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)

While it is premature to provide a simple model for the vulnerability to the development of either borderline (BPD) or schizotypal (SPD) personality disorder, it is clear that these heritable disorders lend themselves to fruitful neurobiological exploration. The most promising findings in BPD suggest that a diminished top-down control of affective responses, which is likely to relate to deceased responsiveness of specific midline regions of prefrontal cortex, may underlie the affective hyperresponsiveness in this disorder. In addition, genetic and neuroendocrine and molecular neuroimaging findings point to a role for serotonin in this affective disinhibition. Clearly SPD falls within the schizophrenia spectrum, but precisely the nature of what predicts full-blown schizophrenia as opposed to the milder symptoms of SPD is not yet clear.
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PMID:Recent advances in the biological study of personality disorders. 1863 45

The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.
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PMID:Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. 1868 45

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a new category of treatment-responsive encephalitis associated with "anti-NMDAR antibodies", which are antibodies to the NR1/NR2 heteromers of NMDAR. The antibodies are detected in the CSF/serum of young women with ovarian teratoma, who typically develop schizophrenia-like psychiatric symptoms, usually preceded by fever, headache, or viral infection-like illness. After reaching the peak of psychosis, most patients developed seizures followed by an unresponsive/catatonic state, decreased level of consciousness, central hypoventilation frequently requiring mechanical ventilation, orofacial-limb dyskinesias, and autonomic symptoms. Brain MRI is usually unremarkable but focal enhancement or medial temporal lobe abnormalities can be observed. The CSF reveals nonspecific changes. EEG often reveals diffuse delta slowing without paroxysmal discharges, despite frequent bouts of seizures. This is a highly characteristic syndrome evolving in 5 stages, namely, the prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and gradual recovery phase. The hyperkinetic phase is the most prolonged and crucial. This disorder is usually severe and can be fatal, but it is potentially reversible. Once patients overcome the hyperkinetic phase, gradual improvement is expected with in months and full recovery can also be expected over 3 or more years. Ovarian teratoma-associated limbic encephalitis (OTLE) was first reported in 1997 when this syndrome was reported independently in 1 Japanese girl and 1 woman, both of whom improved following tumor resection. In 2005, Dalmau and his research group first demonstrated antibodies to novel neuronal cell membrane antigens in 4 women with OTLE in a non-permeabilized culture of hippocampal neurons. Two years later, they identified conformal extracellular epitopes present in the NR1/NR2B heteromers of NMDAR, which are expressed in the hippocampus/forebrain. The target extracellular epitopes are not detectable by immunoblotting, and should not be confused with the linear epitopes of NR2B subunits (also known as epsilon2). The antibodies disappear with clinical improvement, suggesting their pathogenic role. Autopsies revealed IgG deposits in the hippocampus, extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. The nervous tissues of the tumors exhibit not only strong expression of the NR2B subunits but also reactivity with the patients' antibodies. The pathogenesis remains unknown; however, this disorder is considered to be an antibody-mediated encephalitis. Based on the current NMDAR hypofunction hypothesis of schizophrenia, we speculate that the antibodies may cause inhibition rather than stimulation of NMDARs in presynaptic GABAergic interneurons, causing a reduction in GABA release. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate and dopamine dysregulation that might contribute to development of schizophrenia-like psychosis and bizarre dyskinesias. The antibodies were initially found only in young women with teratoma in the ovaries. However, recent studies show that this disorder can occur even in the absence of teratoma in up to 35% of patients, and even boys and adult men had been affected. Although recovery occurs without the need for tumor removal, the severity and extended duration of symptoms support tumor removal. Combined therapy including tumor resection and immunotherapy is recommended. In this review, we also discuss the relationship between anti-NMDAR encephalitis and related disorders, including acute diffuse lymphocytic meningoencephalitis and acute juvenile female non-herpetic encephalitis (AJFNHE).
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PMID:[Anti-nMDA receptor encephalitis--clinical manifestations and pathophysiology]. 1880 39

Autism and schizophrenia are multifactorial disorders with increasing prevalence in the young population. Among candidate molecules, reelin (RELN) is a protein of the extracellular matrix playing a key role in brain development and synaptic plasticity. The heterozygous (HZ) reeler mouse provides a model for studying the role of reelin deficiency for the onset of these syndromes. We investigated whether early indices of neurobehavioral disorders can be identified in the infant reeler, and whether the consequences of ontogenetic adverse experiences may question or support the suitability of this model. A first study focused on the link between early exposure to Chlorpyryfos and its enduring neurobehavioral consequences. Our data are interesting in view of recently discovered cholinergic abnormalities in autism and schizophrenia, and may suggest new avenues for early pharmacological intervention. In a second study, we analyzed the consequences of repeated maternal separation early in ontogeny. The results provide evidence of how unusual stress early in development are converted into altered behavior in some, but not all, individuals depending on gender and genetic background. A third study aimed to verify the reliability of the model at critical age windows. Data suggest reduced anxiety, increased impulsivity and disinhibition, and altered pain threshold in response to morphine for HZ, supporting a differential organization of brain dopaminergic, serotonergic and opioid systems in this genotype. In conclusion, HZ exhibited a complex behavioral and psycho-pharmacological phenotype, and differential responsivity to ontogenetic adverse conditions. HZ may be used to disentangle interactions between genetic vulnerability and environmental factors. Such an approach could help to model the pathogenesis of neurodevelopmental psychiatric diseases.
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PMID:Gene-environment interaction during early development in the heterozygous reeler mouse: clues for modelling of major neurobehavioral syndromes. 1884 82

