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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schizophrenia is a chronic, severe, and disabling brain disorder arising from the adverse interaction of predisposing risk genes and environmental factors. The psychopathology is characterized by a wide array of disturbing cognitive, emotional, and behavioral symptoms that interfere with the individual's capacity to function in society. Contemporary pathophysiological models assume that psychotic symptoms are triggered by a dysregulation of dopaminergic activity in the brain, a theory that is tightly linked to the serendipitous discovery of the first effective antipsychotic agents in the early 1950s. In recent years, the availability of modern neuroimaging techniques has significantly expanded our understanding of the key mediator circuits that bridge the gap between genetic susceptibility and clinical phenotype. This paper discusses the pathophysiological concepts, molecular mechanisms and neuroimaging evidence that link psychosis to disturbances in dopamine neurotransmission.
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PMID:Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes. 1955 45

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.
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PMID:Nonlinear response of the anterior cingulate and prefrontal cortex in schizophrenia as a function of variable attentional control. 1963 77

Violence committed by acute psychiatric inpatients represents an important and challenging problem in clinical practice. Sociodemographic, clinical, and treatment information were collected for 1324 patients (677 men and 647 women) admitted to Italian public and private acute psychiatric inpatient facilities during an index period in 2004, and the sample divided into 3 groups: nonhostile patients (no episodes of violent behavior during hospitalization), hostile patients (verbal aggression or violent acts against objects), and violent patients (authors of physical assault). Ten percent (N = 129) of patients showed hostile behavior during hospitalization and 3% (N = 37) physically assaulted other patients or staff members. Variables associated with violent behavior were: male gender, <24 years of age, unmarried status, receiving a disability pension, having a secondary school degree, compulsory admission, hostile attitude at admission, and a diagnosis of schizophrenia, bipolar disorder, personality disorder, mental retardation, organic brain disorder or substance/alcohol abuse. Violent behavior during hospitalization was a predictive factor for higher Brief Psychiatric Rating Scale scores and for lower Personal and Social Performance scale scores at discharge. Despite the low percentage of violent and hostile behavior observed in Italian acute inpatient units, this study shed light on a need for the careful assessment of clinical and treatment variables, and greater effort aimed at improving specific prevention and treatment programs of violent behavior.
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PMID:Violent behavior in acute psychiatric inpatient facilities: a national survey in Italy. 1982 7

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.
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PMID:The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. 1994 49

Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder.
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PMID:Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency. 2021 56

Schizophrenia (SZ) is a highly polygenic disease with strong genetic predisposition. Although genetic susceptibility factors for SZ are likely to have an influence in some brain regions and related neural circuits during neurodevelopment, direct proof for spatiotemporal causality in the development of SZ, and the alteration of what gene function at what brain region during what developmental stage, remains to be elucidated. Gene manipulation by viral vector stereotaxically injected into a specific brain region is now becoming available for psychiatric research. This technique has several advantages, e.g., the exceptional spatiotemporal control, simultaneous manipulation of multiple genes, and its simple protocol. These properties can make this technique one of the most valuable approaches for research in SZ, which is a complex brain disorder with multifactorial, genetic, and developmental features. This review summarizes the benefits and actual use of this technique together with discussion of spatiotemporal aspect for SZ.
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PMID:Gene manipulation with stereotaxic viral infection for psychiatric research: spatiotemporal components for schizophrenia. 2030 14

The major mental disorders, schizophrenia and bipolar disorder are substantially heritable. Recent genomic studies have identified a small number of common and rare risk genes contributing to both disorders and support epidemiological evidence that genetic susceptibility overlaps between them. Prompted by the question of whether risk genes cluster in specific molecular pathways or implicate discrete mechanisms we and others have developed hypothesis-free methods of investigating genome-wide association datasets at a pathway-level. The application of our method to the 212 experimentally-derived pathways in the Kyoto Encycolpaedia of Genes and Genomes (KEGG) database identified significant association between the cell adhesion molecule (CAM) pathway and both schizophrenia and bipolar disorder susceptibility across three GWAS datasets. Interestingly, a similar approach applied to an autistic spectrum disorders (ASDs) sample identified a similar pathway and involved many of the same genes. Disruption of a number of these genes (including NRXN1, CNTNAP2 and CASK) are known to cause diverse neurodevelopmental brain disorder phenotypes including schizophenia, autism, learning disability and specific language disorder. Taken together these studies bring the CAM pathway sharply into focus for more comprehensive DNA sequencing to identify the critical genes, and investigate their relationships and interaction with environmental risk factors in the expression of many seemingly different neurodevelopmental disorders.
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PMID:Neuronal cell adhesion genes: Key players in risk for schizophrenia, bipolar disorder and other neurodevelopmental brain disorders? 2057 49

Historically, Kraepelin speculated that dementia praecox resulted from damage to the cerebral cortex, most notably the frontal and temporal cortices. It is only recently, however, that tools have been available to test this hypothesis. Now, more than a century later, we know that schizophrenia is a brain disorder. This knowledge comes from critical advances in imaging technology--including computerized axial tomography, magnetic resonance imaging, and diffusion imaging--all of which provide an unprecedented view of neuroanatomical structures, in vivo. Here, we review evidence for structural neuroimaging abnormalities, beginning with evidence for focal brain abnormalities, primarily in gray matter, and proceeding to the quest to identify abnormalities in brain systems and circuits by focusing on damage to white matter connections in the brain. We then review future prospects that need to be explored and pursued in order to translate our current knowledge into an understanding of the neurobiology of schizophrenia, which can then be translated into novel treatments.
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PMID:Structural neuroimaging in schizophrenia: from methods to insights to treatments. 2095 28

Recent data indicate that a significant number of schizophrenic patients are hypercortisolemic and that glucocorticoids are involved in the pathogenesis of schizophrenia. The aim of the present study was to evaluate whether behavioural schizophrenia-like changes in the lipopolysaccharide (LPS)-induced neurodevelopmental model of this brain disorder are associated with alterations in the level of plasma corticosterone, the concentration of glucocorticoid receptors and the amount of the immunophilin FKBP51, the glucocorticoid receptor co-chaperone, in the hippocampus and frontal cortex. We found that the adult offspring of prenatally LPS-treated rats showed a deficit in prepulse inhibition (PPI), an enhancement of amphetamine-induced locomotor activity, an elevated plasma level of corticosterone and a decrease in both the glucocorticoid receptor level in the hippocampus and the FKBP51 concentration in the frontal cortex. Most of these changes were reversed by the atypical antipsychotic drug clozapine, whereas chlorpromazine had no effect on PPI but attenuated the amphetamine-induced hyperactivity and normalised the hippocampal level of glucocorticoid receptors. The changes in the level of plasma corticosterone and cortical FKBP51 were attenuated by chlorpromazine in female offspring only. This study supports the hypothesis of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in schizophrenia and suggests that this hyperactivity results from a decrease in the hippocampal glucocorticoid receptor level and a decrease in FKBP51 in the frontal cortex.
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PMID:Hyperactivity of the hypothalamus-pituitary-adrenal axis in lipopolysaccharide-induced neurodevelopmental model of schizophrenia in rats: effects of antipsychotic drugs. 2103 39

Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches.
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PMID:Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. 2112 77


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