Cloning and analysis of a cDNA encoding the BALB/c murine erythrocyte band 7 integral membrane protein

Phospholipid metabolism abnormalities have been suggested by a number of postmortem brain and red blood cell studies in schizophrenia. 31P magnetic resonance spectroscopy enables the examination of phospholipid metabolism in living patients. These in vivo studies have demonstrated that schizophrenic patients have lower prefrontal levels of phosphomonoesters and higher levels of phosphodiesters compared to matched controls. Patients with psychotic depression also seem to show lower levels of phosphomonoesters compared to controls. This suggests that membrane phospholipid differences may not be specific to schizophrenia. Preliminary 31P magnetic resonance spectroscopy studies at high field strength on postmortem temporal lobe samples show no differences between treated schizophrenic patients and controls for phosphoethanolamine and phosphocholine which are the main constituents of the phosphomonoester peak. Further studies are underway in the prefrontal region. While 31P magnetic resonance spectroscopy studies have demonstrated membrane phospholipid abnormalities in schizophrenia, it is not clear whether these findings are specific to schizophrenia or part of a generalized membrane phospholipid abnormality.     

Neuropsychological disorders after coronary bypass surgery

Pettegrew et al (Arch Gen Psychiatry 48:563-568, 1991) were the first to determine abnormalities concerning phospholipids and high energy metabolites in the dorsolateral prefrontal cortex of drug-naive schizophrenics with 31P magnetic resonance spectroscopy (MRS). Other investigations could not replicate these findings. We included in our study 13 schizophrenic inpatients and 14 age-matched controls. Whereas Pettegrew et al found increased levels of phosphodiesters and decreased levels of phosphomonoesters we measured decreased levels of phosphodiesters in the schizophrenics as compared to controls. One possible explanation for the contradictory findings of the both trials might be the different localization techniques used.     

Synthesis and pharmacological study of some new beta-(dialkylaminomethyl)- gamma-butyrolactones and their tetrahydrofuran analogues

To examine metabolic changes in the left basal ganglia in chronic schizophrenia, we performed proton magnetic resonance spectroscopy (1H-MRS) in 21 medicated schizophrenic patients and 21 gender and age-matched normal controls. Compared to the normal subjects, the schizophrenic patients showed a significantly increased level of choline containing compounds (Cho) (t = 2.60, p < 0.05) and ratio of Cho to N-acetylaspartate (NAA) (t = 2.46, p < 0.05) in the left basal ganglia. No significant correlation was observed between the 1H-MRS measurements in the left basal ganglia and clinical symptom scores as evaluated using the Brief Psychiatric Rating Scale (BPRS). The chlorpromazine equivalent neuroleptic dosage was positively correlated with the level of NAA (r = 0.38, p < 0.05) and negatively correlated with the Cho/NAA ratio (r = -0.34, p < 0.05). These findings suggest that these changes in metabolites in the left basal ganglia may reflect some of the functional and morphological abnormalities reported previously for the brain in schizophrenia.     

Association between striatal reduction and poor Wisconsin card sorting test performance in patients with schizophrenia

Several findings support the hypothesis that the striatum is implicated in executive functions and in the modulation of goal-directed behavior, and could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. We have studied the relationship between the objective measures of the striatal structures, as evaluated by magnetic resonance imaging (MRI), and the Wisconsin Card Sorting Test (WCST) performance in a schizophrenic sample. Thirty-five schizophrenic patients underwent MRI scans of striatal structure and neuropsychological evaluation of executive functions by WCST. Poor WCST performers had a reduction of the left caudate nucleus and putamen, and right total striatum when compared to 24 healthy controls. Significant correlation coefficients were also observed between neuropsychological indexes and left striatal measures. The findings suggest the existence of a relationship between abnormalities of striatal structure and abnormal executive-type or organizational cognitive functions.     

Research and treatment strategies in first-episode psychoses. The Pittsburgh experience

BACKGROUND: Studies of first-episode patients allow investigation of the biological basis of psychotic disorders without the potential confounds of prior treatment and illness chronicity. Prospective studies of this population can clarify the impact of illness course and treatment on neurobiology. METHOD: We summarise preliminary findings from our ongoing magnetic resonance imaging and spectroscopy studies of first-episode schizophrenia patients being conducted prospectively from index evaluations through a period of two years; during this period, patients were treated with either a conventional antipsychotic such as haloperidol, or the atypical risperidone. RESULTS: Baseline neurobiological evaluations in first-episode schizophrenia patients have revealed evidence for structural and functional brain abnormalities consistent with a neurodevelopmental model of this illness. Our preliminary data support the value of risperidone as an antipsychotic drug of first choice among patients with early schizophrenic illness. CONCLUSIONS: Focused studies of first-episode patients have the potential to unravel pathophysiology of schizophrenic illness. Such knowledge is critical for more effective early detection, intervention and even prevention of this enigmatic disorder.     

