Interactions In Schizophrenia Research Articles

Altered neurotensin mrna expression in mice lacking the dopamine transporter

Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT−/− mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT−/− mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT−/− mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT−/− mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.

Functional and effective frontotemporal connectivity and genetic risk for schizophrenia

Background Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative (“inhibitory”) frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.

BackgroundA systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors.Presentation of the hypothesisBased on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia.Testing the hypothesisSupported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations.Implications of the hypothesisThe hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments.

Reversed lateralization of temporal activation during speech production in thought disordered patients with schizophrenia.

Formal thought disorder is a core symptom of schizophrenia. It is associated with a reversed lateralization of the superior temporal cortex volume, an area that is implicated in lexical retrieval. We investigated the neural correlates of word retrieval during continuous speech in patients with formal thought disorder using functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent (BOLD) contrast was measured with fMRI while six patients with schizophrenia and six healthy control subjects spoke about seven Rorschach inkblots for 3 min each. Subjects produced varying amounts of speech during each run. In a within subject design, the number of words produced was correlated with the BOLD contrast in the two runs in each participant who showed the highest variance of speech output. In control subjects, the amount of speech produced was mainly correlated with activation in the left superior temporal gyrus. In the patient group, the main correlations were in the right superior temporal gyrus. During the production of continuous speech, patients with formal thought disorder showed a reversed laterality of activation in the superior temporal cortex. This is consistent with findings of perturbed hemispheric interaction in schizophrenia, particularly in patients with formal thought disorder.

Immune–biochemical interactions in schizophrenia

Immune–biochemical interactions in schizophrenia

Muscarinic cholinergic-dopaminergic interactions in schizophrenia: Effects of anticholinergic modulation on REM sleep measures

Muscarinic cholinergic-dopaminergic interactions in schizophrenia: Effects of anticholinergic modulation on REM sleep measures

Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum

Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine–glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine–glutamate interactions in schizophrenia.

Neurocognitive function in alcoholic, schizophrenic, and dually diagnosed patients

Neurocognitive functions were compared in alcoholic, schizophrenic, and dually diagnosed (schizophrenic and alcoholic) patients and community control volunteers. Participants ( N = 52, n = 13 in each group) completed a brief battery including two measures of neuropsychological function and two affective measures. The neuropsychological tests included the Trail-Making Test Forms A and B and a face-recognition test. The affective measures included assessment of anxiety and depression. The major objective was to compare the patterns of neurocognitive performance among the four groups. The groups did not differ in mean age (35.37) or years of education (12.46). Compared with the community control and alcoholic groups, the schizophrenic groups reported higher mean depression (12.92 vs. 5.54) and mean state anxiety scores (60.73 vs. 46.04). Control subjects were generally, although not always significantly, superior to the other groups. Contrary to expectations, alcoholic patients were not consistently better than the schizophrenic groups, and dually diagnosed participants were not more impaired than schizophrenic patients without substance abuse histories. Thus, the interaction of schizophrenia and substance abuse did not have an additive effect on neurocognitive performance assessed in this study. More research using this complete four-group design and a larger neurocognitive battery is needed.

Gene-Environment Interaction in Schizophrenia: Season-of-Birth Effect Reveals -Etiologically Different Subgroups

Compared to the general population, one consistent finding in schizophrenia research is a significant surplus of schizophrenic births in the winter/spring months. There is little evidence that this is attributed to statistical artefacts. The "harmful effects' hypothesis offers the most plausible explanation for this phenomenon. Exogenous harmful effects, predominant during the cold season, may affect the developing immature fetal brain and thus constitute some of the factors predisposing to schizophrenic breakdown in adulthood. Neuropathological and epidemiological studies point to the second trimenon of gestation as the crucial period of fetal brain maturation. Recently, some studies found that the surplus in schizophrenic winter/spring births is mainly due to sporadic forms. In contrast, patients with high genetic risk of the disease even tended to have a birth deficit during this period. This suggests that schizophrenia is not a disease entity but consists of etiologically distinct subgroups on which the influence of genes and/or environment has to be weighted differently. On the one hand, in sporadic forms of the disease exogenous noxious agents may be of major etiological importance. On the other hand, in fetuses at high genetic risk neurodevelopment may already be disturbed due to a genetic defect and additional environmentally noxious agents can cause abortions, stillbirths and sudden infant deaths.

