Gene expression profiling in Brodmann's area 46 from subjects with schizophrenia

OBJECTIVE: To identify altered gene expression in the dorsolateral prefrontal cortex obtained after death from subjects with schizophrenia. METHOD: Restriction fragment differential display (RFDD) was used to measure levels of mRNA in Brodmann area (BA) 46 from schizophrenia and control subjects. Findings on specific mRNA identified with RFDD were further investigated using real-time polymerase chain reaction (real-time PCR), PCR and western blotting. RESULTS: Levels of mRNA for 63 of approximately 12,500 genes differed in BA 46 in schizophrenia. Subsequent real-time PCR has shown that mRNA for muscleblind protein 1 (MBNL1) and protocadherin 17 (PCDH17) are increased in BA 46 from subjects with schizophrenia of short, but not long, duration. Altered levels of mRNA for neither gene were present in BA 9 from subjects with schizophrenia or in either cortical area from subjects with bipolar 1 disorder. By contrast, both RFDD and real-time PCR failed to show altered expression of the schizophrenia candidate gene disrupted in schizophrenia 1 (DISC1) BA46 from any diagnostic cohort. CONCLUSION: The present study has identified genes that are differentially expressed in BA 46 in schizophrenia. Initial studies have shown that there is a need for a careful validation of genes shown to be affected in schizophrenia using high-throughput technologies. In addition the present study has shown that gene expression may vary considerably depending on the duration of schizophrenia. This raises the hypothesis that changing gene expression may be underlying the change in symptom profile that occurs with disease progression in some subjects with schizophrenia.     

Personality traits in schizophrenia and related personality disorders

We investigated whether schizophrenia spectrum disorders share common personality characteristics or traits. Participants with a diagnosis of schizophrenia or schizoaffective disorder (SZ) or with a schizophrenia spectrum personality disorder (schizophrenia spectrum PD: schizoid, paranoid, and schizotypal personality disorder) were compared with non-psychiatric control subjects on the five-factor model of personality and the psychosis-proneness scales. On the five-factor personality scales, SZ subjects showed higher levels of neuroticism, and lower levels of openness, agreeableness, extraversion, and conscientiousness than control subjects. Higher scores on openness and lower scores on neuroticism distinguished schizophrenia spectrum PD from SZ. On the psychosis-proneness scales, both PD and SZ participants scored high relative to non-psychiatric control participants on magical ideation and perceptual aberration, while PD participants scored intermediate between non-psychiatric control participants and SZ on social anhedonia. Discriminant analysis indicated that schizophrenia spectrum patients could be distinguished from PDs by more severe social withdrawal and maladjustment, while subjects with PDs could be best distinguished from control subjects on the basis of odd or novel ideation and decreased conscientiousness.     

Personality disorders related to schizophrenia]

Personality disorders related to schizophrenia were described since Kraepelin's works. According to the DMS III-R those disorders are gathered into the A cluster of personality disorders consisting in: schizotypal, schizoid and paranoid personality disorders. Schizotypal and paranoid personalities are biologically linked to schizophrenia and support the concept of "schizophrenia spectrum". Until now such a link is not found between schizoid personality and schizophrenia. Future research in the field of those personality disorders will bring a better knowledge in the pathogenesis of schizophrenia.     

Protein expression profiling of postmortem brain in schizophrenia

Surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) enables the sensitive, high-throughput protein profiling of complex biological mixtures. In combination with bioinformatics, this technology has the potential to identify combinations of spectral peaks that can differentiate individuals with a particular disease from normal controls. SELDI-TOF-MS was used to screen postmortem tissue derived from the dorsolateral prefrontal cortex of individuals with schizophrenia (n = 34) and matched controls (n = 35), obtained from the Stanley Foundation Neuropathology Consortium. Tissue samples were homogenized in urea buffer, applied to four different chip arrays which possess different chromatographic surfaces, and analyzed using the Ciphergen ProteinChip Biomarkers System (Model PBS II). Protein expression profiles of the schizophrenia and control groups were compared and analyzed using the Ciphergen Express (CE) and Biomarker Patterns Software (BPS) package. We detected several protein peaks whose intensities differed between the schizophrenia and control groups to a highly significant degree. A combination of these peaks was capable of distinguishing between schizophrenia and controls with a sensitivity and specificity of about 70%. The classification model that distinguished schizophrenia from controls was complex, suggesting that the biochemical abnormalities underlying schizophrenia are heterogeneous. Our results suggest that SELDI-TOF-MS has the potential for distinguishing individuals with schizophrenia from normal controls and may eventually lead to a better understanding of the classification, diagnosis and pathogenesis of this disorder.     