Schizophrenia and brain dysfunction: An integration of recent neurodiagnostic findings.

Reviews and integrates recent evidence demonstrating the frequency, type, and clinical significance of brain dysfunction in schizophrenia. Neuroradiological, neurophysiological, and neuropsychological data suggest brain impairment in 20–35% of schizophrenic patients. The abnormalities are nonspecific and can result from a variety of causes. Preliminary evidence suggests that there are 2 or more syndromes that differ in severity and type of brain abnormality, rather than a unitary schizophrenic illness. A complex, variable picture of brain dysfunction, including ventricular enlargement and cerebral atrophy, disturbances of cerebral metabolism, neuropsychologic deficits, and neurologic "soft" signs, is found especially in chronically impaired schizophrenics with "negative" symptoms. Extent and locus of dysfunction in a corticosubcortical arousal/attention system involving areas of the frontal cortex, limbic system, and brain-stem reticular formation are hypothesized to determine the relative prominence of positive and negative symptoms. Future research on neuroanatomy, etiology, and treatment must consider the heterogeneity of the schizophrenias and might utilize the positive/negative dimension. (8 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Symptom dimensions and brain morphology in schizophrenia and related psychotic disorders

The heterogeneity of symptoms in schizophrenia may reflect heterogeneity of underlying pathophysiological mechanisms. Factor analytic studies have consistently identified three symptom factors, psychotic, negative and disorganized, as independent dimensions of schizophrenic psychopathology. This study examined the relationship of these symptom dimensions with volumes of specific brain regions. One-hundred and sixty-six schizophrenia spectrum patients were clinically evaluated with the Comprehensive Assessment of Symptoms and History (CASH) and scanned with a 1.5 Tesla magnetic resonance imaging scanner. Regions of interest (ROIs) were manually traced on 5 mm and 3 mm coronal slices by a single technician, blind to all aspects of subject identity. Correlations between ROI volumes and indices of symptom severity were determined. Analyses of covariance were then used to test for specific relationships between each of the three symptom dimensions and ROI volumes. Tests were made of each dimension, controlling for all others. Overall symptom severity was significantly correlated with larger ventricle volumes (lateral, third and temporal horns) and smaller temporal lobe, hippocampal and superior temporal gyral volumes. Both psychotic and negative symptom severity predicted increased third ventricular volume. Psychotic symptom severity uniquely predicted decreased superior temporal gyral volume as well as increased temporal horn volume. Within the psychotic symptom dimension, hallucinations alone predicted left superior temporal gyral volume. No significant associations between disorganized symptoms and any ROIs were demonstrated. These results provide clues to the localization of specific brain regions underlying symptom clusters in schizophrenia, and provide further validating evidence for the construct of independent dimensions of psychopathology within schizophrenia and related psychotic disorders.     

Psychopathologic symptoms and cognitive test performance in schizophrenic patients

Psychopathological symptoms and cognitive test performance were examined in 34 acute schizophrenic patients. The results of a clusteranalytic approach in order to distinguish groups of patients with different syndromes were disappointing. Three dimensions of negative, hallucinatory-delusional, and disorganised symptoms could be established by factor analysis. The disorganised symptom dimension showed strong and significant relations to mnestic and intellectual impairments of the patients. Hallucinatory-delusional symptoms were related to deficits in tests of visual memory and visual search. Negative symptoms were not related to cognitive impairments of the patients. The results are discussed in respect of other studies reporting correlations of schizophrenic symptoms and cognitive disturbances, and with regard to hypotheses of brain dysfunction in schizophrenia. In future research, consideration of the three main dimensions of schizophrenic symptoms could be useful to reduce the heterogeneity of schizophrenic samples.     

French translation of the Frankfurt Complaint Questionnaire (Frankfurter Beschwerde-Fragebogen, FBF, Süllwold, 1986)

Observable behaviors play the predominant role in the clinical assessment of schizophrenia, while only secondary emphasis is placed on exclusively subjective complaints. Huber employed the phenomenological approach to obtain subjective symptoms that he named "basic symptoms". Subjective symptoms constitute an important component of the schizophrenic symptomatology. They may play a predominant role during the prodromal or early phases of the disease, they may be useful in elucidating cognitive and perceptual disturbances in schizophrenia. In the last decade, the assessment of patients' subjective experiences has acquired significance with the development of several instruments for their specific evaluation. The Frankfurt Complaint Questionnaire (FCQ, Süllwold, 1986) is the instrument most widely used in Europe for assessing subjective experiences. It covers a wide range of complaints of cognitive deficits that Süllwold compiled from the complaints of schizophrenic patients. We present the French translation of the FCQ. The availability of the FCQ in French could be an important step in promoting the study of subjective experiences in research and clinical activities.     

