Apolipoprotein E epsilon 4 and clinical phenotype in schizophrenia.
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Alleles↗
Biomedical subjects
A Breier
Publications and source records attributed to A Breier.
Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method.
A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outflow. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D2/D3 positron-emission tomography radioligand [11C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n = 4), doubling the amphetamine dose produced a doubling in [11C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg/kg) was 44:1, demonstrating that relatively small binding changes reflect large changes in dopamine outflow. In the clinical study, patients with schizophrenia (n = 11) compared with healthy volunteers (n = 12) had significantly greater amphetamine-related reductions in [11C]raclopride specific binding (mean +/- SEM): -22.3% (+/-2.7) vs. -15.5% (+/-1.8),P = 0.04, respectively. Inferences from the preclinical study suggest that the patients' elevation in synaptic dopamine concentrations was substantially greater than controls. These data provide direct evidence for the hypothesis of elevated amphetamine-induced synaptic dopamine concentrations in schizophrenia.
Amphetamine↗
Borna disease virus antibodies and the deficit syndrome of schizophrenia.
We detected anti-Borna disease virus (BDV) antibodies at a 14.4% rate in patients with schizophrenia. The hypothesis of a higher rate of BDV seropositivity in deficit syndrome was borne out in a subset of 64 patients categorized according to the Schedule for the Deficit Syndrome with 5/15 seropositive deficit and 4/49 seropositive nondeficit (p < 0.05). This suggests that the antibodies and possibly a BDV-like virus are pathogenetically linked to this form of schizophrenia.
Adult↗
D2 dopamine receptor occupancy: a crossover comparison of risperidone with clozapine therapy in schizophrenic patients.
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Adult↗
Effects of acute metabolic stress on plasma progesterone and testosterone in male subjects: relationship to pituitary-adrenocortical axis activation.
Stress effects on progesterone and testosterone as well as the relationship of these effects to the hypothalamic-pituitary-adrenal (HPA) axis activation have been extensively investigated in laboratory animals. There is less information about the impact of stress on sex steroids in humans. The purpose of the present study was to examine the influence of acute arterial levels of progesterone, testosterone, adrenocorticotropic hormone (ACTH), cortisol, gonadotropins and sex hormone binding globulin (SHBG) in healthy male subjects. The stressor used was glucoprivation induced by pharmacological doses of 2-deoxy-D-glucose (2DG) (40mg/kg). This stress resulted in increases in progesterone, decreases in testosterone and no significant change in gonadotropins or SHBG. ACTH and cortisol were robustly elevated and these elevations related significantly to changes in progesterone but not testosterone. The implications of these data for the understanding of the role of sex steroids in the stress response is discussed.
Adrenal Cortex↗
Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics.
The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo-controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine. We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls. Schizophrenics experienced a brief-ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals. These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia. Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls.
Adult↗
Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion.
Positron emission tomography and single-photon emission computer tomography receptor-binding ligands can be used to measure changes in neurotransmitter levels. In particular, amphetamine-induced dopamine release has been assessed with [11C]raclopride by paired bolus injections and with [123I]iodobenzamide by using a single bolus plus infusion (B/I) study. Here, we measured the change in [11C]raclopride-specific binding in rhesus monkeys after i.v. administration of 0.4 mg/kg amphetamine by using both the bolus and B/I paradigms. Paired bolus studies (control and postamphetamine) were analyzed using compartment modeling and graphical analysis with a new plasma metabolite model to measure the total distribution volume (VT). Specific binding, calculated with three measures linearly proportional to the binding potential, demonstrated a 22-42% reduction in the postamphetamine study. VT values from B/I studies were determined by the tissue-to-plasma ratio at equilibrium, in addition to the bolus methods. There was good agreement between the control VT values between bolus and B/I studies. The amphetamine-induced change in specific binding in B/I studies was 19 +/- 16%, measured directly from tissue radioactivity levels. This study demonstrates that stimulus-induced changes in specific binding can be measured with a single [11C]raclopride study using the B/I method.
Amphetamine↗
Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies.
The in vivo binding of D2 receptor ligands can be affected by agents that alter the concentration of endogenous dopamine. To define a more explicit relation between dopamine and D2 receptor binding, the conventional compartment model for reversible ligands has been extended to account for a time-varying dopamine pulse. This model was tested with [11C]raclopride positron emission tomography and dopamine microdialysis data that were acquired simultaneously in rhesus monkeys. The microdialysis data were incorporated into the model assuming a proportional relation to synaptic dopamine. Positron emission tomography studies used a bolus-plus-infusion tracer delivery with amphetamine given at 40 minutes to induce dopamine release. The extended model described the entire striatal time-activity curve, including the decrease in radioactivity concentration after an amphetamine-induced dopamine pulse. Based on these results, simulation studies were performed using the extended model. The simulation studies showed that the percent decrease in specific binding after amphetamine measured with the bolus-plus-infusion protocol correlates well with the integral of the postamphetamine dopamine pulse. This suggests that changes in specific binding observed in studies in humans can be interpreted as being linearly proportional to the integral of the amphetamine-induced dopamine pulse.