Neurocircuitries and neurotransmitter interactions in schizophrenia

This review describes an attempt to widen the perspective on schizophrenia and to go beyond the dopamine hypothesis. In recent animal experiments corticofugal glutamatergic pathways have emerged as powerful regulators of a variety of subcortical mechanisms, where the dorsal and ventral striatum appear to play a major role in feedback loops controlling a thalamic filter function. These loops appear to be important regulators of wakefulness and psychomotor activity. A deficient filter function will lead to an overload of sensory input to the cerebral cortex and hyperarousal and may ultimately cause breakdown of the integrative capacity of the cerebral cortex and psychosis. Both negative and positive feedback loops appear to be driven by corticofugal glutamatergic pathways, and deficient functions of these loops may cause or contribute to the positive and negative symptomatology of schizophrenia, respectively. In addition to dopamine and glutamate, several other neurotransmitters, including gamma-aminobutyric acid, noradrenaline, serotonin and acetylcholine, appear to play an important role in psychomotor activity and psychotogenesis. Behavioural and biochemical animal models illustrate the interplay between the various neurotransmitters in these respects.

Neurocircuitries and neurotransmitter interactions in schizophrenia

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Functional magnetic resonance imaging at 1.5 T: Activation pattern in schizophrenic patients receiving neuroleptic medication

Activation of the cerebral cortex during motor task performance can be visualised with functional MRI. A modified FLASH sequence (TR/TE/α 100/60/40°, first order flow rephased, fat suppression, reduced bandwidth 28 Hz/pixel, 120 repetitions, three cycles of rest and finger movement for each hand) on a standard 1.5 T clinical imager was used to investigate 10 schizophrenic patients receiving clozapine and 10 healthy volunteers. All subjects were right-handed. Color-coded statistical parametric maps (SPM) based on the Student's t-test were calculated. A grid overlay was used for global and regional quantification. Activation strength was defined as the mean t-value of the respective region. All patients and volunteers showed a significant activation in the contralateral and ipsilateral sensorimotor cortex during motor task performance. The schizophrenic patients showed a significantly reduced global activation strength compared with healthy volunteers ( p < .005). Selective evaluation of left-hand compared to right-hand movement demonstrated an increase in global activation strength in volunteers in contrast to a decrease in patients. Furthermore a reduced coactivation in the dominant left hemisphere was found in patients compared to volunteers during movement of the ipsilateral (left) hand. We conclude that alterations of the right and left hemispheric balance can be detected in schizophrenic patients using functional MRI at 1.5 T. These changes may indicate a disturbed interhemispheric interaction in schizophrenia. The reduction in cortical activation may result from several causes, however, taken together with previous studies and the underlying physiological effects, the most likely explanation is a combined effect of the disease and the neuroleptic medication.

Effect of neuroleptic medication on cerebrospinal fluid monoamine metabolite concentrations in schizophrenia. Serotonin-dopamine interactions as a target for treatment.