The dopamine hypothesis of schizophrenia: current status, future prospects

The dopamine hypothesis of schizophrenia is reviewed in the context of recent advances in dopamine research. These include the following: the discovery that there are several subtypes of dopamine receptor, the recognition that the activity of dopamine neurons is controlled by negative feedback systems; insights into the functions of different subsystems of dopamine neurons; the discovery that different subsystems of dopamine neurons interact with one another; and a growing understanding of the functions and mode of operation of the forebrain regions that the dopamine projections innervate. The paper reviews some of the complexities that the dopamine hypothesis has encountered, and continues to encounter, with a particular focus on three issues: the adequacy of our understanding of neuroleptic drug action, the heterogeneity of schizophrenic symptoms and the paucity of direct evidence to support the hypothesis. It is concluded that schizophrenia does not reflect primary abnormalities of dopamine transmission, but probably does reflect abnormalities in systems that have an intimate interaction with the dopamine system. The primary substrates for schizophrenia will probably be found within the major targets of the ascending dopamine projections: the fronto-striato-pallido-thalamic loops, and the limbic structures, such as amygdala and hippocampus, with which the fronto-striatal system interacts.     

Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype

BACKGROUND: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. RESULTS: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable. CONCLUSIONS: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.     

Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters

The absence of an animal model that accurately approximates schizophrenia limits current research into the pathophysiology of this disorder. Obviously, the cognitive disturbances associated with schizophrenia are difficult to evaluate in laboratory animals. Nonetheless, animal studies have provided insight into the anatomy and physiology of the brain systems that have been implicated in schizophrenia. These studies also suggest how brain systems may be involved in information processing in normal and pathological conditions. Thus, a careful assessment of the properties and functions of the brain regions suggested to be involved in schizophrenic symptoms has been a primary objective in several laboratories. In this review, we discuss the interactions among the brain regions implicated in schizophrenia--the ventral striatum, prefrontal cortex, hippocampus, and dopamine systems--and provide an integrative model linking altered function in these regions with specific clusters of symptoms of schizophrenia.     

The etiologic heterogeneity of schizophrenia

Evidence is increasing in support of the etiologic heterogeneity of schizophrenia. Five distinct diseases/disorders are suggested in this paper, and the relevant studies are reviewed. Familial forms of the disorder include a dopamine psychosis (supported by research documenting both altered dopamine activity and early neuroleptic response among some schizophrenic patients), a neurodegenerative psychosis (supported by investigations that document ongoing change in ventricular brain ratio, elevation of products of cell membrane catabolism within the central nervous system, and age-progressive third ventricle enlargement accompanied by delayed response to neuroleptics), and a neurodevelopmental psychosis (supported by evidence of static enlarged ventricles in some schizophrenic patients and neurological soft signs in high-risk offspring of schizophrenic individuals). Nonfamilial forms include a neurodevelopmental psychosis (supported by evidence of neurodevelopmental abnormalities triggered by neurotropic viruses, radiation, or anoxia) and a lithium-responsive psychosis (supported by evidence of a subgroup of psychotic patients who have low risk of either psychosis or mania in their pedigrees and respond to lithium).     

Recent basic findings in support of excitatory amino acid hypotheses of schizophrenia

1. Several clinical and post-mortem tissue findings have suggested a role for excitatory amino acid neuronal systems in the pathophysiology of schizophrenia. 2. These include the ability of NMDA antagonists, phencyclidine and ketamine, to cause both negative and positive symptoms in healthy subjects, and abnormalities in the densities of some types of excitatory amino acid receptors in the postmortem tissue of schizophrenic brains. 3. The present review describes recent basic findings that have examined the involvement of excitatory amino acids in the mechanism of action of antipsychotic drugs. These include studies on the functional links between glutamatergic and dopaminergic systems, effect of acute and chronic antipsychotic drug treatment on excitatory amino acid function, and stress-induced activation of excitatory amino acid release, in particular in the prefrontal cortex.     

Thirty-day mortality and long-term survival following surgery for prosthetic endocarditis: a study from the UK heart valve registry

Age of onset of schizophrenia (AOS) may be largely determined by neurobiological factors. We examined in a diverse sample of schizophrenia out-patients the relationships of AOS with neuropsychological abilities and structural brain abnormalities as measured on cerebral magnetic resonance imaging (MRI). A total of 82 out-patients meeting DSM-III-R criteria for schizophrenia were evaluated with a comprehensive neuropsychological battery and semi-automated quantitatively analysed cerebral MRI. Earlier AOS correlated with poorer performance in learning and abstraction/cognitive flexibility, and with larger volumes of caudate and lenticular nuclei, and smaller volume of thalamus on MRI. A model for predicting AOS consisting of abstraction and thalamic and caudate volumes remained significant after controlling for duration of illness, current age and daily neuroleptic dose. In conclusion, AOS may be related to specific rather than general measures of cognitive performance and structural brain abnormalities.     