Gene polymorphism and gene expression in schizophrenia

The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level.     

White matter neuron alterations in schizophrenia and related disorders

Increased density and altered spatial distribution of subcortical white matter neurons (WMNs) represents one of the more well replicated cellular alterations found in schizophrenia and related disease. In many of the affected cases, the underlying genetic risk architecture for these WMN abnormalities remains unknown. Increased density of neurons immunoreactive for Microtubule-Associated Protein 2 (MAP2) and Neuronal Nuclear Antigen (NeuN) have been reported by independent studies, though there are negative reports as well; additionally, group differences in some of the studies appear to be driven by a small subset of cases. Alterations in markers for inhibitory (GABAergic) neurons have also been described. For example, downregulation of neuropeptide Y (NPY) and nitric oxide synthase (NOS1) in inhibitory WMN positioned at the gray/white matter border, as well as altered spatial distribution, have been reported. While increased density of WMN has been suggested to reflect disturbance of neurodevelopmental processes, including neuronal migration, neurogenesis, and cell death, alternative hypotheses—such as an adaptive response to microglial activation in mature CNS, as has been described in multiple sclerosis -should also be considered. We argue that larger scale studies involving hundreds of postmortem specimens will be necessary in order to clearly establish the subset of subjects affected. Additionally, these larger cohorts could make it feasible to connect the cellular pathology to environmental and genetic factors implicated in schizophrenia, bipolar disorder, and autism. These could include the 22q11 deletion (Velocardiofacial/DiGeorge) syndrome, which in some cases is associated with neuronal ectopias in white matter.     

Quetiapine in the treatment of schizophrenia and related disorders

Quetiapine was developed in 1985 by scientists at AstraZeneca (formerly Zeneca) Pharmaceuticals. It received official US Food and Drug Administration approval in September 1997 and approval in Germany in 2000. Since then, quetiapine has been used in the treatment of severe mental illness in approximately 70 countries including Canada, most Western European countries, and Japan. Quetiapine is a dibenzothiazepine derivative with a relatively broad receptor binding profile. It has major affinity to cerebral serotonergic (5HT_2A), histaminergic (H1), and dopaminergic D₁ and D₂ receptors, moderate affinity to α₁- und α₂-adrenergic receptors, and minor affinity to muscarinergic M1 receptors; it demonstrates a substantial selectivity for the limbic system. This receptor occupancy profile with relatively higher affinity for the 5HT_2A receptor compared with the D₂ receptor is in part responsible for the antipsychotic characteristics and low incidence of extrapyramidal side-effects of quetiapine. The efficacy of quetiapine in reducing positive and negative symptoms of schizophrenia has been proven in several clinical trials with placebo-controlled comparators. Quetiapine has also demonstrated robust efficacy for treatment of cognitive, anxious-depressive, and aggressive symptoms in schizophrenia. Long-term trials show sustained tolerability for a broad spectrum of symptoms. Quetiapine has also proven efficacy and tolerability in the treatment of moderate to severe manic episodes, and in the treatment of juveniles with oppositional-defiant or conduct disorders, and in the geriatric dementia population. Recent data indicate that quetiapine may also be effective in the treatment of bipolar depressive symptoms without increasing the risk of triggering manic episodes, and in borderline personality disorder. In comparison with other antipsychotics, quetiapine has a favorable side-effect profile. In clinical trials only small insignificant prolongations of the QT interval were observed. Weight-gain liabilities and new-onset metabolic side-effects occupy a middle-ground among newer antipsychotics. As a result of its good efficacy and tolerability profile quetiapine has become well established in the treatment of schizophrenia and manic episodes.     

