Schizophrenia, brain disease and meta-analyses: Integrating the pieces and testing Fusar-Poli`s hypothesis

This paper aims to discuss and test the hypothesis raised by Fusar-Poli [Fusar-Poli P. Can neuroimaging prove that schizophrenia is a brain disease? A radical hypothesis. Medical Hypotheses in press, corrected proof] that ""on the basis of the available imaging literature there is no consistent evidence to reject the radical and provocative hypothesis that schizophrenia is not a brain disease"". To achieve this goal, all meta-analyses on `fMRI and schizophrenia` published during the current decade and indexed in Pubmed were summarized, as much as some other useful information, e.g., meta-analyses on genetic risk factors. Our main conclusion is that the literature fully supports the hypothesis that schizophrenia is a syndrome (not a disease) associated with brain abnormalities, despite the fact that there is no singular and reductionist pathway from the nosographic entity (schizophrenia) to its causes. This irreducibility is due to the fact that the syndrome has more than one dimension (e.g., cognitive, psychotic and negative) and each of them is related to abnormalities in specific neuronal networks. A psychiatric diagnosis is a statistical procedure; these dimensions are not identically represented in each diagnosticated case and this explains the existence of more than one pattern of brain abnormalities related to schizophrenia. For example, chronification is associated with negativism while the first psychotic episode is not; in that sense, the same person living with schizophrenia may reveal different symptoms and fMRI patterns along the course of his life, and this is precisely what defines schizophrenia since the time when it was called Dementia Praecox (first by pick then by Kraepelin). It is notable that 100% of the collected meta-analyses on `fMRI and schizophrenia` reveal positive findings. Moreover, all meta-analyses that found positive associations between schizophrenia and genetic risk factors have to do with genes (SNPs) especially activated in neuronal tissue of the central nervous system (CNS), suggesting that, to the extent these polymorphisms are related to schizophrenia`s etiology, they are also related to abnormal brain activity. (C) 2009 Elsevier Ltd. All rights reserved.

Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients

Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.

Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such 'negative' symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

The Integration of the Glutamatergic and the White Matter Hypotheses of Schizophrenia's Etiology

Background: schizophrenia's endophenotipic profile is not only generally complex, but often varies from case to case. The perspective of trying to define specific anatomic correlates of the syndrome has led to disappointing results. In that context, neurophysiologic hypotheses (e. g. glutamatergic hypothesis) and connectivity hypotheses became prominent. Nevertheless, despite their commitment to the principle of denying 'localist' views and approaching the syndrome's endophenotype from a whole brain perspective, efforts to integrate both have not flourished at this moment in time. Objectives: This paper aims to introduce a new etiological model that integrates the glutamatergic and the WM (WM) hypotheses of schizophrenia's etiology. This model proposes to serve as a framework in order to relate to patterns of brain abnormalities from the onset of the syndrome to stages of advanced chronification. Highlights: Neurotransmitter abnormalities forego noticeable WM abnormalities. The former, chiefly represented by NMDAR hypo-function and associated molecular cascades, is related to the first signs of cell loss. This process is both directly and indirectly integrated to the underpinning of WM structural abnormalities; not only is the excess of glutamate toxic to the WM, but its disruption is associated to the expression of known genetic risk factors (e. g., NRG-1). A second level of the model develops the idea that abnormal neurotransmission within specific neural populations ('motifs') impair particular cognitive abilities, while subsequent WM structural abnormalities impair the integration of brain functions and multimodality. As a result of this two-stage dynamic, the affected individual progresses from experiencing specific cognitive and psychological deficits, to a condition of cognitive and existential fragmentation, linked to hardly reversible decreases in psychosocial functioning.

Differential expression of HINT1 in schizophrenia brain tissue

Recent findings in the literature suggest a relation between histidine triad nucleotide-binding protein-1 (HINT1) and psychiatric disorders such as major depression, anxiety, and schizophrenia, although its physiological roles are not completely comprehended. Using Western blot, we compared HINT1 protein expression in the postmortem dorsolateral prefrontal cortex and thalamus of schizophrenia patients and healthy controls for contributing to elucidate the role of HINT1 in schizophrenia pathophysiology. HINT1 was found to be downregulated in the dorsolateral prefrontal cortex and upregulated in the thalamus. Our results combined to previous studies in human samples and preclinical models support the notion that HINT1 must be more explored as a potential target for psychiatric disorders.

Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample

Schizophrenia is a severe psychiatric disorder with frequent recurrent psychotic relapses and progressive functional impairment. It results from a poorly understood gene-environment interaction. The gene encoding catechol-O-methyltransferase (COMT) is a likely candidate for schizophrenia. Its rs165599 (A/G) polymorphism has been shown to be associated with alteration of COMT gene expression. Therefore, the present study aimed to investigate a possible association between schizophrenia and this polymorphism. The distribution of the alleles and genotypes of this polymorphism was investigated in a Brazilian sample of 245 patients and 834 controls. The genotypic frequencies were in Hardy-Weinberg equilibrium and no statistically significant differences were found between cases and controls when analyzed according to gender or schizophrenia subtypes. There was also no difference in homozygosis between cases and controls. Thus, in the sample studied, there was no evidence of any association between schizophrenia and rs165599 (A/G) polymorphism in the non-coding region 3' of the COMT gene.

Decreased Reelin Expression in the Left Prefrontal Cortex (BA9) in Chronic Schizophrenia Patients

Background: Reelin is under epigenetic control and has been reported to be decreased in cortical regions in schizophrenia. Methods: To establish if expression of reelin is altered in specific cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of reelin in a postmortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral postmortem samples (dorsolateral prefrontal cortex BA9 and BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus, CA4, mediodorsal nucleus of the thalamus) from 12 schizophrenia patients with 13 normal subjects investigating gene expression of reelin in the gray and white matter of both hemispheres by in situ-hybridization. Results: The left prefrontal area (BA9) of schizophrenia patients revealed a decreased expression of reelin-mRNA of 29.1% in the white (p = 0.022) and 13.6% in the gray matter (p = 0.007) compared to the control group. None of the other regions examined showed any statistically significant differences. Conclusion: Since reelin is responsible for migration and synapse formation, the decreased gene expression of reelin in the left prefrontal area of schizophrenia patients points to neurodevelopmental deficits in neuronal migration and synaptic plasticity. However, our study group was small, and results should be verified using larger samples. Copyright (C) 2012 S. Karger AG, Basel

The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: Summaries of oral sessions

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. (C) 2012 Elsevier B.V. All rights reserved.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance

These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F; Bandelow et al. 2008b, World J Biol Psychiatry 9: 242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.

Attitudes of mental health professionals towards persons with schizophrenia: a transcultural comparison between Switzerland and Brazil

Background: Stigmatization is an important issue in the treatment and course of schizophrenia. The maintenance of stigmatizing attitudes may be related to socio-cultural factors. Objectives: To compare stigmatizing attitudes of mental health professionals in the culturally diverse countries Brazil and Switzerland. Methods: We analyzed data of two broad stigmatization surveys from Switzerland and Brazil by focusing on the social distance and attitudes of mental health professionals towards the acceptance of side effects of psychopharmacological treatment. Results: Swiss mental health professionals showed significantly higher levels of social distance than their Brazilian counterparts. There was also a weak effect of age as well as an interaction effect between origin and age. With respect to the acceptance of side effects, the effect of origin was rather weak. With the exception of drug dependence, Swiss professionals' acceptance of long-lasting side effects was significantly higher than for their counterparts in Brazil. Discussion: The strong association between origin and social distance may be related to the socio-cultural background of the mental health professionals. In comparison with Switzerland, Brazil is very heterogeneous in terms of ethnicity and socio-economic structure. The distinct acceptance of side effects may additionally be related to the more sophisticated medicaments (i.e. new generation of antipsychotic drugs) commonly used in Switzerland. Hengartner MP, et al. / Rev Psiq Clin. 2012;39(4):115-21

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls

To identify a classifier in schizophrenia, blood gene expression profiling was applied to patients with schizophrenia under different treatments and to controls. Expression of six genes discriminated patients with sensitivity of 89.3% and specificity of 90%, supporting the use of peripheral blood as biological material for diagnosis in schizophrenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Stigma toward schizophrenia: do all psychiatrists behave the same? Latent profile analysis of a national sample of psychiatrists in Brazil