Currently available antipsychotic medications lack satisfactory effectiveness against several symptom clusters of schizophrenia, including affective symptoms (e.g., anhedonia) and cognitive deficits (e.g., impulsivity). Translational animal models analogous to these symptoms are necessary to provide insights into the neurobiological events underlying these impairments and allow the development of improved schizophrenia treatments. We investigated the effects of repeated administration of the psychotomimetic phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, on performance in the intracranial self-stimulation (ICSS) procedure, a test of reward function. We also explored how chronic treatment with clozapine, an atypical antipsychotic with limited effectiveness on affective and cognitive schizophrenia symptoms, would affect PCP-induced disruptions of ICSS performance. A single injection of 2 mg/kg PCP elevated ICSS thresholds, suggesting a reward deficit. Repeated PCP administration (2 mg/kg once daily for 2 consecutive days followed by a 10-day drug free period, and then 5 consecutive days of 2 mg/kg PCP daily, s.c., 30 min pretreatment) resulted in a small, but significant, lowering of ICSS reward thresholds, indicating increased reward function. Chronic clozapine did not alter the effects of repeated PCP on ICSS thresholds. Repeated PCP also increased the number of extra and timeout responses performed during the ICSS procedure, reflecting disinhibition of inappropriate responding and decreased task efficiency. Chronic clozapine attenuated the increase in extra responses induced by repeated PCP and tended to reduce the PCP-induced increase in timeout responses. These results suggest that repeated PCP administration does not produce an anhedonia-like state resembling that seen in schizophrenia. However, the increased impulsivity and reduced task efficiency seen with repeated PCP administration, and the sensitivity of these effects to attenuation with an atypical antipsychotic, suggest that repeated PCP administration may be a useful inducing condition for eliciting cognitive deficits with relevance to schizophrenia.
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PMID:Clozapine attenuates disruptions in response inhibition and task efficiency induced by repeated phencyclidine administration in the intracranial self-stimulation procedure. 1902 29

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a new category of treatment-responsive encephalitis associated with "anti-NMDAR antibodies," which bind to extracellular conformal epitope in the NR1/NR 2 heteromers of the NMDAR. The antibodies are usually detected in CSF/serum of young women with ovarian teratoma, who typically developed schizophrenia-like psychiatric symptoms, usually preceded by viral infection-like illness. Most cases developed seizures, followed by unresponsive/catatonic state, decreased level of consciousness, central hypoventilation, orofacial-limb dyskinesias, and autonomic symptoms. Brain MRI is often unremarkable. CSF reveals nonspecific changes. EEG shows diffuse delta slowing. The pathogenesis remains unknown, however this disorder is considered as an antibodies-mediated encephalitis. The prodromal "viral-like" disorder by itself or in combination with a teratoma sets off the autoimmune response. The antibodies bind to the common autoantigens expressed on the cell membrane of the neurons in the forebrain/hippocampus. Based on the current NMDAR hypofunction hypothesis of schizophrenia, we speculate that the antibodies may cause inhibition of NMDAR, rather than stimulation, in presynaptic GABAergic interneurons, causing a reduction of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate and dopamine dysregulation that might contribute to development of schizophrenia-like psychosis and bizarre dyskinesias.
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PMID:[Clinical features and pathogenesis of anti-NMDA receptor encephalitis]. 1919 18

Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species.
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PMID:The effects of memantine on prepulse inhibition. 1924 6

