizophrenia. Disorders detected by executive tests are consistent with evidence from functional neuroimaging, which have shown PFC dysfunction in patients while performing these kinds of tasks. Schizophrenics also exhibit deficit in odor identifying, decision-making and self-regulation of behavior suggesting dysfunction of the orbital PFC. However, impairment in executive tests is explained by dysfunction of prefronto-striato-thalamic, prefronto-parietal and prefronto-temporal neural networks mainly. Disorders in executive functions may be considered central facts with respect to schizophrenia and it has been suggested that negative symptoms may be explained by that executive dysfunction.

  14. 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

  15. Outpatient management of schizophrenia.

    Science.gov (United States)

    Martin, R L

    1991-03-01

    As effective antipsychotic pharmacotherapy has become available, patients with schizophrenia are increasingly managed in an outpatient setting by primary care physicians. Pharmacotherapy is generally effective in treating "positive," or psychotic, symptoms and lessening the risks of relapse, but ineffective in improving "negative," or deficit, symptoms. Aggressive attempts to totally control positive symptoms and to ameliorate negative symptoms tend to increase side effects and may be detrimental to the patient. Intensive psychotherapeutic and rehabilitative approaches are generally unproductive. Attempting to obtain a cure is unrealistic. A moderate approach is recommended, taking into consideration the limitations of existing treatments, achieving control of extreme symptoms and minimizing social and occupational limitations.