UMLS:C0036341 - FACTA Search

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

Recent years have witnessed increasingly intense research activity concerning early life somatic trauma and dysmorphogenesis which are associated with the later development of schizophrenia. The two somatic factors that have received the most extensive scientific attention as antecedents of schizophrenia are obstetric complications (OCs) and the congenital malformations termed 'minor physical anomalies' (MPAs). Head circumference (HC) at birth has also been studied as a measure of prenatal cerebral development. A great number of studies indicate clearly that schizophrenia patients have a significantly increased history of OCs, representing many different OCs from pregnancy, labor-delivery and the neonatal period. The probable common denominator of these OCs is oxygen deprivation. Especially labor-delivery OCs relate strongly to brain structure abnormality in ill twins from monozygotic pairs discordant for schizophrenia. Schizophrenia patients very consistently have evidenced an increased frequency of MPAs in the global head, eyes, mouth, ears, hands, feet and limbs. Specific MPAs occur with considerable frequency even among normal comparison subjects, but combination models for specific MPAs efficiently discriminate most patients from comparison subjects. Schizophrenia patients also have significantly reduced HC at birth, independently of gestational age, suggesting a disturbance in prenatal cerebral development, and most frequently observed in female patients. Evidence has thus accumulated, increasingly, for the role of various forms of early trauma and dysmorphogenesis in subsequent schizophrenia, and efforts continue to determine the manner in which these early trauma influence both the early developing brain and the brain of the adult patient with manifest schizophrenia.
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PMID:Obstetric complications and congenital malformation in schizophrenia. 1071 45

The purpose of the present study was to evaluate the cortical response to motor stimulation in neuroleptic-naive first episode schizophrenics in comparison to matched controls using a high speed functional magnetic resonance imaging technique (fMRI). Twelve patients satisfying ICD 10 criteria (F20.0) for schizophrenia (paranoid subtype) as well as sex- and age-matched healthy volunteers participated in this study. All subjects underwent fMRI examination on a conventional 1.5 T MR unit equipped with an echo-planar imaging booster. The blood oxygen level dependent (BOLD) response of the sensorimotor cortex and the higher order SMA region was evaluated during performance of a left hand sequential finger opposition task. Special care was taken to minimize performance and motion artifacts. Patients and controls showed no notable difference with respect to laterality, changes of signal intensity or spatial extent of activation within the primary and higher order motor regions. Using high speed fMRI no fundamental motor cortical dysfunction was evident in a group of paranoid neuroleptic-naive first episode schizophrenic patients. In contrast to data previously reported for chronic disorganized medicated patients, these results suggest that motor dysfunction is not part of the phenomenology of acute paranoid first episode patients.
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PMID:Cortical response to motor stimulation in neuroleptic-naive first episode schizophrenics. 1082 97

Even a cursory review of the literature today indicates that two views dominate experimental approaches to metabolic regulation. Model I assumes that cell behavior is quite similar to that expected for a bag of enzymes. Model II assumes that 3-D order and structure constrain metabolite behavior and that metabolic regulation theory has to incorporate structure to ever come close to describing reality. The phosphagen system may be used to illustrate that both approaches lead to very productive experimentation and significant advances are being made within both theoretical frameworks. However, communication between the two approaches or the two 'groups' is essentially nonexistent and in many cases (our own for example) some experiments are done in one framework and some in the other (implying some potential schizophrenia in the field). In our view, the primary paradox and problem which no one has solved so far is that essentially all metabolite concentrations are remarkably stable (are homeostatic) over large changes in pathway fluxes. For muscle cells O2 is one of the most perfectly homeostatic of all even though O2 delivery and metabolic rate usually correlate in a 1:1 fashion. Four explanations for this behavior are given by traditional metabolic regulation models. Additionally, there is some evidence for universal O2 sensors which could help to get us out of the paradox. In contrast, proponents of an ultrastructurally dominated view of the cell assume intracellular perfusion or convection as the main means for accelerating enzyme-substrate encounter and as a way to account for the data which have been most perplexing so far: the striking lack of correlation between changes in pathway reaction rates and changes in concentrations of pathway substrates and intermediates, including oxygen. The polarization illustrated by these two views of living cells extends throughout the metabolic regulation field (and has caused the field to progress along two surprisingly independent paths with minimal communication between them). The time may have come when cross talk between the two fields may be useful.
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PMID:Oxygen, homeostasis, and metabolic regulation. 1084 72