Dopamine (DA) efflux from terminals of the mesocorticolimbic system is linked to incentive motivation, drug dependency and schizophrenia. Strategies for modulating dopaminergic activity have focused on transmitter receptors or the DA transporter, not on DA release, largely due to lack of systemically available drugs acting at this level. Central synapses use two main calcium channels for excitation-secretion coupling, either P/Q-type, N-type, or both. Here we investigate changes in mesocorticolimbic DA efflux following administration of NP078585, a novel orally available calcium channel blocker exhibiting high affinity block of N- and T-types versus P/Q- and L-types. NP078585 was applied either intra peritoneally (i.p.; 2.5-10 mg/kg) or by reverse-dialysis (10-25 microM) into either the Ventral Tegmental Area (VTA) or the Nucleus Accumbens (NAc), and the changes in DA levels in both the VTA and NAc were monitored using microdialysis. We found that both systemic and central administration of NP078585, but not vehicle, enhanced DA efflux in the NAc but not the VTA. The enhancement of DA levels was replicated by local applications of omega-conotoxin GVIA (2.5 microM), a selective peptide N-type channel blocker, to either VTA or NAc, suggesting N-type mediation. Furthermore, application of the GABA(A)-selective antagonist bicuculline (50 microM) to the VTA enhanced DA efflux in both VTA and NAc, and occluded the NP078585-induced enhancement in the latter structure. We propose that the actions of NP078585 and omega-conotoxin largely reflect block of N-type channels in terminals of GABAergic interneurons, leading to reduced GABA release, disinhibition of DA neurons and enhanced DA release in the NAc.
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PMID:Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system. 1937 80

Over the last 30 years, several questionnaires have been developed and validated in order to assess many aspects of the motivation to eat that might be susceptible to impair adequate food intake and body weight control. A few of such questionnaires are described here, in particular, the "Three Factor Eating Questionnaire" also called the "Eating Inventory", and the "Dutch Eating Behavior Questionnaire". Critical aspects of the motivation to eat assessed by these tools are presented, such as dietary restraint, disinhibition, hunger, vulnerability to eat in response to external cues or emotional states, etc. These questionnaires were developed for use in the general population with the aim to identify critical aspects of the motivation to eat that might predispose to weight gain. They have been widely used in many countries and have allowed an improved understanding of the individual characteristics that predispose to body weight gain or resistance to weight loss. Originally, poor body weight control was attributed to a high level of dietary "restraint", or in other words, the tendency to deliberately restrict one's food intake for body weight control purposes. Such dietary restraint was suspected to lead to a number of physical and psychological difficulties, among which poor self-esteem and a paradoxical tendency to gain weight, resulting from the incapacity to maintain strict restraint over time. More recent studies have established that a motivational trait called "Disinhibition" is a strong predictor of body weight gain over time and of poor outcome of dieting. "Disinhibition" corresponds to a tendency to lose control over one's eating behavior and ingest excessively large quantities of food substances, in response to a variety of cues and circumstances. In addition to its untoward effect on weight, disinhibition also predicts various risk factors and pathologies, such as hypertension and diabetes. Other potentially critical dimensions for adequate body weight control are "emotional eating" and "externality", which represent an individual's vulnerability to eat in response to emotional states or external cues, respectively. These questionnaires have been translated into French and validated for the French population. Average data are available for normal weight and obese French men and women. A gender difference is often reported: women, and even young girls, tend to have higher scores than males for most dimensions. These questionnaires have been extensively used in populations without psychiatric disorders, with the only exception of diagnosed eating disorders such as anorexia and bulimia nervosa. The questionnaires have not been used until now in populations with other types of psychiatric disorders, such as schizophrenia or bipolar disease. Their relevance for such populations is now an important question, since last generation pharmaceutical treatments of such psychiatric disorders seem to adversely affect body weight control. It then becomes critical to know whether the psychological dimensions assessed by such questionnaires reflect the action of pharmacological agents that induce weight gain. A research project is now in progress at Sainte-Anne Hospital to investigate many dimensions of the motivation to eat, as assessed by the questionnaires, in psychiatric patients receiving various types of antipsychotic agents. The results of this original study might provide hints about the mechanisms that lead to body weight gain in patients receiving certain types of antipsychotic pharmacological agents and potentially help in preventing or reversing the weight gain associated with such treatments.
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PMID:[Assessing various aspects of the motivation to eat that can affect food intake and body weight control]. 1939 89

The present study explored the premorbid personality traits Neuroticism, Extraversion, and Disinhibition in individuals later diagnosed with psychotic disorders. Results on personality questionnaires and intellectual performance tests were obtained for 213,443 apparently healthy male subjects (mean age: 20.1 years) conscripted into the Finnish Defence Forces during the period 1982-1987. Linkage with the Finnish Hospital Discharge Register (mean follow-up time: 14.1 years, SD = 1.7) identified conscripts later diagnosed with schizophrenia (N = 1,328), bipolar disorder (N = 98), or other psychoses (N = 456). Both before and after controlling for intellectual performance, high Neuroticism predicted future onset of schizophrenia and other psychoses, and high Extraversion predicted future onset of bipolar disorder. The data of the present research showed for the 1st time that premorbid personality traits predict heightened risk for psychotic disorders beyond intellectual performance and also showed for the 1st time an association between premorbid Extraversion and bipolar disorder.
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PMID:Premorbid personality factors in schizophrenia and bipolar disorder: results from a large cohort study of male conscripts. 1941 16

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