Animals↗
Failure of fusion of the septum pellucidum and the heterogeneity of schizophrenia.
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Adult↗
Attentional impairments in deficit and nondeficit forms of schizophrenia.
OBJECTIVE: Previous studies of attention/information processing impairments in schizophrenia suggest that patients with the deficit syndrome should be characterized by impaired performance on measures of visual information processing. Therefore, the authors examined whether two measures of visual information processing, a degraded stimulus version of the continuous performance test and a forced choice span of apprehension task, were uniquely related to the deficit syndrome. METHOD: Performance on the continuous performance test and span of apprehension task was examined in 20 deficit and 56 nondeficit patients with schizophrenia and in 27 subjects in a normal comparison group. RESULTS: Deficit patients performed significantly less well than both nondeficit patients and the normal comparison group on the continuous performance test and span of apprehension task. There were no significant differences between the nondeficit patients and the normal group on the continuous performance test, but nondeficit patients performed significantly less well on the span of apprehension task than the normal group. Differences between the deficit and nondeficit patients in performance on the continuous performance test and span of apprehension task were not related to total scores on the Brief Psychiatric Rating Scale factor 1 or on the Thought, Language, and Communication scale or to neuroleptic level. CONCLUSIONS: The results suggest that deficit patients are uniquely characterized by impaired performance on the continuous performance test. The deficit patients' differential performance on the continuous performance test may be related to either an inability to activate and allocate attention or an impairment in the perceptual organization of visual information.
Adult↗
Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers.
OBJECTIVE: Agents that antagonize the N-methyl-D-aspartic acid (NMDA) receptor, such as phencyclidine and ketamine, produce an acute psychotic state in normal individuals that resembles some symptoms of schizophrenia. The aim of this study was to determine which brain regions are involved in NMDA receptor-mediated psychosis. METHOD: Positron emission tomography with [18F]fluorodeoxyglucose was used to determine cerebral metabolic activity in 17 healthy volunteers while an acute psychotic state was induced simultaneously by the administration of subanesthetic doses of ketamine. RESULTS: Ketamine produced focal increases in metabolic activity in the prefrontal cortex and an acute psychotic state. A change in one psychotic symptom, conceptual disorganization, was significantly related to prefrontal activation. CONCLUSIONS: These data suggest that the prefrontal cortex may be involved in mediating NMDA receptor-induced psychosis.
Adult↗
Mechanisms that may be involved in calcium tolerance of the diabetic heart.
In diabetes the hearts exhibit impaired membrane functions, but also increased tolerance to Ca2+ (iCaT) However, neither the true meaning nor the molecular mechanisms of these changes are fully understood. The present study is devoted to elucidation of molecular alterations, particularly those induced by non-enzymatic glycation of proteins, that may be responsible for iCaT of the rat hearts in the stage of fully developed, but still compensated diabetic cardiomyopathy (DH). Insulin-dependent diabetes (DIA) was induced by a single i.v. dose of streptozotocin (45 mg.kg-1). Beginning with the subsequent day, animals obtained 6 U insulin daily. Glucose, triglycerides, cholesterol and glycohemoglobin were investigated in blood. ATPase activities, the kinetics of activation of (Na,K)-ATPase by Na+ and K+, further the fluorescence anisotropy of diphenyl-hexatriene as well as the order parameters of membranes in isolated heart sarcolemma (SL) were also investigated. In addition, the degree of glycation and glycation-related potency for radical generation in SL proteins were determined by investigating their fructosamine content. In order to study calcium tolerance of DH in a 'transparent' model, hearts were subjected to calcium paradox (Ca-Pa, 3 min of Ca2+ depletion; 10 min of Ca2+ repletion). In this model of Ca(2+)-overload, Ca2+ ions enter the cardiac cells in a way that is not mediated by receptors. Results revealed that more than 83% of the isolated perfused DH recovered, while the non-DIA control hearts all failed after Ca-Pa. DH exhibited well preserved SL ATPase activities and kinetics of (Na,K)-ATPase activation by Na+, even after the Ca-Pa. This was considered as a reason for their iCaT. Pretreatment and administration of resorcylidene aminoguanidine (RAG 4 or 8 mg.kg-1) during the disease prevented partially the pathobiochemical effects of DIA-induced glycation of SL proteins. DIA-induced perturbations in anisotropy and order parameters of SL were completely prevented by administration of RAG (4 mg.kg-1). Although, the latter treatment exerted little influence on the (Na,K)-ATPase activity, it decreased the calcium tolerance of the DH. Results are supporting our hypothesis that the glycation-induced enhancement in free radical formation and protein crosslinking in SL may participate in adaptive mechanisms that may be also considered as 'positive' and are responsible for iCaT of the DH.
Animals↗
Lack of gender differences in neuroleptic response in patients with schizophrenia.