Functional brain imaging studies have reported decreased frontal activations in schizophrenia, but hemispheric dominance for language has rarely been assessed. To investigate regional activation and lateralization during word production, we determined normalized regional cerebral blood flow (rCBF) variations with positron emission tomography (PET) and H2(15)O (water labeled with the isotope oxygen 15) in 14 negative schizophrenia patients and 14 volunteers. Subjects were scanned during two trials of three conditions: rest, vocalized verbal fluency, and spontaneous word production. Images were analyzed using an anatomical volumes of interest method, and the two groups' changes were compared, using rest as a baseline. Differences in the lateralization of changes were detected in homologous frontal and inferior parietal regions. The lateralization effects in patients arose from lower activations in the left frontal regions, abnormal right inferior frontal activations, and weaker right inferior parietal deactivation, during the word production tasks. The right hemisphere changes correlated negatively with the performance in verbal fluency. Thus in negative schizophrenia patients, while the activations were less focused on the left hemisphere regions usually engaged in word generation, rCBF changes in the right hemisphere might reflect a compensatory functional pattern.
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PMID:Altered hemispheric functional dominance during word generation in negative schizophrenia. 1099 8

Schizophrenia is a major psychiatric disease, which affects the centre of the personality, with severe problems of perception, cognition as well as affective and social behaviour. In cerebrospinal fluid of drug-free schizophrenic patients, a significant decrease in the level of total glutathione (GSH) by 27% (P<0.05) was observed as compared to controls, in keeping with the reported reduced level of its metabolite gamma-glutamylglutamine. With a new non-invasive proton magnetic resonance spectroscopy methodology, GSH level in medial prefrontal cortex of schizophrenic patients was found to be 52% (P = 0.0012) lower than in controls. GSH plays a fundamental role in protecting cells from damage by reactive oxygen species generated among others by the metabolism of dopamine. A deficit in GSH would lead to degenerative processes in the surrounding of dopaminergic terminals resulting in loss of connectivity. GSH also potentiates the N-methyl-D-aspartate (NMDA) receptor response to glutamate, an effect presumably reduced by a GSH deficit, leading to a situation similar to the application of phencyclidine (PCP). Thus, a GSH hypothesis might integrate many established biological aspects of schizophrenia.
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PMID:Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. 1102 42

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
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PMID:Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. 1112 99

This review covers certain novel aspects of catecholamine signaling in neurons that involve redox systems and synaptic plasticity. The redox hypothesis suggests that one important factor in neurocomputation is the formation of new synapses and the removal of old ones (synaptic plasticity), which is modulated in part by the redox balance at the synapse between reactive oxygen species (ROS) (such as hydrogen peroxide and the nitric oxide radical) and neuroprotective antioxidants (such as ascorbate, glutathione, and catecholamines). Catecholamines, in particular dopamine, which signals positive reinforcement, may play a key role in this activity. Dopamine has powerful antioxidant properties by several separate mechanisms-direct ROS scavenging, activation of the synthesis of antioxidant proteins, and possibly via dismuting complexes with iron inside endosomes or in catecholaminergic synaptic vesicles. This may contribute to synaptic growth and reinforcement-directed learning. On the other hand, catecholamines are easily oxidized to toxic quinones on the neuromelanin pathway. This might contribute under certain circumstances to synaptic deletion. Evidence is presented that abnormalities in this system may contribute to the pathogenesis of Parkinson's disease and schizophrenia.
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PMID:Redox aspects of signaling by catecholamines and their metabolites. 1122 69

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.
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PMID:Isoprenoid pathway and free radical generation and damage in neuropsychiatric disorders. 1127 6

A revision of an "excitotoxic hypothesis" of schizophrenia is summarized. The hypothesis suggests that in, at least, a subtype of patients with schizophrenia, progressive excitotoxic neuronal cell death in hippocampal and cortical areas occurs via "disinhibition" of glutamatergic projections to these areas. Patients who have excitotoxic damage would be expected to have poor outcomes characterized, perhaps, by anatomic evidence of progressive neurodegeneration, pronounced negative symptoms and cognitive deficits, and profound psychosocial deterioration. Disinhibited glutamatergic activity could result from inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission and a consequent failure to stimulate inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons, and/or anatomic degeneration of inhibitory GABAergic interneurons. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate class of glutamate receptor complexes. In turn, this excessive stimulation of AMPA/kainate receptors could lead to disruption of ionic gradients, depletion of energy reserves expended in an attempt to restore and maintain the ionic disequilibrium across neuronal membranes, generation of reactive oxygen species, and cell death from apoptotic and other mechanisms. The postulated existence of disinhibited glutamatergic neurotransmission and the subsequent cascade of excitotoxic events resulting from NMDA receptor hypofunction (NRH), anatomic degeneration of inhibitory GABAergic interneurons, or a combination of the two has suggested a diverse variety of experimental therapeutic interventions for schizophrenia. These interventions include facilitation of NMDA receptor-mediated neurotransmission, potentiation of GABAergic neurotransmission, antagonism of AMPA/kainate receptors, and "quenching" of locally generated reactive oxygen species. In fact, several of these approaches have already been pursued or are proposed as part of a systematic clinical investigation of the revised excitotoxic hypothesis of schizophrenia.
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PMID:A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. 1129 Aug 81

1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.
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PMID:Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia. 1137 Sep 92

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