This study examined the effect of neuroleptic treatment on indexes of dopamine and serotonin function in schizophrenic patients. We hypothesized that neuroleptic treatment would be effective by changing dopamine and serotonin function and/or by altering their interaction. Lumbar cerebrospinal fluid (CSF) concentrations of the metabolites of dopamine (homovanillic acid, [HVA]) and serotonin (5-hydroxyindoleacetic acid, [5-HIAA]) were measured after a minimum drug-free period of two weeks and again after five weeks of treatment with haloperidol, 20 mg/d orally. Psychiatric symptoms were rated within one day of CSF sampling. Sixteen schizophrenic and three schizoaffective male inpatients. Neuroleptic treatment significantly raised HVA concentrations and significantly increased the ratio between HVA and 5-HIAA. The increase in HVA was not related to symptomatic improvement, whereas the increase in the HVA/5-HIAA ratio was significantly correlated with reduction in overall symptomatology. These findings suggest that the increase in HVA is relative to 5-HIAA, and not the absolute increase in HVA, that is related to symptomatic improvement. This, in turn, suggests that changing dopamine function relative to serotonin function, rather than changing dopamine per se, is associated with the therapeutic effect of haloperidol. Exploring serotonin-dopamine interactions in schizophrenia may be more informative than examining each system in isolation.

Muscarinic cholinergic hyperactivity in schizophrenia: relationship to positive and negative symptoms

Based on the implication of increased muscarinic ACh activity in the production of negative symptoms, the association of decreasing cholinergic activity with positive symptoms, and the covariance of positive and negative symptoms in the psychotic phase of schizophrenia, a model of (DA) dopaminergic/(ACh) cholinergic interactions in schizophrenia was recently formulated. It suggests that DA/ACh balance is of central importance in schizophrenic pathophysiology and that muscarinic ACh activity increases in an attempt to maintain this balance in the face of increasing DA activity that occurs in the psychotic phase of the illness. The model further suggests that the muscarinic system exerts a damping influence on the emergence of positive symptoms associated with DA hyperactivity, but that this compensatory increase in muscarinic activity is accompanied by an intensification of negative symptoms. In the present study, we tested two important postulates of this model. We tested the prediction that muscarinic activity is increased in schizophrenia by comparing the effect of biperiden, an antimuscarinic M-1 agent, on REM latency in 12 drug-free schizophrenic inpatients and matched normal controls. We found that biperiden caused a smaller increase in REM latency in schizophrenic patients, suggesting that muscarinic activity is increased in schizophrenia. We tested the prediction that an anticholinergic agent would increase positive symptoms and decrease negative symptoms by studying the effect of 8 mg of biperiden/day for 2 days on positive and negative symptoms (assessed by the BPRS) in 30 medication-free schizophrenic inpatients. Biperiden produced a significant increase in positive symptoms ( t = 6.36, df = 29, P < 0.001) and reduction in negative symptoms ( t = −2.05, df = 29, P < 0.05). These findings suggest that central muscarinic activity is increased in the psychotic phase of schizophrenia and is relevant to the expression of positive and negative symptoms.

Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia.

Despite renewed interest in negative schizophrenic symptoms, the pathophysiological mechanisms involved in their development remain obscure. Although the cholinergic system has been implicated in schizophrenia, it has not been accorded a major role in current theories of pathophysiology. We present evidence from several lines of research that suggests that muscarinic hyperactivity may be implicated in the pathogenesis of negative schizophrenic symptoms. Specifically, cholinergic overdrive leads to a behavioral syndrome strikingly similar to the negative schizophrenic syndrome, anticholinergic agents may alleviate negative symptoms, schizophrenic patients with negative symptoms tend to "abuse" anticholinergics, and polysomnographic, neuroendocrine, and other pharmacological findings appear to be generally consistent with this hypothesis. The hypothesis is testable and is presented as a heuristic model that focuses on the dynamic interplay between cholinergic and dopaminergic systems in schizophrenia.

Drug and Psychosocial Treatment Interactions in Schizophrenia

In a stress-diathesis approach to schizophrenia, stressful environmental events combine with pre-existing biological and psychosocial vulnerability to produce intermediate states of sensory overload, hyperarousal, and impaired processing of social stimuli. If untreated, these intermediate states often lead to the development of psychotic symptoms or relapse. In this approach assumes an interaction between biological and environmental etiologies and between biological and psychosocial forms of treatment. Evidence from studies which have examined the effects of both treatment strategies in tandem indicates that comprehensive treatment programs for schizophrenic patients should combine drug and psychosocial treatments. For outpatients, behaviorally oriented social skills training and family interventions are especially effective when added to neuroleptic drug therapy. A comprehensive approach to the clinical management of schizophrenia can be described in terms of a clinical decision tree, in which patient c...