Background: An important issue concerning the worldwide fight against stigma is the evaluation of psychiatrists’ beliefs and attitudes toward schizophrenia and mental illness in general. However, there is as yet no consensus on this matter in the literature, and results vary according to the stigma dimension assessed and to the cultural background of the sample. The aim of this investigation was to search for profiles of stigmatizing beliefs related to schizophrenia in a national sample of psychiatrists in Brazil. Methods: A sample of 1414 psychiatrists were recruited from among those attending the 2009 Brazilian Congress of Psychiatry. A questionnaire was applied in face-to-face interviews. The questionnaire addressed four stigma dimensions, all in reference to individuals with schizophrenia: stereotypes, restrictions, perceived prejudice and social distance. Stigma item scores were included in latent profile analyses; the resulting profiles were entered into multinomial logistic regression models with sociodemographics, in order to identify significant correlates. Results: Three profiles were identified. The “no stigma” subjects (n = 337) characterized individuals with schizophrenia in a positive light, disagreed with restrictions, and displayed a low level of social distance. The “unobtrusive stigma” subjects (n = 471) were significantly younger and displayed the lowest level of social distance, although most of them agreed with involuntary admission and demonstrated a high level of perceived prejudice. The “great stigma” subjects (n = 606) negatively stereotyped individuals with schizophrenia, agreed with restrictions and scored the highest on the perceived prejudice and social distance dimensions. In comparison with the first two profiles, this last profile comprised a significantly larger number of individuals who were in frequent contact with a family member suffering from a psychiatric disorder, as well as comprising more individuals who had no such family member. Conclusions: Our study not only provides additional data related to an under-researched area but also reveals that psychiatrists are a heterogeneous group regarding stigma toward schizophrenia. The presence of different stigma profiles should be evaluated in further studies; this could enable anti-stigma initiatives to be specifically designed to effectively target the stigmatizing group.

Personal and Social Performance (PSP) scale for patients with schizophrenia: translation to Portuguese, cross-cultural adaptation and interrater reliability

INTRODUCTION: Schizophrenia is a chronic mental disorder associated with impairment in social functioning. The most widely used scale to measure social functioning is the GAF (Global Assessment of Functioning), but it has the disadvantage of measuring at the same time symptoms and functioning, as described in its anchors. OBJECTIVES:Translation and cultural adaptation of the PSP, proposing a final version in Portuguese for use in Brazil. METHODS: We performed five steps: 1) translation; 2) back translation; 3) formal assessment of semantic equivalence; 4) debriefing; 5) analysis by experts. Interrater reliability (Intraclass correlation, ICC) between two raters was also measured. RESULTS: The final version was applied by two independent investigators in 18 adults with schizophrenia (DSM-IV-TR). The interrater reliability (ICC) was 0.812 (p < 0.001). CONCLUSION: The translation and adaptation of the PSP had an adequate level of semantic equivalence between the Portuguese version and the original English version. There were no difficulties related to understanding the content expressed in the translated texts and terms. Its application was easy and it showed a good interrater reliability. The PSP is a valid instrument for the measurement of personal and social functioning in schizophrenia.

Animal models of prenatal immune challenge and their contribution to the study of schizophrenia: a systematic review

Prenatal immune challenge (PIC) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism. Based on this, the goal of this article was to review the main contributions of PIC models, especially the one using the viral-mimetic particle polyriboinosinic-polyribocytidylic acid (poly-I:C), to the understanding of the etiology, biological basis and treatment of schizophrenia. This systematic review consisted of a search of available web databases (PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge) for original studies published in the last 10 years (May 2001 to October 2011) concerning animal models of PIC, focusing on those using poly-I:C. The results showed that the PIC model with poly-I:C is able to mimic the prodrome and both the positive and negative/cognitive dimensions of schizophrenia, depending on the specific gestation time window of the immune challenge. The model resembles the neurobiology and etiology of schizophrenia and has good predictive value. In conclusion, this model is a robust tool for the identification of novel molecular targets during prenatal life, adolescence and adulthood that might contribute to the development of preventive and/or treatment strategies (targeting specific symptoms, i.e., positive or negative/cognitive) for this devastating mental disorder, also presenting biosafety as compared to viral infection models. One limitation of this model is the incapacity to model the full spectrum of immune responses normally induced by viral exposure.