Serotonergic function and negative and depressive symptomatology in schizophrenia and major depression

BACKGROUND: Serotonergic abnormalities are found in both major depressive disorder (MDD) and schizophrenia. Depressive symptoms commonly occur alongside the negative or defect symptoms in schizophrenia and antiserotonergic drugs may be particularly effective in their treatment. We wished to explore whether these symptoms could be distinguished biologically by directly comparing serotonergic function in these two illnesses. METHOD: Fifteen patients with MDD and 13 patients with schizophrenia underwent testing with the specific serotonin releasing agent D-fenfluramine (D-FEN). Prolactin and cortisol responses were measured to ascertain central serotonergic function. Individual patient results were compared with their own carefully matched control to correct for the effect of age, sex, weight and menstrual cycle, before the two patient groups were then compared. RESULTS: Prolactin responses differed significantly between the two patient groups, being lower in MDD patients and higher in schizophrenia patients than their individually matched controls. Cortisol responses did not differ. Within the schizophrenia group, increased serotonergic function correlated positively with depressive symptoms, but there was no such correlation with defect symptoms. Depressive scores were negatively correlated with the presence of negative symptoms in the schizophrenic group. CONCLUSIONS: Schizophrenia and MDD have distinct and opposite neuroendocrine responses to D-FEN. There is no evidence that depressive symptoms in these two conditions have a common serotonergic basis. Moreover, these responses distinguished between negative and depressive symptoms in our schizophrenic group.     

Hand therapy education: a global perspective

BACKGROUND: Identifying brain changes in schizophrenia has been a major research focus for many years. Although impressive gains have been made in neuroimaging and brain electrophysiology, molecular and cellular markers of schizophrenia have lagged. There are no consistent biochemical markers for schizophrenia pathophysiology and none that reflect treatment course. METHODS: Samples were obtained from 25 postmortem schizophrenic brains and 31 nonschizophrenic controls. These samples were processed, and the synaptosomal fraction was isolated. Ten micrograms of protein from each of these samples was solubilized in a sodium dodecylsulfate sample buffer and separated on 10% (wt/vol) polyacrylamide gels. Monoclonal antibody (SMI-81) was incubated with the blots and, using quantitative Western blotting, we measured the relative amounts of SNAP-25 in these samples. RESULTS: We report altered levels of SNAP-25 in both the inferior temporal cortex (Brodmann area 20) and prefrontal association cortex (Brodmann areas 9 and 10) in postmortem brains of patients with schizophrenia relative to nonschizophrenic controls. Normal levels of SNAP-25 are noted in schizophrenics in area 17, decreased levels in areas 10 and 20, and an elevated level in area 9. CONCLUSIONS: These data support cytoarchitectural observations that the cerebral cortex of schizophrenic patients has extensive pathology. The data presented here, along with data on other brain-specific proteins, indicate a complicated molecular adaptation to the causative factors of schizophrenia.     

Visceral afferent stimulation-evoked changes in the release of peptides into the parabrachial nucleus in vivo

OBJECTIVE: Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia. METHOD: Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions. RESULTS: No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied. CONCLUSIONS: These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.     

Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine.

The enhanced locomotor and stereotypic responses of the rat to repeated amphetamine (AMPH) administration are considered to be an animal model of positive schizophrenic symptoms. In contrast, behaviors observed during withdrawal from repeated AMPH are believed to model depression or anxiety. In the present study, the authors tested whether AMPH withdrawal might also elicit behaviors consistent with animal models of schizophrenia, specifically, disruptions in latent inhibition (LI) of 2-way active avoidance and prepulse inhibition (PPI) of startle. Rats treated with escalating doses of AMPH (6 days, 1–5 mg/kg ip) or saline were tested for LI and PPI during withdrawal. LI was eliminated by prior AMPH treatment in rats tested at 4, 13, and 28 days of withdrawal. In contrast, PPI did not differ between AMPH and control groups. These results support an interrelationship between repeated-AMPH and LI-disruption, but not PPI-disruption, models of schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Magnetic resonance spectroscopy in psychiatry: basic principles and applications

In vivo magnetic resonance spectroscopy (MRS) is a safe and non-invasive tool which can be used to study aspects of brain chemistry and metabolism. Although a relatively recent technique in the field of psychiatric research, it has already been used in the study of anxiety and affective disorders, dementia, schizophrenia, and neurodevelopmental disorders. This review outlines the basic principles of MRS and summarises the research findings in psychiatric disorders. Although mostly preliminary, these findings highlight the capacity of MRS to detect subtle neurobiological abnormalities in mental disorders. They also suggest a future role for MRS in differential diagnosis and monitoring illness progression. Initial MRS studies have also focused on the metabolic effects of psychiatric treatments and could provide information about their relationship to clinical variables.