OBJECTIVE: The authors sought to determine if there were gender differences in neuroleptic response in male and female patients with schizophrenia who were matched for clinical and demographic variables and participated in a double-blind trial of traditional antipsychotic drugs. METHODS: 24 males (m) and 20 females (f) with schizophrenia or schizoaffective disorder who did not differ in clinical characteristics (age of onset, course of illness, prior hospitalizations, premorbid functioning) participated in an extended drug-free period followed by a neuroleptic trial under double-blind, placebo-controlled conditions. RESULTS: Males and females showed significant improvement in total, positive and negative BPRS symptoms during neuroleptic treatment. However, there were no significant differences in treatment response between sexes. No sex differences were found in baseline drug-free symptomatology, neuroleptic dose or dosage by weight. CONCLUSIONS: There were no significant sex differences in neuroleptic treatment response in male and female patients well-matched for clinical, treatment and demographic characteristics. Methodological issues which distinguish this study from prior studies reporting gender differences in neuroleptic response are examined.
Adult↗
Clozapine response and the 5HT2C Cys23Ser polymorphism.
The presence of the 5HT2C receptor allele, Ser23, has recently been reported to predict favorable response to the antipsychotic drug, clozapine. This finding is of interest as Ser23, compared with the more abundant Cys23, alters pharmacological characteristics of the receptor and therefore may provide insights into the mechanism of action of antipsychotic drugs. We determined 5HT2C receptor genotype at the Cys23Ser locus in 66 subjects participating in double-blind studies of clozapine. There was no relationship between Ser23 and clozapine response (p = 0.30, Fisher's exact) nor was there any effect of Ser23 upon absolute levels of psychiatric symptoms after 10 weeks of clozapine treatment (t = -0.57, p = 0.57). These data suggest that this 5HT2C receptor polymorphism is not associated with clozapine response.
Alleles↗
5HT 2a receptor T102C polymorphism and schizophrenia.
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Alleles↗
Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.
BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with later-onset disorder has not been established. In this study quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/- 2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P = .002, and analysis of covariance, P = .03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively); and the lateral ventricles tended to be larger in the patients (analysis of covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in childhood-onset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.
Adolescent↗
Diabetic cardiomyopathy in rats: biochemical mechanisms of increased tolerance to calcium overload.
Abundant information is now available about changes in subcellular organelles that are responsible for the impaired intracellular calcium homeostasis in diabetic cardiomyopathy. Some of these changes concern heart sarcolemma and include decrease in the following variables: calcium binding, influx of calcium through the L-type calcium channels, (Na,K)-ATPase activity and its affinity to sodium, Na(+)-Ca2+ exchange, H(+)-Na+ exchange, etc. Diabetic hearts also exhibited increased tolerance to calcium, but none of the above membrane perturbations were clearly identified as the source of this effect. The present study was undertaken in order to identify those alterations appearing in diabetes which are specific for the diabetic heart only. Our interest was focused on changes in sarcolemmal ATPase activities, particularly those of the (Na,K)-ATPase and its activation by increasing concentrations of sodium and potassium. Studies were performed in the acute (8 days) and chronic (63 days) phase of development of insulin-dependent diabetic cardiomyopathy. Wistar rats were made diabetic by administration of streptozotocin. To test the effect of excess calcium, the well-established model of calcium paradox was used. From the results obtained the following conclusions have been made: (a) diabetic hearts exceed normal hearts in their tolerance to calcium overload. In this respect the effect of chronic diabetes is more pronounced than the effect of acute diabetes; (b) the activities of sarcolemmal ATPases in diabetic hearts remain relatively well preserved. For this reason and with respect to modulation of calcium tolerance, the changes in specific properties of the ATPases, particularly those in the (Na,K)-ATPase, outweigh the importance of perturbations in their activities; (c) the enormous decrease in affinity of the (Na,K)-ATPase to sodium (increased K(m) value) monitored in calcium paradox in acute diabetic hearts was absolutely missing in "calcium-tolerant" chronic diabetic hearts. This observation pointed to a possible relation that may exist between the specific properties (Na,K)-ATPase adapted to work in chronic diabetic hearts and the enhanced calcium tolerance of those hearts; (d) the specific mechanism responsible for improved activation of the (Na,K)-ATPase by sodium and also partially responsible for potassium ions, which is clearly manifested in chronic diabetic hearts upon calcium paradox, still remains to be elucidated. Nevertheless, it could be assumed that the same mechanism may be also co-responsible for the enhanced tolerance of diabetic hearts to calcium.
Adenine Nucleotides↗
NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers.
A rapidly growing body of preclinical data has implicated the glutamatergic N-methyl-d-aspartate (NMDA) receptor in memory and other cognitive processes. There is comparatively less information about this receptor system in human cognition. We examined the effects of subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, on two forms of memory, free recall and recognition, as well as attention and behavior in a double-blind, placebo-controlled, 1-hour infusion in 15 healthy volunteers. Ketamine produced decrements in free recall, recognition memory, and attention. In addition, ketamine induced a brief psychosis in our healthy volunteers marked by thought disorder and withdrawal-retardation. Ketamine-induced memory impairments were not accounted for by changes in subject's attention and were not significantly related to psychosis ratings. These data suggest that the NMDA receptor plays a direct role in two types of explicit memory. The implications of these data for the pathophysiology of schizophrenia are discussed.
Adult↗