Studies on the offspring of two schizophrenic parents

IT IS now generally agreed that both heredity and environment are important in producing schizophrenia. Indeed, this is so well recognized that, as Kringlen (1967) has recently pointed out, the conclusion is a “trivial” one. The key to schizophrenia, therefore, may be understood to lie in the nature of the interaction between genie products and environmental factors. The question to be asked is not “What are the reiative contributions of heredity and environment”, but rather “What kinds of environmental input trigger manifestations of the disorder in genotypically vulnerable persons, and why are these important, in a psychophysiological sense?’ If schizophrenia were a disease occurring in self-reproducing plants, it would only be necessary to submit the clones to a spectrum of environments to obtain an index of the range of reaction of the genotype-or series of genotypes if different clones were found to express the disease under certain conditions. As it is, there are at least two approaches to the problem of interaction in schizophrenia. One is a retrospective approach that seeks to analyze interaction through intensive historical probing of the environmental dissimilarities experienced by genotypically identical individuals, i.e., monozygotic twins, who are discordant for the manifestation of schizophrenia (Allen, 1954; Pollin et al., 1966). The second is a prospective design. It involves developmental studies of high-risk populations in which the attempt is made to chart, in medias res, the impact of environmental factors upon the course of behavioral maturation and to correlate these longitudinally with mental status outcome in later years. High-risk populations for developmental studies are, by definition, children with schizophrenia in one or both parents. There are, to my knowledge, two longitudinal investigations on high-risk populations now active, viz. those of Mednick and Schulsinger in Denmark and of Rosenthal and colleagues in 1srael.l These studies deal chiefly with the children of one affected parent. In this paper I should like to consider the offspring of two schizophrenic parents (dual matings) as candidates for longitudinal research and to present, in a tentative way, a design

Family interaction in schizophrenia.

Despite considerable agreement amongst psychiatrists that family relations play a critical role in the post-hospital adjustment of the mentally ill, there is disagreement as to how this operates. Combining clinical and social study methods, a study of this interaction was conducted following the method of Freeman-Simmons in Boston and Brown et al in London. One hundred and twenty-two mental hospital patients, male and female schizophrenics, discharged to families, were followed from the time of leaving hospital for one year. All patients were interviewed in the hospital. Patients were seen with their relatives at home shortly after, and direct ratings of the interaction then made. Subsequently, relatives were re-interviewed, in almost all cases, at the end of the follow-up year. The interaction data consists of: 1) direct observations; 2) attitude of the key relatives regarding their expectations for the patient; 3) systematic description of self and other collected for both the patients and the relatives; and 4) the interviewer's descriptions of the home context, including other family members. Predictive factors of one-year community tenure (expressed emotion of the relative, previous disability, clinical state at discharge) do not hold up for a Canadian population of mixed sex. The over-all rate of hospital return was low for this group, and as many from high risk subgroups returned as from more favoured groups. Particularly difficult to interpret is the finding that patients return to treatment at a constant rate each month. Re-hospitalization follows an acute flare-up, and is a rapid process when once suggested. In general, the results support the Freeman-Simmons interpretation that post-hospital social performance is closely related to the relatives' expectancy, but that symptomatic course and re-hospitalization are relatively independent of either the relatives' expectancy or the emotional climate in the family.

An investigation of social interaction in schizophrenia.

An investigation of social interaction in schizophrenia.

Direct study of childparent interactions. Workshop, 1959. 1. The structured situational test: a method for studying family interaction in schizophrenia.

Direct study of childparent interactions. Workshop, 1959. 1. The structured situational test: a method for studying family interaction in schizophrenia.