精神分裂症的精神残疾及其相关因素的调查分析

目的:评定山东省精神分裂症患者的精神残疾现状,并探讨其危险因素,方法:采用国际统一的调查流程,调查工具和抽样方法在山东省范围内进行抽样调查,对检出的精神分裂症患者用SDSS进行精神残疾评定,用SANS和PSE评定其症状,并收集有关危险因素.结果:84767人中共检出精神分裂症296例,有247例存在不同程度的精神残疾,致残率为83.43%,精神残疾与SANS和PSE评分,论断分型,起病形式,复发次数,治疗缓解情况及家庭环境有关,SANS评分是导致精神残疾的第一位因素,结论:精神分裂症致残较高,精神症状特别是阴性症状是导致精神残疾的主要因素,精神残疾还与疾病特征及家庭环境有关.     

Gene expression profiling in multiple sclerosis brain

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. Microarray-based comparative gene profiling provides a snapshot of genes underlying a particular condition. Several large scale microarray studies have been conducted using brain tissue from MS patients. In this review, we summarize existing data from different gene expression profiling studies and how they relate to understand the pathogenesis of MS.     

Gene expression profiling in developing human hippocampus

The gene expression profile of developing human hippocampus is of particular interest and importance to neurobiologists devoted to development of the human brain and related diseases. To gain further molecular insight into the developmental and functional characteristics, we analyzed the expression profile of active genes in developing human hippocampus. Expressed sequence tags (ESTs) were selected by sequencing randomly selected clones from an original 3'-directed cDNA library of 150-day human fetal hippocampus, and a digital expression profile of 946 known genes that could be divided into 16 categories was generated. We also used for comparison 14 other expression profiles of related human neural cells/tissues, including human adult hippocampus. To yield more confidence regarding differential expression, a method was applied to attach normalized expression data to genes with a low false-positive rate (<0.05). Finally, hierarchical cluster analysis was used to exhibit related gene expression patterns. Our results are in accordance with anatomical and physiological observations made during the developmental process of the human hippocampus. Furthermore, some novel findings appeared to be unique to our results. The abundant expression of genes for cell surface components and disease-related genes drew our attention. Twenty-four genes are significantly different from adult, and 13 genes might be developing hippocampus-specific candidate genes, including wnt2b and some Alzheimer's disease-related genes. Our results could provide useful information on the ontogeny, development, and function of cells in the human hippocampus at the molecular level and underscore the utility of large-scale, parallel gene expression analyses in the study of complex biological phenomena.     

Victimization of patients with schizophrenia and related disorders

BACKGROUND: Previous research has predominately focused on patients with mental illness as the instigators, rather than the victims, of violence and criminal activity. However, patients with schizophrenia appear to experience a higher degree of victimization compared to general community samples. We aimed to establish the 1-month prevalence of violent and non-violent victimization in a sample of patients with schizophrenia spectrum disorders and to investigate the determinants of victimization. METHOD: Reports of violent and non-violent victimization were recorded in 348 patients in Dandenong, an outer metropolitan suburb of Melbourne, Australia along with the subjective perception of patients as to their degree of protection from being robbed or attacked. Patients reporting victimization were compared with those who did not, across a range of clinical and psychosocial variables. RESULTS: 11.2% of the sample reported being the victim of non-violent crime and 4.3% the victim of violent crime in the 1-month period. 23.2% reported dissatisfaction with their protection against being attacked or robbed. The major determinant of victimization was the lack of any meaningful daily activity. CONCLUSIONS: Patients with schizophrenia spectrum disorders are at increased risk of victimization, both of the violent and non-violent type. Further research is required to understand the pathways through which victimization occurs and to understand whether psychosocial interventions can reduce victimization in this patient population.     

酒中毒所致精神障碍的磁共振检查

对２５例酒中毒所致精神障碍患者与２１例正常人头颅磁共振作比较，结果显示，患者组大脑侧脑室前角，侧脑室体部，三脑室宽径，顶叶脑沟，额叶脑的比正常组明显增宽，患者磁共振异常率为３２％。     

Mobile assessment guide for research in schizophrenia and severe mental disorders

Mobile assessment techniques have been used for nearly 3 decades in mental health research, including in investigations of individuals with schizophrenia and other severe disorders. This article reviews the benefits of these data collection strategies relative to traditional self-report or clinician-administered measures administered in hospital or laboratory settings. A detailed discussion of the technical decisions facing researchers in the field is then presented, covering study design issues, questionnaire content development, and choices in hardware and software selection. Following these points, sample recruitment and retention strategies are discussed, as well as the main statistical issues that are necessary to consider in the exploitation of repeated measures data generated by this methodology.